piperidines and Diabetes-Mellitus--Type-2

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Observational studies and meta-analyses of randomized trials on dipeptidyl peptidase-4 inhibitors (DPP4i) reported discordant results on the risk of malignancies with this class of drugs. Aim of the present meta-analysis is the assessment of the effect of DPP4i treatment on the incidence of different types of cancer, collecting all available evidence from randomized controlled trials.. An extensive MEDLINE, EMBASE, and Cochrane database search for sitagliptin or vildagliptin or omarigliptin or saxagliptin or alogliptin or trelagliptin or anagliptin or linagliptin or gemigliptin or evogliptin or teneligliptin was performed up to September 30th, 2019. All trials performed on type 2 diabetes, with duration ≥ 24 weeks, and comparing of DPP4i with placebo or active drugs were collected. The study has been registered on PROSPERO (#153344). Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes.. A total of 157 eligible trials were identified. DPP-4i were not associated with an increased risk of overall cancer (MH-OR 0.93 [0.86, 1.00]; p = 0.07), with no significant differences across individual molecules of the class. When compared with placebo/none, a lower risk of cancer with DPP-4i was observed in placebo-controlled trials (MH-OR 0.90 [0.82, 0.99], p = 0.030), whereas no significant differences have been detected with any other comparators. DPP-4i was associated with a significant reduction in colorectal cancer (MH-OR 0.70 [0.53, 0.94], p = 0.020).. Available data do not support the hypothesis of an association of DPP4i treatment with malignancies, with a possible beneficial effect for colon-rectal cancer.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incidence; Neoplasms; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil; Vildagliptin

Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.. To assess the effects of metformin monotherapy in adults with T2DM.. We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).. We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.. Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.. We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trial. There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

Topics: Adult; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Myocardial Infarction; Piperidines; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Sulfonylurea Compounds

The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.. To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.. We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).. We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention.. Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.. We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups ve. Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Topics: Acarbose; Bias; Carbamates; Cardiovascular Diseases; Confidence Intervals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Placebos; Randomized Controlled Trials as Topic; Risk

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic drugs that safely reduce the blood glucose level over the long term. In Japan, DPP-4 inhibitors have become the oral antidiabetic drugs most frequently prescribed for patients with type 2 diabetes. However, the results of several cardiovascular outcomes studies have suggested that some DPP-4 inhibitors may increase the risk of hospitalization for heart failure. In patients with diabetes, heart failure is the most frequent cardiovascular condition, and it has a negative impact on the quality of life as well as being a potentially fatal complication. Therefore, it is important to determine whether an increased risk of heart failure is associated with certain DPP-4 inhibitors or is a class effect of these drugs. This review explores the mechanism by which DPP-4 inhibitors may increase the risk of heart failure and possible differences among these drugs. The available research suggests that DPP-4 inhibitors cause sympathetic activation as a class effect and this may increase the risk of heart failure. Unlike other DPP-4 inhibitors, sitagliptin and alogliptin are mainly excreted in the urine and suppress renal sodium-hydrogen exchanger 3 activity. These two drugs did not increase the risk of hospitalization for heart failure in large-scale cardiovascular outcomes studies.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Quality of Life; Sitagliptin Phosphate; Uracil

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.

Topics: Adiponectin; Animals; Diabetes Mellitus, Type 2; Humans; Kidney; Lipid Metabolism; Obesity; Oxidative Stress; Piperidines; Receptors, Adiponectin

Topics: Benzoates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Half-Life; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Uracil

This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM).. We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States.. SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors - at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy.. The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c.. BP = blood pressure; CI = confidence interval; CVOT = cardiovascular outcomes; DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; EXAMINE = EXamination of cArdiovascular outcoMes with alogliptiN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HR = hazard ratio; MACE = major adverse cardiovascular events; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus; SBP = systolic blood pressure; SGLT2 = sodium glucose cotransporter 2; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin; T2DM = type 2 diabetes mellitus; XR = extended release.

Topics: Adamantane; Benzhydryl Compounds; Blood Glucose; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Metformin; Piperidines; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Uracil

Prevention of cognitive impairment and dementia is an important public health goal. Epidemiological evidence shows a relationship between cognitive impairment and Type 2 diabetes mellitus. The risk of dementia increases with duration of disease. This updated systematic review investigated the effect on cognitive function of the type of treatment and level of metabolic control in people with Type 2 diabetes.. To assess the effects of different strategies for managing Type 2 diabetes mellitus on cognitive function and the incidence of dementia.. We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG)), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL and LILACS on 15 October 2016. ALOIS contains records from all major health care databases, (CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many trials' registers and grey literature sources.. We included randomised controlled trials (RCTs) which compared two or more different treatments for Type 2 diabetes mellitus and in which cognitive function was measured at baseline and after treatment.. Two review authors independently extracted data and assessed the quality of the included RCTs. We pooled data for comparable trials and estimated the effects of treatment by using risk ratios (RRs) and mean differences (MDs), according to the nature of the outcome. We assessed the quality of the evidence using GRADE methods.. We identified seven eligible studies but only four provided data we could include in efficacy analyses. Two of these studies compared intensive versus standard glycaemic control and two compared different pharmacological treatments. All studies were at unclear risk of bias in at least two domains and one large study was at high risk of performance and detection bias.(a) Two studies with 13,934 participants at high cardiovascular risk provided efficacy data on intensive versus standard glycaemic control. A third study with 1791 participants provided additional data on hypoglycaemic episodes and mortality. There is probably no difference between treatment groups in the number of participants who decline by at least 3 points on the Mini-Mental State Examination (MMSE) over five years (RR 0.98, 95% CI 0.88 to 1.08; 1 study; n = 11,140; moderate-quality evidence); and there may also be little or no difference in the incidence of dementia (RR 1.27, 95% CI 0.87 to 1.85; 1 study; n = 11,140; low-quality evidence). From another study, there was probably little or no difference in MMSE score after 40 months (MD -0.01, 95% CI -0.18 to 0.16; 1 study; n = 2794; moderate quality evidence). Participants exposed to the intensive glycaemic control strategy probably experience more episodes of severe hypoglycaemia than those who have standard treatment (RR 2.18, 95% CI 1.52 to 3.14; 2 studies; n = 12,827; moderate-quality evidence). The evidence from these trials suggests that the intensity of glycaemic control may have little or no effect on all-cause mortality (RR 0.99, 95% CI 0.87 to 1.13; 3 studies; n = 15,888; low-quality evidence).(b) One study with 156 participants compared glibenclamide (glyburide) with repaglinide. There may be a small advantage of glibenclamide on global cognitive function measured with the MMSE after 12 months (MD -0.90, 95% CI -1.68 to -0.12; low-quality evidence). No data were reported on the incidence of dementia, hypoglycaemic events or all-cause mortality.(c) One study with 145 participants compared rosiglitazone plus metformin to glibenclamide (glyburide) plus metformin over 24 weeks. It reported only on cognitive subdomains and not on global cognitive function, incidence of MCI or dementia, hypoglycaemic events or all causes of mortality.. We found no good evidence that any specific treatment or treatment strategy for Type 2 diabetes can prevent or delay cognitive impairment. The best available evidence related to the comparison of intensive with standard glycaemic control strategies. Here there was moderate-quality evidence that the strategies do not differ in their effect on global cognitive functioning over 40 to 60 months.

Topics: Carbamates; Cause of Death; Cognition Disorders; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Memory Disorders; Metformin; Piperidines; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones

Data on the possible relationship of gliptin treatment with the incidence of acute pancreatitis have been controversial. The aim of the current study was to combine data on the incidence of acute pancreatitis from three large randomized controlled trials.. Three trials designed to test cardiovascular safety and efficacy of add-on treatment with a gliptin were included in the analysis, as follows: SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin). The trials included 18,238 gliptin-treated patients and 18,157 placebo-treated patients. Data were combined using a random-effects model meta-analysis.. The incidence of acute pancreatitis was significantly increased in the gliptin-treated patients when compared with the control groups (odds ratio 1.79 [95% CI 1.13-2.82], P = 0.013). The difference in the absolute risk was small (0.13%).. Treatment with gliptins significantly increased the risk for acute pancreatitis in a combined analysis of three large controlled randomized trials.

Topics: Acute Disease; Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incidence; Pancreatitis; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil

Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.. A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.. Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.. Overall, incretin therapy does not appear to increase risk for MACE in the short term.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; 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Dipeptidyl peptidase-4 (DPP-4) inhibitors such as alogliptin are becoming more widely established as treatment options for patients with type 2 diabetes (T2DM) because of their ability to improve glycemic control without increasing the risk of hypoglycemia or weight gain. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.. In this article, the overall safety and tolerability of alogliptin are evaluated based upon a review of the literature. In particular, adverse events (AEs) that have been of interest for the DPP-4 class of drugs, such as the risk of major cardiovascular (CV) events and acute pancreatitis, will be investigated in detail.. Alogliptin is generally well-tolerated in a broad range of patient populations including different ethnic groups and the elderly. In the pivotal EXAMINE clinical trial, alogliptin was found not to be associated with an increased risk of major CV events or acute pancreatitis/pancreatic cancer.

Topics: Aged; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Uracil

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Topics: Adamantane; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Piperidines; Sitagliptin Phosphate; Uracil

Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue.. Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit.. It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endpoint Determination; Humans; Hypoglycemic Agents; Linagliptin; Meta-Analysis as Topic; Observational Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil

Several randomized, controlled clinical trials were initiated some years ago in order to evaluate the cardiovascular safety of the new antidiabetic drugs in patients with type 2 diabetes due to requirements from regulatory bodies. Four trials with incretin-based drugs (saxagliptin, alogliptin, sitagliptin and lixisenatide) have been completed so far. Based on the primary outcome endpoints of these trials no cardiovascular risks were found with incretins in patients with type 2 diabetes. As for saxagliptin, the hospitalization for heart failure was investigated as a secondary endpoint, and an increased risk was observed in the respective trial; however, this observation was widely debated later in the literature. Together with ongoing trials of other novel antihyperglycemic agents, these data will provide more robust evidence about the cardiovascular safety of incretin-based antidiabetic treatment in patients with type 2 diabetes.

Topics: Adamantane; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Uracil

Alogliptin is the newest dipeptidyl peptidase 4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes either alone or in combination with other antidiabetic agents. The purpose of this review is to highlight the clinical studies that led to Food and Drug Administration approval of alogliptin and to provide insight into the place in therapy for the management of type 2 diabetes mellitus.. As a DPP-4 inhibitor, alogliptin raises postprandial levels of glucagon-like peptide 1, leading to insulin secretion and glucose homeostasis. When given as monotherapy, alogliptin has the ability to reduce glycoslate hemoglobin A1c (HbA1c) by 0.4% to 1.0%. Combination therapy yielded similar reductions with some variability depending on the agent with which alogliptin was combined. The mean HbA1c reduction seen with alogliptin is relative to the degree of HbA1c elevation at baseline. Alogliptin appears to be weight neutral and is relatively well tolerated with few adverse effects. Furthermore, alogliptin has proven to result in comparable efficacy and tolerability in the elderly as in the younger population.. Alogliptin alone or in combination with other antidiabetic agents has shown a significant reduction in HbA1c while remaining safe and tolerable. The efficacy profile of alogliptin is comparable to other DPP-4 inhibitors. Additional long-term research is necessary with regard to long-standing efficacy and effects on beta-cell function.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Piperidines; Randomized Controlled Trials as Topic; Uracil

Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoindoles; KATP Channels; Nateglinide; Pharmacogenetics; Phenylalanine; Piperidines

Type 2 diabetes mellitus (T2DM) has become a worldwide health problem, and the rate of it is growing greatly in the People's Republic of China every year. T2DM could cause macrovascular and microvascular complications that lead to an increase in arterial wall thickness, endothelial dysfunction, calcification, and - finally - to an increase in arterial stiffness and arterial dysfunction. Alogliptin, a new selective inhibitor of dipeptidyl peptidase 4, has shown its great antihyperglycemia effect in T2DM patients. The clinical trial data from the People's Republic of China was similar to other global and Asian trials. This could provide some choice for clinical physicians to the treatment of T2DM.

Topics: Animals; Arteries; Asian People; China; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Piperidines; Risk Factors; Treatment Outcome; Uracil; Vascular Stiffness

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incidence; Myocardial Infarction; Patient Outcome Assessment; Patient Selection; Piperidines; Research Design; Time Factors; Uracil

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, improving glycaemic control alone has not decreased CV events. Therapies that improve glycaemic control, CV disease risk factors and CV function are more likely to be successful. Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent breakdown of incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide and improve glycaemic control in patients with T2DM. DPP-4 acts on other substrates, many associated with cardioprotection. Thus, inhibition of DPP-4 may lead to elevations in these potentially beneficial substrates. Data from animal studies and small observational studies in humans suggest that DPP-4 inhibitors may potentially reduce CV risk. However, recently completed CV outcome trials in patients with T2DM and CV disease or at high risk of adverse CV events have shown that the DPP-4 inhibitors saxagliptin and alogliptin neither increased nor decreased major adverse CV events.

Topics: Adamantane; Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Piperidines; Protective Factors; Risk Assessment; Risk Factors; Treatment Outcome; Uracil

The dipeptidyl peptidase-4 inhibitor alogliptin (Nesina®, Vipidia®) is approved in numerous countries worldwide for the treatment of type 2 diabetes mellitus. Fixed-dose combinations of alogliptin/metformin (Kazano®, Vipdomet®) and alogliptin/pioglitazone (Oseni®, Incresync®) are also available. This article reviews the clinical efficacy and tolerability of oral alogliptin in the treatment of type 2 diabetes. Results of randomized controlled trials demonstrated that oral alogliptin improved glycaemic control when administered as monotherapy, as dual therapy in combination with metformin, pioglitazone, a sulfonylurea, voglibose or insulin, or as triple therapy in combination with metformin plus pioglitazone. Alogliptin was generally well tolerated in patients with type 2 diabetes and was weight neutral, with a low risk of hypoglycaemia. Results of the large, well designed EXAMINE trial revealed that alogliptin was not associated with an increased risk of major cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome. In conclusion, alogliptin is a useful option for the treatment of patients with type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Piperidines; Randomized Controlled Trials as Topic; Uracil

Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, augment glucose-dependent insulin secretion and suppress glucagon levels through enhancement of the action of endogenous incretin by inhibiting DPP-4, an incretin-degrading enzyme. DPP-4 inhibitors are generally well tolerated because of their low risk of hypoglycemia and other adverse events. Moreover, with their potential to improve beta cell function, a core defect of type 2 diabetes, DPP-4 inhibitors are becoming a major component of treatment of type 2 diabetes. Alogliptin benzoate is a newly developed, highly selective DPP-4 inhibitor which has been approved in many countries throughout the world. Once-daily administration of alogliptin as either monotherapy or combination therapy with other oral antidiabetic drugs or insulin has a potent glucose-lowering effect which is similar to that of other DPP-4 inhibitors, with a low risk of hypoglycemia and weight gain. The cardiovascular safety of this drug has been confirmed in a recent randomized controlled trial. This review summarizes the efficacy and safety of alogliptin, and discusses the role of DPP-4 inhibitors in the treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Piperidines; Treatment Outcome; Uracil

Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin).. An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy.. Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Humans; Hypoglycemic Agents; Insulin; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain.

Topics: Carbamates; Clinical Trials as Topic; Coronary Artery Disease; Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Metformin; Nateglinide; Phenylalanine; Piperidines; Sodium-Glucose Transport Proteins; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor that is a class of relatively new oral hypoglycaemic drugs used in patients with type 2 diabetes (T2DM), can be used as monotherapy or in combination with other anti-diabetic agents, including metformin, pioglitazone, sulfonylureas and insulin with a considerable therapeutic effect. Alogliptin exhibits favorable pharmacokinetic and pharmacodynamic profiles in humans. Alogliptin is mainly metabolized by cytochrome P450 (CYP2D6) and CYP3A4. Dose reduction is recommended for patients with moderate or worse renal impairment. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections and headache. Hypoglycaemia is seen in about 1.5% of the T2DM patients. Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema and severe cutaneous reactions such as Stevens-Johnson syndrome have been reported from post-marketing monitoring. Pharmacokinetic interactions have not been observed between alogliptin and other drugs including glyburide, metformin, pioglitazone, insulin and warfarin. The present review aimed to update the clinical information on pharmacodynamics, pharmacokinetics, adverse effects and drug interactions, and to discuss the future directions of alogliptin.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Piperidines; Uracil

Owing to the close association of cardiovascular (CV) disease with type 2 diabetes and the uncertainty surrounding the CV safety of antidiabetes agents, in 2008 the Food and Drug Administration issued guidance for the demonstration of CV safety for new antidiabetes drugs. Recently the results from CV outcomes trials of three dipeptidyl peptidase-4 (DPP-4) inhibitors and a glucagon-like peptide-1 receptor agonist have been reported. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial, and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the safety of saxagliptin, alogliptin, and sitagliptin, respectively, in patients with type 2 diabetes with CV disease or at high risk for CV disease. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) assessed the safety of lixisenatide in patients with type 2 diabetes and a recent acute coronary syndrome event. The results show that these agents neither increased nor deceased major adverse CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke) compared with placebo. However, the resources needed to conduct these studies may detract from the ability to understand the potential long-term benefit and risk in the majority of patients that are candidates for use of these medications.

Topics: Adamantane; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Piperidines; Sitagliptin Phosphate; Treatment Outcome; Uracil

Dipeptidyl peptidase-4 (DPP-4) inhibitors are weight neutral and well tolerated, and provide better glycaemic control for a longer period compared to conventional therapies. Despite the fact that various drugs are available, glycaemic control remains suboptimal in approximately half of patients with type 2 diabetes mellitus; one of the major reasons for low medication adherence.. A novel DPP-4 inhibitor, trelagliptin, was approved in Japan in March 2015, and is the first once-weekly oral antidiabetic agent in the world. In this review, current issues concerning medication adherence for the treatment of diabetes are discussed followed by a summary of the characteristics and future expectations of trelagliptin, by reviewing the recent phase I, II, and III clinical studies of trelagliptin.. Trelagliptin has demonstrated superiority to placebo and non-inferiority to alogliptin, indicating its efficacy and tolerance in Japanese patients. Trelagliptin is expected to improve adherence and prevent complications. Due to the convenient dosing regimen, it is expected to be widely used in the clinical setting. A large-scale long-term study will help further confirm its long-term efficacy and safety, patients' satisfaction, and medication adherence.

Topics: Asian People; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Japan; Piperidines; Uracil

The treatment of diabetes mellitus type 2 is effective, but still is not optimal. DPP4 inhibitors (gliptins) are a new group of peroral antidiabetic drugs. The third clinical mortality study with gliptins in patients with diabetes mellitus type 2 was finished in 2015. The studies are known under acronym TECOS, SAVOR and EXAMINE and the tested drugs are sitagliptin, saxagliptin and alogliptin. The studies included about 37,000 patients. The studies confirmed the cardiovascular safety of the DPP4 inhibitors, but the question about increased heart failure remains open. The effectiveness of lowering glycaemia (glycated haemoglobin) was confirmed and also the pancreatic safety is confirmed.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemic Agents; Piperidines; Sitagliptin Phosphate; Uracil

The pharmacology, pharmacodynamics, pharmacokinetics, safety, efficacy, and place in therapy of alogliptin and its combinations for managing type 2 diabetes mellitus are reviewed.. Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). It works by slowing the inactivation of the incretin hormones, thereby increasing their concentrations in the bloodstream and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin has a moderate degree of absorption, estimated to exceed 75%, and its absorption is not affected by food. No drug interactions are known to be associated with alogliptin monotherapy. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The clinical efficacy and safety of alogliptin have been demonstrated in several clinical trials, reducing patients' glycosylated hemoglobin level by 0.4-1.0% in 26 weeks. Alogliptin does not require any dosage adjustment when coadministered with ketoconazole, fluconazole, gemfibrozil, warfarin, metformin, glyburide, and pioglitazone. Alogliptin selectively binds to and inhibits DPP-4 in vitro at concentrations approximating therapeutic exposures. The most common adverse events associated with alogliptin are nasopharyngitis, headache, and upper respiratory tract infection. As with the other DPP-4 inhibitors, use of alogliptin may be associated with the development of pancreatitis during therapy.. Alogliptin, a selective DPP-4 inhibitor, does not differ greatly from the other DPP-4 inhibitors currently available. It can be used as monotherapy or in combination with metformin for the management of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.. Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.. Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.. Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Peptides; Piperidines; Purines; Pyrazines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Weight Loss

We performed a systematic review to identify which genetic variants predict response to diabetes medications.. We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance.. Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication-gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis.. We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.

Topics: Acarbose; Biomarkers, Pharmacological; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Pharmacogenetics; Pioglitazone; Piperidines; Polymorphism, Genetic; Prediabetic State; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones

Type 2 diabetes mellitus continues to be a global problem, placing an enormous burden on healthcare systems and resources. Effective treatment options to minimize the effects of hyperglycemia are essential. Most patients eventually need to take multiple drugs to maintain glycemic control, and many antidiabetic drugs are associated with adverse effects, such as hypoglycemia, weight gain or gastrointestinal effects. Dipeptidyl peptidase (DPP)-4 inhibitor is one of the newer classes of oral antidiabetic drug, and alogliptin is the most recently approved drug in this class.. This paper reviews the pharmacodynamic and pharmacokinetic properties of alogliptin and the results of clinical trials evaluating its efficacy at improving glycemic control in patients with type 2 diabetes both as monotherapy and in combination with other antidiabetic drugs. The drug's tolerability and safety profiles are also considered.. Alogliptin is a DPP-4 inhibitor that can help in improving glycemic control in patients with type 2 diabetes, including the elderly. It is generally well tolerated and does not increase the risk of hypoglycemia or weight gain.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Piperidines; Uracil

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of blood glucose-lowering therapy with proven efficacy, tolerability and safety. Four of the five commercially available DPP-4 inhibitors are subject to significant renal clearance, and pharmacokinetic studies in people with renal impairment have led to lower recommended doses based on creatinine clearance in order to prevent drug accumulation. Data from these pharmacokinetic studies and from supratherapeutic doses in healthy individuals and people with uncomplicated diabetes during development suggest, however, that there is a wide therapeutic margin. This should protect against toxicity if people with renal impairment are inadvertently prescribed higher doses than recommended. Doses appropriate to renal function are associated with reductions in HbA1c that are equivalent to those observed in people with type 2 diabetes who do not have renal impairment. Recent large-scale cardiovascular safety trials of saxagliptin and alogliptin have identified heart failure as a potential concern and renal impairment may increase the risk of this complication. Although the incidence of pancreatitis does not appear to be significantly increased by DPP-4 inhibitor therapy, renal impairment is also an independent risk factor. Additional data from other ongoing DPP-4 inhibitor cardiovascular safety trials should provide a more precise assessment of the risks of these uncommon complications, including in people with renal impairment.

Topics: Adamantane; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Piperidines; Renal Insufficiency; Risk Factors; Treatment Outcome; Uracil

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a class of anti-hyperglycemic agents with proven efficacy in patients with type 2 diabetes mellitus (T2DM).. This review considers the pharmacokinetic profile, adverse effects and drug interactions of DPP-4 inhibitors. DPP-4 inhibitors have certain differences in their structure, metabolism, route of elimination and selectivity for DPP-4 over structurally related enzymes, such as DPP-8/DPP-9. They have a low potential for drug interactions, with the exception of saxagliptin that is largely metabolized by cytochrome CYP3A4/A5. Reports of pancreatitis and pancreatic cancer have raised concerns regarding the safety of DPP-4 inhibitors and are under investigation. Post-marketing surveillance has revealed less common adverse effects, especially a number of skin- and immune-related adverse effects. These issues are covered in the present review.. DPP-4 inhibitors are useful and efficient drugs. DPP-4 inhibitors have similar mechanism of action and similar efficacy. However, DPP-4 inhibitors have certain differences in their pharmacokinetic properties that may be associated with different clinical effects and adverse event profiles. Although clinical trials indicated a favorable safety profile, post-marketing reports revealed certain safety aspects that need further investigation. Certainly, more research is needed to clarify if the differences among DPP-4 inhibitors could lead to a different clinical and safety profile.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Nitriles; Piperidines; Piperidones; Purines; Pyrazines; Pyrazoles; Pyrimidines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Thiazolidines; Triazoles; Uracil; Vildagliptin

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are effective and safe oral incretin-based antihyperglycemic drugs. In preclinical studies, DPP-4 inhibitors have demonstrated cardiovascular benefits, independent of glycemic control, in patients with type-2 diabetes mellitus. Since 2005, various DPP-4 inhibitors (sitagliptin, linagliptin and saxagliptin) have been clinically available in the United States. Since 2013, alogliptin is the 4(th) approved DPP-4 inhibitor available on the market. Studies have shown that alogliptinis non-inferior to comparator drugs among newly diagnosed type 2 diabetes mellitus patients. Alogliptin can effectively be used as a single agent or as an add-on drug in combination with other glucose lowering drugs with favorable outcomes on glycemic control and HbA1C levels.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Uracil

We conducted a meta-analysis to compare the efficacy and safety of repaglinide plus metformin with metformin alone on type 2 diabetes. Twenty-two studies were included in this meta-analysis. Results showed combination therapy was safe and could gain better outcomes in glycemic control. Well-designed studies are required to confirm this conclusion.

Topics: Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Piperidines

Although recent reports suggest an association between saxagliptin and an increased risk of admissions for heart failure, it is not clear whether dipeptidyl peptidase IV (DPP-IV) inhibition contributes to heart failure in high-risk patients. The purpose of this research is to understand heart failure risk among high-risk patients with type 2 diabetes.. This is a systematic review of data published in full papers and abstract form using the terms DPP-IV inhibitors and heart failure published since October 2013. Data from insurance and hospital databases were combined with those from multiple published trials, including the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial; Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE), and Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial as well as pooled analyses of linagliptin and saxagliptin placebo-controlled trials to examine heart failure among patients represented in those datasets.. A meta-analysis of the 9 datasets showed an increase in heart failure with dipeptidyl peptidase IV inhibitors of 15% (P = 0.017). There was no statistical heterogeneity, nor was there a statistical difference between cohort studies and randomized, controlled trials (P = 0.3), even though cohort studies alone were not significant (relative risk: 1.1; P = 0.32). Removing SAVOR-TIMI 53 data produced an insignificant increase in heart failure of 12% (P = 0.09) in the rest of the studies. In the randomized, controlled trials, the increased risk was 24% (P = 0.002). There was no statistical difference between those studies with and without baseline cardiovascular disease (P = 0.58), although the cardiovascular disease studies were borderline significant (P = 0.06). There was no publication bias.. There are data from studies using sitagliptin, saxagliptin, and alogliptin showing that these agents may increase the risk of hospitalization for heart failure. More data are required for a definitive conclusion.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Nitriles; Piperidines; Pyrrolidines; Sitagliptin Phosphate; Uracil; Vildagliptin

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Topics: Adamantane; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Treating patients with diabetes is one of the most challenging and important activities a physician (primary care physician or specialist) can undertake. A key to successful therapy for type 2 diabetes is the insight that this condition is progressive and that the need for additional agents over time is normative. The ability to individualize therapy by patient and medication characteristics comes from experience and knowledge of pertinent clinical studies. However, guidelines from expert bodies such as the American Diabetes Association/European Association for the Study of Diabetes and American Association of Clinical Endocrinologists/American College of Endocrinology can help clinicians of all levels of expertise to approach therapy choices more rationally. There is unity across these guidelines about the role and benefits of metformin as first-line pharmacological treatment, probability of good efficacy, low risk of hypoglycemia, modest weight loss, and overall long-term data. Unfortunately, this unity does not extend to recommendations for subsequent pharmacological agents and their use in combination to intensify treatment when insulin is not (yet) appropriate. Across both statements, some drug classes seem more prominent, and looking at their benefit-risk profile, it is clear why this is the case. The most profound recent change in diabetes therapy has been the introduction of incretin therapies. Incretin therapies minimize 2 important adverse effects seen with many other therapies: hypoglycemia and weight gain. These agents have increased the range of options available for early intensification of treatment of type 2 diabetes. In combination with more established therapies, there are more opportunities than ever to accommodate patient preferences while improving glycemic control and harnessing extraglycemic benefits of a second (or third) agent.

Topics: Algorithms; Carbamates; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Metformin; Peptides; Piperidines; Practice Guidelines as Topic; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Venoms

Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%-0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.

Topics: Adult; Aged; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Molecular Targeted Therapy; Piperidines; Uracil

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Topics: Anti-Obesity Agents; Appetite; Combined Modality Therapy; Comorbidity; Cost-Benefit Analysis; Cyclobutanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Combinations; Exercise Therapy; Fructose; Gastrointestinal Hormones; Humans; Incretins; Insulin; Insulin Secretion; Intestines; Lactones; Leptin; Life Style; Models, Biological; Neuropeptides; Obesity; Orlistat; Phentermine; Phytotherapy; Piperidines; Plant Preparations; Pyrazoles; Rimonabant; Topiramate

To review the pharmacology, pharmacokinetics, safety, and efficacy of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in the management of type 2 diabetes mellitus (T2DM).. Searches were conducted in MEDLINE (1946-August 2013) and Embase (1974-August 2013) for English language articles using key words alogliptin, SYR-332, Nesina, Oseni, and Kazano. References of articles were reviewed to identify any additional sources.. Articles with adequate sample sizes, evaluating clinically relevant end points were included.. Alogliptin is a highly selective and potent competitive inhibitor of DPP-4. The DPP-4 enzyme rapidly inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. GLP-1, which releases postprandial insulin in response to meals, is thought to be deficient in patients with T2DM. Studies evaluating the role of alogliptin in T2DM have shown significant reductions in blood glucose and hemoglobin A1C (A1C) levels. Alogliptin doses of 12.5 to 25 mg once daily reduced A1C by 0.56% to 0.59% as monotherapy. Patients given alogliptin in addition to other antidiabetic agentsexperienced additional A1C lowering of 0.4% to 0.8%. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections, and headache. Alogliptin demonstrates a neutral effect on weight. A large trial evaluating the cardiovascular safety of alogliptin is currently being conducted.. Alogliptin is the fourth DDP-4 inhibitor approved in the US for the treatment of T2DM. It is available alone (Nesina) and in fixed-dose combinations with metformin (Kazano) and pioglitazone (Oseni). It has no demonstrable advantages over other agents in its class.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Piperidines; Treatment Outcome; Uracil

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Topics: Benzazepines; Diabetes Mellitus, Type 2; Heart Valve Diseases; Humans; Molecular Structure; Obesity; Parkinson Disease; Piperidines; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population.

Topics: Adamantane; Biomarkers; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Models, Biological; Nitriles; Piperidines; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials.

Topics: Adamantane; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin; Weight Gain

Oral repaglinide (GlucoNorm®; NovoNorm®; Prandin®; Surepost®) is a rapid-acting insulin secretagogue that lowers postprandial glucose (PPG) excursions by targeting early-phase insulin release, with reductions in PPG considered to be important in reducing long-term cardiovascular complications of diabetes mellitus. Repaglinide, a carbamoylbenzoic acid derivative, is chemically related to the meglitinide class of insulin secretagogues, but unrelated to the sulfonylurea insulin secretagogues. Meglitinides, including repaglinide, have a distinct binding site at the β-cell membrane, which differs from that of sulfonylureas, and corresponds to greater insulinotropic effects with repaglinide than with glibenclamide and/or glimepiride and a more rapid onset of action in in vitro and in vivo studies. This article reviews the clinical efficacy and tolerability of oral repaglinide in the treatment of patients with type 2 diabetes and provides an overview of its pharmacological properties. In well designed clinical trials of up to 52 weeks' duration and in the clinical practice setting, recommended dosages of repaglinide (0.5-4 mg three times daily up to 30 minutes prior to a meal) provided effective glycaemic control and were generally well tolerated in treatment-naive or -experienced adult patients with type 2 diabetes, including elderly patients and those with renal impairment. Furthermore, as monotherapy or in combination with other oral antihyperglycaemic drugs, repaglinide was at least as effective as other oral antihyperglycaemic drugs at improving or maintaining glycaemic control, with a tolerability profile that was generally similar to that of sulfonylurea drugs and nateglinide. Thus, repaglinide remains an effective option for the management of patients with type 2 diabetes.

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines; Randomized Controlled Trials as Topic

Alogliptin is a highly selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). It is one of several agents of this class now available for treatment of type 2 diabetes.. This review is based upon a PubMed search and personal experience with alogliptin. The pharmacokinetics and pharmacodynamics of alogliptin are reviewed. The glucose-lowering effect of this agent is discussed as monotherapy and in combination with metformin, sulfonylurea, piogilitazone and insulin. The potential adverse effects of alogliptin are summarized. Alogliptin is compared with the other available DPP-4 inhibitors.. Alogliptin is an additional choice in the group of DPP-4 inhibitors. As a group, these agents have a relatively modest glucose-lowering effect, inferior to that of metformin, sulfonylureas, and insulin. They do not have the benefit of weight loss offered by the glucagon-like polypeptide (GLP)-1 agonists. The primary use of DPP-4 inhibitors is in combination with other hypoglycemic agents, mainly metformin. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. A greater use of alogliptin and other DPP-4 inhibitors will occur if long-term studies show reduced cardiac events or long-term retention of insulin secretory capacity. The Examine Trial, a large study of alogliptin in coronary disease patients, is now underway and could provide important supportive data.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Piperidines; Randomized Controlled Trials as Topic; Uracil

Topics: Aged; Azepines; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypnotics and Sedatives; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines; Sleep Wake Disorders

Dipeptidyl peptidase -4 inhibitors represent a novel way to augment the incretin system and one of the newest class of medications in the treatment of type 2 diabetes mellitus. Their mechanism of action is to decrease the inactivation of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, both of which are involved in maintaining euglycemia subsequent to carbohydrate intake. Currently investigated agents include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Each agent has been shown to provide significant improvements in glycemic control compared to placebo. They are effective when added to other oral diabetes agents and in the cases of sitagliptin, vildagliptin, and alogliptin in addition to insulin. These agents may not provide as significant improvement in glucose concentrations as some other medications including metformin, thiazolidinediones, or glucagon-like peptide 1 agonists. The lack of head to head clinical data comparing the various dipeptidyl peptidase 4 inhibitors does not allow for specific recommendations if one agent is more effective or safer than another within the class. Their side effect profile suggests they are very well tolerated and have few drug interactions. For patients with mildly elevated glucose concentrations, they are therapeutic options in both drug-naive patients as well as those not optimally controlled on other diabetes medications.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Female; Glucagon-Like Peptide 1; Humans; Linagliptin; Male; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Vildagliptin

Topics: Adult; Animals; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Piperidines; Rats; Uracil

The pharmacologic management of type 2 diabetes has changed dramatically in the past two decades. We have moved from a situation of only having two choices, insulin and sulfonylureas, to a position of myriad choices from 11 categories of medications (insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, gliptins (dipeptidyl peptidase 4 [DPP IV] inhibitors), bromocriptine, glucagon-like peptide analogues, thiazolidinediones, glinides, amylin analogues and bile acid sequestrants. One of the most recent additions to this list are the DPP IV inhibitors commonly known as gliptins. Currently, there are four DPP IV inhibitors available in various countries-alogliptin, sitagliptin, vildagliptin and saxagliptin (1). Of these, two have been approved for clinical use in the United States: sitagliptin and saxagliptin. Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2). Alogliptin was approved for use in Japan under the trade name Nesina® in April 2010 (3). This manuscript will review alogliptin, its chemistry, pharmacokinetics/pharmacodynamics, drug interactions, clinical trials and its current state of FDA review. Preclinical animal data have been reviewed elsewhere and will not be outlined in this manuscript. The interested reader is referred to those recent reviews (4, 5).

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Drug Interactions; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Piperidines; Treatment Outcome; Uracil

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Topics: Adamantane; Age Factors; Aged; Aging; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Male; Middle Aged; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Vildagliptin

A recent treatment advance for type 2 diabetes is the oral therapy with DPP IV inhibitors. New substances of this class are in development in order to increase alternatives for treating this important metabolic disease. The reader will gain detailed pharmacological and clinical information on alogliptin, dutogliptin and linagliptin and will learn how these DPP IV inhibitors may widen the whole drug class. Possible special indications for the various DPP IV inhibitors are discussed.. The DPP IV inhibitors and their current role in type 2 diabetes are highlighted. Preclinical and clinical studies of the novel DPP IV inhibitors alogliptin, dutogliptin and linagliptin, including published data since 2007, are presented and a comparison of these compounds is made.. The efficacy and safety profile of DPP IV inhibitors are promising and advantageous so far. In contrast to sulfonylureas, DPP IV inhibitors do not have an intrinsic risk for causing hypoglycemia and they are body weight neutral. Their tolerability profile is good and no specific adverse reactions have been reported. Experience so far suggests that there are no safety issues associated with inhibition of DPP IV activity by itself. Novel DPP IV inhibitors with distinct properties may offer alternative choices within this drug class.

Topics: Administration, Oral; Animals; Boronic Acids; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Hypoglycemic Agents; Linagliptin; Piperidines; Purines; Quinazolines; Uracil

Alogliptin, a dipeptidyl peptidase-4(DPP-4) inhibitor, is launched in Japan in advance of other countries in the world. Alogliptin has high-selectivity to inhibit DPP-4 activity compared to other DPP-4 inhibitors due to its unique formula of chemical structure. Clinical studies provided evidences that alogliptin monotherapy with daily doses of 12.5 and 25 mg decreased the HbAlc level approximately 0.4-0.8% accompanied with an elevation of active glucagon-like peptide(GLP)-1 level. Neither body weight change nor apparent adverse events was observed. In type 2 diabetic patients who already treated with pioglitazone or voglibose, addition of alogliptin further decreased HbAlc by 0.9% from basal level during 12-week study period. Here, we entirely reviewed pharmacological and clinical profiles of alogliptin by introducing preclinical and clinical studies conducted inside and outside of Japan.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Piperidines; Uracil

Type 2 diabetes is characterized by insulin resistance and pancreatic beta cell dysfunction, and the latter is known to usually progress during the entire disease history. Thus, monotherapy cannot ameliorate both aspects of these and often fails to achieve the target level of glucose control. Pioglitazone, a thiazolidinedione class agent, is an insulin sensitizer and alogliptin belongs to DPP-4 (dipeptidyl peptidase-4) inhibitor class agents, which promote postprandial insulin secretion and suppress glucagon secretion in a blood glucose dependent fashion. Both agents have been shown to protect beta cell from apoptosis in animal models, which is one of major causes of beta cell dysfunction in human. Therefore, the combination therapy or more ideally a compounding agent of pioglitazone and alogliptin is expected to be effective and beneficial for a large number of people with type 2 diabetes in terms of strict glycemic control.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Humans; Hypoglycemic Agents; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

Treatment of patients with type 2 diabetes mellitus (T2DM) traditionally has involved a progression of phases, from conventional lifestyle interventions and monotherapy, to combination therapy involving oral agents, to insulin initiation and its use either alone or with oral pharmacotherapy. Currently, the need for antidiabetic therapies with fewer adverse effects (eg, weight gain, reduced rates of hypoglycemia) is unmet. In addition, most treatments fail to adequately control postprandial hyperglycemia. Traditional options have generally been directed at the "insulin demand" aspect and have targeted insulin secretion or insulin resistance in peripheral tissues. Only recently have agents been available to address the "glucose supply" aspect that leads to fasting hyperglycemia in patients with T2DM. Incretin-based therapies, however, address both aspects. Two classes of incretin-directed therapies are available and work by either increasing endogenous levels of glucagon-like peptide-1 (GLP-1) (ie, dipeptidyl peptidase-4 inhibitors) or by mimicking the activity of endogenous GLP-1 (ie, GLP-1 agonists). These therapies treat the key metabolic abnormalities associated with T2DM but do so with reduced rates of hypoglycemia and do not promote weight gain as compared with conventional therapies.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Piperidines; Pyrazines; Sitagliptin Phosphate; Triazoles; Uracil

Successful management of type 2 diabetes mellitus (T2DM) requires attention to additional conditions often associated with hyperglycemia including overweight or obesity, dyslipidemia and hypertension, as each has some relationship with microvascular or macrovascular complications. Because control of cardiovascular risk factors is as important as glucose control in T2DM, these risk factors need to be addressed, and it is critical that antidiabetes medications do not exacerbate these risk factors. A patient-centered approach to treatment in which clinicians maximize patient involvement in the selection of antidiabetes therapy may lead to increased adherence and improved clinical outcomes. The incretin hormones, which include glucagon-like peptide-1 (GLP-1), are involved in glucoregulation and have become an important focus of T2DM research and treatment. Incretin-based therapies, such as the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-IV inhibitors, have shown beneficial effects on hyperglycemia, weight, blood pressure and lipids with a low incidence of hypoglycemia.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Obesity; Patient Compliance; Peptides; Piperidines; Precision Medicine; Primary Health Care; Pyrazines; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagli

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Attenuation of the prandial incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), contributes to hyperglycemia in type 2 diabetes mellitus (T2DM). Since the launch of sitagliptin in 2006, a compelling body of evidence has accumulated showing that dipeptidyl peptidase-4 (DPP-4) inhibitors, which augment endogenous GLP-1 and GIP levels, represent an important advance in the management of T2DM. Currently, three DPP-4 inhibitors - sitagliptin, vildagliptin and saxagliptin - have been approved in various countries worldwide. Several other DPP-4 inhibitors, including linagliptin and alogliptin, are currently in clinical development. As understanding of, and experience with, the growing number of DPP-4 inhibitors broadens, increasing evidence suggests that the class may offer advantages over other antidiabetic drugs in particular patient populations. The expanding evidence base also suggests that certain differences between DPP-4 inhibitors may prove to be clinically significant. This therapeutic diversity should help clinicians tailor treatment to the individual patient, thereby increasing the proportion that safely attain target HbA(1c) levels, and reducing morbidity and mortality. This review offers an overview of DPP-4 inhibitors in T2DM and suggests some characteristics that may provide clinically relevant differentiators within this class.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Intestinal Mucosa; Linagliptin; Neurons; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in type 2 diabetes mellitus (T2DM). Pioglitazone is a potent insulin sensitizer, improves pancreatic beta cell function and has been shown in several outcome trials to lower the risk of atherosclerotic and cardiovascular events. Glucagon-like peptide-1 deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Alogliptin is a new DPP-4 inhibitor that reduces glycosylated hemoglobin (HbA(1c)), is weight neutral, has an excellent safety profile, and can be used in combination with oral agents and insulin. Alogliptin has a low risk of hypoglycemia, and serious adverse events are uncommon. An alogliptin-pioglitazone combination is advantageous because it addresses both insulin resistance and islet dysfunction in T2DM. HbA(1c) reductions are significantly greater than with either monotherapy. This once-daily oral combination medication does not increase the risk of hypoglycemia, and tolerability and discontinuation rates do not differ significantly from either monotherapy. Importantly, measures of beta cell function and health are improved beyond that observed with either monotherapy, potentially improving durability of HbA(1c) reduction. The alogliptin-pioglitazone combination represents a pathophysiologically sound treatment of T2DM.

Topics: Animals; Cardiovascular System; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucose; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Mice; Pioglitazone; Piperidines; Rats; Thiazolidinediones; Uracil

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. It is characterized by high circulating levels of glucose resulting from insulin resistance and impaired insulin secretion. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. The results of Phase II and Phase III human studies, upon evaluation for clinical efficacy, safety and tolerability in patients with type 2 diabetes, have demonstrated that Alogliptin is effective and well tolerated as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin, with an excellent safety profile.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Incretins; Insulin-Secreting Cells; Piperidines; Structure-Activity Relationship; Uracil

Alogliptin (Nesina®) is a dipeptidyl peptidase-4 inhibitor that is approved in Japan for the treatment of adult patients with type 2 diabetes mellitus that is inadequately controlled by diet and exercise alone or by diet plus treatment with an α-glucosidase inhibitor. Alogliptin plus diet and exercise is also approved in Japan for use in combination with a thiazolidinedione in patients with type 2 diabetes. In several large (n >250), double-blind, multinational trials of up to 26 weeks' duration, oral alogliptin as monotherapy or in combination with other oral antihyperglycaemic agents (metformin, glibenclamide or pioglitazone) or insulin therapy improved glycaemic control and was generally well tolerated in adult patients with inadequately controlled type 2 diabetes, including elderly patients. Significant improvements in glycaemic control were evident from as early as 1 week in terms of improvements in mean fasting plasma glucose levels and from 4 weeks onwards for improvements in mean glycosylated haemoglobin levels. In general, the incidence of hypoglycaemia was similar to that seen in placebo groups and alogliptin treatment had neutral effects on bodyweight and lipid parameters. The long-term safety of alogliptin therapy remains to be established in clinical studies and with clinical experience. A planned clinical trial evaluating long-term clinical outcomes in patients with acute coronary syndrome and other planned or ongoing short-term trials will help to more definitively determine the position of alogliptin therapy in relation to other available antihyperglycaemic therapies. In the meantime, alogliptin is a promising new option for the treatment of patients with type 2 diabetes, including elderly patients.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Piperidines; Uracil

The purpose of this study is to evaluate efficacy and safety of nateglinide tablet administration in comparison with those of repaglinide tablet as control on treating type 2 diabetes mellitus in China. Pooled-analysis with analysis of covariance (ANCOVA) method was applied to assess the efficacy and safety based on original data collected from four independent randomized clinical trials with similar research protocols. However meta-analysis was applied based on the outcomes of the four studies. The results by meta-analysis were comparable to those obtained by pooled-analysis. The means of HbA(1c), and fasting blood glucose in both the nateglinide and repaglinide groups were reduced significantly after 12 weeks duration but no statistical differences in reduction between the two groups. The adverse reaction rates were 9.89 and 6.51% in the nateglinide and repaglinide groups respectively, with the rate difference showing no statistical significance, and the Odds Ratio of adverse reaction rate (95% confidence interval) was 1.59 (0.99, 2.55). Both nateglinide and repaglinide administration have similarly significant effects on reducing HbA(1c) and FBG. However, the adverse reaction rate in the nateglinide group is higher than that in the latter using repaglinide but no statistical significance difference as revealed in the four clinical trials detailed below.

Topics: Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes.. To provide an overview of the mechanism by which alogliptin reduces hyperglycemia and to summarize the pharmacology, efficacy and safety of the drug.. A Medline search was conducted and abstracts and presentations from recent American Diabetes Association and European Association for the Study of Diabetes (EASD) meetings were reviewed. The results of Phase II and Phase III human studies were evaluated for clinical efficacy, safety and tolerability in patients with type 2 diabetes.. Alogliptin is effective as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin. It is well tolerated and has an excellent safety profile. Additional studies are needed to evaluate the long-term safety and efficacy of alogliptin.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Piperidines; Sulfonylurea Compounds; Thiazolidinediones; Uracil

Abdominal obesity (high waist circumference) is more strongly associated with cardiovascular disease and type 2 diabetes than generalized adiposity (high body mass index). Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB(1) receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDL-cholesterol, hypertriglyceridemia, inflammation and low adiponectin. Evidence suggests that these cardiometabolic risk factors/markers are not optimally managed by current treatments. Improving the nutrition and physical activity/exercise habits of patients remains the cornerstone of management of elevated global cardiometabolic risk. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardiometabolic risk markers/factors. Randomized trials of rimonabant in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and C-reactive protein (a marker of systemic inflammation). Further analyses suggested that about half of the improvements of several cardiometabolic risk markers were independent from concomitant weight loss. Blood pressure also improved with rimonabant treatment, this effect being consistent with the blood pressure lowering effect of weight loss. The tolerability and safety of rimonabant have been extensively studied and most transient side effects include some gastrointestinal side effects, anxiety, mood changes and incidence of depressive disorders, particularly in patients with previous history of depression. Rimonabant is a useful option for patients with abdominal obesity and with related cardiometabolic risk abnormalities such as an atherogenic dyslipidemia and/or type 2 diabetes.

Topics: Abdominal Fat; Animals; Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors

Obesity is considered as a major health problem, as its prevalence continuously rises worldwide. One of the common health consequences of obesity is type 2 diabetes mellitus. Therefore, antiobesity management is a prerequisite in treating diabetic patients. Lifestyle modifications combined with pharmacological agents appear to be an effective approach. Sibutramine is a serotonin-noradrenaline reuptake inhibitor, which acts centrally by promoting the feeling of satiety and decreasing caloric intake, thus resulting in weight loss. A potential association with cardiovascular side effects has been noted. Orlistat, a gastric and pancreatic lipase inhibitor, also achieves significant weight loss and improves glycaemic status, but it has gastrointestinal side effects. Rimonabant, the first endocannabinoid CB1 antagonist, is associated with weight reduction and it improves diabetic parameters; nevertheless, it is associated with psychiatric disorders; indeed, a recently conducted safety review led to the temporal suspension of its commercialization. The above-mentioned medications seem to be currently useful agents for treating obesity in patients with type 2 diabetes mellitus. Other medications used for diabetes management, such as exenatide, liraglutide and pramlintide, have also shown body weight reduction. Ongoing research is needed to scrutinize the precise impact of these agents in the daily clinical practice of management of obesity in patients with type 2 diabetes mellitus.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Appetite Depressants; Body Weight; Cyclobutanes; Diabetes Mellitus, Type 2; Female; Humans; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome; Weight Loss; Young Adult

Diabetes mellitus (DM) is currently considered to be an epidemic disease. A safe and effective treatment has long been sought by scientists. Incretin mimetics and dipeptidyl peptidase-4 (DPP4) inhibitors represent a new class of agents that have recently been included as antidiabetic drugs. Although only a limited number of studies exist regarding the treatment of DM based on the incretin effect, DPP4 inhibitors have so far proved to be safe and effective, both when administered alone or in combination with other antidiabetic medication. This review focuses on incretin-effect physiology, as well as the DPP4 inhibitors, from sitagliptin to the new alogliptin-pioglitazone combination agent, given as monotherapy and in combination with other antidiabetic agents.

Topics: Adamantane; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Pioglitazone; Piperidines; Pyrazines; Sitagliptin Phosphate; Thiazolidinediones; Triazoles; Uracil

Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.

Topics: Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Hypoglycemic Agents; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Abdominal obesity is associated with numerous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia with low high-density lipoprotein (HDL) cholesterol, high triglycerides, and increased small dense low-density lipoprotein (LDL) cholesterol. A proportion of these metabolic disorders may be attributed to increased endocannabinoid activity. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant has been shown to reduce body weight, waist circumference, insulin resistance, triglycerides, dense LDL, C-reactive protein (CRP), and blood pressure, and to increase HDL and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. Besides an improvement in glucose tolerance in non-diabetic subjects, a reduction of 0.5-0.7% in haemoglobin A1C (HbA(1c)) levels was consistently observed in various groups of patients with type-2 diabetes. Almost half the metabolic changes could not be explained by weight loss, supporting direct peripheral effects of rimonabant. Ongoing studies should demonstrate whether improved metabolic disorders with CB1 receptor antagonists (rimonabant, taranabant, etc.) would translate into fewer cardiovascular complications among high-risk individuals.

Topics: Atherosclerosis; Blood Glucose; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Fasting; Glucose; Glycated Hemoglobin; Humans; Lipid Metabolism; Metabolic Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Weight gain, during and after the menopause is common. Contributing factors include ethnicity, reduced physical activity, reduced lean mass, reduced resting metabolic rate and treatment with certain drugs, e.g. steroids, insulin, glitazones. Excess body weight increases the risk of medical conditions including type 2 diabetes, hypertension, osteoarthritis, certain cancers and is associated with increased mortality. This review examines pharmacological approaches to promote weight loss. Pharmacological therapy should be considered as an adjunct to diet and lifestyle changes. The licensed drugs orlistat, sibutramine and rimonabant are discussed. Obesity increases the risk of type 2 diabetes. Thus, the effects of metformin and exenatide are examined.

Topics: Anti-Obesity Agents; Bariatric Surgery; Cyclobutanes; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Lactones; Menopause; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Venoms

Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes.. Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, the gut, the liver, the skeletal muscle and even the pancreas, all organs playing a key role in glucose metabolism and type 2 diabetes. Rimonabant, the first selective cannabinoid 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, glycated haemoglobin, triglycerides, insulin resistance index, and to increase HDL cholesterol and adiponectin concentrations in patients with type 2 diabetes, confirming data on nondiabetic overweight/obese patients. Almost half of the metabolic changes, including glycated haemoglobin reduction, could not be explained by weight loss, in agreement with direct peripheral effects.. Cannabinoid 1 blockade reduces food intake and body weight and improves metabolic regulation beyond just weight loss. Because of its positive effect on glucose metabolism, rimonabant deserves consideration in the treatment of overweight/obese patients with type 2 diabetes.

Topics: Animals; Blood Glucose; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Rimonabant

Topics: alpha-Galactosidase; Biguanides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine; Piperidines; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Triazoles

Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of beta-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Metabolic Syndrome; Metformin; Piperidines; Pyrazoles; Rimonabant; Safety; Sulfonylurea Compounds; Thiazolidinediones

Endocannabinoid system is overactivated in individuals with abdominal obesity. CBI receptors, first individualized in the brain, are also expressed in the adipocyte, the skeletal muscle, the liver, the gut, and the pancreas. Their blockade improves glucose tolerance and lipid profile, thanks increased insulin sensitivity and adiponectin levels. Rimonabant, a selective antagonist of CBI receptors, improves glucose control in patients with type 2 diabetes, treated with diet alone, metformin, sulfonylurea or insulin, while it also reduces body weight and other risk factors. Ongoing studies aim at further demonstrating the potential of rimonabant in the management of type 2 diabetes, in the prevention of type 2 diabetes and in the protection against cardiovascular complications in (diabetic) patients with abdominal obesity.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Type 2 diabetes mellitus (T2DM) is a progressive disorder caused by a combination of insulin resistance and beta cell dysfunction. It is associated with an increased and premature risk of cardiovascular disease as well as specific microvascular complications such as retinopathy, nephropathy and neuropathy. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched, such as the glucagon-like peptide (GLP-1) agonists (exenatide) and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and vildagliptin. This review looks at these new agents in terms of their mode of action, pharmacokinetics and use in clinical practice. This review also includes new agents in the area of weight loss that may have a positive effect for glucose management-for example, rimonabant.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Incretins; Piperidines; Pyrazoles; Rimonabant

Inhibitors of dipeptidyl peptidase IV (DPP-4) have emerged as an important new class of therapeutic agents for type two diabetes. Various medicinal chemistry approaches have been applied to this area and have resulted in the identification of numerous late-stage development compounds. The discoveries of several of the most advanced DPP-4 inhibitors are reviewed.

Topics: Adamantane; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Nitriles; Piperidines; Pyrrolidines; Uracil; Vildagliptin

The increase of obesity and type 2 diabetes on a global scale has increased the interest in how to counteract this epidemic. Improved lifestyle in general is a fundamental approach, but other remedies such as specific weight reduction or diabetes preventive drugs and surgery have also been tested. One problem to understand is what really happens after weight loss. Ongoing studies will try to address this question, such as the Swedish Obese Subjects (SOS) surgery study, the Look AHEAD (Action for Health in Diabetes) trial in the U.S. (recruiting obese type 2 diabetic patients), and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points and Outcomes (CRESCENDO) trial (by use of rimonabant versus placebo). This is very important, since previously, several observational studies in large population-based cohorts have indicated some detrimental effects of weight loss, even after intentional weight loss, with increased morbidity and mortality rates.

Topics: Bariatric Surgery; Cannabinoids; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Life Style; Multicenter Studies as Topic; Obesity; Piperidines; Power, Psychological; Pyrazoles; Rimonabant; Self Concept; Weight Loss

The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a role in the regulation of various aspects of eating behavior and energy balance through central and peripheral mechanisms. In the central nervous system, cannabinoid type 1 receptors and their endogenous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume palatable food. Moreover, the ECS is present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it seems to be involved in the regulation of lipid and glucose homeostasis. Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may provide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease.

Topics: Adipose Tissue; Animals; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Eating; Endocannabinoids; Energy Metabolism; Humans; Hypothalamus; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reward; Rimonabant

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. Clinical trials showed that, compared to placebo, rimonabant 20 mg/ day consistently increases weight loss, reduces waist circumference, improves atherogenic dyslipidaemia (low HDL cholesterol, high triglycerides, high small dense LDL), diminishes insulin resistance, reduces HbA1c levels, and contributes to lower blood pressure and C-reactive protein levels. Almost half of the most important metabolic effects occur beyond weight loss, suggesting direct peripheral effects of rimonabant, especially in visceral adipose tissue as suggested by the increase in adiponectin levels. Rimonabant at a daily dose of 20 mg is indicated as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s) such as type 2 diabetes or dyslipidaemia. Adverse effects concern digestive tract (nausea, mostly transient) and psychological disorders (depressed mood, anxiety), in relation to the mechanism of action of the drug. Therefore, rimonabant is contra-indicated in case of depression and/or in patients receiving antidepressants.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Piperidines; Pyrazoles; Rimonabant

Takeda San Diego Inc is developing alogliptin, a small-molecule, orally available dipeptidyl peptidase IV (DPP IV) inhibitor, for the potential treatment of type 2 diabetes. In January 2008, Takeda announced that an NDA for alogliptin had been submitted to the FDA.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Drug Interactions; Humans; Hypoglycemic Agents; Molecular Structure; Patents as Topic; Piperidines; Structure-Activity Relationship; Treatment Outcome; Uracil

Rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1-2 year placebo-controlled randomised clinical trials recruiting more than 6600 overweight/obese patients with or without co-morbidities. Rimonabant 20 mg daily consistently reduced body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and increased HDL cholesterol concentrations in both non-diabetic and type-2 diabetic overweight/obese patients. Adiponectin levels were increased, an effect that correlated with HDL cholesterol augmentation, while small dense LDL cholesterol levels were decreased in patients receiving rimonabant 20 mg compared with those receiving placebo in RIO Lipids. Furthermore, in RIO Diabetes, a 0.7% reduction in glycated haemoglobin (HbA1c) levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes, an effect recently confirmed in the 6-month SERENADE (Study Evaluating Rimonabant Efficacy in drug-NAive DiabEtic patients) trial in drug-naive diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. The positive effects observed after 1 year were maintained after 2 years. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared with placebo. In clinical practice, rimonabant has to be prescribed to the right patient, i.e. overweight/obese subjects with cardiometabolic risk factors and with no major depressive illness and/or ongoing antidepressive treatment, in order to both maximise efficacy and minimise safety issues. New trials are supposed to confirm the potential role of rimonabant in patients with abdominal adiposity, atherogenic dyslipidaemia and/or type-2 diabetes, i.e. at high cardiometabolic risk.

Topics: Algorithms; Anti-Obesity Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metabolic Syndrome; Metformin; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity.

Topics: Adipose Tissue, White; Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Glucose; Homeostasis; Humans; Liver; Models, Biological; Muscles; Obesity; Pancreas; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Rodentia

Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Piperidines; Treatment Outcome; Weight Gain

Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies.

Topics: Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Humans; Lipids; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

In type 2 diabetes mellitus, impairment of insulin secretion is an important component of the disease. Meglitinide analogues are a class of oral hypoglycaemic agents that increase insulin secretion, in particular, during the early phase of insulin release.. The aim of this review was to assess the effects of meglitinide analogues in patients with type 2 diabetes mellitus.. We searched several databases including The Cochrane Library, MEDLINE and EMBASE. We also contacted manufacturers and searched ongoing trials databases, and the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) websites.. We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin.. Two authors independently extracted data and assessed trial quality.. Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide). Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. Nateglinide had a similar or slightly less marked effect on glycosylated haemoglobin than metformin (one study, 355 participants). Weight gain was generally greater in those treated with meglitinides compared with metformin (up to three kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance.. Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

Topics: Acarbose; Carbamates; Chromans; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Troglitazone

The development of a variety of new substances will considerably expand the therapeutic choices in the treatment of type 2 diabetes. In 2006, the endocannabinoid receptor blocker Rimonabant has been approved for the treatment of type 2 diabetes in Germany. This compound has led to significant reductions of body weight along with improvements of HbA1c levels and lipid profiles, but the lack of health insurance coverage limits its large scale use in germany. In April 2007, the first members of the GLP 1 analogues/incretin mimetics (exenatide, Byetta) and DPP 4 inhbitors (sitagliptin, Januvia) have become available for the treatment of type 2 diabetes in Germany. Both drugs have significantly lowered HbA1c levels in clinical studies. In addition, the incretin mimetics have caused a progressive reduction of body weight, while the DPP 4 inhibitors have been rather weight neutral. Sitagliptin can be administered orally, whereas exenatide has to be injected subcutaneously. Neither the DPP 4 inhibitors, nor the incretin mimetics have led to the development of hypoglycaemia, unless combined with sulfonylureas. Overall, the introduction of these new drug classes will certainly broaden our therapeutic choices in the management of type 2 diabetes. The long-term effects of these drugs on the development of diabetic complications in long-term trials remains to be awaited.

Topics: Adamantane; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Nitriles; Peptides; Piperidines; Pyrazines; Pyrazoles; Pyrrolidines; Rimonabant; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to "fix" the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.

Topics: Adipocytes; Adiponectin; Animals; Appetite Regulation; Arachidonic Acids; Cannabinoid Receptor Modulators; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Dronabinol; Eating; Endocannabinoids; Energy Metabolism; Humans; Lipid Metabolism; Obesity; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

Diabetes and cardiovascular disease have emerged as major threats to human health, and the risk of developing these chronic conditions is increased in individuals with abdominal obesity and the metabolic syndrome. Excess visceral abdominal tissue (VAT) accumulation appears to be a key feature of abdominal obesity contributing to the development of the metabolic syndrome. For instance, excess VAT is accompanied by elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure, and/or elevated fasting plasma glucose. In addition, the rather normal or only marginally elevated low-density lipoprotein (LDL) cholesterol concentrations in patients with excess VAT could provide misleading information as viscerally obese patients have an increased plasma concentration of small, dense LDL particles. Prospective studies have suggested that even among patients with LDL cholesterol concentrations within normal limits, an increased concentration of small LDL particles is associated with higher risk of cardiovascular disease. With the treatment of abdominal obesity and excess VAT, an increase in patients' LDL particle size and improvements in other cardiovascular risk factors (eg, insulin levels, glucose tolerance, HDL, C-reactive protein [CRP], and adiponectin levels) can be achieved. Waist circumference can be used in clinical practice as a first approach and as a crude index to identify patients who have excess VAT, particularly when the elevated waistline is accompanied by the clinical features of the metabolic syndrome, among which an elevated fasting triglyceride concentration appears to be predictive of a reduced LDL particle size and of further metabolic abnormalities frequently referred to as the metabolic syndrome. Lifestyle changes, including more physical activity and healthier nutritional habits, are the cornerstone of therapy for high-risk abdominally obese patients with an excess of VAT. In addition, results from the RIO-Lipids study, which was conducted in high-risk obese, dyslipidemic patients, have provided evidence that CB1 receptor blockade with rimonabant can induce significant weight loss, and, more importantly, improve the cardiometabolic risk profile beyond what could be explained by the weight loss effects of the drug.

Topics: Adiponectin; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Prospective Studies; Pyrazoles; Rimonabant; Risk Factors

Interventions that reduce weight and abdominal adiposity have been shown to improve obesity-associated disorders of glucose and lipid metabolism, reduce blood pressure, and promote other beneficial effects on cardiometabolic risk parameters. When long-term adherence to diet/exercise recommendations is suboptimal, management of overweight and obese patients at high cardiometabolic risk includes the use of adjunctive pharmacologic agents to facilitate weight loss and weight loss maintenance. Rimonabant, a cannabinoid-1 (CB1) receptor blocker, has been shown to induce weight loss and improve cardiometabolic parameters, implying that the endocannabinoid system is a promising target for obesity-related health improvement. Herein we summarize the results of the Rimonabant in Obesity (RIO) studies, which have evaluated the effectiveness of CB1 receptor blockade in facilitating weight loss and improving cardiometabolic health in >6,600 patients from the United States and Europe. As compared with placebo, 20 mg/day of rimonabant consistently produced greater reductions in weight and waist circumference, as well as improvements in dyslipidemia and parameters of glucose metabolism. The improvements that were noted for several cardiometabolic parameters with rimonabant were greater than what would be expected from the weight loss alone, suggesting there may be an independent effect of the drug on metabolic function. The results of these studies suggest that CB1 receptor blockade may be a useful treatment for multiple cardiometabolic risk factors in overweight and obese patients.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Evaluation; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Treatment Outcome; Waist-Hip Ratio

The growing prevalence of obesity is associated with a dramatic increase in a number of related risk factors for cardiovascular disease and diabetes, including high triglyceride and fasting glucose levels, reduced high-density lipoprotein cholesterol, and increased blood pressure. For many patients, lifestyle interventions (eg, exercise and a reduced-calorie diet) are insufficient for overcoming obesity, and pharmacotherapy becomes necessary. Unfortunately, the currently available agents are associated with side effects such as gastrointestinal distress and increased blood pressure. A new class of drugs targeting the cannabinoid receptors is poised to join the obesity-management armamentarium, with one agent-rimonabant-demonstrating efficacy in 4 recent phase III multinational trials. Patients randomized to rimonabant 20 mg/d showed significant reductions in weight and significant improvements in lipid profiles and other measures of cardiometabolic risk factors.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Humans; Insulin Resistance; Life Style; Lipids; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; Treatment Outcome; Weight Loss

Factors derived from adipose tissue are believed to play a central role in the development and progression of diabetes and its vascular complications. Insulin resistance and vascular function are directly affected these factors, i.e., by free fatty acids, inflammatory adipocytokines, thrombotic and antifibrinolytic factors and by adiponectin, and adipokine with insulin sensitizing and anti-inflammatory actions. Targeting these factors by antidiabetic agents should result in improved metabolism and in a reduction of vascular risk. We therefore analyzed antidiabetic treatment strategies with regard to improvements of adipose tissue derived risk factors. This shows that weight loss remains an extremely powerful tool to reduce all of these risk factors. Thiazolidinediones and rimonabant are most potent in improving numerous adipose derived risk factors but studies demonstrating reduced mortality are not yet available. Metformin has little effect on any of the adipose tissue derived factors but appears to reduce diabetes related mortality according to limited evidence. Sulfonylureas and insulin have rather limited effects on adipose tissue derived factors and are likely to exert beneficial effects mainly by improved glucose metabolism and its consequences.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Drug Delivery Systems; Humans; Hypoglycemic Agents; Insulin; Metformin; Models, Biological; Piperidines; Pyrazoles; Rimonabant; Sulfonylurea Compounds; Thiazolidinediones; Weight Loss

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to a combination of insulin resistance and impaired insulin secretion. The hyperglycemia is associated with an increased risk for micro- and macrovascular complications, and lowering fasting and postprandial hyperglycemia may be protective against these complications. Repaglinide is an insulin secretagogue that lowers blood glucose levels in patients with T2DM. We review the effects of repaglinide in patients with T2DM, its impact on glycemia and its non-glycemic effects, and its effects when used in special situations or patient populations. Results from randomized controlled trials, observational studies, and safety reports involving humans and published in the English-language through 1 May 2007 identified by a search in PubMed/MEDLINE were evaluated. Present knowledge indicates that repaglinide reduces fasting and postprandial hyperglycemia and the level of glycosylated hemoglobin (HbA1c) in patients with T2DM. It is at least as effective in reducing HbA1c and fasting plasma glucose as sulphonylureas, metformin, or the glitazones and in combination therapy with other drugs, repaglinide is as effective as any other combination. Some studies show a better effect of repaglinide on postprandial glycemia than the comparators. Its propensity to induce hypoglycemia is similar to or a little less than that of sulphonylureas. Repaglinide is associated with less weight gain than sulphonylureas and the glitazones. Repaglinide has primarily a role in the treatment of T2DM when metformin cannot be used due to adverse effects, when metformin fails to adequately control blood glucose levels, when there is a need for flexible dosing (i.e. the elderly or during Ramadan fasting), or when there is a specific wish to lower postprandial glucose. Repaglinide may also have an advantage when an oral agent is needed in diabetic patients with renal impairment. Because of its short duration of action, repaglinide should be taken before each meal, usually at least three times a day. Although no study has investigated whether repaglinide lowers total mortality or cardiovascular endpoints, several studies indicate beneficial effects on cardiovascular surrogate endpoints, such as carotid intima-media thickening, markers of inflammation, platelet activation, lipid parameters, endothelial function, adiponectin, and oxidative stress. In conclusion, repaglinide is a compound that can be used in both mono- and combina

Topics: Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Piperidines

The obesity pandemic will likely have a significant impact on the global incidence of cardiovascular disease. Although the mechanisms linking obesity and cardiovascular disease are unclear, recent studies have implicated the adipocyte as a potentially important mediator of vascular complications. The adipocyte is no longer considered a passive storage depot for triglycerides and fatty acids, but rather an active metabolic organ capable of producing several factors, commonly referred to as adipokines, that may have effects on many physiological and pathophysiological processes. With increasing fat mass, several adipose-related factors are upregulated that may affect local and distant inflammatory processes, including atherothrombosis. Other factors, such as adiponectin, are downregulated with increasing fat mass. Although most adipokines are thought to promote vascular disease, several studies over the past few years indicate adiponectin is actually protective against both diabetes and vascular disease. There are now available pharmacologic agents capable of altering the adipocyte transcription profile. This review will focus on the potential impact of adipocyte-derived factors towards vascular disease and emerging therapeutic strategies that may alter these effects.

Topics: Adiponectin; Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB(1) receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in HbA1c levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes and in drug-naïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally well-tolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration.

Topics: Animals; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Feeding Behavior; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Diabetes mellitus and obesity have become increasingly prevalent problems worldwide. Unfortunately, with traditionally prescribed glucose-lowering medications most individuals with diagnosed diabetes do not achieve and maintain adequate glycemic control over time; it may be even more challenging to lower blood glucose to an appropriate level without inducing a significant associated weight gain. Exenatide and rimonabant are recently developed agents that have demonstrated benefit in both glucose lowering and reduction of body weight. These medications may well prove to be attractive alternatives or additions to our more established diabetes therapies; however, these drugs have a side-effect profile that may limit their applicability to certain populations.

Topics: Appetite Depressants; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Obesity; Peptides; Piperidines; Pyrazoles; Rimonabant; Venoms

Diabetes mellitus and cognitive decline are major public health concerns among the elderly. In diabetic subjects without dementia, certain cognitive domains are impaired, such as memory, attention, and executive/frontal lobe function (diabetic cognitive dysfunction). Recent epidemiological studies have suggested that diabetes increases the risks for vascular dementia as well as Alzheimer's disease. There are accumulating evidences that indicate biological linkage between impaired brain glucose metabolism homeostasis and cognitive decline. Diabetes may cause serious brain damages through several mechanisms and induce a variety of cognitive decline. Most critical issue to be resolved is to identify the mechanism of dementia leading from diabetic cognitive dysfunction. Once elderly diabetics had severe cognitive decline, effective treatment of diabetes were hardly obtained. Thus, diabetic cognitive decline should be considered as an important comorbidity of the elderly diabetes and long-term management of hyperglycemia is required from a view point to sustain healthy brain function. In this short review, we are summarizing the clinical features and current biological findings of diabetic cognitive decline. Also, we introduce the comprehensive treatment of demented diabetic elderly, including therapeutic strategy, nursing and care.

Topics: Aged; Antihypertensive Agents; Brain; Cognition Disorders; Dementia; Diabetes Mellitus, Type 2; Donepezil; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypertension; Indans; Piperidines; Risk; Risk Factors

The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence.. Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date.. Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Weight Gain

Type 2 diabetes is recognised as a major cardiovascular risk factor, and future therapies must therefore address more than just blood glucose levels. Novel approaches to the treatment of type 2 diabetes are now at various stages of development or regulatory approval. Exenatide and pramlintide, analogues of gut-derived hormones glucagon-like peptide-1 (GLP-1) and amylin, respectively, have demonstrated improvements in glycaemic control and bodyweight in clinical studies and have been recently approved for treatment of type 2 diabetes. Initial studies have indicated that agents that activate both peroxisome proliferator-activated receptor (PPAR)alpha and gamma improve glycaemic control and have beneficial effects on lipid profiles. Two dual PPARalpha/gamma agonists, muraglitazar and tesaglitazar, are under regulatory review and in phase III trials, respectively. Modulation of the endogenous endocannabinoid system by rimonabant, which is under regulatory review, has been shown to improve body weight, atherogenic lipid profiles and glycaemic control. In addition, enhanced understanding of the pathophysiology underlying the microvascular complications of type 2 diabetes has led to the development of targeted therapies for conditions such as diabetic retinopathy, including the protein kinase C (PKC)-antagonist ruboxistaurin, now in phase III trials. Such therapies should enable physicians to achieve more for their patients with type 2 diabetes.

Topics: Adamantane; Alkanesulfonates; Amyloid; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Exenatide; Glycine; Humans; Hypoglycemic Agents; Indoles; Islet Amyloid Polypeptide; Maleimides; Nitriles; Oxazoles; Peptides; Phenylpropionates; Piperidines; PPAR alpha; PPAR gamma; Protein Kinase C; Pyrazoles; Pyrrolidines; Receptor, Cannabinoid, CB1; Receptors, Glucagon; Rimonabant; Venoms; Vildagliptin

Rimonabant is a first selective blocker of the cannabinoid receptor type 1 (CB1) being developed for the treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking. In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is also associated with favorable changes in serum lipid levels and an improvement in glycemic control in prediabetes patients and in type 2 diabetic patients. At the same dose, rimonabant significantly increased cigarette smoking quit rates as compared with placebo. Rimonabant seems to be well tolerated, with a primary side effect of mild nausea. As an agent with a novel mechanism of action, rimonabant has a potential to be a useful adjunct to lifestyle and behavior modification in treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking.

Topics: Animals; Atherosclerosis; Blood Glucose; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Lipid Metabolism; Marijuana Abuse; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking Cessation

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.

Topics: Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus, Type 2; Drugs, Investigational; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thiazolidinediones

Repaglinide (Prandin), NovoNorm, GlucoNorm, an oral insulin secretagogue, was the first meglitinide analogue to become available for use in patients with type 2 diabetes mellitus. The drug lowers postprandial glucose excursions by targeting early-phase insulin release, an effect thought to be important in reducing long-term cardiovascular complications of diabetes. Repaglinide provided similar overall glycaemic control to that achieved with glibenclamide (glyburide), as assessed by glycosylated haemoglobin (HbA(1c)) and fasting blood glucose levels, and was generally well tolerated in well designed clinical trials. Its rapid onset and relatively short duration of action allow for flexible meal schedules. Two modelled US cost-effectiveness analyses projected lifetime costs and outcomes for a hypothetical cohort of patients with type 2 diabetes. Both analyses projected long-term complications using data on HbA(1c) level changes from short-term clinical trials. Repaglinide plus rosiglitazone was dominant over rosiglitazone in one analysis, and repaglinide plus metformin was dominant over nateglinide plus metformin in the other. A similar Canadian analysis showed a favourable incremental cost-effectiveness ratio (

Topics: Administration, Oral; Carbamates; Clinical Trials as Topic; Cost of Illness; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Interactions; Economics, Pharmaceutical; Humans; Hypoglycemic Agents; Piperidines; Quality of Life; Randomized Controlled Trials as Topic

[symbol: see text] Nateglinide (Starlix-Novartis) and [symbol: see text] repaglinide (NovoNorm-Novo Nordisk) are two of a new class of orally active antidiabetic drugs, the meglitinides. They have a rapid-onset and short-lasting stimulating effect on insulin secretion. Both are licensed for combination therapy with metformin in patients with type 2 diabetes mellitus who are inadequately controlled by maximally tolerated doses of metformin alone. In addition, repaglinide is licensed for use as monotherapy in patients with type 2 diabetes whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Here we discuss whether repaglinide and nateglinide offer worthwhile advantages in the management of patients with type 2 diabetes.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Since the development and release of sulfonylureas for the treatment of T2DM, additional oral glycemic control agents with different mechanisms of action have allowed for more flexibility in targeting drug to patient. Based on available evidence, metformin monotherapy is preferred for the vast majority of T2DM patients who are overweight or obese. Combination therapy has further improved glycemic control. However, limitations in use, including the challenges of side effects, to that of secondary oral agent failure will inevitably occur over time. These challenges leave ample room for the development of agents that address the pathophysiology not only of treating insulin resistance and decreasing insulin production but also of preventing or delaying the development of diabetes in populations at risk.

Topics: Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucosamine; Humans; Hypoglycemic Agents; Life Style; Piperidines; Sulfonylurea Compounds; Thiazolidinediones

Topics: 1-Deoxynojirimycin; Acarbose; Aged; Blood Glucose; Carbamates; Contraindications; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Fasting; Follow-Up Studies; Germany; Glucosamine; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Imino Pyranoses; Insulin; Metformin; Middle Aged; Nateglinide; Obesity; Patient Compliance; Phenylalanine; Pioglitazone; Piperidines; Practice Guidelines as Topic; Risk Factors; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Time Factors

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a sing

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

Existing oral insulin secretagogues, sulphonylureas, are associated with hyperinsulinaemia, risk of hypoglycaemia and weight gain. Furthermore, they are not able to offer durable glycaemic control in patents with type 2 diabetes and are associated with progressive decline of beta-cell function. New insulin secretagogues offer an exciting opportunity. Repaglinide, the first prandial glucose regulator, now has convincing data that, compared to sulphonylurea use, it has a lower risk of hypoglycaemia. When used in a flexible dosing regime in a large cohort of patients, it is associated with better glycaemic control, a reduction in HbA1c, weight loss and improved quality of life compared to sulphonylureas. Early data shows the possibility of an effective combination with night time isophane insulin with significant falls in HbA1c and lower doses of insulin required. Nateglinide is an amino acid derivative. It again acts directly on the pancreatic beta-cell. Because of its very short duration of action, and the fact that it appears to secrete insulin in a glucose-dependent manner, it appears to secrete insulin in the closest way to that seen in a person without diabetes. Early data, both in monotherapy and in combination with metformin, show that it is an effective agent in terms of lowering HbA1c, has a low risk of hypoglycaemia and potentially less risk of significant weight gain. These characteristics mean that it may be the ideal agent to be used very early in the disease process, or even in subjects with impaired glucose tolerance, in whom early-phase insulin response is already lost. However these concepts, at the present time, are unproven.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Sulfonylurea Compounds; United Kingdom

Topics: Adenosine Triphosphate; Administration, Oral; Calcium Channels; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Piperidines; Potassium Channels

Peripheral insulin concentrations oscillate because of insulin secretory bursts every 6-10 min, which are the main source of overall insulin release. Regulation of insulin secretion occurs by modification of the mass and to some extent the frequency of the individual insulin secretory bursts. This oscillatory pattern, which is important for insulin action, is observed at the level of the individual beta-cells and in the islets, both in vitro (in the isolated perfused pancreas) and in vivo. It has therefore been suggested that beta-cells act as pacemakers and that co-ordination among islets is achieved by a neuronal network within the pancreas. Type 2 diabetes mellitus is characterised both by impaired release of insulin and by resistance to the action of insulin. Routine screening procedures for insulin secretion yield little predictive value for later development of diabetes but more sophisticated methods using time-series analysis of diurnal, ultradian and rapid oscillatory insulin secretion reveal the presence of profound defects in glucose-intolerant individuals. Furthermore, studies of rapid pulsatile insulin secretion have revealed defects in glucose-tolerant first-degree relatives of patients with Type 2 diabetes. Application of repeated minimal glucose infusions has further improved the discrimination between insulin release in health and diabetes, suggesting that this method may be suitable for smaller prospective studies of the development of diabetes. Repaglinide, a novel prandial glucose regulator, improves the insulin secretory burst mass in healthy people.

Topics: Carbamates; Circadian Rhythm; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Pancreas; Piperidines; Predictive Value of Tests; Pulsatile Flow

The major contributory factor to increasing hyperglycaemia in established Type 2 diabetes mellitus (T2DM) appears to be the progressive delay and attenuation of the prandial insulin response. An important consequence of this derangement is that hepatic glucose production is no longer suppressed during times of prandial glucose intake. Together with a relative impairment in the rate of peripheral glucose disposal, this leads to supra-physiological plasma glucose excursions, which may damage the vasculature. An obvious therapeutic strategy, therefore, would be to increase insulin availability when most needed--in the early prandial phase. In experiments with exogenous insulin interventions, peak post-prandial blood glucose increments were curtailed without undue increases in total insulin exposure. However, available evidence suggests that the sulphonylurea glibenclamide does not effectively alter early-phase prandial insulin release but predominately increases late-phase and basal insulin output, thus incurring the risk of hypoglycaemia. The novel insulin secretagogue repaglinide, by contrast, augments early-phase prandial insulin secretion when taken before meals, as shown by studies in non-diabetic people and patients with newly diagnosed, previously untreated T2DM. Repaglinide exerts its greatest effect on the insulin secretion rate during the first 30 min after a meal is started, thereby going some way to restoring the early insulin secretion curve seen after a meal in non-diabetic people. No residual secretagogue activity is seen 4 hr after taking a single dose of up to 2 mg. Prandial glucose regulation with repaglinide could be associated with lower post-prandial glucose excursions and less risk of post-prandial hypoglycaemia than glibenclamide.

Topics: Area Under Curve; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Kinetics; Liver; Piperidines

Post-prandial hyperglycaemia, which occurs early in the development of impaired glucose tolerance and Type 2 diabetes mellitus (T2DM), has been receiving increased attention recently. Post-prandial hyperglycaemia is likely to promote or aggravate fasting hyperglycaemia and contributes entirely to HbA1c elevation, which is associated with microvascular and macrovascular complications in people with T2DM. Moreover, post-prandial hyperglycaemia is coupled with coagulation activation and may be associated with an increased risk of cardiovascular disease in people with or without diabetes. For these reasons, reduction of post-prandial hyperglycaemia is an important target in patients with impaired glucose tolerance or T2DM. Several treatments have therefore been developed to reduce post-prandial hyperglycaemia; of these, repaglinide, a prandial glucose regulator taken orally before each meal, is now available. Drugs that reduce post-prandial hyperglycaemia significantly also decrease HbA1c (up to 2% with repaglinide) and fasting glucose concentrations (up to 3.9 mmol/l with repaglinide), with consequent decreases in coagulation activation and, in some studies, post-prandial lipidaemia. In clinical trials in patients with T2DM, repaglinide significantly reduced 2-hr post-prandial glucose concentrations and significantly reduced the risk of hypoglycaemia, compared with sulphonylureas, especially when participants missed or postponed a meal. Treatment with the prandial glucose regulator repaglinide allows patients with T2DM to have a more flexible lifestyle, which is likely to improve their quality of life and compliance.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Patient Compliance; Piperidines; Postprandial Period; Quality of Life

Type 2 diabetes mellitus (T2DM) is a progressive disorder requiring increasingly aggressive treatment to achieve and maintain target blood glucose concentrations in the presence of deteriorating insulin secretion and increasing insulin resistance. Diet and lifestyle modification are often sufficient initially; however, most patients eventually require pharmacological intervention. With disease progression, monotherapy becomes less effective, so combination therapy is required, using drugs with complementary modes of action to maximise glycaemic control. The prandial glucose regulator repaglinide has been studied in combination with metformin (an inhibitor of hepatic glucose production), neutral protamine Hagedorn (NPH)-insulin (which has a long duration of effect, but at the risk of early hypoglycaemia and late hyperglycaemia in the dosing interval) and three thiazolidinediones (TZDs--troglitazone, rosiglitazone and pioglitazone, which stimulate nuclear receptors to increase insulin sensitivity and reduce insulin resistance) in patients whose diabetes was inadequately controlled by previous monotherapy or combination therapy. The combination of repaglinide and metformin resulted in reduced fasting plasma glucose concentrations (by 2.2 mmol/l) and HbA1c (by 1.4%). Combination therapy with repaglinide and bedtime NPH-insulin resulted in reductions in fasting plasma glucose (by 5.4 mmol/l) and HbA1c (by 0.7%). The combination of repaglinide and each TZD also resulted in consistent decreases in fasting plasma glucose concentrations and HbA1c. No severe hypoglycaemic episodes were reported in the three studies. In conclusion, repaglinide has additive, and often synergistic, effects on glycaemic control when given in combination regimens and should be a valuable option in the management of patients with T2DM.

Topics: Carbamates; Chromans; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Metformin; Pioglitazone; Piperidines; Postprandial Period; Rosiglitazone; Thiazoles; Thiazolidinediones; Treatment Outcome; Troglitazone

Care of patients with type 2 diabetes has been revolutionized throughout the past several years-first, by the realization of the importance of tight glycemic control in forestalling complications, and second, by the availability of several unique classes of oral antidiabetic agents. Deciphering which agent to use in certain clinical situations is a new dilemma facing the primary care physician.. To systematically review available data from the literature regarding the efficacy of oral antidiabetic agents, both as monotherapy and in combination.. A MEDLINE search was performed to identify all English-language reports of unique, randomized controlled clinical trials involving recently available oral agents for type 2 diabetes. Bibliographies were also reviewed to find additional reports not otherwise identified.. Studies (63) were included in the analysis if they had a study period of at least 3 months; if each group contained at least 10 subjects at the study's conclusion; and if hemoglobin A(1c) was reported. When multiple dosages of a drug were tested, the results of the highest approved dosage were used. In placebo-controlled trials, hemoglobin A(1c) data are presented as the difference between the change in treated vs placebo subjects.. Five distinct oral drug classes are now available for the treatment of type 2 diabetes. Compared with placebo treatment, most of these agents lower hemoglobin A(1c) levels approximately 1% to 2%. Equivalent efficacy is usually demonstrated when different agents are compared with one another in the same study population. When they are used in combination, there are additional glycemic benefits. Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin.. With few exceptions, the available oral antidiabetic agents are equally effective at lowering glucose concentrations. Their mechanisms of action are different, however, and as a result they appear to have distinct metabolic effects. These are reflected in their adverse effect profiles and their effect on cardiovascular risk, which may influence drug choice.

Topics: Administration, Oral; Biguanides; Blood Glucose; Carbamates; Chromans; Diabetes Mellitus, Type 2; Diet; Drug Therapy, Combination; Enzyme Inhibitors; Exercise; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Metformin; Piperidines; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

Diabetes is a major and growing health problem in the US. An incredible array of different oral medications is now on the market. Clinicians should understand all these new medications and in which clinical picture they will work best.

Topics: Benzamides; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones

Increasingly, type 2 diabetes takes a toll on public health and healthcare costs in the United States. Although the remedy for this growing problem is very complex, two critical components of its control are prevention and effective therapy. Progress in diabetes prevention is likely to take decades. But fortunately, growth in our understanding of what occurs in this chronic disease has led to advances in the pharmacologic options aimed at decreasing hyperglycemia, the main clinically measurable metabolic consequence of diabetes. In this article, Drs Ahmann and Riddle provide an overview of the oral agents now available for the treatment of diabetes and discuss the clinical factors that help determine when to use which medication and what outcome to expect.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Glycoside Hydrolases; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Receptors, Cytoplasmic and Nuclear; Sulfonylurea Compounds; Transcription Factors

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Hypoglycemic Agents; Liver Diseases; Male; Piperidines; Renal Insufficiency; Rifampin

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Patient Compliance; Piperidines; Postprandial Period; Randomized Controlled Trials as Topic

Topics: Carbamates; Chromans; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin, Isophane; Metformin; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.

Topics: Animals; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose; Guanidines; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Piperidines

In about 25% of type 2 diabetes patients, good diabetes control is not attainable with oral blood-glucose lowering drugs. Furthermore, in many people with diabetes the disease deteriorates, despite the use of blood-glucose lowering medication, due to the decline of the pancreatic beta cells. The development of new drugs, such as repaglinide, is therefore important. Repaglinide is an insulin secretion enhancer with a different mechanism of action to the sulphonylureas, which means it does not continuously stimulate insulin secretion. The tablets should be taken with each meal. After oral ingestion repaglinide is resorbed quickly, with a half-life of between 30 minutes to an hour. In clinical trials repaglinide has been found to be equally effective as glibenclamide. Repaglinide has been found to be particularly effective in sulphonylurea-naïve patients. Skipping the meal plus tablet combination results in less frequent hypoglycaemic symptoms compared to glibenclamide. Repaglinide results in greater reductions in postprandial glucose levels than glibenclamide. It does not affect insulin resistance. Long-term data are lacking, both with regard to efficacy and side effects. Repaglinide deserves a place in the diabetes treatment of newly-diagnosed type 2 diabetes patients who are well-informed about their disease, as well as in patients with renal failure. It should also be considered for patients whose diabetes is poorly controlled on metformin monotherapy.

Topics: Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Metformin; Piperidines; Therapeutic Equivalency

United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated definitively that patients with type 2 diabetes mellitus (DM) benefit from intensive blood glucose control, because it diminishes the risk to develop microvascular complications. The therapeutic targets in the type 2 DM have been modified in order to reduce the risk of these complications. However, aggressive treatment may be disastrous for patients with microvascular complications and/or an increased risk of hypoglycemic unawareness, and neither it would be advised in older patients or with short life expectancy. The available drugs for treatment of type 2 DM offer many options for achieving these therapeutic targets, based on the need of the individual patient. In this job we review the targets in the metabolic control of type 2 DM and their backgrounds, and we describe briefly the therapeutic strategy recommended for reaching these targets, with special attention to the new oral antidiabetic agents (repaglinide and thiazolidinediones).

Topics: Carbamates; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Piperidines; Thiazoles

Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic beta-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) < or = 15 mg/day and greater control than patients receiving glipizide < or = 15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in I short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemi

Topics: Administration, Oral; Adult; Aged; Aging; Animals; Biological Availability; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Intestinal Absorption; Metabolic Clearance Rate; Piperidines

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.

Topics: Adult; Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Piperidines; Rats

The complications of diabetes mellitus, arising from inadequate glycemic control, have serious consequences for society as well as individuals. It is now urged that tight glycemic control be the goal for all patients, regardless of type of diabetes. Unfortunately, hypoglycemia can be a consequence of this aggressive approach. Treatment with a combination of agents and improved therapies are needed to maintain glycemic balance in patients. A better understanding of the pathophysiology of diabetes has yielded many treatment options based on various mechanisms of action. The sulfonyluereas, repaglinide, metformin, acarbose and the thiazolidinediones are effective in decreasing fasting plasma glucose levels, but their limitations may include adverse effects, such as weight gain and hypoglycemia, and an inability to modify some of the important comorbidities of diabetes. Therapies aimed at treating mealtime hyperglycemia are gaining attention. One promising investigational agent in this category is nateglinide. Early data suggest that its rapid onset and short duration of action result in increased early mealtime insulin release, reduced mealtime glucose excursions, and improved glycemic control.

Topics: Acarbose; Administration, Oral; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic; Thiazolidinediones; United States; Weight Gain

Type 2 diabetes mellitus is a progressive disorder, and although oral monotherapy is often initially successful, it is associated with a high secondary failure rate, which contributes to the development of long-term diabetes complications resulting from persistent hyperglycemia. For patients not taking insulin, accumulating evidence suggests that combination therapy using oral antidiabetic agents with different mechanisms of action may be highly effective in achieving and maintaining target blood glucose levels. Low-dose combination therapy may be associated with fewer side effects than higher-dose monotherapy and may achieve similar or better glycemic control. The best-studied combination is that of sulfonylurea compounds plus metformin, a therapeutic approach that addresses both underlying defects in the disorder: insulin deficiency and insulin resistance. Other multidrug regimens under investigation are sulfonylurea compounds plus either alpha-glucosidase inhibitors or thiazolidinediones, and combinations of various insulin-sensitizing agents. For many patients, combination oral therapy may be used appropriately as primary management early in the course of type 2 diabetes, along with diet modification and exercise. Later in the course of the disease, the use of combinations of oral agents may delay the need for insulin while maintaining glycemic control, thus making aggressive oral treatment more acceptable for many patients.

Topics: Acarbose; Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glyburide; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Thiazoles; Thiazolidinediones

Repaglinide (NovoNorm((R))) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic beta-cells by binding to a unique site on the beta-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a 'one meal, one tablet; no meal, no tablet' basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA(1c)) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone.

Topics: Animals; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Eating; Humans; Hypoglycemic Agents; Piperidines

Type 2 diabetes mellitus is characterised by abnormal beta-cell function (present at the time of diagnosis) that is often associated with insulin resistance. An important and consistent pathophysiological finding is the failure to produce adequate increments in insulin secretion in response to carbohydrate intake. Therefore, insulin secretagogue therapy, particularly when focused on prandial glucose regulation, is a logical approach to treatment because it addresses one of the most fundamental pathophysiological aspects of the disease. However, the traditional secretagogues-the sulphonylureas--have long been associated with the unwanted effect of hypoglycaemia. This is particularly likely to occur when drugs with lengthy plasma half-lives, prolonged drug-receptor interactions, active metabolites or a reliance on renal clearance are used. The problem is most prevalent in elderly patients, where sulphonylurea-induced hypoglycaemia may be related to failure to comply with strict mealtimes or the need for supplementary food intake, often in the context of compromised renal function. Data from large-scale outcome studies demonstrate that when tight glycaemic control is achieved through aggressive antidiabetic therapy, late diabetic complications can be significantly reduced. However, the pursuit of stricter HbA1c targets with more aggressive interventions may increase the risk of hypoglycaemia. This is an irony because the clinical need to avoid hypoglycaemia and patients' apprehension of it present barriers to the achievement of beneficial glycaemic targets. However, an increased risk of hypoglycaemia may not be inevitable with insulin secretagogue therapy. The recently introduced carbamoylmethyl benzoic acid derivative, repaglinide, has pharmacological properties that are well suited to its intended role as a prandial glucose regulator. When taken prior to main meals, the rapid onset and relatively short duration of action of repaglinide aid disposal of the mealtime glucose load, without continued stimulation of pancreatic beta-cells in the postprandial fasting period. Repaglinide is also characterised by hepatic metabolism and elimination, which is an advantage in the context of impaired renal function. Prandial glucose regulation with repaglinide selectively increases insulin secretion, and hence limits glucose excursions, in the prandial phase. If a meal is omitted, so too is the corresponding dose. This more flexible approach to the management of Type 2

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Eating; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Patient Compliance; Piperidines; Risk Factors; Sulfonylurea Compounds; Time Factors

Type 2 diabetes is characterised by a progressive deterioration of the prandial insulin response, in a situation of continuing insulin resistance. Early phase insulin release is attenuated and delayed and there is a consequent failure to suppress glucagon secretion and curtail hepatic glucose production and gluconeogenesis. Postprandial plasma glucose concentration rises to pathological levels and fails to return to normal before the patient consumes their next meal, creating a problem of continuous daytime hyperglycaemia. Although late insulin secretion is preserved it does not rectify the hyperglycaemia. The pathology of excessive prandial glucose excursions and continual daytime hyperglycaemia can be normalised, at least in part, if early-phase insulin availability is restored through pharmacologic intervention. Initially, the feasibility of this approach was demonstrated experimentally with the use of carefully controlled insulin infusions or insulin analogue injections. More recently, the availability of the rapid or early augmentor of insulin secretion--repaglinide--provides a means for restoring prandial glucose regulation with oral therapy. Placebo-controlled and oral hypoglycaemic agent (OHA) comparative studies of repaglinide have established its antidiabetic efficacy and flexible mealtime/dosing studies have confirmed the importance of the prandial approach to treatment. Prandial glucose regulation with repaglinide has also been demonstrated to provide synergies when used as combination therapy with insulin sensitising agents. As a strategy, prandial glucose regulation has a number of theoretical advantages over the use of fixed doses of conventional insulin secretagogues, and these have been borne out in clinical trials. As well as offering a more flexible approach to treatment, prandial repaglinide is associated with a reduced risk of severe hypoglycaemia.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Eating; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Piperidines; Time Factors

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Molecular Structure; Nateglinide; Phenylalanine; Piperidines

Repaglinide is a novel insulin secretagogue that was developed as a prandial glucose regulator for the treatment of people with Type 2 diabetes mellitus. It is used flexibly, taken prior to meals, in order to limit subsequent postprandial blood glucose excursions as well as the dependent basal blood glucose concentration. In theory, the pharmacological profile of repaglinide is well suited for this role. Taken at mealtimes, its relatively rapid-onset and short-duration of action counteract a fundamental pathophysiological aspect of this disease: attenuation of the prandial insulin response. The predominantly hepatic elimination profile and a lack of drug-drug interactions with repaglinide are also properties well suited for patients with Type 2 diabetes. Importantly, the pharmacokinetic properties of repaglinide, are expected to reduce the risk of hypoglycaemia in comparison to the conventional insulin secretagogues (sulphonylureas). A reduced risk of hypoglycaemia carries the advantage that patients are not obliged to consume meals at regular intervals supplemented by snacks, so caloric restriction is feasible and lifestyle not compromised. These theoretical advantages have now been largely borne-out by clinical studies and empirical experience. Placebo-controlled studies have consistently demonstrated the antidiabetic efficacy of repaglinide, with improvements having been shown in all indicators of glycaemic control. Double-blind, active-comparator studies have shown repaglinide to have an antidiabetic efficacy that is at least equivalent to sulphonylureas, even when food intake and dosing intervals were controlled according to the requirements of sulphonylureas. Pooled data from these studies have shown that the risk of severe hypoglycaemia is reduced by 60% (p = 0.03) when repaglinide is used in preference to sulphonylureas. There is also evidence that the blood glucose threshold at which symptoms of hypoglycaemia are perceived by patients may be better preserved during treatment with repaglinide than with sulphonylureas. Studies examining flexible prandial dosing with repaglinide have shown that good glycaemic control and a low risk of hypoglycaemia are achievable goals that are independent of the meal (and, hence, dosing) pattern chosen by the patient. Furthermore, when used in this way, repaglinide has not been associated with weight gain. In combination therapy, repaglinide has been shown to act in synergy with both metformin and troglitazone. The

Topics: Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Piperidines; Postprandial Period

Repaglinide is a new carbamoylmethyl benzoic acid derivative that is structurally related to meglitinide. In common with all active oral hypoglycaemic agents, it displays a comparable U-shaped configuration. Repaglinide exerts its effects by binding to a site on the plasma membrane of beta-cells, thereby closing ATP-sensitive potassium channels. This causes depolarization of the beta-cell and the opening of voltage-sensitive calcium channels allowing the influx of extracellular calcium ions. This increase in intracellular calcium, in turn, stimulates insulin release. The insulinotropic effect of repaglinide is not related to its ionophoretic capacity. Repaglinide does not cause insulin release in the absence of exogenous glucose, nor does it inhibit the biosynthesis of proinsulin. In vivo administration of an ester of succinic acid potentiates the insulin secretory response to concomitantly administered repaglinide. Repaglinide causes a more rapid increase in plasma insulin levels in rats than either glibenclamide or glimepiride.

Topics: Administration, Oral; Animals; Carbamates; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Piperidines; Rats

Repaglinide, a carbamoylmethyl benzoic acid derivative, is rapidly absorbed, metabolized by the liver and eliminated primarily via the bile. It has a short duration of action and is taken immediately before each main meal. This regimen has been shown to provide superior glycaemic control compared with regular morning and evening dosing. A flexible preprandial only dosing regimen of repaglinide significantly lowers the risk of hypoglycaemia if a meal is missed or postponed. Combination therapy with metformin improves glycaemic control significantly compared with therapy with either drug alone in overweight patients. Repaglinide has an equivalent safety and efficacy profile to the sulphonylureas, although it is superior to glipizide in maintaining long-term glycaemic control The postprandial glucose levels are significantly lower with repaglinide compared with glibenclamide. In naive patients with Type 2 diabetes, repaglinide lowers fasting glucose concentrations and functions also as a prandial glucose regulator.

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Piperidines

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.

Topics: Acarbose; Administration, Oral; Algorithms; Carbamates; Chromans; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Insulin; Metformin; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Trisaccharides; Troglitazone

The action of repaglinide, a carbamoylmethyl benzoic acid derivative, mimics the physiological insulin secretion that is deficient in Type 2 diabetes mellitus. Repaglinide stimulates insulin release from beta-cells only in the presence of glucose. Two placebo-controlled studies were performed to establish the effective dose range of repaglinide. In one study, repaglinide (0.25-4.0 mg preprandially) caused a dose-dependent decrease in blood glucose and a non-dose-dependent increase in insulin over 4 weeks (all doses p < 0.001 vs. placebo). In the second study, repaglinide (0.25-8.0 mg preprandially) was titrated over 6 weeks to obtain the optimum response (fasting plasma glucose < 8.9 mmol/L). The titration period was followed by a 12-week dose-maintenance period. At the end of the study, repaglinide had decreased fasting plasma glucose by 3.4 mmol/L (p < 0.05) and 2-h postprandial blood glucose by 5.8 mmol/L (p < 0.001) versus placebo. Glycated haemoglobin (HbA1c) decreased significantly from 8.5% to 7.9% in the repaglinide group and increased significantly from 8.1% to 9.2% in the placebo group (p < 0.001 between groups). In five 1-year, multicentre, randomized, double-blind, phase III trials, repaglinide (0.5-4.0 mg preprandially) was compared with the sulphonylureas glibenclamide, glipizide and gliclazide. Repaglinide was more effective than glipizide at maintaining glycaemic control and was equivalent to glibenclamide and gliclazide on the basis of change in HbA1c. Hypoglycaemic events were reported in 16% of repaglinide-treated patients and 15-20% of sulphonylurea-treated patients. These data indicate that repaglinide monotherapy, with diet and exercise, is effective in patients with Type 2 diabetes.

Topics: Blood Glucose; Carbamates; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Food; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Piperidines

Repaglinide, an insulinotropic benzoic acid derivative, has been tested extensively in the preclinical and clinical setting for safety and tolerability. In preclinical safety trials, no clinically relevant laboratory or histopathological changes were found and repaglinide was not found to be genotoxic, immunogenic, teratogenic or tumorigenic at levels 50 times greater than the exposure in humans. In an ascending-dose tolerability study in Type 2 diabetic patients, no clinically relevant changes in liver enzymes or ECG occurred during the trial. A total of five active-controlled, long-term trials of identical design have been carried out (with 12 months of maintenance on a fixed, pretitrated dose), including 1228 patients on repaglinide and 597 on sulphonylureas, 417 of whom were on glibenclamide. The most common adverse event in the phase II studies was hypoglycaemia. The frequency of hypoglycaemia was identical for repaglinide and sulphonylureas; however, fewer nocturnal hypoglycaemic events were observed with repaglinide and no increase in the frequency of hypoglycaemic events occurred in elderly patients (> 65 years) compared with younger patients. Severe reactions (assistance required) were approximately twice as frequent in the comparator group. During these studies, two serious hypoglycaemic reactions were reported (coma, seizure or hospitalization), both occurring in patients on glibenclamide. The frequency of serious adverse events and serious cardiovascular events was comparable between repaglinide and sulphonylureas.

Topics: Aged; Animals; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Randomized Controlled Trials as Topic

Secretatogues are a class of agents that achieve their hypoglycemic effects through stimulating insulin release. They include the sulfonylureas, repaglinide, and the investigational agent glucagon-like peptide. The secretagogue agents have been studied extensively as monotherapy and in conjunction with other classes of oral agents, including alpha-glucosidase inhibitors, bijuanides, and thiazolidinediones, for the treatment of type 2 diabetes. This article reviews the pharmacodynamic and pharmacokinetic differences of the secretagogues, as well as the most recent clinical trials. Such information should be helpful when deciding which agent or agents will yield the best glycemic control for an individual patient.

Topics: Acarbose; Carbamates; Chromans; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Metformin; Peptide Fragments; Piperidines; Protein Precursors; Risk Factors; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

Topics: Carbamates; Chromans; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Phenylalanine; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

Repaglinide is a new oral blood glucose lowering agent, a member of the carbamoylmethyl benzoic acid (CMBA) family. Its mechanism of action is partly similar to that of the sulphonylurea: the release of insulin from the pancreatic beta cells is stimulated by closure of ATP-dependent potassium channels. However, repaglinide regulates these channels via a different binding site on the beta cell than glibenclamide, and the drug does not cause insulin release in the absence of glucose, or during voltage-clamping. After oral administration the drug is rapidly absorbed and eliminated. It is therefore used in a meal-related dosing regimen; repaglinide is taken with each main meal. This meal-related use may give a more physiological mimick of daytime insulin requirement than once-daily or twice-daily use of sulphonylurea. Patients using repaglinide are less likely to develop hypoglycaemic symptoms when they miss or postpone a meal in comparison with patients on glibenclamide treatment. In long-term comparative phase 3 clinical studies it was found that repaglinide is equally effective in maintaining glycaemic control as existing sulphonylurea, but it gives significantly better control of postprandial blood glucose levels. Repaglinide can be used as monotherapy both in obese and non-obese type 2 diabetic patients, and is also very effective in combination with drugs like metformin or thiazolidines. Because of its excretion through liver and bile it is also an attractive drug for diabetic patients with diminished kidney function, especially the elderly diabetic. Although the overall incidence of hypoglycaemia was similar during use of repaglinide and of sulphonylurea, fewer serious hypoglycaemic episodes were observed in repaglinide-treated patients.

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Feeding Behavior; Humans; Hypoglycemia; Hypoglycemic Agents; Intestinal Absorption; Metabolic Clearance Rate; Piperidines

This article reviewed the relevant literature including published clinical trials and reviews on currently available oral hypoglycemic agents. Results showed that the benefits of glycemic control have been established through multiple clinical trials. Long-term control of blood glucose levels in type 1 and type 2 diabetic patients will decrease the incidence and prolong the time until progression of diabetic retinopathy, nephropathy, and neuropathy. Our increased understanding of the pathophysiology behind type 2 diabetes has led to the development of many new agents that are aimed at treating the underlying insulin resistance and relative insulinopenia. The sulfonylureas as a group have been used for many years and act by stimulating insulin secretion. They are useful alone or as combination therapy with insulin or another oral hypoglycemic agent. The biguanides act by decreasing hepatic glucose production and by increasing peripheral insulin sensitivity. The alpha-glucosidase inhibitors act nonsystemically by blocking the metabolism of digested polysaccharides and therefore lowering the amount of carbohydrate absorbed in a meal. Benzoic acid derivatives act in a manner similar to that of sulfonylureas by enhancing pancreatic insulin production. They offer a shorter duration of action, lowering the risk of hypoglycemia. The thiazolidinediones increase peripheral insulin sensitivity and are effective as both monotherapy and combination therapy. Oral hypoglycemic agents, when properly administered, are very effective in controlling type 2 diabetes and preventing long-term complications.

Topics: Carbamates; Chromans; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.

Topics: Anti-Obesity Agents; Carbamates; Chromans; Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Insulin Resistance; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Troglitazone

Repaglinide is a novel insulin secretagogue being developed for the management of type 2 (non-insulin-dependent) diabetes mellitus. It stimulates release of insulin from the pancreatic beta-cell, but appears to bind to a different receptor site from sulphonylureas. Repaglinide lowers fasting and postprandial blood glucose levels in animals, healthy volunteers and patients with type 2 diabetes mellitus. Repaglinide is rapidly absorbed and eliminated, which may allow a relatively fast onset and offset of action. Excretion occurs almost entirely by non-renal mechanisms. In comparative clinical trials in patients with type 2 diabetes mellitus, repaglinide 0.5 to 4 mg twice or 3 times daily before meals provided similar glycaemic control to glibenclamide (glyburide) 2.5 to 15 mg/day. Addition of repaglinide to existing metformin therapy resulted in improved glycaemic control. In contrast with glibenclamide, use of repaglinide allowed patients to miss a meal without apparently increasing the risk of hypoglycaemia.

Topics: Animals; Carbamates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Islets of Langerhans; Piperidines; Randomized Controlled Trials as Topic; Stereoisomerism

In older patients with type 2 diabetes, life expectancy and the presence of microvascular complications determine the appropriate intensity of glucose control. The available antidiabetic agents offer many options for achieving glycemic targets, based on the needs of the individual patient. New stimulators of insulin secretion include glimepiride (a sulfonylurea) and repaglinide (a meglitinide). The biguanide metformin is especially useful in obese, insulin-resistant patients. Alpha-glucosidase inhibitors such as acarbose and miglitol act locally in the GI tract to reduce postprandial excursion in glucose levels. The insulin-sensitizing drug troglitazone enhances insulin-mediated glucose disposal. When troglitazone is used, careful monitoring of patients' liver function is required.

Topics: 1-Deoxynojirimycin; Acarbose; Age Factors; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Glucosamine; Humans; Hypoglycemic Agents; Imino Pyranoses; Metformin; Piperidines; Sulfonylurea Compounds; Trisaccharides

The highest demand on insulin secretion occurs in connection with meals. In normal people, following a meal, the insulin secretion increases rapidly, reaching peak concentration in the blood within an hour. The mealtime insulin response in patients with Type 2 diabetes is blunted and delayed, whereas basal levels often remain within the normal range (albeit at elevated fasting glucose levels). Restoration of the insulin secretion pattern at mealtimes (prandial phase)--without stimulating insulin secretion in the 'postabsorptive' phase--is the rationale for the development of 'prandial glucose regulators', drugs that are characterized by a very rapid onset and short duration of action in stimulating insulin secretion. Repaglinide, a carbamoylmethyl benzoic acid (CMBA) derivative is the first such compound, which recently has become available for clinical use. Repaglinide is very rapidly absorbed (t(max) less than 1 hour) with a t1/2 of less than one hour. Furthermore, repaglinide is inactivated in the liver and more than 90% excreted via the bile. The implications of tailoring repaglinide treatment to meals were examined in a study where repaglinide was dosed either morning and evening, or with each main meal (i.e. breakfast, lunch, dinner), with the total daily dose of repaglinide being identical. The mealtime dosing caused a significant improvement in both fasting and 24-hour glucose profiles, as well as a significant decrease in HbA1c. In other studies, repaglinide caused a decrease of 5.8 mmol x l(-1) in peak postprandial glucose levels, and a decrease of 3.1 mmol x l(-1) in fasting levels with a reduction in HbA1c of 1.8% compared with placebo. In comparative studies with either sulphonylurea or metformin, repaglinide caused similar or improved control (i.e. HbA1c, mean glucose levels) and the drug was well tolerated (e.g. reported gastrointestinal side-effects were more than halved when patients were switched from metformin to repaglinide). A hallmark of repaglinide treatment is that this medication follows the eating pattern, and not vice versa. Hence the risk of developing severe hypoglycaemia (BG < or = 2.5 mmol x l(-1)) in connection with flexible lifestyles should be reduced. This concept was examined in a study in which patients well controlled on repaglinide skipped their lunch on one occasion. When a meal (i.e. lunch) was skipped--so was the repaglinide dose, whereas in the comparative group on glibenclamide the recommended morning and evenin

Topics: Administration, Oral; Animals; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Eating; Fasting; Humans; Hypoglycemic Agents; Metabolic Clearance Rate; Piperidines; Postprandial Period

Diabetes mellitus is a common disease in older people, with almost 50% of Type 2 diabetic patients being over 60 years of age; despite this, half of older people with frank diabetes are not diagnosed. While insulin resistance is common in older people, large numbers also have impaired insulin secretion. Age, body habitus and physical activity all play a role in the pathogenesis of hyperglycaemia associated with diabetes mellitus. Leptin levels relate to insulin resistance in older people and amylin secretion is associated with delayed return of glucose levels to baseline. Depression, impaired cognitive function, and lack of recognition of thirst and subsequent dehydration are important factors to be taken into account in the management of older diabetic patients, who may also have impaired physical function, an increased rate of injurious falls, and increased prevalence of pressure ulcers, amputations and tuberculosis. Hyperglycaemia can result in a decreased pain threshold and incontinence. Dietary management plays less of a role in older diabetic patients but exercise, with a particular emphasis on balance and stability, is an important component of the management and treatment of older diabetic patients. The use of metformin as a treatment should be avoided in patients over 80 years of age because of declining kidney function. Insulin therapy is an option but as hypoglycaemia is related to advancing age, patients should be monitored carefully for the development of hypoglycaemia. Care providers also play an important role in the management of older people with diabetes mellitus. Glycaemic control can be obtained with minimal side-effects in most older diabetics including those patients in nursing homes.

Topics: Aged; Amyloid; Blood Glucose; Carbamates; Cognition Disorders; Depression; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Islet Amyloid Polypeptide; Male; Piperidines

Topics: Animals; Blood Glucose; Carbamates; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Piperidines; Protein Precursors

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.

Topics: Administration, Oral; Biological Availability; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Intestinal Absorption; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Reference Values; Stereoisomerism

To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).. This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of. A total of 93 patients were randomized; 85 patients completed treatment. The mean (standard deviation [SD]) change in LFF was -0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (-1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of. Although the study did not meet one of the primary outcomes, AZD4017 blocked the conversion of

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Liver; Niacinamide; Non-alcoholic Fatty Liver Disease; Piperidines

To demonstrate the noninferiority of alogliptin to acarbose, in terms of antidiabetic efficacy, in Chinese people with uncontrolled type 2 diabetes (T2D) and high cardiovascular risk.. ACADEMIC (NCT03794336) was a randomized, open-label, phase IV study conducted at 46 sites in China. Antidiabetic treatment-naive or metformin-treated adults with uncontrolled T2D (glycated haemoglobin [HbA1c] 58.0-97.0 mmol/mol) were randomized 2:1 to alogliptin 25 mg once daily or acarbose 100 mg three times daily for 16 weeks. All participants had a documented history of coronary heart disease or high cardiovascular risk at screening and received aspirin (acetylsalicylic acid) 100 mg daily throughout the trial. The primary endpoints were change in HbA1c versus baseline, and the incidence of gastrointestinal adverse events (AEs). Safety and tolerability were also assessed.. A total of 1088 participants were randomized. Alogliptin was noninferior to acarbose for the change in Week-16 HbA1c (least-squares mean change [standard error] -11.9 [0.4] vs. -11.4 [0.5] mmol/mol, respectively; difference between arms -0.5 [0.7] mmol/mol; 95% confidence interval -1.9 to 0.8 mmol/mol), and was associated with a lower incidence of gastrointestinal AEs (8.9% vs. 33.6%, respectively; P < 0.0001). More alogliptin than acarbose recipients achieved HbA1c <53.0 mmol/mol without gastrointestinal AEs (48.0% vs. 32.7%; P < 0.0001). Discontinuations due to treatment-related AEs were less frequent with alogliptin than acarbose (0.3% vs. 2.5%).. Glycaemic control was comparable between alogliptin and acarbose, but the gastrointestinal tolerability of alogliptin was better. More patients achieved target HbA1c without gastrointestinal AEs with alogliptin, suggesting that this agent may be preferred in clinical practice.

Topics: Acarbose; Adult; Aspirin; Coronary Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Metformin; Piperidines; Prospective Studies; Treatment Outcome; Uracil

Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.. Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.. Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.. Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.. Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: -3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69-104%). Wound diameter was 34% (7-63%) smaller with AZD4017 at day 2, and 48% (12-85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.. A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.. Stress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Foot; Double-Blind Method; Epidermis; Female; Humans; Male; Middle Aged; Niacinamide; Pilot Projects; Piperidines; Quality of Life; Skin; Treatment Outcome; Wound Healing

The choice of an optimal oral hypoglycemic agent in the initial treatment periods for type 2 diabetes mellitus (T2DM) patients remains difficult and deliberate. We compared the efficacy and safety of glimepiride (GLIM), alogliptin (ALO), and alogliptin-pioglitazone (ALO-PIO) in poorly controlled T2DM patients with drug-naïve or metformin failure.. In this three-arm, multicenter, open-label, randomized, controlled trial, poorly controlled T2DM patients were randomized to receive GLIM (n=35), ALO (n=31), or ALO-PIO (n=33) therapy for 24 weeks. The primary endpoint was change in the mean glycosylated hemoglobin (HbA1c) levels at week 24 from baseline. Secondary endpoints were changes in HbA1c level at week 12 from baseline, fasting plasma glucose (FPG) levels, lipid profiles at weeks 12 and 24, and parameters of glycemic variability, assessed by continuous glucose monitoring for 24 weeks.. At weeks 12 and 24, the ALO-PIO group showed significant reduction in HbA1c levels compared to the ALO group (-0.96%±0.17% vs. -0.37%±0.17% at week 12; -1.13%±0.19% vs. -0.18%±0.2% at week 24). The ALO-PIO therapy caused greater reduction in FPG levels and significant increase in high-density lipoprotein cholesterol levels at weeks 12 and 24 than the ALO therapy. Compared to low-dose GLIM therapy, ALO-PIO therapy showed greater improvement in glycemic variability. The adverse events were similar among the three arms.. ALO-PIO combination therapy during the early period exerts better glycemic control than ALO monotherapy and excellency in glycemic variability than low-dose sulfonylurea therapy in uncontrolled, drug-naïve or metformin failed T2DM patients.

Topics: Autoimmune Diseases; Blood Glucose; Blood Glucose Self-Monitoring; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Lipoproteins, HDL; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Treatment Outcome; Uracil

Imigliptin is a novel dipeptidyl peptidase-4 inhibitor. In the present study, we aimed to evaluate the effects of imigliptin and alogliptin on insulin resistance and beta-cell function in Chinese patients with type-2 diabetes mellitus (T2DM).. A total of 37 Chinese T2DM patients were randomized to receive 25 mg imigliptin, 50 mg imigliptin, placebo, and 25 mg alogliptin (positive drug) for 13 days. Oral glucose tolerance tests were conducted at baseline and on day 13, followed by the oral minimal model (OMM).. Imigliptin or alogliptin treatment, compared with their baseline or placebo, was associated with higher beta-cell function parameters (. After 13 days of treatment, imigliptin and alogliptin could decrease glycemic levels by improving beta-cell function. By comparing OMM with HOMA or SUIT results, glucose stimulation might be more sensitive for detecting changes in beta-cell function.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; China; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Imidazoles; Insulin; Insulin-Secreting Cells; Male; Middle Aged; Piperidines; Pyridines; Treatment Outcome; Uracil; Young Adult

Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes.. 93 circulating proteins (92 from the Olink® CVDII plus troponin) were assessed in 5131 patients. Cox, competing risks, and reclassification measures were applied.. The clinical model showed good discrimination and calibration for all outcomes. On top of the clinical model that included age, sex, smoking, diabetes duration, history of MI (prior to the index MI of inclusion), history of HF hospitalization, history of stroke, atrial fibrillation, hypertension, systolic blood pressure, statin therapy, estimated glomerular filtration rate, and study treatment (alogliptin or placebo), troponin and BNP added prognostic information to the composite of cardiovascular death, MI, or stroke (∆C-index + 5%) and cardiovascular death alone (∆C-index + 7%). Troponin, BNP, and TRAILR2 added prognostic information on all-cause death and the composite of cardiovascular death or HF hospitalization. HF hospitalization alone was improved by adding BNP and Gal-9. For MI, troponin, FGF23, and AMBP added prognostic value; whereas for stroke, only troponin added prognostic value (multi-proteomics improved C-index > 3% [p < 0.001] for all the studied outcomes). The addition of the final biomarker selection to the clinical model improved event reclassification (cNRI from + 23% to + 64%). Specifically, the addition of the biomarkers allowed a better classification of patients at low risk (as having "true" low risk) and patients and high risk (as having "true" high risk). These results were consistent for all the studied outcomes with even more marked differences in the fatal events.. The addition of multi-proteomic biomarkers to a clinical model in this population with diabetes and a recent MI allowed a better risk prediction and event reclassification, potentially helping for better risk assessment and targeted treatment decisions. T2D type 2 diabetes, MI myocardial infarction, CV cardiovascular, HFH heart failure hospitalization, Δ delta, cNRI continuous net reclassification index, BNP brain natriuretic peptide, TRAILR2 trail receptor 2 (or death receptor 5), Gal-9 galectin-9, FGF23 fibroblast growth factor 23.

Topics: Biomarkers; Cause of Death; Comorbidity; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factor-23; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Piperidines; Prognosis; Proteomics; Risk Assessment; Survival Rate; Uracil

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; 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Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; 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Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

This study investigated the pharmacokinetics, pharmacodynamics, and safety of fotagliptin benzoate (fotagliptin), a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Chinese patients with type 2 diabetes mellitus (T2DM). In a randomized, double-blinded, placebo-controlled study, 10 and 4 patients with T2DM were randomized and received, respectively, once-daily oral fotagliptin (24 mg) or placebo, for 14 days. The pharmacokinetics and pharmacodynamics were assessed throughout the study, including monitoring DPP-4, glucagon-like peptide-1 (GLP-1), glycosylated hemoglobin, and fasting blood glucose. Fotagliptin was rapidly absorbed, and the median time to maximum concentration value was ∼1.5 hours. Plasma fotagliptin levels were stable after 14 days of once-daily dosage. The accumulation ratios for the area under the plasma concentration-time curve of fotagliptin, M1, and M2-1, were 1.19 ± 0.10, 1.59 ± 0.27, and 1.39 ± 0.26, respectively. The durations for DPP-4 inhibition >80% in the fotagliptin group on days 1 and 14 were 23.5 and 24.0 hours, respectively. The concentrations of GLP-1 were higher on days 1 and 14 than at the baseline. No serious complications occurred. Fotagliptin showed favorable pharmacokinetics and pharmacodynamics and was well tolerated. Treatment with fotagliptin can achieve high DPP-4 inhibition and increase plasma GLP-1. A once-per-day dosing regimen may be recommended as clinically efficacious.

Topics: Administration, Oral; Adult; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Male; Middle Aged; Piperidines; Triazines

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Gastrointestinal Hormones; Glucose Intolerance; Glucose Tolerance Test; Glycemic Control; Humans; Insulin Secretion; Islets of Langerhans; Japan; Male; Middle Aged; Piperidines; Pyridines; Receptors, G-Protein-Coupled; Young Adult

Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia.. We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes.. We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system.. The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase.. Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inositol; Isoindoles; Japan; Piperidines

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Blood Proteins; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Galectin 3; Galectins; Growth Differentiation Factor 15; Heart Disease Risk Factors; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Piperidines; Prognosis; Risk Assessment; Troponin I; Uracil

Compared with newer prandial anti-diabetes agents, repaglinide and acarbose are unique in being globally available in generic versions, being oral, and being the cheapest of all. The aim of this study was to compare their efficacy when used alone or in combination.. In a randomized, double-blind, prospective study, 358 recently diagnosed type 2 diabetes (T2D) patients, who on a combined therapy with metformin and insulin glargine had a fasting plasma glucose (FGP) of <7.2 mmol/L but a 2-h postprandial plasma glucose (2hPPG) >10 mmol/L, were assigned to three groups of additional treatment with either repaglinide, acarbose, or repaglinide-plus-acarbose for 4 months.. With intention-to-treat analysis, 63% of repaglinide group, 45.4 percent of acarbose group, and 75.7% of repaglinide-plus-acarbose group reached the primary endpoint of 2hPPG < 10 mmol/L while maintaining FPG < 7.2 mmol/L. Treatment adherence rate was 75.6% with repaglinide, 61.4% with acarbose, and 81.3% with repaglinide-plus-acarbose (p = 0.001). Among the groups, weight was significantly lower in acarbose group (p < 0.05). Twenty-one percent of repaglinide patients, 4.9% of acarbose subjects, and 10.3% of repaglinide-plus-acarbose cases reported at least one episode of hypoglycemia (p < 0.005). HbA1C and basal insulin requirement were significantly lower in repaglinide group (p = 0.004, p = 0.0002). Triglycerides were lowest in acarbose group (p = 0.005).. Both acarbose and repaglinide were vastly effective in lowering postprandial hyperglycemia of recently diagnosed T2D. When combined, they were even more efficacious and the disease had a better outcome. Compared with newer peers, these two are particularly useful where and when cost consideration in diabetes treatment is a prime concern.

Topics: Acarbose; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Piperidines; Prospective Studies

The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Understanding the timing and type of clinical events after an ACS will allow for clinicians to better tailor evidence-based treatments to optimize therapeutic effect. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes.. EXAMINE was a randomized trial of alogliptin versus placebo in 5,380 patients with T2DM and a recent ACS from October 2009 to March 2013. The primary outcome was a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8-34, 35-56, and 57-141 days.. Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs 33.0%), prior coronary artery bypass graft (9.6% vs 15.9%), or atrial fibrillation (5.9% vs 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio 1.47; 95% CI 1.21-1.74). Similarly, patients randomized early had an increased risk of recurrent MI (adjusted hazard ratio 1.51; 95% CI 1.17-1.96) and HF hospitalization (1.49; 95% CI 1.05-2.10).. In a contemporary cohort of T2DM with a recent ACS, the risk for recurrent CV events including MI and HF hospitalization is elevated early after an ACS. Given the emergence of antihyperglycemic therapies that reduce the risk of MI and HF among patients with T2DM at high CV risk, future studies evaluating the initiation of these therapies in the early period following an ACS are warranted given the large burden of potentially modifiable CV events.

Topics: Acute Coronary Syndrome; Comorbidity; Diabetes Mellitus, Type 2; Evidence-Based Practice; Female; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Outcome and Process Assessment, Health Care; Patient Selection; Piperidines; Random Allocation; Risk Assessment; Stroke; Time Factors; Uracil

This open-label, parallel-group, exploratory study examined the effects of two dipeptidyl peptidase 4 (DPP4) inhibitors on glycemic variability (GV) in patients with type 2 diabetes.. Randomized patients with glycated hemoglobin A1c of at least 6.5% to less than 8.5% received trelagliptin 100 mg (n = 13) once weekly or alogliptin 25 mg (n = 14) once daily for 29 days. Continuous glucose monitoring was performed before the start of the treatment period (baseline) and from day 21 to 29, inclusive. The primary endpoint was change from baseline in the standard deviation (SD) of 24-h blood glucose values, measured daily for 7 days (day 22-28) of the treatment period. Secondary and additional efficacy endpoints included changes in glycemic parameters and the rate of DPP4 inhibition, respectively. Adverse events (AEs) were monitored to assess safety.. Mean change from baseline in the SD of 24-h blood glucose (95% confidence interval) at day 28 was - 7.35 (- 15.13, 0.44) for trelagliptin and - 11.63 (- 18.67, - 4.59) for alogliptin. In both treatment groups, glycemic parameters improved and the rate of DPP4 inhibition was maintained. Three patients reported AEs; no severe treatment-emergent AEs were reported in either group.. Once-weekly trelagliptin and once-daily alogliptin improved glycemic control and reduced GV without inducing hypoglycemia.. ClinicalTrials.gov (NCT02771093) and JAPIC (JapicCTI-163250).. Takeda Pharmaceutical Company, Ltd.

Topics: Aged; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Pilot Projects; Piperidines; Uracil

We investigated the effect of alogliptin and gliclazide on endothelial progenitor cells (EPCs) in type 2 diabetes.. Eighty patients with type 2 diabetes and HbA1c between 7.5% and 8.5% were randomized to receive either alogliptin (25 mg/daily) or gliclazide extended-release (30 mg/daily for HbA1c 7.5-8.0% and 60 mg/daily for HbA1c 8.0-8.5%) in combination with metformin for 4 months. At baseline and 4 months, clinical and laboratory parameters of EPCs were determined.. After 4 months of treatment, alogliptin and gliclazide resulted in a similar significant reduction in HbA1c (%) (8.0±0.3 vs. 7.1±0.2, and 8.0±0.3 vs. 7.0±0.2, respectively; P<0.05) and a similar and significant increase in EPC count (cells/10. Both alogliptin and gliclazide demonstrated a beneficial effect in increasing EPCs in poorly controlled type 2 diabetes. As alogliptin and gliclazide exhibit different mechanisms of action, the observed increase in EPCs seems to be due to their glucose-lowering effect.

Topics: Aged; Diabetes Mellitus, Type 2; Endothelial Progenitor Cells; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Uracil

Glinides are antidiabetic drugs that enhance the early phase of insulin secretion, but have been considered to be less effective at lowering blood glucose than sulfonylureas. However, glinides show a lower risk of hypoglycemia and a greater effect on postprandial hyperglycemia, and are particularly recommended for use in elderly patients with type 2 diabetes. We investigated the efficacy and safety of repaglinide compared with sulfonylurea for the treatment of elderly patients.. In the present multicenter, prospective, randomized, open-label, controlled trial, 57 elderly lean patients with type 2 diabetes who were being treated with sulfonylureas were studied. They were either switched to repaglinide (Repa group) or continued a sulfonylurea (SU group) for 12 weeks. The primary outcome comprised the change in glycemic control, and among the secondary outcomes was the presence of hypoglycemia and drug compliance.. Although glycated hemoglobin (HbA1c) was not significantly different between the two groups (SU +0.02% vs Repa -0.07%), greater improvements in the glycated albumin (GA) and GA to HbA1c ratio (GA/HbA1c) were observed in the Repa group (ΔGA, SU +0.12% vs Repa -1.15%; ΔGA/HbA1c, SU +0.01 vs Repa -0.13; each P < 0.01) without increasing hypoglycemia. When the Repa group was subdivided according to whether GA improved, the SU dose before switching to repaglinide was significantly smaller and the homeostatic model assessment of β-cell function was significantly higher in the GA improvement subgroup.. Switching from SU to Repa improved GA and GA/HbA1c, and had favorable effects on glucose fluctuation in elderly patients with type 2 diabetes.

Topics: Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Prognosis; Prospective Studies; Sulfonylurea Compounds

Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.. This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.. Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

Topics: Adult; Aged; Albuminuria; Benzimidazoles; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Morpholines; Piperidines; Protease Inhibitors; Renin; Time Factors; Treatment Outcome; Young Adult

Topics: Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Patient Preference; Physician-Patient Relations; Piperidines; Practice Patterns, Physicians'; Surveys and Questionnaires; Uracil

Anagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase-4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients.. The study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase-4 inhibitors for ≥8 weeks and had a low-density lipoprotein cholesterol (LDL-C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks.. There was no significant difference in percentage change in LDL-C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL-C levels, one of the secondary end-points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B-100 levels, and the percentage change in LDL-C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B-100 levels in the ANA group.. The LDL-C-lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL-C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B-100 synthesis.

Topics: Aged; Apolipoprotein B-100; Blood Glucose; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Lipid Metabolism; Lipids; Male; Piperidines; Pyrimidines; Treatment Outcome; Uracil

We sought to assess the risk of major adverse cardiovascular events (MACE) by utilizing high-sensitivity C-reactive protein (hsCRP) level and low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and recent acute coronary syndrome.. Study participants enrolled in the EXAMINE trial (Clinical trials registration number: NCT00968708) and were stratified by baseline hsCRP levels (<1, 1-3 and >3 mg/L). They were also sub-divided into 4 groups according to baseline hsCRP (≤3 or >3 mg/L) and achieved LDL-C (<70 or ≥70 mg/dL) levels. Among 5380 patients, the MACE rate, a composite of cardiovascular death, non-fatal acute myocardial infarction and non-fatal stroke, was evaluated during the 30 months of follow-up.. Cumulative incidence of MACE was 11.5% (119 events), 14.6% (209 events) and 18.4% (287 events) in patients with hsCRP levels of <1, 1 to 3 and >3 mg/L, respectively (P < .001). In patients with hsCRP >3 mg/L, the adjusted hazard ratio (95% confidence interval) was 1.42 (1.13, 1.78; P = .002) for MACE compared with patients with hsCRP <1 mg/L. MACE cumulative incidences were 11.0% (128 events), 14.4% (100 events), 15.6% (194 events) and 21.3% (182 events) in patients with low LDL-C and low hsCRP, low LDL-C and high hsCRP, high LDL-C and low hsCRP, and high LDL-C and high hsCRP levels, respectively (P < .001).. Levels of hsCRP were associated with recurrent cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome, and this association appears to be independent of and additive to the achieved LDL-C level.

Topics: Acute Coronary Syndrome; C-Reactive Protein; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Heart Failure; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Piperidines; Standard of Care; Treatment Outcome; Uracil

As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs.. We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA. Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin.. Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; Carbamates; Child; Cystic Fibrosis; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Piperidines; Prognosis; Young Adult

Curcuminoids have been shown to reduce glycemia and related complications in diabetes. In the present study, we evaluated the impact of curcuminoids plus piperine administration on glycemic, hepatic and inflammatory biomarkers in type 2 diabetes (T2D) patients.. T2D patients aged 18-65 years were enrolled in a randomized double-blind placebo-controlled trial and randomly allocated to standard-of-care treatment and dietary advises plus either curcuminoids (daily dose of 500 mg/day co-administered with piperine 5 mg/day) or placebo for a period of 3 months. Glycemic, hepatic and inflammatory parameters were measured at baseline and final conditions.. A total of 100 subjects (50 in each group) completed the 3-month period of trial. A significant reduction was found in serum levels of glucose (-9±16 mg/dL vs. -3±11 mg/dL in curcuminoids and placebo groups, respectively; p=0.048), C-peptide (-0.6±0.8 ng/mL vs. 0.02±0.6 ng/mL; p<0.001) and HbA1c (-0.9±1.1% vs. -0.2±0.5%; p<0.001) after curcuminoids supplementation versus placebo group. Additionally, participants in the intervention group showed lower serum alanine aminotransferase (-2±6 vs. -1±5; p=0.032) and aspartate aminotransferase (-3±5 vs. -0.3±4; p=0.002) levels compared with the placebo group. Finally, no significant differences in high-sensitivity C-reactive protein (hs-CRP) concentrations were observed between curcuminoids and placebo groups (p>0.05).. The results of the present trial revealed a beneficial effect of curcuminoids plus piperine supplementation on glycemic and hepatic parameters but not on hs-CRP levels in T2D patients.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaloids; Antioxidants; Aspartate Aminotransferases; Benzodioxoles; Biomarkers; Blood Glucose; C-Reactive Protein; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Young Adult

We evaluated the antihyperglycemic efficacy and safety of adding the dipeptidyl dipeptidase-4 inhibitor alogliptin to metformin and sulphonylurea in the treatment of type 2 diabetes in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care Trial.. Patients with type 2 diabetes and recent acute coronary syndrome were randomized to alogliptin or placebo and standard of care. Participants were followed for up to 40 (median 18) months. In a subgroup taking metformin and sulphonylurea at baseline, we evaluated change from baseline in glycated hemoglobin (HbA1c), adverse events, cardiovascular outcomes, laboratory data, and other safety parameters.. There were 1398 patients receiving baseline dual therapy (metformin and sulphonylurea only) randomized to alogliptin (N = 693) or placebo (N = 705); 550 patients receiving alogliptin and 505 patients receiving placebo completed the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care without addition of other antihyperglycemic therapies (P = .008). Changes from baseline to last visit in HbA1c were -0.4% on alogliptin and +0.1% on placebo (P < .001) in all those with baseline dual therapy and -0.4% for alogliptin and +0.2% for placebo (P < .001) in those without additional therapies. Reported rates of hypoglycemia were 8.8% for alogliptin and 6.7% for placebo (P = .16). Cardiovascular death and all-cause mortality rates were lower in those receiving alogliptin compared with those receiving placebo (hazard ratio, 0.49; 95% confidence interval, 0.28-0.84 and hazard ratio, 0.61; 95% confidence interval, 0.38-0.96, respectively).. Addition of the dipeptidyl peptidase-4 inhibitor alogliptin to dual therapy with metformin plus sulfonylurea significantly reduced HbA1c and was well tolerated. Lower mortality rates were seen in patients treated with alogliptin in this subgroup.

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sulfonylurea Compounds; Treatment Outcome; Uracil

Alogliptin, a dipeptidyl peptidase-4 inhibitor, is approved for the treatment of patients with type 2 diabetes (T2DM). EXAMINE was a randomized controlled clinical trial designed to demonstrate the cardiovascular (CV) safety of alogliptin. In the trial, 5380 patients with established T2DM who had a recent acute coronary syndrome event (between 15 and 90 days) were randomized to treatment with either alogliptin or placebo. To better understand and describe the CV safety of alogliptin, we analyzed data from the EXAMINE trial to determine whether treatment with alogliptin affected recurrent and total CV events. Poisson regression analysis compared the total number of occurrences of CV death, MI, stroke, unstable angina, and coronary revascularization between all patients randomized to alogliptin vs placebo groups. Patients with recurrent CV events were older and more likely to have renal disease and history of heart failure. There were 1100 first CV events and an additional 666 recurrent events over a median of 18 months of follow-up. There were no significant differences with regard to total number of events in patients treated with alogliptin (n = 873) or placebo (n = 893; P = 0.52). Furthermore, there were no differences in the types of events seen in patients treated with alogliptin or placebo. Alogliptin did not increase the risk of either first or recurrent CV events when compared with placebo in patients with T2DM and recent acute coronary syndrome. These data support the CV safety of alogliptin in patients who are at increased risk of future CV events.

Topics: Acute Coronary Syndrome; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Piperidines; Stroke; Survival Rate; Treatment Outcome; United States; Uracil

Post-Market Research We aimed to investigate the impact of G protein-coupled receptor kinase 5 (GRK5) rs10886471 polymorphism on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). A total of 300 T2DM patients and 210 healthy controls were genotyped for GRK5 rs10886471 on a three-dimensional polyacrylamide gel-based DNA microarray. Eighty-five patients with the same genotypes of cytochrome P450 (CYP) 2C8*3 139Arg and organic anion-transporting polypeptide 1B1 (OATP1B1) 521TT were randomly selected to orally take repaglinide for eight consecutive weeks. Then, the biochemical indicators and pharmacodynamic parameters were measured before and after repaglinide treatment. The T allelic frequency of GRK5 rs10886471 was higher in T2DM patients than in healthy subjects (p < .01). T2DM patients with genotypes CC and CT at GRK5 rs10886471 had a significant reduction in terms of fasting plasma glucose (FPG) compared with those with genotype TT (p < .01). In addition, the carriers of genotypes CC and CT at GRK5 rs10886471 had higher differential values of postprandial serum insulin (PINS) compared with genotype TT carriers (p < .05). These findings suggest that GRK5 rs10886471 polymorphism may influence the therapeutic efficacy of repaglinide in Chinese Han T2DM patients.

Topics: Asian People; Blood Glucose; Carbamates; Cytochrome P-450 CYP2C8; Diabetes Mellitus, Type 2; Female; G-Protein-Coupled Receptor Kinase 5; Genotype; Humans; Hypoglycemic Agents; Insulin; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Treatment Outcome

Antihyperglycemic therapies may increase the risk of cardiovascular events including hospitalization for heart failure. There is a paucity of data evaluating the cardiovascular safety of antihyperglycemic therapies in the high-risk period following an acute coronary syndrome (ACS).. The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial randomized 5380 patients who were 15 to 90 days post ACS to the dipeptidyl dipeptidase-IV (DPP-IV) inhibitor alogliptin versus placebo; mean follow-up was 18 months. Using a landmark analysis, we assessed the (1) burden of cardiovascular events from randomization to 6 months (early period) and from 6 months to the end of follow-up (late period) and (2) the risk of cardiovascular events associated with early (up to 6 months) and chronic (6 months to end of follow-up) DPP-IV inhibition with alogliptin. Patients with early versus late events had similar baseline demographic profiles. Overall, 42.1% of the composite of cardiovascular death/myocardial infarction/stroke and 47.5% of hospitalization for heart failure occurred in the early period. Early DPP-IV inhibition did not increase the risk of early cardiovascular death/myocardial infarction/stroke (hazard ratio 0.96, 95% confidence interval, 0.76-1.21) or hospitalization for heart failure (1.23, 95% confidence interval, 0.84-1.82). Similarly, chronic DPP-IV inhibition did not increase the risk of late cardiovascular death/myocardial infarction/stroke (hazard ratio 1.03, 95% confidence interval, 0.89-1.26) or hospitalization for heart failure (hazard ratio 1.02, 95% confidence interval, 0.85-1.22).. Early after an ACS, patients with type 2 diabetes mellitus experience a significant burden of HF events and recurrent ACS. DPP-IV inhibition with alogliptin appears to be safe even in the high-risk period following an ACS.

Topics: Acute Coronary Syndrome; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Recurrence; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Uracil

This study aims to compare the effect of repaglinide and metformin among Chinese patients with newly diagnosed diabetes, and explore the possible mechanisms by which repaglinide alters insulin secretion.Sixty subjects with glycated hemoglobin (HbA1c) < 10.0% were randomly selected to receive repaglinide or metformin monotherapy for 15 weeks. Blood glucose levels, glycemic variability, β-cell function, and first-phase insulin secretion were compared between these 2 groups at baseline and at 15 weeks. Mouse insulinoma (MIN-6) cells were divided into 3 groups: low glucose, high glucose, and repaglinide 50 nm groups. Cells and cell culture mediums were collected at different timepoints. The expression of pericentrin (PCNT), F-actin, and insulin were tested with immunofluorescence and enzyme-linked immunosorbent assay.All glycemic parameters and variability indexes significantly decreased from baseline to 15 weeks, while no significant difference was found between these 2 groups at baseline or at 15 weeks. Furthermore, there was no significant difference found in fasting insulin and postprandial insulin at baseline and at 15 weeks, while homeostasis model assessment β significantly increased. The first-phase glucose and insulin secretion of the intravenous glucose tolerance test improved in both groups, especially in the repaglinide group. Insulin, PCNT, and F-actin expression in MIN-6 cells decreased after 15 minutes of stimulation with repaglinide, while no difference was observed at 2, 6, and 12 hours. The insulin levels of the cell medium in the repaglinide group remained significantly higher at all timepoints.This study manifests that repaglinide has a noninferiority effect on the glycemic parameters of Chinese patients with newly diagnosed diabetes, when compared with metformin. The PCNT-F-actin pathway plays an important role in the repaglinide regulation process of on-demand insulin secretion.

Topics: Actins; Adult; Aged; Aged, 80 and over; Antigens; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines; Treatment Outcome; Young Adult

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazards model with adjustment for baseline covariates in 10-mm Hg increments of clinician-measured systolic BP from ≤100 to >160 mm Hg and diastolic BP from ≤60 to >100 mm Hg averaged during the 24 months after randomization. Based on 2015 guidelines from the American College of Cardiology, the American Heart Association and the American Society of Hypertension and 2017 American Diabetes Association guidelines, systolic BP s of 131 to 140 mm Hg and diastolic BP s of 81 to 90 mm Hg were the reference groups. A U-shaped relationship between cardiovascular outcomes and BP s was observed. Importantly, compared with the systolic BP reference group, adjusted hazard ratios for major adverse cardiac events and cardiovascular death or heart failure were significantly higher in patients with systolic BP s <130 mm Hg. Similarly, compared with the diastolic BP reference group, adjusted hazard ratios for major adverse cardiac events and for cardiovascular death or heart failure were significantly higher for diastolic BP s <80 mm Hg. Conclusions In patients with type 2 diabetes mellitus and recent acute coronary syndrome, average BP s <130/80 mm Hg were associated with worsened cardiovascular outcomes. These data suggest that intensive control of BP in patients with type 2 diabetes mellitus and ischemic heart disease should be evaluated in a prospective randomized trial. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00968708.

Topics: Aged; Analysis of Variance; Blood Pressure Determination; Cause of Death; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prognosis; Prospective Studies; United States; Uracil

Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR.. In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m. ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.

Topics: Adult; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Meals; Metformin; Obesity; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prediabetic State; Prevalence; Slovenia; Thiazolidinediones; Uracil

Type 2 diabetes (T2D) is an established risk factor for cardiovascular disease (CVD) and is associated with disturbed metabolism of lipids and lipoproteins. Curcuminoids are natural products with anti-diabetic and lipid-modifying actions but their efficacy in improving dyslipidemia in diabetic individuals has not been sufficiently studied.. To investigate the efficacy of supplementation with curcuminoids, plus piperine as an absorption enhancer, in improving serum lipids in patients with T2D.. In this 12-week randomized double-blind placebo-controlled trial, subjects with T2D (n=118) were assigned to curcuminoids (1000mg/day plus piperine 10mg/day) or placebo plus standard of care for T2D. Serum concentrations of lipids including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of trial.. Between-group comparison of change in the study parameters revealed significant reductions in serum levels of TC (-21.86±25.78 versus -17.06±41.51, respectively; p=0.023), non-HDL-C (-23.42±25.13 versus -16.84±41.42, respectively; p=0.014) and Lp(a) (-1.50±1.61 versus -0.34±1.73, respectively; p=0.001) and elevations in serum HDL-C levels (1.56±4.25 versus -0.22±4.62, respectively; p=0.048) in the curcuminoids group as compared with the placebo group (p<0.05). Serum TG and LDL-C changes did not show any significant difference between the study groups (p>0.05).. Curcuminoids supplementation can reduce serum levels of atherogenic lipid indices including non-HDL-C and Lp(a). Therefore, curcuminoids supplementation could contribute to a reduced risk of cardiovascular events in dyslipidemic patients with T2D.

Topics: Adult; Alkaloids; Benzodioxoles; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Dyslipidemias; Female; Humans; Lipids; Lipoprotein(a); Male; Middle Aged; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Triglycerides

Curcumin is a naturally occurring polyphenol derived from tumeric that has been reported to have anti-inflammatory properties with effects on adipokine and ghrelin levels. Adiponectin, leptin and ghrelin modulate energy homeostasis but each has modulatory effects on inflammatory cytokines and the immune system. Therefore, this analysis was performed to investigate the effect of curcumin on adiponectin, leptin and ghrelin.. A double blind randomised control trial comparing curcumin 1000mg with 10mg of piperine daily to placebo over a 12 week period. 118 patients with type 2 diabetes were recruited out of which 50 control and 50 active subjects completed the trial. Adiponectin, leptin, ghrelin and tumor necrosis factor-α (TNF-α) were measured at baseline and 12 weeks.. Between group comparison of the magnitude of changes showed serum levels of leptin (p<0.001), TNF-α (p<0.001) and leptin:adiponectin ratio (p<0.001) to be significantly reduced while serum adiponectin levels were elevated in the curcuminoids versus placebo group (p=0.032). Changes in serum ghrelin levels did not differ between the study groups (p=0.135).. Curcumin supplementation increased adiponectin, whilst the the leptin:adiponectin ratio (a measure of atherosclerosis) and leptin levels were decreased independent of weight change and reflected a decrease in the inflammatory TNF-α levels.

Topics: Adipokines; Adiponectin; Adult; Alkaloids; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Curcumin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Piperidines; Polyunsaturated Alkamides; Tumor Necrosis Factor-alpha

This study determined the efficacy and safety of once-daily oral alogliptin in patients from mainland China, Taiwan, and Hong Kong with type 2 diabetes mellitus.. In this Phase 3 multicenter double-blind placebo-controlled 16-week trial, 506 patients were randomized to receive once-daily alogliptin 25 mg or placebo: 185 in the monotherapy group, 197 in the add-on to metformin group, and 124 in the add-on to pioglitazone group. The primary efficacy variable was the change from baseline (CFB) in HbA1c at Week 16; other efficacy measures included CFB to Week 16 in fasting plasma glucose (FPG), incidence of marked hyperglycemia (FPG ≥11.1 mmol/L), and the incidence of clinical HbA1c ≤6.5 % (48 mmol/mol) and ≤7.0 % (53 mmol/mol) at Week 16. Safety was assessed throughout the trial.. Alogliptin monotherapy provided a significantly greater decrease in HbA1c from baseline to Week 16 compared with placebo (-0.58 %; 95 % confidence interval [CI] -0.78 %, -0.37 %; P < 0.001). As an add-on to metformin or pioglitazone, alogliptin also significantly decreased HbA1c compared with placebo (-0.69 % [95 % CI -0.87 %, -0.51 %; P < 0.001] and -0.52 % [95 % CI -0.75 %, -0.28 %; P < 0.001], respectively). In any treatment group versus placebo, alogliptin led to greater decreases in FPG (P ≤ 0.004) and a higher percentage of patients who achieved an HbA1c target of ≤6.5 % and ≤7.0 % (P ≤ 0.003). No weight gain was observed in any treatment group. A similar percentage of patients experienced drug-related, treatment-emergent adverse events in the alogliptin and placebo arms. Four and two patients in the alogliptin and placebo arms, respectively, experienced mild or moderate hypoglycemia.. Alogliptin 25 mg once daily reduced HbA1c and FPG and enhanced clinical response compared with placebo when used as monotherapy or as an add-on to metformin or pioglitazone. Therapy with alogliptin was well tolerated.

Topics: Adult; Aged; Asian People; Blood Glucose; China; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Hong Kong; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Piperidines; Taiwan; Thiazolidinediones; Treatment Outcome; Uracil

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose; Glycated Hemoglobin; Humans; Male; Middle Aged; Nitriles; Piperidines; Pyrrolidines; Treatment Outcome; Uracil; Vildagliptin

This randomized, double-blind, phase III study evaluated the efficacy and safety of once-daily treatment with alogliptin (25 mg once daily), alone or with metformin hydrochloride (500 mg once daily or 250 mg twice daily), in Japanese patients with type 2 diabetes. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to the end of treatment (week 24). The least squares (LS) mean (standard error) change in HbA1c from baseline to the end of treatment (week 24) was 0.16 (0.072)% in alogliptin alone, -0.49 (0.049)% in alogliptin/metformin once daily, and -0.60 (0.049)% in alogliptin/metformin twice daily. The LS mean difference in HbA1c change from baseline between alogliptin/metformin once daily and alogliptin alone (alogliptin/metformin once daily minus alogliptin alone) was -0.65% (95% confidence interval [CI] -0.821, -0.480) and between alogliptin/metformin once daily and twice daily (once daily minus twice daily) was 0.11% (95% CI -0.026, 0.247). The overall frequency of adverse events was similar among the groups. This study showed that the efficacy of alogliptin/metformin once daily was superior to alogliptin alone and non-inferior to alogliptin/metformin twice daily, and that alogliptin/metformin once daily was safe and well tolerated in Japanese patients with type 2 diabetes.

Topics: Acute Disease; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Metformin; Middle Aged; Nasopharyngitis; Pancreatitis; Piperidines; Treatment Outcome; Uracil

The aim of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 12.5- or 25-mg dose of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in pediatric (children and adolescents) and adult subjects with type 2 diabetes mellitus (T2DM).. A randomized, open-label, multicenter study was conducted in pediatric and adult subjects. Subjects in two pediatric groups (children and adolescents) were randomized 1:1 to receive a single oral dose of alogliptin 12.5 or 25 mg, respectively; all gender- and race-matched adult subjects received alogliptin 25 mg. Blood and urine samples were collected at prespecified time points for PK/PD analyses. A PK/PD model was developed using data from the study for steady-state simulations. Safety was also assessed.. A 25-mg dose of alogliptin in pediatric subjects achieved alogliptin exposures and DPP-4 inhibition similar to those in adult T2DM patients without safety concerns; therefore, this dose is recommended for a pediatric phase 3 trial.

Topics: Adolescent; Adult; Area Under Curve; Child; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Half-Life; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil; Young Adult

To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).. The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.. Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P. There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Piperidines; Risk Factors; Secondary Prevention; Severity of Illness Index; Uracil

This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + metformin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was -0.19% with placebo, -0.86% with alogliptin, -1.04% with metformin and -1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P  < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes.

Topics: China; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exercise; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunity, Mucosal; Incidence; Malaysia; Metformin; Middle Aged; Piperidines; Republic of Korea; Respiratory Tract Infections; Taiwan; Uracil

To investigate adiponectin levels and cardiovascular (CV) outcomes in patients with diabetes and recent acute coronary syndrome (ACS).. We analysed baseline adiponectin concentration and CV outcomes in 5213 patients with type 2 diabetes enrolled in the EXAMINE trial of alogliptin vs placebo 15 to 90 days (median 45 days) after ACS. Event rates at 18 months are reported.. The median (interquartile range) baseline adiponectin concentration was 5.2 (3.5-7.9) μg/mL. Patients with the highest baseline adiponectin concentration (quartile [Q]4) were at significantly higher risk of death from a CV event (8.4% vs 1.7%; P < .0001), hospitalization for heart failure (HF; 7.5% vs 1.7%; P < .0001), and all-cause mortality (10.8% vs 2.4%; P < .0001) compared with those in Q1. After adjusting for age, sex, index event, HF, estimated glomerular filtration rate and hypertension, adiponectin concentration in Q4 remained associated with an increased risk of death from CV causes (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.52, 3.88), all-cause mortality (HR 2.45, 95% CI 1.65, 3.64), and HF (HR 2.44, 95% CI 1.47, 4.05), without change after stratification by body mass index. There was no significant difference in the rate of myocardial infarction or stroke.. In this contemporary population of patients with diabetes and ACS, adiponectin concentration was independently associated with increased risk of death from CV causes, all-cause mortality, and hospitalization for HF. The relationship between adiponectin and CV outcomes is complex and deserves further study.

Topics: Acute Coronary Syndrome; Adiponectin; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Mortality; Piperidines; Proportional Hazards Models; Risk; Secondary Prevention; Uracil

We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes.. The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point.. Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00968708.

Topics: Acute Coronary Syndrome; Aged; Biomarkers; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Standard of Care; Treatment Outcome; Troponin I; Uracil

Despite the current guideline's recommendation of a timely stepwise intensification therapy, the "clinical inertia", termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Topics: Acarbose; Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

This study investigated the effects of switching from combination therapy with either alogliptin (Alo) or pioglitazone (Pio) to fixed-dose combination therapy (FDCT) with alogliptin and pioglitazone (Alo-Pio FDCT). The usefulness and efficacy of Alo-Pio FDCT were investigated. A total of 50 outpatients with type 2 diabetes mellitus (T2DM) treated with Alo and 47 outpatients with T2DM treated with Pio were switched to Alo-Pio FDCT, and its efficacy and usefulness were evaluated. Significant improvements were observed in hemoglobinA1c (HbA

Topics: Aged; Alanine Transaminase; Blood Glucose; Body Mass Index; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; gamma-Glutamyltransferase; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Piperidines; Uracil

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

It has been reported that dipeptidyl peptidase-4 (DPP-4) inhibitors improve hemoglobin A1c (HbA1c) levels in diabetic patients and may also improve the serum lipids. However, few studies have examined relationship between the effects of the DPP-4 inhibitor and the pretreatment HbA1c levels in diabetic patients. Furthermore, it has been reported that prolonged treatment with DPP-4 inhibitors may make glycemic control difficult in some patients. In the present study, we investigated (1) the effect of the DPP-4 inhibitor alogliptin on HbA1c, blood glucose (BG), and serum lipid in Japanese patients with type 2 diabetes, (2) the relationship between the HbA1c levels at baseline and the effects of alogliptin, and (3) the effects of switching of the DPP-4 inhibitor to alogliptin after 12 months' administration of sitagliptin on glycemic control and serum lipids. After 6-months' treatment with alogliptin, we found reductions of HbA1c, BG, and serum total cholesterol, and LDL cholesterol levels. Pretreatment level of HbA1c was well correlated with the degree of reduction of both HbA1c and BG levels after the treatment. Also, alogliptin kept levels of HbA1c and BG reduced by sitagliptin for 12 months, and relapsing of these levels and serum lipids were not observed. This study revealed that alogliptin improved HbA1c, BG, and serum lipid profiles in type 2 diabetic patients, and the effect of alogliptin on HbA1c and BG levels was correlated with HbA1c level at pretreatment. Furthermore, long-term treatment with alogliptin did not cause relapsing of glycemic control and serum lipids.

Topics: Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Piperidines; Sitagliptin Phosphate; Uracil

Recent experimental studies have shown that dipeptidyl peptidase 4 (DPP-4) inhibitors have antiatherosclerotic benefits in glucagon-like peptide 1-dependent and -independent manners. The current study investigated the effects of alogliptin, a DPP-4 inhibitor, on the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).. This prospective, randomized, open-label, blinded-end point, multicenter, parallel-group, comparative study included 341 patients with T2DM free of a history of apparent cardiovascular diseases recruited at 11 clinical units and randomly allocated to treatment with alogliptin (n = 172) or conventional treatment (n = 169). Primary outcomes were changes in mean common and maximum intima-media thickness (IMT) of the carotid artery measured by carotid arterial echography during a 24-month treatment period.. Alogliptin treatment had a more potent glucose-lowering effect than the conventional treatment (-0.3 ± 0.7% vs. -0.1 ± 0.8%, P = 0.004) without an increase of hypoglycemia. Changes in the mean common and the right and left maximum IMT of the carotid arteries were significantly greater after alogliptin treatment than after conventional treatment (-0.026 mm [SE 0.009] vs. 0.005 mm [SE 0.009], P = 0.022; -0.045 mm [SE 0.018] vs. 0.011 mm [SE 0.017], P = 0.025, and -0.079 mm [SE 0.018] vs. -0.015 mm [SE 0.018], P = 0.013, respectively).. Alogliptin treatment attenuated the progression of carotid IMT in patients with T2DM free of apparent cardiovascular disease compared with the conventional treatment.

Topics: Aged; Atherosclerosis; Blood Glucose; Carotid Arteries; Carotid Artery Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Prospective Studies; Uracil

This was a post hoc analysis of a 2-year, double-blind study of 2639 patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin monotherapy, which assessed achievement of a composite endpoint of sustained glycated haemoglobin (HbA1c) reduction (≤7.0% at week 104 or ≥0.5% decrease from baseline) with no weight gain and no hypoglycaemic events with alogliptin 12.5 and 25 mg daily or glipizide (≤20 mg daily), each added to metformin. With an HbA1c target of ≤7.0%, 24.2 and 26.9% of patients treated with alogliptin 12.5 and 25 mg, respectively, achieved the composite endpoint versus 10.7% of patients treated with glipizide (both p < 0.001). With a criterion of ≥0.5% decrease in HbA1c, the composite endpoint was reached in 22.5, 25.2 and 10.4% of patients treated with alogliptin 12.5 mg, alogliptin 25 mg and glipizide, respectively. Odds ratios for achieving the composite endpoint favoured alogliptin in the primary analysis set and in all subgroups of patients. Patients with T2DM failing metformin monotherapy were more likely to achieve sustained glycaemic control with no hypoglycaemia or weight gain at 2 years with alogliptin than with glipizide.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Endpoint Determination; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil; Weight Gain; Young Adult

The aim of this study is to investigate ipragliflozin as an initial type 2 diabetes (T2DM) drug.. Ipragliflozin 25-50 mg/day monotherapy was performed with drug naïve subjects with T2DM (n=31). As a comparator, 12.5-25 mg/day alogliptin monotherapy was undertaken (n=32). At 3 months, levels of metabolic parameters were compared with those at baseline.. 4 subjects discontinued ipragliflozin due to intolerance or adverse events, while none dropped out with alogliptin. At 3 months, similar decreases of HbA1c levels were observed with these 2 drugs (10.21-8.31%, p<0.00001, with ipragliflozin, and 10.08-8.25%, p<0.00001, with alogliptin), however fasting blood glucose (FBG) levels decreased with significant inter-group differences (- 23.5% with iprgliflozin and - 10.8% with alogliptin). While similar increases of homeostasis model assessment (HOMA)-B levels were observed with these 2 drugs, HOMA-R levels significantly decreased only with ipragliflozin (-19.4%, p<0.02). Un-correlative link between HOMA-R and HOMA-B levels at baseline became significantly correlative (R=0.6017, p<0.001) only with ipragliflozin. Significant reductions of body mass index (BMI, -2.6%, P<0.05) were observed with ipragliflozin, however, no correlations between the changes of BMI and those of HbA1c or FBG were noted.. These results suggest that ipragliflozin has good glycemic efficacy as an initial therapy in subjects with T2DM, although certain adverse events or tolerability issues are concerned. It improves insulin sensitivity and may restore the impaired beta-cell function. However body weight reduction with ipragliflozin is not associated with its glycemic efficacy.

Topics: Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Prospective Studies; Thiophenes; Uracil

Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post-acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE.. Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline.. There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease.. EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

Topics: Acute Coronary Syndrome; Aged; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Myocardial Revascularization; Outcome and Process Assessment, Health Care; Piperidines; Risk Assessment; Standard of Care; Stroke; Uracil

We evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event.. The study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event.. Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo.. In patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Multivariate Analysis; Piperidines; Proportional Hazards Models; Risk; Uracil

Objective Switching from sulfonylureas to repaglinide in patients with type 2 diabetes improves glycemic control; however, the optimal dosage has not been fully evaluated. We designed to show that repaglinide was equivalent to sulfonylurea in Japanese patients with type 2 diabetes. We herein evaluated whether we could switch from sulfonylureas to repaglinide twice or thrice daily in Japanese adult patients who had been treated with anti-diabetic drugs, including sulfonylureas, and whose conditions were moderately well-controlled. Methods A total of 78 patients taking less than half the Japanese maximum dose of sulfonylurea were randomized into three groups: 26 in group A (switching from sulfonylureas to taking 0.25 or 0.5 mg of repaglinide just before breakfast and dinner twice daily), 27 in group B (switching from sulfonylureas to taking 0.25 or 0.5 mg of repaglinide just before meals thrice daily), and 25 in group C (continuing to take sulfonylurea). Blood samples were collected at 0, 1, 2, 3, and 4 months following the initiation of the maintenance period. Results The HbA1c and glycoalbumin levels did not significantly differ among the three groups after 4 months of treatment. Conclusion With the assumption that 1 mg of glimepiride is equivalent to 1.25 mg of glibenclamide or 40 mg of gliclazide, the administration of repaglinide (0.44 mg/meal) twice and thrice daily is similar to the efficacy of sulfonylurea (glimepiride 1.63-1.98 mg/day) after four months of treatment in Japanese patients with moderately well-controlled type 2 diabetes (HbA1c, 7-7.5%).

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Serum Albumin; Sulfonylurea Compounds

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

Topics: Acute Coronary Syndrome; Aged; Angiotensin-Converting Enzyme Inhibitors; Confidence Intervals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Prognosis; Proportional Hazards Models; Prospective Studies; Reference Values; Risk Assessment; Survival Rate; Treatment Outcome; Uracil

The present study determined whether dipeptidyl peptidase-4 (DPP-4) inhibition by alogliptin improves coronary flow reserve (CFR) and left ventricular election fraction (LVEF) in patients with type 2 DM and CAD.. Twenty patients with type 2 DM and known or suspected CAD were randomly allocated to receive diet therapy plus alogliptin (n=10; mean age, 73.3±6.6y) or a control group given diet therapy and glimepiride (n=10; mean age, 76.7±7.3y). Breath-hold PC cine MR images of the coronary sinus (CS) were acquired using a 1.5T MR scanner and 32 channel cardiac coils to assess blood flow of the CS at rest and during adenosine triphosphate (ATP) infusion. The CFR was calculated as CS blood flow during ATP infusion divided by that at rest. The CFR and LVEF were evaluated by MRI at baseline and at three months after starting therapy.. Hemoglobin A1c (HbA1c) was significantly reduced in both groups (alogliptin, 7.2±0.6% to 6.6±0.5%, p=0.034; control, 6.9±0.4% to 6.4±0.3%, p=0.008). However, CFR and LVEF significantly improved only in the alogliptin group (alogliptin: CFR, 2.15±0.61 to 2.85±0.80, p=0.042; LVEF, 59.4±6.3% to 68.0±8.6%, p=0.03; control: CFR, 2.17±0.37 to 2.38±0.32, p=0.19; LVEF, 58.2±9.1 to 60.3±8.8%, p=0.61). The % increases in CFR and in LVEF positively correlated (R=0.47 by Spearman's correlation coefficient; p=0.036).. The inhibition of DPP-4 by alogliptin improved CFR and LVEF evaluated by MRI in patients with type 2 DM and CAD and the improvement in CFR was associated with increased LV systolic function.

Topics: Aged; Aged, 80 and over; Cohort Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractional Flow Reserve, Myocardial; Humans; Magnetic Resonance Imaging, Cine; Male; Piperidines; Prospective Studies; Uracil; Ventricular Function, Left

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Substitution; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines; Postprandial Period; Sitagliptin Phosphate; Treatment Outcome

Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. The current study was designed to investigate the impact of KCNQ1 genetic polymorphism on the efficacy of repaglinide and furthermore to identify the potential mechanism of action in patients with type 2 diabetes. A total of 305 patients and 200 healthy subjects were genotyped for the KCNQ1 rs2237892 polymorphism, and 82 patients with T2DM were randomized for the oral administration of repaglinide for 8 weeks. HepG2 cells were incubated with repaglinide in the absence or presence of a KCNQ1 inhibitor or the pcDNA3.1-hKCNQ1 plasmid, after which the levels of Akt, IRS-2 and PI(3)K were determined. Our data showed that repaglinide significantly decreased HOMA-IR in patients with T2DM. Furthermore, the level of HOMA-IR was significantly reduced in those patients with CT or TT genotypes than CC homozygotes. The KCNQ1 inhibitor enhanced repaglinide efficacy on insulin resistance, with IRS-2/PI(3)K/Akt signaling being up-regulated markedly. As in our clinical experiment, these data strongly suggest that KCNQ1 genetic polymorphism influences repaglinide response due to the pivotal role of KCNQ1 in regulating insulin resistance through the IRS-2/PI(3)K/Akt signaling pathway. This study was registered in the Chinese Clinical Trial Register on May 14, 2013. (No. ChiCTR-CCC13003536).

Topics: Adult; Asian People; Carbamates; China; Diabetes Mellitus, Type 2; Female; Hep G2 Cells; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; KCNQ1 Potassium Channel; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Piperidines; Polymorphism, Genetic; Proto-Oncogene Proteins c-akt; Signal Transduction

The aim of this study is to evaluate the effects of alogliptin on metabolic profiles in relation to those of glycemic control.. Treatment naïve subjects with type 2 diabetes received 12.5-25 mg/d alogliptin monotherapy (n = 59). A novel parameter called A1c index was used to assess the glycemic efficacy. The subjects were divided into three groups according to this index; super-responders, average responders and poor-responders. At 3 months, levels of the metabolic parameters were compared with those at baseline between super-responders (n = 20) and poor-responders (n = 21).. At baseline, total cholesterol, non-high density lipoprotein cholesterol and atherogenic index were significantly higher in super-responders than poor-responders. At 3 months, significant increases of beta-cell function (HOMA-B) and decreases of insulin resistance (HOMA-R) or these atherogenic lipids were observed in super-responders, while significant increases of HOMA-R were observed in poor-responders. Significant correlations were observed between A1c index and the changes of these atherogenic lipids. In super-responders, significant correlations were observed between the changes (Δ) of glycemic parameters (A1c index or fasting blood sugar) and ΔHOMA-R and/or ΔHOMA-B, while in poor-responders, significant correlations were observed between ΔHOMA-R and ΔHOMA-B. Lean subjects gained weight and the changes of body mass index had significant negative correlations with A1c index.. These results indicate that (1) glucose lowering efficacy of alogliptin is closely linked to atherogenic lipids. (2) alogliptin can down-regulate atherogenic lipids. (3) glycemic efficacy of alogliptin appears to be determined by the balance of its capacity in modulating insulin resistance and beta-cell function.

Topics: Adult; Aged; Atherosclerosis; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Insulin-Secreting Cells; Lipids; Male; Middle Aged; Piperidines; Uracil

Repaglinide is a short-acting insulin secretagogue, which often results in considerable interindividual variability in therapeutic efficacy when widely used in a clinical setting. Among various reasons under discussion is genetic polymorphism, especially the genes related to insulin secretion and resistance. Recent studies have described the importance of PPARD in regulating the secretion and resistance of insulin. However, little is known about the impacts of PPARD genetic polymorphism on the efficacy of repaglinide. Therefore, the current study was designed to investigate the associations of PPARD rs2016520 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. A total of 338 T2DM patients and 200 healthy subjects were genotyped for PPARD rs2016520 polymorphism by polymerase chain reaction-restriction fragment length polymorphism assay. A total of 84 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take repaglinide for 8 weeks. Then the pharmacodynamic parameters of repaglinide and biochemical indicators were determined before and after repaglinide treatment. No significant difference was found in either allelic frequency (P = 0.298) or genotype distribution (P = 0.151) of PPARD rs2016520 between T2DM patients and healthy subjects. However, T2DM patients carrying genotype TC showed a significantly lower increase in postprandial serum insulin (mU/L) than those with wild-type TT (P < 0.05). These findings suggest that PPARD rs2016520 polymorphism might influence the therapeutic effect of repaglinide rather than T2DM susceptibility in Chinese Han T2DM patients.

Topics: Adult; Asian People; Carbamates; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Postprandial Period; PPAR delta; Treatment Outcome

Trelagliptin is a novel once-weekly oral DPP-4 inhibitor. We assessed the efficacy and safety of trelagliptin versus the daily oral DPP-4 inhibitor alogliptin in Japanese patients with type 2 diabetes.. We did a randomised, double-blind, active-controlled, parallel-group, phase 3, non-inferiority study at 26 sites in Japan. We included individuals with type 2 diabetes inadequately controlled by diet and exercise. We randomly assigned patients (2:2:1) to receive trelagliptin (100 mg) once per week, alogliptin (25 mg) once per day, or placebo for 24 weeks. Randomisation was done electronically and independently from the study with permuted blocks of ten patients. Patients and clinicians were masked to group assignment. Patients in the trelagliptin group were given trelagliptin once a week and oral alogliptin placebo every day, whereas patients in the alogliptin group were given oral trelagliptin placebo once a week and oral alogliptin every day (double-dummy design). Patients in the placebo group were given an oral alogliptin placebo once a day and an oral trelagliptin placebo once a week. Our primary outcome was between-groups difference in change in HbA1c concentration from baseline to the end of treatment. The non-inferiority margin was 0·4%. Our analysis included all patients who were randomised and received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT01632007.. Between May 26, 2012, and Nov 20, 2012, we enrolled 357 patients. 243 patients were included in the analysis (101 for trelagliptin, 92 for alogliptin, and 50 for placebo). In the primary analysis, the least squares mean change in HbA1c concentration was -0·33% in the trelagliptin group (SE 0·059) and -0·45% in the alogliptin group (0·061) based on the ANCOVA model. The least squares mean difference (trelagliptin minus alogliptin) of change from baseline in HbA1c concentration was 0·11% (95% CI -0·054 to 0·281). Trelagliptin was non-inferior to alogliptin. Both active groups had significantly reduced mean HbA1c concentrations at end of treatment compared with placebo (p<0·0001). The frequency of adverse events was similar between groups. No hypoglycaemia was reported with trelagliptin and the drug was well tolerated.. The once-weekly DPP-4 inhibitor trelagliptin showed similar efficacy and safety to alogliptin once daily in Japanese patients with type 2 diabetes. Trelagliptin could be a useful new antidiabetes drug that needs to be given once a week.. Takeda Pharmaceutical Company.

Topics: Administration, Oral; Asian People; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Glycated Hemoglobin; Humans; Piperidines; Uracil

The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial.. Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708.. 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups.. In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes.. Takeda Development Center Americas.

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Piperidines; Risk Factors; Stroke; Uracil

A phase IV, multicentre, randomized, double-blind, parallel-group, comparative study was conducted in Japanese subjects with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control, despite treatment with alogliptin in addition to diet and/or exercise therapy. Subjects with glycated haemoglobin (HbA1c) concentrations of 6.9-10.5% were randomized to receive 16 weeks' double-blind treatment with pioglitazone 15 mg, 30 mg once daily or placebo added to alogliptin 25 mg once daily. The primary endpoint was the change in HbA1c from baseline at the end of treatment period (week 16). Both pioglitazone 15 and 30 mg combination therapy resulted in a significantly greater reduction in HbA1c than alogliptin monotherapy [-0.80 and -0.90% vs 0.00% (the least squares mean using analysis of covariance model); p < 0.0001, respectively]. The overall incidence rates of treatment-emergent adverse events were similar among the treatment groups. Pioglitazone/alogliptin combination therapy was effective and generally well tolerated in Japanese subjects with T2DM and is considered to be useful in clinical settings.

Topics: Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Exercise; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Japan; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

To evaluate the efficacy and safety of alogliptin in Chinese patients with type 2 diabetes (T2DM).. This was a multicenter, randomized, double-blind, placebo-controlled phase III trial. A total of 491 subjects with T2DM were randomized in a 1:1 ratio to receive alogliptin (25 mg once daily) or placebo for 16 weeks. Among them, 181 were in the monotherapy group (group A), 186 were in the add-on to metformin group (group B), and 124 were in the add-on to pioglitazone group (group C).. After 16 weeks of therapy, glycosylated hemoglobin A1c (HbA1c) levels decreased in both alogliptin and placebo groups. The mean changes in HbA1c for alogliptin and placebo were 1.00% and 0.43% (P<0.001), 0.91% and 0.23% (P<0.001), and 0.76% and 0.25% (P<0.001) in group A, B and C, respectively. Compared with placebo, alogliptin treatment led to a greater decrease in fasting plasma glucose (FPG) and a higher percentage of subjects who achieved HbA1c targets of ≤ 6.5% and ≤ 7.0%. The percentage of subjects who experienced all adverse events including hypoglycemia with alogliptin were comparable to those with placebo.. Alogliptin 25 mg once daily reduced HbA1c and FPG, and increased a greater proportion of subjects achieving HbA1c goals of ≤6.5% and ≤7.0% compared with placebo when used as a monotherapy, add-on to metformin, or add-on to pioglitazone. The hypoglycemia rates and safety profiles with alogliptin were similar to those with placebo.

Topics: Asian People; Blood Glucose; China; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Safety; Thiazolidinediones; Uracil

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 (GLP-1). To elucidate whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker (ARB) provides greater renal protective effects, we performed a crossover study with two DPP-4 inhibitors, sitagliptin and alogliptin, in twelve type 2 diabetic patients with incipient nephropathy taking ARBs. This study consisted of three treatment periods: sitagliptin 50 mg/day for 4 weeks (first period), alogliptin 25 mg/day for 4 weeks (second period), and sitagliptin 50 mg/day for 4 weeks (third period). Significant changes in body mass index, blood pressure, serum lipids, serum creatinine, estimated glomerular filtration rate, and HbA1c were not observed among the three treatment periods. Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), increased urinary cAMP levels, and elevated plasma levels of stromal cell-derived factor-1α (SDF-1α) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin. Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α, the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control, via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Chemokine CXCL12; Cross-Over Studies; Cyclic AMP; Deoxyguanosine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Pyrazines; Receptor, Angiotensin, Type 1; Sitagliptin Phosphate; Triazoles; Up-Regulation; Uracil

To investigate the associations of NOS1AP rs12742393 polymorphism with the risk of type 2 diabetes mellitus (T2DM) and repaglinide therapeutic efficacy in Chinese patients with T2DM.. Prospective case-control study.. Academic medical center.. A total of 300 patients with T2DM and 200 healthy volunteers were enrolled to identify NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay. Eighty-four patients with various genotypes were randomly selected to receive oral repaglinide as a single-agent therapy (3 mg/day) for 8 weeks.. Anthropometric measurements and fasting plasma glucose (FPG), postprandial plasma glucose, hemoglobin A1c , fasting serum insulin (FINS), postprandial serum insulin, homeostasis model assessment for insulin resistance (HOMA-IR), triglyceride, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol tests were obtained before and after repaglinide treatment. The risk C allelic frequency of NOS1AP rs12742393 was higher in patients with T2DM than in healthy volunteers (p<0.001). Patients with T2DM and genotypes AA and AC at NOS1AP rs12742393 had a significant reduction in FPG (mmol/l) compared with those with genotype CC (p<0.01). Patients with CC homozygotes and AC heterozygotes had a greater increase in FINS (mU/l) than those with wild-type AA (p<0.05). In addition, the carriers of genotype CC at NOS1AP rs12742393 had higher differential values of HOMA-IR compared with genotypes AC and AA carriers (p<0.001). The effects of repaglinide treatment on FPG (p<0.01), FINS (p<0.05) and HOMA-IR (p<0.001) were reduced in patients with T2DM carrying the NOS1AP rs12742393 risk C allele compared with the AA genotype carriers.. The NOS1AP rs12742393 polymorphism is associated with therapeutic efficacy of repaglinide in Chinese T2DM patients.

Topics: Adaptor Proteins, Signal Transducing; Adult; Alleles; Asian People; Blood Glucose; Carbamates; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prospective Studies

To evaluate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin plus metformin (A + M) initial combination therapy versus either as monotherapy in drug-naïve T2DM patients.. This international, randomized, double-blind, placebo-controlled, 26-week study involved T2DM patients with hyperglycaemia (HbA1c 7.5-10.0%) following diet/exercise therapy. Patients (N = 784) received placebo, alogliptin (A, 12.5 mg BID or 25 mg QD), metformin (M, 500 or 1000 mg BID) or A + M (12.5/500 or 12.5/1000 mg BID); placebo, A25 for secondary analyses only.. week 26 changes from baseline in HbA1c (primary), fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG); incidences of clinical response and hyperglycaemic rescue.. Week 26 mean HbA1c reductions from baseline (8.45%) were -1.22 and -1.55% with A + M 12.5/500 and 12.5/1000 versus -0.56, -0.65, and -1.11% with A12.5, M500 and M1000 (p<0.001, A + M vs. component monotherapies). FPG reductions were -1.76 and -2.55 mmol/L with 12.5/500 and 12.5/1000 versus -0.54, -0.64 and -1.78 mmol/L with A12.5, M500 and M1000 (p < 0.05, A + M vs. component monotherapies). Significantly more A + M-treated patients achieved HbA1c < 7% (47.1-59.5% vs. 20.2-34.3% with monotherapy), significantly fewer required hyperglycaemic rescue (2.6-12.3% vs. 10.8-22.9% with monotherapy). A + M caused only mild/moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2 kg).. Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil

Type 2 diabetes mellitus (T2DM) management requires continuous treatment intensification due to progressive decline in β-cell function in insulin resistant individuals. Initial combination therapy of a dipeptidyl peptidase (DPP)-4 inhibitor with a thiazolidinedione (TZD) may be rational. We assessed the effects of the DPP4 inhibitor alogliptin (ALO) combined with the TZD pioglitazone (PIO), vs ALO monotherapy or placebo (PBO), on β-cell function and glycemic control in T2DM.. A 16-week, two-center, randomized, double-blind, PBO-controlled, parallel-arm intervention study in 71 patients with well-controlled T2DM (age 59.1±6.3 years; A1C 6.7±0.1%) treated with metformin, sulfonylurea, or glinide monotherapy was conducted. Patients were treated with combined ALO 25 mg and PIO 30 mg daily or ALO 25 mg daily monotherapy or PBO. Main outcome measures included change in A1C and fasting plasma glucose (FPG) from baseline to week 16. In addition, change in β-cell function parameters obtained from standardized meal tests at baseline and at week 16 was measured.. ALO/PIO and ALO decreased A1C from baseline by 0.9±0.1 and 0.4±0.2% respectively (both P<0.001 vs PBO). FPG was decreased to a greater extent by ALO/PIO compared with ALO monotherapy (P<0.01). ALO/PIO treatment improved β-cell glucose sensitivity (vs PBO; P<0.001) and fasting secretory tone (vs PBO; P=0.001), while ALO monotherapy did not change β-cell function parameters. All treatments were well tolerated.. Short-term treatment with ALO/PIO or ALO improved glycemic control in well-controlled T2DM patients, but only combined ALO/PIO improved β-cell function. These data support that initial combination therapy with a DPP4 inhibitor and TZD to address multiple core defects in T2DM may be a sensible approach.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome; Uracil

We investigated the efficacy of once- and thrice-daily voglibose, an alpha-glucosidase inhibitor, as an add-on therapy to alogliptin, a dipeptidyl peptidase-4 inhibitor, on glycemic control in Japanese type 2 diabetic patients. In this 12-week, parallel-group, randomized, open-label, three-arm trial, 151 participants treated with alogliptin were randomly allocated to the following three arms; one was the group to initiate once-daily voglibose, another was to initiate thrice daily voglibose, and the other was the control group. The primary endpoint was the change of hemoglobin A1c levels at the end of the study, which was revealed to be significantly different among groups (p < 0.001). The once- and thrice-daily voglibose groups had a significantly greater reduction than the control group; the difference was -0.27% and -0.33% in the once- and thrice-daily voglibose group, respectively (both p < 0.001). No significant difference was observed between the two voglibose groups (p = 0.615). On the other hand, the increase of 1,5-anhydroglucitol levels were 3.3 and 5.5 μg/ml greater in the once- and thrice-daily voglibose groups than the control group (both p < 0.001). The thrice-daily voglibose group had a greater increase of 1,5- anhydroglucitol levels compared to the once-daily voglibose group (p = 0.005). In conclusion, once- and thrice-daily voglibose as an add-on to alogliptin significantly improved glycemic control in Japanese type 2 diabetic patients.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Male; Middle Aged; Piperidines; Treatment Outcome; Uracil

We aimed to compare the effect of repaglinide and metformin monotherapy as an initial therapy in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM).. In this 15-week, open-labelled, parallel-controlled, randomised study, 60 Chinese drug-naive patients with newly diagnosed T2DM were randomised (2:1) to receive repaglinide or metformin monotherapy. Primary endpoint was change in HbA1c from baseline to the end of the trial. Secondary endpoints included changes in glycaemic variability, insulin sensitivity and β-cell function.. Patients in both repaglinide and metformin groups achieved significant reductions in HbA1c (-1.8 ± 1.5 vs -1.6 ± 1.5%), FPG (fasting blood glucose) (-1.7 ± 1.7 vs -2.1 ± 1.7  mmol/l) and 2-h PPG (post-prandial glucose) (-3.8 ± 3.1 vs -3.8 ± 3.6  mmol/l), with no statistical differences between the groups. Glycaemic variability, glucose infusion rate and β-cell function were all significantly improved from baseline in the two groups (all P<0.05), without any statistical differences in the improvement between the groups.. Repaglinide and metformin achieved comparable efficacy in improving glycaemic control, reducing glycaemic variability, enhancing insulin sensitivity and ameliorating β-cell function. Therefore, repaglinide is an optional agent for initial therapy in Chinese patients with newly diagnosed T2DM.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Young Adult

This study was designed to compare the effects of metformin and repaglinide on the fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) in newly diagnosed type 2 diabetes in China.. A total of 107 newly diagnosed type 2 diabetic patients (46 women and 61 men) participated in the study. All patients received 3-month treatment of metformin or repaglinide. Fasting blood glucose and HbA1c were determined at baseline and at the end of the 3-month of treatment.. FPG and HbA1c decreased in both metformin and repaglinide groups after 3 months treatment (P < 0.01). The reduction of HbA1c was significantly greater in the repaglinide group (P < 0.01). Metformin decreases fasting insulin concentration and HOMA-IR (P < 0.01), and repaglinide improves HOMA-β(P < 0.01). Triglycerides (TG) were reduced in both groups (P < 0.01 in metformin group; P < 0.05 in repaglinide group), but total cholesterol (TC) and low-density lipoprotein (LDL) were decreased only after metformin treatment (P < 0.05).. Both repaglinide and metformin were effective in glycaemic control in new onset patients with type 2 diabetes in China. Repaglinide had no effect on insulin sensitivity, but it improved β-cell function.

Topics: Body Mass Index; Carbamates; China; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Drug Monitoring; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Overweight; Piperidines; Weight Loss

To compare the efficacy, safety and compliance of repaglinide, administered either two or three times daily, regarding glycaemic control in patients with type 2 diabetes mellitus.. Japanese adults with type 2 diabetes mellitus, who had been treated without sulphonylureas or glinides for >3 months, were randomly assigned to two groups to receive either 0.25 mg repaglinide, oral, twice daily (group A) or 0.25 mg repaglinide, oral, three times daily (group B). Glycosylated haemoglobin (HbA1c), glycoalbumin (GA) and 1,5-anhydroglucitol (1,5-AG) levels were measured at 0, 1, 2 and 3 months after treatment commenced.. Out of 43 patients who enrolled (group A, n = 22; group B, n = 21), 33 patients completed the trial (group A, n = 16; group B, n = 17). No significant between-group differences in HbA1c, GA, or 1,5-AG levels were seen at 1-3 months. No severe hypoglycaemic episodes or other adverse events were observed.. Minimal-dose repaglinide administered twice daily was similar in efficacy and safety to three-times-daily administration, in Japanese patients with type 2 diabetes mellitus. Administration of repaglinide twice daily could be an alternative regimen for patients who cannot take repaglinide three times daily.

Topics: Administration, Oral; Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Follow-Up Studies; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Prognosis

Topics: Administration, Oral; Angina, Unstable; Biomarkers; Diabetes Mellitus, Type 2; Double-Blind Method; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Myocardial Infarction; Piperidines; Practice Guidelines as Topic; Research Design; Risk Factors; Treatment Outcome; Uracil

To evaluate the long-term durability of the efficacy of alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin.. This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18-80 years to 104 weeks of treatment with metformin in addition to alogliptin 12.5 mg once daily (n = 880), alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks.. The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were -0.68%, -0.72% and -0.59% for alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were -0.68, -0.89 and 0.95 kg for alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the alogliptin 25 mg group and three in the glipizide group.. Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pancreatitis; Piperidines; Treatment Outcome; Uracil

The main purpose of the current study was to investigate the effect of a combination of alogliptin [a dipeptydil peptidase (DPP)-4 inhibitor] and lansoprazole [a proton pump inhibitor (PPI)] compared with alogliptin mono-therapy on glycemic control in patients with type 2 diabetes. This study was a multicenter randomized open-label study. One hundred type 2 diabetic patients were randomly assigned to either the alogliptin with lansoprazole group or the alogliptin mono-therapy group. After 3 months of treatment, the changes in hemoglobin (Hb)A1c, fasting plasma glucose (FPG), serum gastrin, homeostasis model assessment (HOMA)-β, and HOMA-insulin resistance (IR) were evaluated. A significant decrease in HbA1c and FPG, and a significant increase in HOMA-β were observed in both groups (all with P <0.0001). However, there were no significant differences in changes in HbA1c, FPG, or HOMA-β before and after therapy between the combination and alogliptin mono-therapy group (P =0.2945, P =0.1901, P =0.3042, respectively). There was a significant elevation of serum gastrin in the combination group compared with the alogliptin mono-therapy group (P =0.0004). This study showed that, although combination therapy with alogliptin and lansoprazole more effectively elevated serum gastrin levels compared with alogliptin mono-therapy, the effect of the combination therapy on glycemic control was equal to that of alogliptin mono-therapy during a 3-month study period.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Lansoprazole; Male; Middle Aged; Piperidines; Treatment Outcome; Uracil

To evaluate the efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes mellitus (T2DM) who are poorly controlled with insulin and diet or exercise.. This was a randomized, double-blind, 12-week comparative trial of alogliptin and insulin versus placebo and insulin in 179 patients with T2DM followed by a 40-week, open-label phase in 169 patients on alogliptin and insulin.. Change in glycated hemoglobin (HbA1c) from baseline to the end of double-blind phase (week 12).. The change in HbA1c (least squares means) from baseline to week 12 was -0.96% for the alogliptin and insulin group and -0.29% for the placebo and insulin group. The point estimate (95% confidence interval) intergroup difference was -0.66% ([-0.824%, -0.503%]). In the alogliptin and insulin group, HbA1c started to decrease from week 2 onward and peaked by week 12. The proportions of patients who achieved HbA1c < 8.0, < 7.0 and < 6.0% at week 12 were significantly higher in alogliptin and insulin group (73.0, 23.3 and 1.1%) than in placebo and insulin group (25.0, 5.7 and 0%). Incidences of adverse effects were comparable between groups, with no relevant increases in hypoglycemia or weight gain seen.. Alogliptin 25 mg/day was effective and well tolerated when added to insulin in Japanese patients with inadequately controlled T2DM.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Middle Aged; Piperidines; Placebo Effect; Uracil; Weight Gain

Patients with type 2 diabetes are at increased susceptibility to a prolonged QT interval. Furthermore, insulin secretagogues, drugs used to treat diabetes, may prolong QT interval and provoke arrhythmias. We evaluated whether secretagogues can affect QTc interval during cardiac stress test in 20 patients with type 2 diabetes treated with secretagogues. ECG stress test was performed in all patients. QTc interval was calculated both before cardiac stress test (BCST) and at acme of cardiac stress test (ACST). Diabetic patients treated with secretagogues showed longer QTc-ACST values than those treated with metformin only. QTc-ACST values resulted shorter than QTc-BCST values in control group. Diabetic patients treated with secretagogues showed QTc-ACST values significantly longer than QTc-BCST values. In our study, diabetic patients treated with secretagogues did not show the QTc physiologic decrease that is a protective against arrhythmias. These results suggest to evaluate, in these patients, QT length, even during routine cardiac stress test.

Topics: Aged; Arrhythmias, Cardiac; Carbamates; Diabetes Mellitus, Type 2; Electrocardiography; Exercise Test; Female; Glyburide; Heart Rate; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines

As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin.. We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke.. The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.. These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Proportional Hazards Models; Severity of Illness Index; Uracil

Endothelial dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes (T2DM). Glucagon like peptide-1 (GLP-1) reportedly exerts vasodilatory actions, and inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme-degrading GLP-1, are widely used to treat T2DM. We therefore hypothesized that DPP-4 inhibitors (DPP-4Is) improve endothelial function in T2DM patients and performed 2 prospective, randomized crossover trials to compare the DPP-4I sitagliptin and an α-glucosidase inhibitor, voglibose (in study 1) and the DPP-4Is sitagliptin and alogliptin (in study 2).. In study 1, 24 men with T2DM (46±5 years) were randomized to sitagliptin or voglibose for 6 weeks without washout periods. Surprisingly, sitagliptin significantly reduced flow-mediated vasodilatation (FMD; -51% compared with baseline, P<0.05) of the brachial artery despite improved diabetic status. In contrast, voglibose did not affect FMD. To confirm this result and determine whether it is a class effect, we conducted another trial (study 2) to compare sitagliptin and alogliptin in 42 T2DM patients (66±8 years) for 6 weeks with 4-week washout periods. Both DPP-4Is improved glycemic control but significantly attenuated FMD (7.2/4.3%, P<0.001, before/after sitagliptin; 7.0/4.8%, P<0.001, before/after alogliptin, respectively). Interestingly, FMD reduction was less evident in subjects who were on statins or whose LDL cholesterol levels were reduced by them, but this was not correlated with parameters including DPP-4 activity and GLP-1 levels or diabetic parameters.. Our 2 independent trials demonstrated that DPP-4 inhibition attenuated endothelial function as evaluated by FMD in T2DM patients. This unexpected unfavorable effect may be a class effect of DPP-4Is.. URL: http://center.umin.ac.jp, Unique Identifiers: UMIN000005682 (sitagliptin versus voglibose) and UMIN000005681 (sitagliptin versus alogliptin).

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cholesterol, LDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inositol; Japan; Linear Models; Male; Middle Aged; Piperidines; Prospective Studies; Pyrazines; Regional Blood Flow; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles; Uracil; Vasodilation

To prospectively evaluate the efficacy and safety of alogliptin versus glipizide in elderly patients with type 2 diabetes mellitus (T2DM) over 1 year of treatment.. This was a randomized, double-blind, active-controlled study of elderly T2DM patients (aged 65-90 years) with mild hyperglycaemia on diet/exercise therapy alone [glycosylated haemoglobin (HbA1c) 6.5-9.0%] or plus oral antidiabetic monotherapy (HbA1c 6.5-8.0%). Patients were randomized to once-daily alogliptin 25 mg or glipizide 5 mg titrated to 10 mg, if needed. Hypoglycaemic episodes were systematically captured under predefined criteria.. In the primary analysis, HbA1c mean changes from a baseline of 7.5% were -0.14% with alogliptin (n = 222) and -0.09% with glipizide (n = 219) at the end of the study, demonstrating non-inferiority of alogliptin to glipizide [least squares (LS) mean difference = -0.05%; one-sided 97.5% confidence interval (CI): -∞, 0.13%]. More clinically relevant HbA1c reductions occurred among patients who completed the study: -0.42 and -0.33% with alogliptin and glipizide, with non-inferiority again confirmed (LS mean difference = -0.09%; one-sided 97.5% CI: -∞, 0.07%). Overall, alogliptin was safe and well tolerated, with notably fewer hypoglycaemic episodes than glipizide [5.4% (31 episodes) vs. 26.0% (232 episodes), respectively]; three patients experienced severe hypoglycaemia, all with glipizide. Alogliptin also resulted in favourable weight changes versus glipizide (-0.62 vs. 0.60 kg at week 52; p < 0.001).. Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dizziness; Double-Blind Method; Female; Glipizide; Glycated Hemoglobin; Headache; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Piperidines; Prospective Studies; Treatment Outcome; Triglycerides; Uracil; Weight Gain

We investigated the effect of addition of alogliptin, while continuing the α-glucosidase inhibitor (αGI) administration at the same or reduced dose, or discontinuing the drug, on the glycemic control in type 2 diabetic patients showing inadequate response to αGI treatment.. A prospective, randomized, controlled, multicenter interventional study trial. Subjects were randomly assigned to treatment with alogliptin alone (Intake 0 group), or alogliptin in addition to an αGI administered once-/twice-/thrice-daily (Intake 1, 2 and 3 groups).. Changes in glycemic control were measured.. The HbA1c and glycoalbumin levels at 1 and 3 months were significantly lower than the values at the baseline in the Intake 1, 2 and 3 groups, but not the Intake 0 group. The body weight at 3 months was significantly lower than that at the baseline in the Intake 3 group. There were no significant differences in the degree of satisfaction or participating volition recorded, before and after the start of the study treatments.. Addition of alogliptin to once-/twice-daily administration of an αGI may be effective for obtaining improved glycemic control, without lowering the treatment satisfaction level, in type 2 diabetic patients.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Prospective Studies; Serum Albumin; Time Factors; Treatment Outcome; Uracil

To evaluate the long-term efficacy of monotherapy with the dipeptidase-4 inhibitor alogliptin benzoate in hemodialysis (HD) patients with type 2 diabetes.. Sixteen diabetic HD patients with inadequate glycemic control (hemoglobin A1c (HbA1c) level >6.5% and glycated albumin (GA) level >20%) on diet and exercise participated in the study. No patients were taking other oral antidiabetic drugs or receiving insulin therapy. Alogliptin 6.25 mg was administered to patients once daily. HbA1c, GA levels were obtained before and after 2 years of treatment. Body weight and active glucagon-like peptide-1, blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels were also examined before and after treatment.. Both HbA1c and GA levels decreased after starting alogliptin administration. As compared to the pretreatment levels, HbA1c and GA levels significantly decreased at 3 and 18 months, respectively, after starting alogliptin administration. HbA1c and GA levels decreased from 7.1 ± 0.2 to 5.8 ± 1.6% and from 22.5 ± 0.7 to 19.6 ± 0.6%, respectively, 24 months after beginning treatment. Glucagon-like peptide-1 levels (8.9 ± 5.7 pmol/l before treatment) doubled after treatment. Body weight and blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels did not change with treatment. Only one significant adverse effect, a drug-related rash, was seen in 1 patient.. Long-term (2-year) effects of alogliptin benzoate monotherapy suggest its efficacy as a new treatment strategy in diabetic HD patients.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemic Agents; Japan; Longitudinal Studies; Male; Middle Aged; Piperidines; Prevalence; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Uracil

To examine the effects of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes patients.. Sixty-one patients whose HbAlc  ≥ 6.1% (mean age 64.7 years; 67% men; mean HbAlc 7.4%; 57% were pharmacologically treated) underwent blood and urine sampling and analysis before and after 12 weeks of treatment with alogliptin (25 mg once daily).. Alogliptin treatment significantly reduced fasting glucose (160.3 mg/dL at baseline versus 138.0 mg/dL at 12 weeks), glycoalbumin (21.1% at baseline versus 18.9% at 12 weeks), HbAlc (7.4% at baseline versus 6.9% at 12 weeks), circulating soluble form of RAGE concentrations (847.3 pg/mL at baseline versus 791.4 pg/mL at 12 weeks) and urine albumin to creatinine ratio (31.6 mg/g Cr at baseline versus 26.5 mg/g Cr at 12 weeks), whereas 1,5-anhydroglucitol concentrations were significantly increased (7.5 µg/mL at baseline versus 11.6 µg/mL at 12 weeks; all P < 0.05). Circulating AGEs concentrations were reduced only in patients with baseline AGEs ≥7 U/mL (n = 33, from 8.2 U/mL to 7.2U /mL; p < 0.01) after alogliptin treatment. The treatment-induced change of soluble form of sRAGE concentrations was associated with changes of 1,5-anhydroglucitol and HbAlc concentrations (rho = -0.32 and 0.29, respectively). Meanwhile, the treatment-induced change of urine albumin to creatinine ratio was associated with a change in the fasting glucose concentration (rho = 0.25; all p < 0.05). During the intervention, alogliptin treatment was well tolerated without any hypoglycemia or side effects.. Alogliptin treatment improved the AGE-RAGE axis and reduced albuminuria in Japanese type 2 diabetes patients.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Piperidines; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Uracil

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.. We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.. A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.. Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Topics: Aged; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Piperidines; Uracil

To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone.. This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events.. A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced.. The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.

Topics: Adult; China; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Research Design; Treatment Outcome; Uracil

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

Topics: Acarbose; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Overweight; Piperidines; Uracil; Weight Gain

The potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. In this study, the efficacy and safety of alogliptin in type 2 diabetic patients undergoing hemodialysis (HD) were evaluated.. A prospective, open-label study of 30 patients (male/female: 24/6; mean age: 69.7 ± 1.7 years) with type 2 diabetes who were undergoing HD without insulin injection therapy was conducted. Patients were administered 6.25 mg/day alogliptin and efficacy and safety were determined by monitoring clinical and laboratory parameters during the 48-week study period.. After 48 weeks, alogliptin had decreased postprandial plasma glucose levels from 212 ± 8 mg/dL baseline to 156 ± 7 mg/dL, hemoglobin A1c levels from 7.1 ± 0.2% baseline to 6.3 ± 0.2% and glycated albumin (GA) levels from 25.6 ± 0.6% baseline to 20.7 ± 0.4% (all p < 0.0001). Alogliptin efficacy did not differ according to median age or body mass index, but the GA reduction was significantly greater in the antidiabetic agents-naïve group. The magnitude of GA reduction was baseline GA-dependent, being greater at higher baseline GA levels. No serious adverse effects, such as hypoglycemia or liver impairment, were observed in any patient.. Alogliptin as monotherapy or in combination with other oral antidiabetic agents improved glycemic control and was generally well tolerated in patients with HD over a 48-week period.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Male; Piperidines; Prospective Studies; Renal Dialysis; Serum Albumin; Uracil

Postprandial hyperlipidemia impairs endothelial function and participates in the development of atherosclerosis. We investigated the postprandial effects of a dipeptidyl peptidase IV inhibitor, alogliptin, on endothelial dysfunction and the lipid profile.. A randomized cross-over trial design in 10 healthy volunteers (8 males and 2 females, 35 ± 10 years) was performed. The postprandial effects before and after a 1-week treatment of 25 mg/day alogliptin on endothelial function were assessed with brachial artery flow-mediated dilation (FMD) and changing levels of lipids, apolipoprotein B48 (apoB-48), glucose, glucagon, insulin, and glucagon-like peptide-1 (GLP-1) during fasting and at 2, 4, 6, and 8 h after a standard meal loading test.. Alogliptin treatment significantly suppressed the postprandial elevation in serum triglyceride (incremental area under the curve [AUC]; 279 ± 31 vs. 182 ± 32 mg h/dl, p = 0.01), apoB-48 (incremental AUC; 15.4 ± 1.7 vs. 11.7 ± 1.1 μg h/ml, p = 0.04), and remnant lipoprotein cholesterol (RLP-C) (incremental AUC: 29.3 ± 3.2 vs. 17.6 ± 3.3 mg h/dl, p = 0.01). GLP-1 secretion was significantly increased after alogliptin treatment. Postprandial endothelial dysfunction (maximum decrease in%FMD, from -4.2 ± 0.5% to -2.6 ± 0.4%, p = 0.03) was significantly associated with the maximum change in apoB-48 (r = -0.46, p = 0.03) and RLP-C (r = -0.45, p = 0.04).. Alogliptin significantly improved postprandial endothelial dysfunction and postprandial lipemia, suggesting that alogliptin may be a promising anti-atherogenic agent.

Topics: Adult; Cross-Over Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Hyperlipidemias; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Postprandial Period; Uracil

Dipeptidyl peptidase-4 (DPP-4) inhibition is a well- characterized treatment for type 2 diabetes mellitus (T2DM). The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and drug and random effects for intertrial variability and residual error. The relationship between WAI and outcome was nonlinear, with an increasing response up to 98% WAI. Response to DPP-4 inhibitors could be described with a single drug effect. The WAI appears to be a useful index of DPP-4 inhibition related to HbA1c. Biomarker to response relationships informed by model-based meta-analysis can be leveraged to support study designs including optimization of dose, duration of therapy, and patient population.

Topics: Adamantane; Biomarkers; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Models, Biological; Nitriles; Piperidines; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Vildagliptin

Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal.. Seventy-one patients (age 18-70 years), who did not reach HbA(1c) 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0 mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo (n = 25), Alo/Pio (n = 22) or Pbo (n = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion.. At week 16, Alo (n = 25) and Alo/Pio (n = 21) vs Pbo (n = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p < 0.001), as well as in chylomicron TG (p < 0.001) and VLDL1 TG iAUCs (p < 0.001 and p = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p = 0.028), and a non-significant trend towards a decrease with Alo/Pio (p = 0.213). The incidence of adverse events was low and consistent with previous studies.. Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells.. ClinicalTrials.gov number NCT00655863.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Pioglitazone; Piperidines; Postprandial Period; Thiazolidinediones; Treatment Outcome; Uracil

The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naïve subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naïve patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles.

Topics: Adult; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Fat-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Hospitals, Municipal; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemia; Insulin Resistance; Japan; Male; Middle Aged; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Uracil; Weight Loss

We aimed to determine whether NeuroD1/BETA2 and PAX4 polymorphisms were associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetes mellitus (T2DM) patients.. Three hundred and sixty-eight T2DM patients and 132 healthy control subjects were genotyped by restriction fragment length polymorphism. Forty-three patients with various genotypes were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg day(-1)). Fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin, fasting and postprandial serum insulin (FINS, PINS), homeostasis model assessment for insulin resistance, serum triglyceride, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol were determined before and after repaglinide treatment.. The allelic frequency of NeuroD1/BETA2 T45 was higher in T2DM patients than in the control subjects [13.45 vs. 6.82%, P < 0.01, odds ratios = 2.342 (1.365, 4.019), P= 0.002]. Type 2 diabetes mellitus patients with the mutated allele of NeuroD1/BETA2 A45T polymorphism showed higher FINS (13.46 ± 12.57 vs. 10.04 ± 7.09 mU l(-1) , P < 0.05) (11.67, 14.83 vs. 8.38, 11.37) and PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than individuals with the T allele. The PAX4 R121W R allele carriers had higher PINS (52.11 ± 40.93 vs. 68.66 ± 43.87 mU l(-1), P < 0.05) (44.89, 58.35 vs. 55.35, 88.87) than subjects with the W allele. After repaglinide treatment, patients with the T allele of NeuroD1/BETA2 A45T polymorphisms had attenuated efficacy on fasting plasma glucose (-2.79 ± 2.14 vs.-0.99 ± 1.80 mmol l(-1), P < 0.01) (-3.53, -1.84 vs.-1.99, -0.13) and postprandial plasma glucose (-6.71 ± 5.90 vs.-2.54 ± 3.39 mmol l(-1), P < 0.01) (-9.28, -4.62 vs.-4.34, -0.84). Patients with the RR genotype of PAX4 R121W showed better efficacy with respect to the level of postprandial plasma glucose than R/W genotypes (-6.53 ± 6.52 vs.-2.95 ± 1.17 mmol l(-1), P < 0.05) (-8.20, -4.89 vs.-3.92, -1.20).. The NeuroD1/BETA2 and PAX4 polymorphisms were substantially associated with plasma glucose level after repaglinide monotherapy.

Topics: Adult; Aged; Alleles; Asian People; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Carbamates; Case-Control Studies; China; Diabetes Mellitus, Type 2; Female; Genotype; Homeodomain Proteins; Humans; Hypoglycemic Agents; Male; Middle Aged; Paired Box Transcription Factors; Piperidines; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length

Microcirculatory and endothelial dysfunction are signs of cardiovascular engagement in patients with type 2 diabetes. This study tested whether glucose normalisation may reverse this.. Thirty-nine T2DM patients (age 61±7 years, 58% females) with signs of mild diastolic dysfunction were randomised to strict glucose control based on insulin (I-group; n=21) or oral agents (O-group; n=18) for four months. Skin microcirculation was studied with laser Doppler fluxmetry and endothelial function with brachial artery flow-mediated dilatation.. Glucose control improved (reduction of HbA(1c) I-group = -0.5%; O-group -0.7%; p=0.69). Microcirculation improved in the entire group (n=39) determined by foot laser Doppler fluxmetry (32.2±13.6 vs. 35.3±13.1 perfusion units; p<0.001) and laser Doppler fluxmetry following heating (68.8±34.0 vs. 69.3±25.1 PU; p=0.007). Improvement was more consistent with oral agents than insulin. Endothelial function expressed as flow-mediated dilatation decreased in the I-group (6.0±2.2 to 4.7±3.0%; p=0.037) but remained unchanged in the O-group (4.8±2.3 to 5.0±3.7%; n.s.).. Glycaemic normalisation improved skin microcirculation but not endothelial function in patients with type 2 diabetes with mild cardiovascular engagement.

Topics: Administration, Oral; Aged; Biomarkers; Blood Glucose; Brachial Artery; Carbamates; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diastole; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Aspart; Insulin Glargine; Insulin, Long-Acting; Laser-Doppler Flowmetry; Male; Metformin; Microcirculation; Middle Aged; Piperidines; Prospective Studies; Regional Blood Flow; Skin; Sweden; Time Factors; Treatment Outcome; Vasodilation; Ventricular Dysfunction; Ventricular Function

The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment. The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA-IR values (P < 0.01) than those with the A allele. Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes. In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.

Topics: Adult; Asian People; Carbamates; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genotype; Humans; KCNQ1 Potassium Channel; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Risk Factors; Treatment Outcome

Optimal management of type 2 diabetes remains an elusive goal. Combination therapy addressing the core defects of impaired insulin secretion and insulin resistance shows promise in maintaining glycemic control.. The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients.. We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes.. The study consisted of 26-wk treatment with alogliptin (12.5 or 25 mg qd) alone or combined with pioglitazone (15, 30, or 45 mg qd) in 1554 patients on stable-dose metformin monotherapy (≥1500 mg) with inadequate glycemic control.. The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and β-cell function. Primary analyses compared pioglitazone therapy [all doses pooled, pioglitazone alone (Pio alone); n = 387] with alogliptin 12.5 mg plus any dose of pioglitazone (A12.5+P; n = 390) or alogliptin 25 mg plus any dose of pioglitazone (A25+P; n = 390).. When added to metformin, the least squares mean change (LSMΔ) from baseline HbA(1c) was -0.9 ± 0.05% in the Pio-alone group and -1.4 ± 0.05% in both the A12.5+P and A25+P groups (P < 0.001 for both comparisons). A12.5+P and A25+P produced greater reductions in fasting plasma glucose (LSMΔ = -2.5 ± 0.1 mmol/liter for both) than Pio alone (LSMΔ = -1.6 ± 0.1 mmol/liter; P < 0.001). A12.5+P and A25+P significantly improved measures of β-cell function (proinsulin:insulin and homeostasis model assessment of β-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSMΔ body weight was 1.8 ± 0.2, 1.9 ± 0.2, and 1.5 ± 0.2 kg in A12.5+P, A25+P, and Pio-alone groups, respectively. Hypoglycemia was reported by 1.0, 1.5, and 2.1% of patients in the A12.5+P, A25+P, and Pio-alone groups, respectively.. In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA(1c) by alogliptin and pioglitazone was additive. The decreases in HbA(1c) with A12.5+P and A25+P were similar. All treatments were well tolerated.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

To investigate a potential relationship between Solute carrier family 30 (zinc transporter) member 8 (SLC30A8) rs13266634 variant and efficacy of rosiglitazone or repaglinide in treating newly diagnosed Chinese type 2 diabetes patients.. A total of 209 diabetic patients without any antihyperglycemic history were recruited and treated with repaglinide or rosiglitazone randomly for 48 weeks (104 and 105 patients, respectively). Anthropometric measurements and clinical laboratory tests were carried out before and after the treatment. An non-synonymous variant rs13266634 was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectroscopy.. Ninety-one patients in repaglinide group and ninety-three patients in rosiglitazone group completed the study. Δ value of homeostasis model assessment of beta cell function (HOMA-B) and Δ value of fasting proinsulin levels were statistically significant between three genotype groups (P=0.0149 and 0.0246, respectively) after rosiglitazone treatment. However, no genotype association was observed in the repaglinide or rosiglitazone group with other parameters.. The SLC30A8 variant was associated with the efficacy of insulin sensitizer monotherapy on insulin secretion in patients with newly diagnosed type 2 diabetes mellitus in Shanghai, China.

Topics: Carbamates; Cation Transport Proteins; China; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Polymorphism, Single Nucleotide; Rosiglitazone; Thiazolidinediones; Zinc Transporter 8

To evaluate the efficacy and safety of alogliptin added to metformin versus metformin monotherapy in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on metformin (500 or 750 mg/day) + diet/exercise.. In a randomized, double-blind trial, 288 patients with type 2 diabetes mellitus T2DM received either 12.5 or 25 mg alogliptin once daily + metformin or placebo + metformin for 12 weeks. Thereafter, 276 patients continued on one of the two alogliptin dosages + metformin in an open-label extension for 40 weeks. The primary efficacy endpoint in the randomized, double-blind phase was the change in HbA1c from baseline (week 0) to the end of treatment (week 12). The primary endpoint during the long-term extension phase was adverse events.. After 12 weeks both dosages of alogliptin + metformin produced significantly greater changes from baseline in HbA1c than placebo (metformin monotherapy: with changes in LS means - 0.55 and - 0.64% vs. 0.22%, respectively; p < 0.0001). Incidences of adverse effects were comparable between groups, with no increases in hypoglycaemia. Over 52 weeks, there were no safety or tolerability concerns with alogliptin when added to metformin.. Alogliptin 12.5 and 25 mg once daily was safe and effective when added to metformin (500 or 750 mg/day) in Japanese patients with inadequately controlled type 2 diabetes on metformin alone.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Medication Adherence; Metformin; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome; Uracil

studies in younger patients with diabetes have shown that insulin profiles are more physiologic and postprandial glucose levels are lower with repaglinide than with glyburide. We conducted this study to determine if the differences in insulin/glucose profiles between repaglinide and glyburide were similar or different in the elderly.. thirteen elderly patients with diabetes were given glyburide or repaglinide in randomized crossover design, followed by a meal tolerance test. Samples were taken at regular intervals to measure glucose and insulin values.. the 0-30 min area under the curve (AUC) for insulin was higher (glyburide, 294  ±  37 pM; repaglinide, 382  ±  39 pM) (P < 0.01), and the 180-240 min AUC for insulin was lower (glyburide, 325  ±  50 pM; repaglinide, 196 ± 20 pM) (P < 0.01) with repaglinide. The 0-240 min AUC for glucose was not different between treatments (glyburide, 7.4 ±  0.5 mM; repaglinide, 7.1 ±  0.3 mM) (P = not significant). Five subjects treated with glyburide and no subjects treated with repaglinide required glucose from 180 to 240 min (P < 0.05, Fisher's exact test).. we conclude that repaglinide results in a more physiologic insulin profile and less frequent hypoglycemia than glyburide in the elderly.

Topics: Aged; Area Under Curve; Blood Glucose; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin; Male; Piperidines; Postprandial Period

Metformin has been reported to reduce α-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of α-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the α-dicarbonyl 3-deoxyglucosone (3DG).. We conducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions.. 3DG levels decreased after both metformin (-19.3% (95% confidence interval (CI): -23.5, -14.8)) and repaglinide (-20.8% (95% CI: -24.9, -16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: -3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per s.d. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per s.d. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per s.d. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per s.d. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per s.d. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers.. Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.

Topics: Carbamates; Confidence Intervals; Deoxyglucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Piperidines

The aim of this study was to explore the impact of KCNQ1 variants on the responses to oral antidiabetic drugs in a Chinese study population. A 48-week randomized pharmacogenetics study compared the effects of repaglinide and rosiglitazone in 209 newly diagnosed patients with type 2 diabetes. In the repaglinide cohort, individuals who were rs2237892 TT homozygotes exhibited lower 2-h glucose levels and significantly higher cumulative attainment rates of target 2-h glucose levels (P(log-rank) = 0.0383) than the C allele carriers; patients with a greater number of rs2237892 C alleles showed larger augmentations in both fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.0166 and 0.0026, respectively); moreover, the rs2237895 C allele was also associated with greater increments in both fasting insulin and HOMA-IR (P = 0.0274 and 0.0259, respectively). In contrast, only an association between rs2237897 and decrease in 2-h glucose levels was detected in the rosiglitazone cohort (P = 0.0321). Our results indicated that KCNQ1 polymorphisms are associated with repaglinide efficacy, and might also be associated with rosiglitazone response, in Chinese patients with type 2 diabetes.

Topics: Administration, Oral; Adult; Alleles; Asian People; Blood Glucose; Carbamates; China; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; KCNQ1 Potassium Channel; Male; Middle Aged; Pharmacogenetics; Piperidines; Polymorphism, Single Nucleotide; Rosiglitazone; Thiazolidinediones

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Early Termination of Clinical Trials; Female; Humans; Male; Middle Aged; Obesity; Overweight; Patient Dropouts; Piperidines; Purines; Receptor, Cannabinoid, CB1; Secondary Prevention; Weight Loss; Young Adult

Both repaglinide and gliclazide are insulin secretagogues widely used in the treatment of type 2 diabetes. They stimulate insulin secretion through distinct mechanisms and may benefit patients from different aspects. The present study was to evaluate the effects of repaglinide or gliclazide on glycaemic control, insulin secretion, and lipid profiles in type 2 diabetes patients.. A total of 47 newly diagnosed type 2 diabetes patients were randomized 1:1 to receive a 4-week treatment with repaglinide or gliclazide. The standard mixed meal tolerance test was performed before and after the treatment. Plasma glucose (PG), insulin concentration, and lipid profiles were measured. The area under insulin concentration curve (AUC(ins)) and the early-phase insulin secretion index (ΔI(30)/ΔG(30)) were calculated.. After the trial, fasting and postprandial PG and postprandial insulin improved significantly in both groups (P < 0.05). The maximum insulin concentration occurred earlier in the repaglinide group than that in the gliclazide group. AUC(ins) increased in both groups (P < 0.05), but no significant difference was found between groups. ΔI(30)/ΔG(30) increased in both groups (P < 0.05), especially in the repaglinide group (P < 0.05). Triglyceride and total cholesterol decreased significantly in the repaglinide group in some time points, while no significant change was observed in the gliclazide group.. Repaglinide and gliclazide had similar effects on glycaemic control and total insulin secretion, while repaglinide had more effects on improvements in β-cell function and lipid metabolism.

Topics: Adult; Blood Glucose; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Fasting; Female; Gliclazide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines; Postprandial Period; Treatment Outcome; Triglycerides

To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise.. Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of 6.9-10.4% were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone).. The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs. -0.19%; p < 0.0001). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor.. Once-daily alogliptin was effective and generally well tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks.

Topics: Asian People; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diet; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Exercise; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome; Uracil

To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone.. In this randomized, double-blind, active-controlled, parallel-group study, patients with type 2 diabetes and A1c ≥7.0 and ≤10.0% on metformin (≥1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52.. Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, -0.70 vs. -0.29%; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c ≤7.0 (33.2 vs. 21.3%) and ≤6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs. -0.2 mmol/L; p < 0.001); and greater improvements in measures of β-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments.. Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially improved β-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Maximum Tolerated Dose; Metformin; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome; Uracil

The aim of this research is to determine efficacy and safety of repaglinide alone and in combination with metformin in Chinese subjects with type 2 diabetes naive to oral antidiabetes therapy.. A 16-week, open-label, randomized, active-controlled, parallel-group trial was carried out. Subjects were randomized (1:1) to repaglinide 1 mg t.i.d. (maximum dose, 4 mg t.i.d.) or repaglinide plus metformin 1 mg/500 mg t.i.d. (maximum dose, 4 mg/500 mg t.i.d.). Eligible subjects (18 - 75 years old) had type 2 diabetes, A1C > 8.5%, BMI ≤ 35 kg/m(2), and were naive to oral antidiabetes agents.. The primary outcome was A1C reduction. Secondary end points included fasting plasma glucose (FPG), 2-h postprandial glucose (PPG), and 7-point plasma glucose. Baseline characteristics (repaglinide/metformin, n = 218; repaglinide-only, n = 214) were similar between groups. Mean A1C reduction (± SD) was 4.51 ± 1.64% (combination) and 4.05 ± 1.59% (monotherapy). Estimated mean treatment difference for repaglinide/metformin versus repaglinide-only was -0.30% (95% CI -0.49 to -0.11; p < 0.01). Combination treatment demonstrated significant improvements versus monotherapy in FPG, 7-point plasma glucose, and lunchtime and dinnertime 2-h PPG (all p < 0.05). Hypoglycemia rates were 2.04 (combination) versus 1.35 (monotherapy) events/subject-year (p = 0.058). Adverse events were comparable between groups.. Repaglinide plus metformin and repaglinide alone provided significant improvements in glycemic control and were well tolerated in Chinese patients naive to treatment with oral antidiabetes agents. Combination therapy with repaglinide plus metformin showed superiority to repaglinide monotherapy in this population. Limitations of this study are that subjects were newly diagnosed and had high mean baseline A1C, which may affect generalizability of results.

Topics: Adolescent; Adult; Aged; Blood Glucose; Carbamates; China; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Young Adult

To compare the efficacy and safety of different dosages of alogliptin with that of placebo and voglibose in drug-naïve Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.. In the double-blind, placebo-controlled phase of this two-part study, 480 patients aged ≥20 years with type 2 diabetes mellitus (HbA1c ≥6.9% to <10.4%) were randomized to monotherapy with alogliptin 6.25, 12.5, 25 or 50 mg once daily, placebo, or voglibose 0.2 mg three times daily for a period of 12 weeks. In a subsequent open-label, long-term extension phase, patients continued on the same treatment for an additional 40 weeks (patients in the placebo group were reassigned equally to one of the four alogliptin dosages).. The primary efficacy endpoint was the change in HbA1c from the baseline value at week 12 of treatment. Safety endpoints were the occurrence of adverse events, vital sign measurements, physical examination and ECG findings, and laboratory test results recorded over the entire 52-week period.. HbA1c was dose-dependently reduced by alogliptin, and the changes versus baseline were statistically significant with all four dosages in comparison with both placebo and voglibose. In addition, changes in fasting plasma glucose and postprandial plasma glucose AUC(0-2h) values were significantly greater with all four dosages of alogliptin in comparison with placebo. The incidence of adverse events with alogliptin over 52 weeks was not dose-dependent and was lower than with voglibose. Hypoglycemia occurred infrequently and was generally rated as mild. Changes in body weight with alogliptin were minimal (<0.5 kg) and not clinically meaningful.. Alogliptin was well tolerated and dose-dependently improved glycemic parameters in patients with type 2 diabetes inadequately controlled on diet and exercise.

Topics: Aged; Algorithms; Asian People; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Placebos; Time Factors; Treatment Outcome; Uracil

To examine the effects of glibenclamide and repaglinide on glucose stimulated insulin release, incretins, oxidative stress and cell adhesion molecules in patients with type 2 diabetes suboptimally treated with metformin.. A randomized clinical trial was performed recruiting 27 subjects (HbA(1c) between 7.5 and 10.5%) free from cardiovascular and renal disease. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), total antioxidant status, F(2)-isoprostane, interleukin-6 and cell adhesion molecules were measured during an oral glucose load at baseline and after eight weeks of treatment. The areas under the curve were analysed at 45, 60 and 120 min (AUC(45), AUC(60), AUC(120)).. Significant improvements in glucose were observed with repaglinide (HBA(1c): -1.5%, fasting glucose: -2.8 mmol/L, 2-h glucose: -3.7 mmol/L, AUC(120): -18.9%) and glibenclamide (-1.0%, -2.2 mmol/L, -2.5 mmol/L, -17.5%). Repaglinide was also associated with an increase in the AUC(60) and AUC(120) for insulin (+56%, +61%) and C-peptide (+41%, +36%). GLP-1, GIP, IL-6, ICAM-1 and E-selectin levels did not change in either group. No association was observed between GLP-1, GIP-1 and plasma markers of oxidative stress.. Repaglinide is associated with improved postprandial glycaemic control via insulin and C-peptide release. We observed no direct effects of glibenclamide or repaglinide on plasma levels of GLP-1 or GIP. We observed no associations of GLP-1 and GIP with plasma markers of oxidative stress.

Topics: Adult; Aged; Analysis of Variance; Biomarkers; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; E-Selectin; F2-Isoprostanes; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Metformin; Middle Aged; Oxidative Stress; Piperidines; Postprandial Period; Time Factors; Treatment Outcome; Wales

Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Treatment Outcome; Uracil

To compare the efficacy and safety of alogliptin and placebo as add-on therapy in Japanese patients with type 2 diabetes who experienced inadequate glycemic control on voglibose plus diet/exercise therapy.. During an 8 week screening phase, patients aged ≥ 20 years were stabilized on voglibose 0.2 mg three times daily plus diet/exercise therapy. Those with HbA1c between ≥ 6.9% and <10.4% were randomly assigned to 12 weeks' double-blind treatment with once daily alogliptin 12.5 or 25 mg, or placebo. The primary endpoint was the change in HbA1c at 12 weeks from baseline. Patients then entered an open-label, 40 week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25 mg).. www.clinicaltrials.gov ; pivotal trial NCT01263483; Long term trial NCT01263509.. Least square mean change in HbA1c after 12 weeks' therapy from baseline (primary endpoint) was significantly greater in the alogliptin 12.5 mg (-0.96%; P < 0.0001) and 25 mg (-0.93%; P < 0.0001) groups compared with placebo (+0.06%). This was associated with statistically significant improvements in other measures of glycemic control, in particular sustained reductions in fasting plasma glucose and postprandial plasma glucose. These benefits were maintained for the duration of the 1 year study and, importantly, they were achieved without detrimental effects on tolerability/safety. In particular, there was no increase in the rate of hypoglycemia and almost no changes in mean body weight.. Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled type 2 diabetes produced clinically significant improvements in glycemic control, and was well tolerated.

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Male; Middle Aged; Piperidines; Time Factors; Uracil

OBJECTIVE To examine the efficacy and safety of rimonabant, a selective cannabinoid receptor type-1 antagonist, in patients with type 2 diabetes receiving insulin monotherapy. RESEARCH DESIGN AND METHODS Patients (n = 368; A1C > or =7%) were randomized to 20 mg/day rimonabant or placebo in this 48-week, double-blind, placebo-controlled multicenter trial. Change in baseline A1C to week 48 (primary outcome) and changes in body weight, waist circumference, and lipid levels (secondary outcomes) were assessed. RESULTS Rimonabant significantly reduced baseline A1C versus placebo (-0.89 vs. -0.24%; P < 0.0001), and significantly greater improvements were observed in cardiometabolic risk factors. More rimonabant patients achieved >10% reduction in mean total daily insulin dose versus placebo (P = 0.0012), and fewer required rescue medication (P < 0.0001). Hypoglycemia, nausea, dizziness, anxiety, and depression were more frequent with rimonabant. CONCLUSIONS Rimonabant improved glycemic control and cardiometabolic risk factors in patients with type 2 diabetes receiving insulin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Obesity Agents; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Hormone Antagonists; Humans; Insulin; Middle Aged; Obesity; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Young Adult

This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8-week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.

Topics: Adult; Alleles; Amino Acid Substitution; Asian People; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Glutamic Acid; Humans; Lysine; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Risk Factors; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Treatment Outcome

To compare effects of three different insulin secretagogues on early-phase insulin secretion, metabolism of glucose and lipids, and lipid peroxidation in newly diagnosed Type 2 Diabetes Mellitus (T2DM).. Totally 60 newly diagnosed T2DM outpatients were randomized to three groups with 1-month monotherapy of repaglinide (Rg), glimepiride (Gm) or gliclazide MR (Gli), respectively. Some indexes of early-phase insulin secretion, glucose, lipids, and lipid peroxidation were inspected.. Fasting plasma glucose (FPG), glycosylated hemoglobin (HbA(1c)) and fructosamine (FA) were improved in all groups similarly (p>0.05). Rg group was with the highest early-phase insulin secretion index (DeltaI30/DeltaG30) (p=0.026), lower mean amplitude of glycaemic excursion (MAGE) (p<0.05), lowest mean peak value of post-lunch glucose (p=0.043), and lowest postprandial triglyceride (TG) (p=0.039). Postprandial free fatty acid (FFA) was lower after Rg and Gli treatment (p<0.05). Serum 8-iso prostaglandin F(2alpha) (8-iso PGF(2alpha)) was improved in all groups, but the improvement showed statistically significant only in Rg group (p=0.04).. Rg, Gm and Gli can all decrease blood glucose effectively in newly diagnosed T2DM patients, while Rg performs outstandingly in the aspects of improving early-phase insulin secretion, glucose excursion, postprandial lipids and 8-iso PGF(2alpha).

Topics: Adult; Aged; Analysis of Variance; Blood Glucose; Carbamates; Chi-Square Distribution; Diabetes Mellitus, Type 2; Female; Fructosamine; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Lipids; Male; Middle Aged; Oxidative Stress; Piperidines; Postprandial Period; Sulfonylurea Compounds; Treatment Outcome

A progressive weight gain is associated with various pharmacological options improving glycemic control in type 2 diabetes mellitus (T2DM). Ghrelin has been implicated in the regulation of feeding behavior and energy balance in humans. Based on evidence that functional ATP-sensitive channels are present in ghrelin-producing cells, we hypothesized that meglitinides may affect circulating ghrelin levels in subjects with type 2 diabetes.. In a single-blinded randomized three-period crossover study (n = 20), repaglinide or nateglinide was given in combination with metformin for two treatment periods over a 1-week period, respectively, separated by a 1-week treatment with placebo. Liquid meal challenge tests (LMCTs) with single preprandial doses of repaglinide (2 mg), nateglinide (120 mg), or placebo were performed at the end of each treatment period. Ten control subjects without diabetes underwent a single LMCT without any medication.. Fasting ghrelin concentrations were not different between all treatments and between patients with diabetes and control subjects. Subjects with T2DM treated with placebo showed no suppression of ghrelin in the LMCT. After administration of meglitinides a nadir of serum ghrelin was observed at 60 min (8.6% of baseline [P = 0.038] for repaglinide and 7.5% of baseline [P = 0.081] for nateglinide), which was similar to the secretion pattern seen in control subjects. No correlations between postprandial insulin or glucose levels and circulating ghrelin concentrations were observed.. Treatment with meglitinides reconstructed postprandial ghrelin secretion patterns to those of controls without diabetes. This observation may help to improve the control of feeding behavior in patients with T2DM.

Topics: Adult; Aged; Benzamides; Blood Glucose; Body Mass Index; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Feeding Behavior; Ghrelin; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Piperidines; Reference Values; Single-Blind Method

The traditional sulfonylureas with long half-lives have sustained stimulatory effects on insulin secretion compared to the short-acting insulin secretagogue. In this study, we used the frequently sampled intravenous glucose tolerance test (FSIGT) to evaluate the insulin sensitivity (IS), glucose sensitivity (SG), and acute insulin response after glucose load (AIRg) after 4 months treatment with either gliclazide or repaglinide. The design of study was randomizedcrossover. We enrolled 20 patients with new-onset type 2 diabetes (mean age, 49.3 years). Totally three FSIGTs were performed, one before and one after each of the two treatment periods as aforementioned. No significant differences in fasting plasma glucose, insulin, body mass index, blood pressure, glycated hemoglobin, or lipids were noted between the two treatments. After the repaglinide treatment, higher AIRg, lower IS, and lower SG were noted, but they did not reach statistical significance. The disposal index (DI) was also not significantly different between the two treatments. In conclusion, since non-significantly higher DI, AIRg, lower IS and SG were noted after repaglinide treatment, it might be a better treatment for diabetes, relative to gliclazide.

Topics: Adult; Blood Glucose; Blood Pressure; Body Mass Index; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gliclazide; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Piperidines; Time Factors; Treatment Outcome

To assess the efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naïve type 2 diabetic patients.. This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25+P30) versus each monotherapy.. Combination therapy with A25+P30 resulted in greater reductions in A1C (-1.7±0.1% from an 8.8% mean baseline) vs. A25 (-1.0±0.1%, P<0.001) or P30 (-1.2±0.1%, P<0.001) and in fasting plasma glucose (-2.8±0.2 mmol/l) vs. A25 (-1.4±0.2 mmol/l, P<0.001) or P30 (-2.1±0.2 mmol/l, P=0.006). The A25+P30 safety profile was consistent with those of its component monotherapies.. Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome; Uracil

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

Topics: Aged; Apolipoproteins; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Aspart; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Lipids; Lipoproteins; Male; Middle Aged; Piperidines; Proinsulin

To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy.. After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings].. The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively.. In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Uracil; Young Adult

To evaluate the efficacy and safety of alogliptin, a new dipeptidyl peptidase-4 inhibitor, for 26 weeks at once-daily doses of 12.5 and 25 mg in combination with metformin in patients whose HbA(1c) levels were inadequately controlled on metformin alone.. Patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 7.0-10.0%) were randomised to continue a stable daily metformin dose regimen (> or = 1500 mg) plus the addition of placebo (n = 104) or alogliptin at once-daily doses of 12.5 (n = 213) or 25 mg (n = 210). HbA(1c), insulin, proinsulin, C-peptide and fasting plasma glucose (FPG) concentrations were determined over a period of 26 weeks.. Alogliptin at either dose produced least squares mean (SE) decreases from baseline in HbA(1c) of -0.6 (0.1)% and in FPG of -17.0 (2.5) mg/dl [-1.0 (0.1) mmol/l], decreases that were significantly (p < 0.001) greater than those observed with placebo. The between treatment differences (alogliptin - placebo) in FPG reached statistical significance (p < 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events (AEs) observed with alogliptin were not substantially different from those observed with placebo. This includes low event rates for gastrointestinal side effects and hypoglycaemic episodes. There was no dose-related pattern of AE reporting between alogliptin groups and few serious AEs were reported.. Alogliptin is an effective and safe treatment for type 2 diabetes when added to metformin for patients not sufficiently controlled on metformin monotherapy.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil

The purpose of this study is to evaluate efficacy and safety of nateglinide tablet administration in comparison with those of repaglinide tablet as control on treating type 2 diabetes mellitus in China. Pooled-analysis with analysis of covariance (ANCOVA) method was applied to assess the efficacy and safety based on original data collected from four independent randomized clinical trials with similar research protocols. However meta-analysis was applied based on the outcomes of the four studies. The results by meta-analysis were comparable to those obtained by pooled-analysis. The means of HbA(1c), and fasting blood glucose in both the nateglinide and repaglinide groups were reduced significantly after 12 weeks duration but no statistical differences in reduction between the two groups. The adverse reaction rates were 9.89 and 6.51% in the nateglinide and repaglinide groups respectively, with the rate difference showing no statistical significance, and the Odds Ratio of adverse reaction rate (95% confidence interval) was 1.59 (0.99, 2.55). Both nateglinide and repaglinide administration have similarly significant effects on reducing HbA(1c) and FBG. However, the adverse reaction rate in the nateglinide group is higher than that in the latter using repaglinide but no statistical significance difference as revealed in the four clinical trials detailed below.

Topics: Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

To compare the metabolic effects of acarbose and repaglinide in type 2 diabetic patients who are being treated with a sulphonylurea-metformin combination therapy. The primary endpoint of the study was to evaluate which add-on treatment between acarbose and repaglinide is more efficacious in reducing PPG. The second endpoint was to evaluate which of these two treatment is more efficacious in the global management of glucose homeostasis in the enrolled patients.. After a 4-week run-in period with a sulphonylurea-metformin combination, 103 patients were randomised to receive in addition either repaglinide, up to 6 mg/day (2 mg three times a day) or acarbose, up to 300 mg/day (100 mg three times a day) with forced titration (independently of their glycaemic control, unless side-effects developed due to the drug dosage) for 15 weeks. The treatment was then crossed-over for further 12 weeks until the 27th week. We assessed body mass index (BMI), glycosylated haemoglobin (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostatic model assessment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (Tg), at baseline and at 1, 2, 15 and 27 weeks of treatment.. Seven patients did not complete the study, comprising one patient who was lost to follow-up and a further six through side-effects (two in week 1, one in week 15 and three after cross-over) Side-effects were classified as nausea (one in acarbose group), gastrointestinal events (four in acarbose group), and hypoglycaemia (one in repaglinide group). After 15 weeks of therapy, the repaglinide-treated patients experienced a significant decrease in HbA(1c) (-1.1%, p < 0.05), FPG (-9.5%, p < 0.05), and PPG (-14.9%, p < 0.05), when compared to the baseline values. However, the same treatment was associated with a significant increase in body weight (+2.3%, p < 0.05), BMI (+3.3%, p < 0.05) and FPI (+22.5%, p < 0.05); The increase was reversed during the cross-over phase. After 15 weeks of therapy, the acarbose-treated patients experienced a significant decrease in body weight (-1.9%, p < 0.05), BMI (-4.1%, p < 0.05), HbA(1c) (-1.4%, p < 0.05), FPG (-10.7%, p < 0.05), PPG (-16.2%, p < 0.05), FPI (-16.1%, p < 0.05), PPI (-26.9%, p < 0.05), HOMA index (-30.1%, p < 0.05), when compared to the baseline values. All these changes were reversed during the cross-over study phase, except those relating to HbA(1c), FPG and PPG. The only changes that significantly differed when directly comparing acarbose- and repaglinide-treated patients were those relating to FPI (-16.1% vs. +22.5%, respectively, p < 0.05) and HOMA index (-30.1% vs. +2.7%, p < 0.05).. In addition from having a similar effect to repaglinide on PPG, acarbose appeared to have a more comprehensive positive effect on glucose metabolism compared to repaglinide in this relatively small sample of type 2 diabetic patients when used as add-on therapy to sulphonylureas and metformin.

Topics: Acarbose; Administration, Oral; Adult; Blood Glucose; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sulfonylurea Compounds

Combinations of insulin and oral antidiabetic drugs (OAD) are often prescribed instead of insulin alone. In this study, the effects of insulin glargine (IG) in combination with repaglinide or acarbose on glycemic parameters were investigated. Obese Type 2 diabetic patients with fasting blood glucose (FBG) levels >or= 7.7 mmol/l [corrected] and hemoglobin glycated (A1C) >or=9% under maximal OAD combination therapy were enrolled. Previous therapies were discontinued, and patients were randomized into 2 groups. The combinations of IG and repaglinide were administered to group 1, and of IG and acarbose to group 2 for 13 weeks. Twenty patients in group 1 and 18 patients in group 2 completed the study. A1C levels were significantly decreased from 10.9+/-1.4% to 7.7+/-1.1% in group 1 and 11.0+/-1.4% to 8.1+/-1.4% in group 2. FBG levels were significantly decreased from 11.9+/-2.7 to 7.1+/-2.3 mmol/l in group 1 and 11.1+/-2.5 to 6.8+/-1.4 mmol/l in group 2. Post-prandial glucose levels were significantly decreased from 15.3+/-3.8 to 10.3+/-3.0 mmol/l in group 1 and 14.0+/-3.1 to 8.9+/-2.2 mmol/l in group 2. Intergroup comparisons indicated no significant differences. More weight gain was detected in group 1, compared to the baseline. Symptomatic hypoglycemia incidence was similar in both groups. Severe hypoglycemic attacks were seen in two patients in group 1. Flatulence incidence was higher in acarbose group. Conclusively, repaglinide and acarbose were equally effective when combined with IG for obese Type 2 diabetic patients controlled inadequately with OAD alone. Furthermore, acarbose seems to have advantages over repaglinide concerning weight gain and severe hypoglycemic attacks.

Topics: Acarbose; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Obesity; Piperidines; Weight Gain

To assess the use of a new repaglinide/metformin fixed-dose combination (FDC) tablet for the treatment of type 2 diabetes.. In this 26-week, multicentre, open-label, parallel-group trial, subjects poorly controlled with mono- or dual-oral antidiabetic therapy were randomized 1 : 1 : 1 to receive a repaglinide/metformin FDC tablet either two times daily (BID) or three times daily (TID) or a rosiglitazone/metformin FDC tablet BID. The primary objective comprised two hypotheses tested in a hierarchical order: (i) that treatment with the repaglinide/metformin FDC BID is non-inferior to that of a rosiglitazone/metformin FDC tablet BID as measured by changes in haemoglobin A1c (HbA1c) (results presented here) and (ii) if true, that treatment with the repaglinide/metformin FDC BID was non-inferior to that of the repaglinide/metformin FDC TID as measured by changes in HbA1c (results presented in a companion paper). Additional efficacy and safety end-points were also assessed.. Of the 561 subjects randomized, 383 completed the study. Reductions in HbA1c values became apparent at earlier times for repaglinide/metformin FDC BID treatment than rosiglitazone/metformin FDC BID, and final changes in HbA1c were not significantly different between treatment arms (p = 0.8186); thus, the predefined statistical criterion for non-inferiority was met. Overall adverse event profiles were comparable between treatment groups, and no major hypoglycaemic episodes were reported during the study.. The repaglinide/metformin FDC BID regimen showed efficacy that was non-inferior to that of the rosiglitazone/metformin FDC BID regimen currently in clinical use and a more rapid reduction of HbA1c values. Thus, repaglinide/metformin FDC BID is a clinically feasible alternative to rosiglitazone/metformin FDC BID.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Patient Satisfaction; Piperidines; Rosiglitazone; Tablets; Thiazolidinediones; Young Adult

To assess the efficacy and safety of a new repaglinide/metformin fixed-dose combination (FDC) tablet administered either twice a day (BID) or three times a day (TID) for the management of type 2 diabetes.. This was a 26-week, multicentre, open-label parallel trial in which subjects poorly controlled with mono- or dual-oral antidiabetic therapy were randomized 1 : 1 : 1 to instead receive repaglinide/metformin FDC either BID or TID or a rosiglitazone/metformin FDC BID. Two primary hypotheses were tested in a hierarchical manner: (i) treatment with the repaglinide/metformin FDC BID is non-inferior to that of the rosiglitazone/metformin FDC BID as measured by changes in haemoglobin A1c (HbA1c) (results presented in companion paper) and (ii) repaglinide/metformin BID is non-inferior to repaglinide/metformin TID (as measured by changes in HbA1c). Additional efficacy and safety end-points were also assessed.. A total of 561 subjects were randomized; 383 completed the study. Repaglinide/metformin FDC BID was non-inferior to repaglinide/metformin FDC TID with respect to HbA1c. Additionally, changes in mean fasting plasma glucose values from baseline to end of study were not significantly different between the BID and the TID dose groups. There were no major hypoglycaemic episodes reported in either group during the trial, and overall adverse event profiles were similar.. The efficacy of twice-daily dosing of a repaglinide/metformin FDC tablet was non-inferior to that of three-times-daily dosing.

Topics: Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Patient Satisfaction; Piperidines; Tablets; Young Adult

An impaired early phase of insulin secretion in the type 2 diabetes mellitus (DM) is very important for the postprandial hyperglycemia. The aim of the study was to compare the efficacy of metformin/repaglinid and metformin/glimepirid regimes in type 2 diabetics uncontrolled with metformin monotherapy.. Totally, 60 type 2 diabetics with haemoglobin A1c > or = 7.5% and 2000 mg of metformin monotherapy for at least three months were divided in the following groups: A-30 patients with metformin+repaglinid (2 mg for each meal) and B metformin+glimepirid (3 mg in the morning). Assessment of the regimes efficacy comprised of haemoglobin A1c, fasting blood glucose (FBG) and postprandial blood glucose (PBG). Assessment of the safety was performed on the basis of recorded hypoglycemia (<4.0 mmol/l).. In both groups, FBG was significantly lower at the end of the study. In the group A it decreased from 9.03 +/- 1.00 to 7.32 +/- 0.65 (p < 0.001), in the group B from 8.94 +/- 1.01 to 7.23 +/- 0.70 (p < 0.001). There was no statistical difference between the groups. PBG was significantly lower after 12 weeks in both groups.. Metformin/repaglinid is an efficient and safe therapeutic regime in the treatment of the type 2 DM that ensure a better control of PBG levels (Tab. 4, Ref. 18).

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Sulfonylurea Compounds

To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).. In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18-80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] 7.0-10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.. The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG > or = 200 mg/dL [11.10 mmol/L]) and rescue for hyperglycemia.. Least squares (LS) mean change in HbA(1c) was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p < or = 0.016) larger proportion of patients achieved HbA(1c) < or = 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (-19.7 mg/dL [-1.09 mmol/L]) or 25 mg (-19.9 mg/dL [-1.10 mmol/L]) than with placebo (-5.7 mg/dL [-0.32 mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (< or =25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.. Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.. NCT00286494, clinicaltrials.gov.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Pioglitazone; Piperidines; Placebos; Thiazolidinediones; Uracil; Young Adult

To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin.. In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A(1C) (HbA(1C)) at week 26.. At week 26, mean HbA(1C) changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg (-0.63 +/- 0.08%) and alogliptin 25 mg (-0.71 +/- 0.08%) than placebo (-0.13 +/- 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA(1C) decreases of > or =0.5, > or =1.0 and > or =1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 +/- 0.2 kg), alogliptin 12.5 mg (0.7 +/- 0.2 kg) and alogliptin 25 mg (0.6 +/- 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups.. Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Treatment Outcome; Uracil; Weight Gain; Young Adult

To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes.. Randomised, double blind, double dummy, parallel trial.. Secondary care in Denmark between 2003 and 2006.. Non-obese patients (BMI

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Aspart; Male; Metformin; Middle Aged; Patient Compliance; Piperidines; Treatment Outcome; Weight Gain

The purpose of this study was to assess the glucose-lowering efficacy and safety of rimonabant monotherapy in drug-naive type 2 diabetic patients.. The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients (SERENADE) was a 6-month, randomized, double-blind, placebo-controlled trial of 20 mg/day rimonabant in drug-naive patients with type 2 diabetes (A1C 7-10%). The primary end point was A1C change from baseline; secondary end points included body weight, waist circumference, and lipid profile changes.. A total of 281 patients were randomly assigned; 278 were exposed to treatment, and 236 (84.9%) completed the study. Baseline A1C (7.9%) was reduced by -0.8% with rimonabant versus -0.3% with placebo (Delta A1C -0.51%; P = 0.0002), with a larger rimonabant effect in patients with baseline A1C >or=8.5% (Delta A1C -1.25%; P = 0.0009). Weight loss from baseline was -6.7 kg with rimonabant versus -2.8 kg with placebo (Delta weight -3.8 kg; P < 0.0001). Rimonabant induced improvements from baseline in waist circumference (-6 vs. -2 cm; P < 0.0001), fasting plasma glucose (-0.9 vs. -0.1 mmol/l; P = 0.0012), triglycerides (-16.3 vs. +4.4%; P = 0.0031), and HDL cholesterol (+10.1 vs. +3.2%; P < 0.0001). Adverse events of interest that occurred more frequently with rimonabant versus placebo were dizziness (10.9 vs. 2.1%), nausea (8.7 vs. 3.6%), anxiety (5.8 vs. 3.6%), depressed mood (5.8 vs. 0.7%), and paresthesia (2.9 vs. 1.4%).. Rimonabant monotherapy resulted in meaningful improvements in glycemic control, body weight, and lipid profile in drug-naive type 2 diabetic patients. Further ongoing studies will better establish the benefit-to-risk profile of rimonabant and define its place in type 2 diabetes management.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Lipid Metabolism; Lipids; Male; Middle Aged; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome

To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes.. This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at the final visit.. At week 26, mean change in A1C was significantly greater (P < 0.001) for 12.5 mg (-0.56%) and 25 mg (-0.59%) alogliptin than placebo (-0.02%). Reductions in fasting plasma glucose were also greater (P < 0.001) in alogliptin-treated patients than in those receiving placebo. Overall, incidences of adverse events (67.4-70.3%) and hypoglycemia (1.5-3.0%) were similar across treatment groups.. Alogliptin monotherapy was well tolerated and significantly improved glycemic control in patients with type 2 diabetes, without raising the incidence of hypoglycemia.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Uracil

To evaluate the efficacy and safety of the association of repaglinide, metformin and bedtime NPH insulin compared to two classic regimens: metformin plus NPH and two doses of NPH in patients with poorly controlled type 2 diabetes despite two or more oral antidiabetic drugs (OADs).. Random, parallel and open study of 24 weeks with 37 patients randomized into three therapeutic groups: group A (n=12) (repaglinide/metformin/NPH), group B (n=12) (metformin/NPH) and group C (n=13) (NPH/NPH). The insulin was adjusted in the visits to obtain a basal blood glucose <110 mg/dl. The endpoint criteria included HbA1c, blood glucose profile, hypoglycemias and body weight.. At the end of the study, group A presented HbA1c (mean+/-standard deviation) 7.2+/-0.7%, which was significantly less than B (8.8+/-0.1%) and C (8.4+/-1.2%). In terms of absolute reduction, there were only differences (p=0.01) between group A (-2.4+/-1.1%) and B (-0.7+/-1.2%). Group A presented lower postprandial blood glucose values (p<0.01). Nor were there any significant differences in weight gain and incidence of hypoglycemia.. The combination of repaglinide, metformin and bedtime NPH is safe and effective and it provides better postprandial blood glucose control. The association of metformin and a dose of NPH does not obtain suitable control in patients with a long evolution who have already received two or more OADs.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin, Isophane; Male; Metformin; Middle Aged; Piperidines; Prospective Studies; Safety; Weight Gain

Non-obese patients with type 2 diabetes (T2DM) are characterized by predominant defective insulin secretion. However, in non-obese T2DM patients, metformin, targeting insulin resistance, is non-inferior to the prandial insulin secretagogue, repaglinide, controlling overall glycaemia (HbA1c). Whether the same apply for postprandial glucose and lipid metabolism is unknown. Here, we compared the effect of metformin versus repaglinide on postprandial metabolism in non-obese T2DM patients.. Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index < or = 27 kg/m2) insulin-naïve T2DM patients. At enrolment, patients stopped prior oral hypoglycaemic agents therapies and after a 1-month run-in period on diet-only treatment, patients were randomized to repaglinide (2 mg) thrice daily followed by metformin (1 g) twice daily or vice versa each during 4 months with 1-month washout between interventions.. Postprandial metabolism was evaluated by a standard test meal (3515 kJ; 54% fat, 13% protein and 33% carbohydrate) with blood sampling 0-6 h postprandially.. Fasting levels and total area under the curve (AUC) for plasma glucose, triglycerides and free fatty acids (FFA) changed equally between treatments. In contrast, fasting levels and AUC of total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and serum insulin were lower during metformin than repaglinide (mean (95% confidence intervals), LDL cholesterol difference metformin versus repaglinide: AUC: -0.17 mmol/l (-0.26; -0.08)). AUC differences remained significant after adjusting for fasting levels.. In non-obese T2DM patients, metformin reduced postprandial levels of glycaemia, triglycerides and FFA similarly compared to the prandial insulin secretagogue, repaglinide. Furthermore, metformin reduced fasting and postprandial cholesterolaemia and insulinaemia compared with repaglinide. These data support prescription of metformin as the preferred drug in non-obese patients with T2DM targeting fasting and postprandial glucose and lipid metabolism.

Topics: Aged; Area Under Curve; Blood Glucose; Carbamates; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Piperidines; Postprandial Period; Triglycerides

Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme.. RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment.. After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%).. Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Topics: Adult; Blood Pressure; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Alogliptin is a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes (T2D).. This study was conducted to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles and explore the efficacy of multiple oral doses of alogliptin in patients with T2D.. In this randomized, double-blind, placebo-controlled, parallel-group study, patients with T2D between the ages of 18 and 75 years were assigned to receive a single oral dose of alogliptin 25, 100, or 400 mg or placebo (4:4:4:3 ratio) once daily for 14 days. PK profiles and plasma DPP-4 inhibition were assessed on days 1 and 14. Tolerability was monitored based on adverse events (AEs) and clinical assessments. Efficacy end points included 4-hour postprandial plasma glucose (PPG) and insulin concentrations, and fasting glycosylated hemoglobin (HbA(1c)), C-peptide, and fructosamine values.. Of 56 enrolled patients (57% women; 93% white; mean age, 55.6 years; mean weight, 89.8 kg; mean body mass index, 31.7 kg/m(2)), 54 completed the study. On day 14, the median T(max) was ~1 hour and the mean t(1/2) was 12.5 to 21.1 hours across all alogliptin doses. Alogliptin was primarily excreted renally (mean fraction of drug excreted in urine from 0 to 72 hours after dosing, 60.8%-63.4%). On day 14, mean peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24 hours after dosing ranged from 82% to 97% across all alogliptin doses. Significant decreases from baseline to day 14 were observed in mean 4-hour PPG after breakfast with alogliptin 25 mg (-32.5 mg/dL; P=0.008), 100 mg (-37.2; P=0.002), and 400 mg (-65.6 mg/dL; P<0.001) compared with placebo (+8.2 mg/dL). Significant decreases in mean 4-hour PPG were also observed for alogliptin 25, 100, and 400 mg compared with placebo after lunch (-15.8 mg/dL [P=0.030]; -29.2 mg/dL [P=0.002]; -27.1 mg/dL [P=0.009]; and +14.3 mg/dL, respectively) and after dinner (-21.9 mg/dL [P=0.017]; -39.7 mg/dL [P<0.001]; -35.3 mg/dL [P=0.003]; and +12.8 mg/dL). Significant decreases in mean HbA(1c) from baseline to day 15 were observed for alogliptin 25 mg (-0.22%; P=0.044), 100 mg (-0.40%; P<0.001), and 400 mg (-0.28%; P=0.018) compared with placebo (+0.05%). Significant decreases in mean fructosamine concentrations from baseline to day 15 were observed for alogliptin 100 mg (-25.6 micromol/L; P=0.001) and 400 mg (-19.9 micromol/L; P=0.010) compared with placebo (+15.0 micromol/L). No statistically significant changes were noted in mean 4-hour postprandial insulin or mean fasting C-peptide. No serious AEs were reported, and no patients discontinued the study because of an AE. The most commonly reported AEs for alogliptin 400 mg were headache in 6 of 16 patients (compared with 0/15 for alogliptin 25 mg, 1/14 for alogliptin 100 mg, and 3/11 for placebo), dizziness in 4 of 16 patients (compared with 1/15, 2/14, and 1/11, respectively), and constipation in 3 of 16 patients (compared with no patients in any other group). No other individual AE was reported by >2 patients receiving the 400-mg dose. Apart from dizziness, no individual AE was reported by >1 patient receiving either the 25- or 100-mg dose.. In these adult patients with T2D, alogliptin inhibited plasma DPP-4 activity and significantly decreased PPG levels. The PK and PD profiles of multiple doses of alogliptin in this study supported use of a once-daily dosing regimen. Alogliptin was generally well tolerated, with no dose-limiting toxicity.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fructosamine; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Piperidines; Placebos; Time Factors; Treatment Outcome; Uracil

In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients.. Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index< or =27 kg/m(2)) insulin-naïve T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions.. Levels of tumour necrosis factor-alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment effects.. In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.

Topics: Aged; Blood Glucose; Body Weight; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Risk Factors; Treatment Outcome; Vasculitis

Ischemic preconditioning is an increased tolerance to myocardial ischemia during the second of two consecutive exercise tests. ATP-sensitive K(+) channel blockers, such as glinides and sulfonylurea drugs, can induce loss of ischemic preconditioning. This study aimed to investigate the effects of repaglinide, a hypoglycemic agent with an affinity for myocardial ATP-sensitive K (+)channels, on the results of consecutive exercise tests in patients with diabetes and multivessel coronary artery disease.. Forty-two patients with type 2 diabetes and chronic stable angina pectoris, and two-vessel or three-vessel disease participated in this study. The patients underwent two consecutive treadmill exercise tests (phase 1). On the day after these exercise tests, 2 mg of oral repaglinide was given to the patients. One week later, two exercise tests were repeated consecutively (phase 2).. All patients achieved 1.0-mm ST-segment depression during the four exercise tests (T1, T2, T3, and T4). In phase 2, seven patients improved in time to onset of 1.0-mm ST-segment depression. The worsening of the time to onset of 1.0-mm ST-segment depression in phase 2 demonstrated ischemic preconditioning block in 83.3% of patients (P=0.0001). Even the postexercise electrocardiographic parameters (ST-segment depression morphology and magnitude and arrhythmias) were significantly different between the groups with and without pharmacologic ischemic preconditioning block (P=0.031).. Repaglinide, an oral hypoglycemic agent with ATP-sensitive K(+) channel-blocker activity, eliminated the myocardial ischemic preconditioning in patients with coronary disease and diabetes.

Topics: Angina Pectoris; Carbamates; Diabetes Mellitus, Type 2; Electrocardiography; Exercise Test; Female; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Male; Middle Aged; Piperidines; Time Factors

Treatment with K-ATP channel openers, such as diazoxide, can have beneficial effects on insulin secretion in both Type 1 and Type 2 diabetes. However, the precise conditions for obtaining beneficial effects without untoward events have not been determined. We tested the hypothesis that intermittent administration of diazoxide at bedtime for 12 weeks could produce beneficial effects in the absence of side-effects in Type 2 diabetic patients who were not taking insulin.. After an 8-week run-in period, during which treatment with repaglinide and metformin was optimized, we randomized 26 patients to either diazoxide, 100 mg at bedtime, or placebo.. Side-effects were absent or minimal. HbA(1c) did not change. However day-time glucose concentrations by home glucose monitoring were approximately 1.5 mmol/l higher with diazoxide vs. placebo. Stimulation tests (C-peptide-glucagon and breakfast) did not indicate improved pancreatic B-cell function, except by posthoc analysis, in a subgroup of younger age.. Compared with previous results with diazoxide together with bedtime insulin, the present results are less favourable and indicate that concomitant insulin treatment is needed during intervention with K-ATP channel openers.

Topics: Carbamates; Diabetes Mellitus, Type 2; Diazoxide; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome

Rimonabant significantly reduces weight and waist circumference and improves dyslipidemias in overweight and obese patients without diabetes mellitus. Numerous other metabolic changes, including reduced prevalence of the metabolic syndrome and associated cardiovascular disease (CVD) risk factors, reduced fasting glucose, and elevated adiponectin, have been demonstrated with the administration of rimonabant. The Rimonabant-in-Obesity (RIO)-Diabetes trial studied the safety and efficacy of rimonabant in overweight and obese patients with type 2 diabetes who were treated with metformin or sulfonylureas. RIO-Diabetes was a 1-year, randomized, double-blind, placebo-controlled, parallel-group study of 1,047 overweight/obese patients with type 2 diabetes in 151 centers in 11 countries. The body mass index of participants ranged from 27 to 40. Glycosylated hemoglobin (HbA1c) at screening ranged from 6.5% to 10.0%. All patients were receiving either metformin or sulfonylurea therapy and were asked to follow a hypocaloric diet (600 kcal/day deficit [1 kcal = 4.2 kJ]) for the duration of the trial. After a 4-week placebo plus diet run-in period, patients were randomized to receive placebo or rimonabant 5 mg or 20 mg once daily. At 1 year, absolute change in weight from baseline in the intention-to-treat, last observation carried forward analysis of the rimonabant 5 mg and 20 mg groups, respectively, was loss of 2.3 kg and 5.3 kg compared with 1.4 kg in the placebo group (P = 0.013 and P <0.001, respectively). Waist circumference was significantly decreased in the rimonabant 5-mg and 20-mg groups by 2.9 cm and 5.2 cm compared with 1.9 cm in the placebo group (P = 0.034 and P <0.001, respectively). HbA1c reductions of 0.1% and 0.6% were significant in the rimonabant 5-mg and 20-mg groups (P = 0.034 and P <0.001, respectively). Some 57% of the improvements in HbA(1c) and high-density lipoprotein cholesterol could not be attributed to observed weight loss. Compared with placebo, rimonabant 20 mg also demonstrated significant improvements in the prevalence of metabolic syndrome and improvement in its constituents, as well as systolic blood pressure and C-reactive protein levels (assay by ICON Laboratories, Farmingdale, NY and Dublin, Ireland). Rimonabant is the first selective cannabinoid1 blocker studied for type 2 diabetes and associated CVD risk factor therapy. Its ability to improve the numerous metabolic pathologies associated with diabetes and CVD risk and concomit

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

Metformin is the 'drug-of-first-choice' in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM.. A single-centre, double-masked, double-dummy, crossover study during 2 x 4 months involved 96 non-obese (body mass index < or = 27 kg/m(2)) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions.. End-of-treatment levels of haemoglobin A(1c) (HbA(1c)), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated.. In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 x 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM.

Topics: Adiponectin; Biomarkers; Blood Glucose; Body Weight; C-Peptide; C-Reactive Protein; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Patient Compliance; Piperidines; Prospective Studies; Waist-Hip Ratio

To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM).. Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25).. Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002).. The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.

Topics: Adult; Aged; Aged, 80 and over; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Isophane; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Weight Gain

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

To evaluate the efficacy of nateglinide vs. repaglinide in blood glucose (BG) control and the effect on insulin resistance and beta-Cell function in patients with type 2 diabetes.. A randomized controlled double-blind and double-dummy multicentre clinical trial was conducted. A total of 230 Chinese patients with type 2 diabetes were enrolled in five clinical centres. The patients were divided randomly into group A [repaglinide 1.0 mg three times daily (t.i.d.), n = 115] or group B (nateglinide 90 mg t.i.d., n = 115). At baseline and end of the 12-week clinical trial, standard mixed meal tolerance tests were performed.. A total of 223 patients (96.9%) completed the trial. There was no significant difference between repaglinide and nateglinide groups in the effects of reducing fasting blood glucose (FBG), 30-, 60- and 120-min BG during 12 weeks (p > 0.05). At week 12, no significant difference was shown between the two groups in BG or haemoglobin A(1c) (HbA(1c)) (p > 0.05). However, the effect on HbA(1c) in repaglinide group was stronger than that in nateglinide group (p < 0.05). After 12-week treatment, area under the curve (AUC) of BG decreased (p < 0.05), and AUC of insulin and C-peptide (CP) increased in both groups (p < 0.05). The effects of nateglinide on AUC of BG, insulin and CP were similar to that of repaglinide (p > 0.05). There was no significant difference between the two groups in AUC of BG, insulin or CP in week 12 (p > 0.05). Furthermore, homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function indexes measured by HOMA-beta, DeltaI(30)/DeltaG(30) and (DeltaI(30)/DeltaG(30))/HOMA-IR were improved significantly in both groups during 12 weeks (p < 0.05). The effects of improving HOMA-IR and beta-cell function indexes in nateglinide group were comparable with that of repaglinide group (p > 0.05).. The efficacy of repaglinide and nateglinide in FBG, postprandial glucose excursion and early-phase insulin secretion is similar. But the effect of repaglinide 1.0 mg t.i.d. on HbA(1c) is stronger than that of nateglinide 90 mg t.i.d.. This trial had shown that nateglinide and repaglinide could comparably improve insulin sensitivity and beta-cell function.

Topics: Adult; Age of Onset; Aged; Area Under Curve; Asian People; Blood Glucose; Carbamates; China; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Middle Aged; Nateglinide; Phenylalanine; Piperidines

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Rimonabant is a selective blocker of the CB(1) cannabinoid receptor that has been developed for treatment of abdominal obesity, dyslipidemia, and control of diabetes. Four randomized clinical trials have demonstrated that following 1 year of treatment, 20 mg/d of rimonabant is associated with greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is associated with favorable changes in serum high-density lipoprotein and triglycerides, as well as with an improvement in glycemic control among obese type 2 diabetic patients. Rimonabant appears to be well tolerated, with the most common side effects being nausea, anxiety, and depressive symptoms. Rimonabant is a novel agent that has the potential to be a useful adjunct to lifestyle and behavior modification in treatment of abdominal obesity, dyslipidemia, and dysglycemia.

Topics: Behavior; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Lipid Metabolism; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Appetite Depressants; Cannabinoids; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Obesity; Overweight; Patient Dropouts; Piperidines; Placebos; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

To compare the effects of treatment with repaglinide and glibenclamide on platelet function and endothelial markers in patients with Type 2 diabetes mellitus, before and after a standardized meal.. Fifteen patients with Type 2 diabetes were investigated on three occasions: at baseline without oral hypoglycaemic drug treatment, and after 6 weeks' treatment with repaglinide or glibenclamide, respectively, in an open randomized cross-over study. Agonist-induced platelet P-selectin expression and platelet aggregation, urinary thromboxane, soluble P-selectin, von Willebrand factor (VWF), soluble E-selectin, intercellular adhesion molecule (ICAM-1) and C-reactive protein (CRP) were measured. In addition, pre-meal data were compared with non-diabetic control subjects (n = 15), matched for sex, age and BMI.. Adenosine diphosphate (ADP)-induced platelet P-selectin expression increased post-meal in Type 2 diabetic patients both at baseline and after treatment with repaglinide and glibenclamide (P < 0.01 for all; repeated measures anova). Repaglinide treatment reduced fasting ADP-induced P-selectin expression compared with baseline (P = 0.01), but did not influence meal-induced platelet hyper-reactivity (P = 0.32). No significant anti-platelet effects of glibenclamide treatment were found. Plasma concentrations of VWF and ICAM-1 were elevated in patients with Type 2 diabetes compared with control subjects (P < 0.05 for both) and were reduced during treatment with repaglinide (P < 0.01 for both) but did not change during glibenclamide treatment.. The post-meal state is associated with enhanced platelet reactivity in patients with Type 2 diabetes mellitus. Pre-meal treatment with repaglinide or glibenclamide does not inhibit postprandial platelet activation, but repaglinide treatment is associated with attenuated platelet and endothelial activity in the fasting state.

Topics: Adenosine Diphosphate; Blood Glucose; C-Reactive Protein; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Fasting; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin; Intercellular Adhesion Molecule-1; Male; Middle Aged; P-Selectin; Piperidines; Platelet Activation; Platelet Function Tests; Postprandial Period; Treatment Outcome; von Willebrand Factor

This study was conducted to compare the treatment efficacy between a prandial glucose regulator, repaglinide and a new sulphonylurea, glimepiride in Muslim Type 2 diabetic patients who practice Ramadan fasting. Forty-one patients, previously treated with a sulphonylurea or metformin, were divided to receive either repaglinide (n=20, preprandially three-times daily) or glimepiride (n=21, preprandially once daily) 3 months before the month of Ramadan. During Ramadan, patients modified their eating pattern to two meals daily, and the triple doses of repaglinide were redistributed to two preprandial doses. Four point blood glucose monitoring were performed weekly during the month of Ramadan and the subsequent month. Measurements of the 4-point blood glucose were significantly lower in the glimepiride group compared to the repaglinide group both during and after Ramadan. The glycaemic excursion was better in the morning for the repaglinide group and better in the afternoon and evening for the glimepiride group during the Ramadan period. There was no statistically significant difference in the incidence of hypoglycaemia between the two groups during and after Ramadan. There was no difference in the glycaemic excursion post-Ramadan. The longer duration of action of glimepiride may offer an advantage over repaglinide during the 13.5 hours of fast in Ramadan for diabetic patients.

Topics: Adult; Aged; Blood Glucose; Carbamates; Ceremonial Behavior; Diabetes Mellitus, Type 2; Fasting; Female; Humans; Hypoglycemic Agents; Islam; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Time Factors; Treatment Outcome

Topics: Aged; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Glyburide; Humans; Piperidines

Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.. 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848.. 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.. These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Overweight; Patient Satisfaction; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

In this study, we investigated the effects of combining preprandial repaglinide to the insulin therapy for reducing the exogenous insulin requirements and serum HbA(1c) levels in type 2 diabetic patients whose blood glucose levels were previously regulated by multiple dose intensive insulin therapy. Fifty patients with type 2 diabetes who had been initially treated with oral antidiabetic agents without a satisfactory response were included in this study. After adequate glycemic control was achieved with intensive insulin therapy, the patients were divided into two subgroups. The first group continued with intensive insulin therapy. The second group received a combination of multiple insulin injections and oral repaglinide (1.5 mgr tid). The doses of insulin injections were gradually decreased accordingly in the second group. Both groups were followed-up for 3 months. Repaglinide was well tolerated and had no toxicity. A significant reduction regarding exogenous insulin requirements and serum HbA(1c) levels were demonstrated in patients taking preprandial repaglinide (p<0.01). Combining repaglinide to intensive insulin therapy could be a safe and effective alternative to intensive insulin therapy alone for the glycemic control and for reducing exogenous insulin requirements in type 2 diabetic patients.

Topics: Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

The effect of repaglinide and gliclazide on postmeal suppression of endogenous glucose production (EGP) has been studied using a variable-rate tracer methodology. Groups of age-, sex-, and weight-matched type 2 diabetic subjects randomized to gliclazide or repaglinide were studied after ingesting a standard mixed meal (550 kcal; 67% carbohydrate, 19% fat, 14% protein). Plasma glucose profiles were similar in each group and markedly different from that of a nondiabetic control group. Endogenous glucose production was similar basally (3.01 +/- 0.30 vs 3.06 +/- 0.19 mg/kg per minute, gliclazide and repaglinide, respectively). After glucose ingestion, EGP declined rapidly in both the groups until 30 minutes and the greatest suppression was reached earlier in the repaglinide group [0.88 mg/kg per minute at 120 minutes vs 0.77 mg/kg per minute at 210 minutes in gliclazide group (P < .05); median time, 85 vs 195 minutes, respectively (P < .05)]. The area under the curve (30-150) for EGP was significantly greater in the gliclazide group than in the nondiabetic control group (109 +/- 11 vs 198 +/- 22 mg/kg per min 2 ; P > .02) but not significantly different in the repaglinide group (153 +/- 25 mg/kg per min 2 ; P = .17). Repaglinide has minimal physiological advantage over gliclazide, but both therapies for type 2 diabetes fall far short of correcting the endocrine and metabolic abnormalities.

Topics: Adult; Carbamates; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Gliclazide; Glucagon; Glucose; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Oxidation-Reduction; Piperidines; Postprandial Period

Several studies have demonstrated that endothelial dysfunction plays a central role in diabetic mortality and that the prooxidative effect of postprandial hyperglycemia may actively contribute to atherogenesis. Thus, we investigated the possible effect of short-acting (repaglinide) and long-acting (glibenclamide) insulin secretagogues on endothelial function in type 2 diabetic patients.. Sixteen type 2 diabetic patients undergoing diet treatment and with poor glucose control volunteered for the study. The study was designed as a 4-month, randomized, cross-over, parallel-group trial of repaglinide (1 mg twice a day) versus glibenclamide (5 mg twice a day). All patients underwent the following investigations: 1) anthropometrics determinations, 2) blood sampling for routine laboratory analyses and for assessment of oxidative stress indexes, and 3) a brachial reactivity test to evaluate the endothelial function through the study of arterial diameter and flow changes with and without intraarterial infusion of N(G)-monomethyl-l-arginine, an inhibitor of nitric oxide synthase and tetraethylammonium chloride (TEA), a Ca(2+)-activated K(+) (K(Ca)) channel blocker. All patients were randomly assigned to receive repaglinide or glibenclamide for a period of 4 weeks.. Repaglinide administration was associated with a significant reduction in 2-h plasma glucose levels (P < 0.001) and in plasma thiobarbituric acid-reactive substances (TBARS) concentrations (P < 0.001) and with a significant increase in plasma antioxidant power, assessed as Trolox equivalent antioxidant capacity (TEAC) (P < 0.001), effects not observed after glibenclamide administration. With regard to brachial reactivity parameters, repaglinide but not glibenclamide was associated with a significant improvement in brachial reactivity parameters (P < 0.003 for all parameters). In contrast, intra-arterial infusion of L-NMMA and TEA reduced the beneficial effect of repaglinide.. Repaglinide administration, through good control of postprandial glucose levels, improves brachial reactivity and declines oxidative stress indexes.

Topics: Aged; Blood Glucose; Brachial Artery; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Glyburide; Humans; Hypoglycemic Agents; Male; Middle Aged; Oxidative Stress; Piperidines

Repaglinide, a new insulin secretagogue, is purported to be as effective as sulphonylurea but is less hypoglycemic-prone.. To assess the efficacy of repaglinide and its proclivity for hypoglycemia in a post-marketing study.. The study group comprised 688 patients, aged 26-95 years, clinically diagnosed with non-insulin-dependent type 2 diabetes. The patients were divided into three groups based on previous therapy: a) sulphonylurea-treated (group 1, n = 132); b) metformin with or without sulphonylurea where sulphonylurea was replaced with repaglinide (group 2, n = 302); and c) lifestyle modification alone (drug-naive) (group 3, n = 254). At initiation of the study, all patients were transferred from their current treatment to repaglinide. Only patients in group 2, with combined sulphonylurea plus metformin, continued with metformin plus repaglinide. Fasting blood sugar, hemoglobin A1c and weight were measured at study entry and 4-8 weeks following repaglinide therapy. A questionnaire documented the number of meals daily and the presence of eating from fear of hypoglycemia.. The fasting blood sugar level of the entire cohort dropped from 191 +/- 2.4 to 155 +/- 2.0 mg/dl (P < 0.0001); HbA1c from 8.8 +/- 0.1 to 7.7 +/- 0.1% (P < 0.0001). The drop of HbA1c in groups 1, 2 and 3 respectively were: 1.04 +/- 0.22% (P < 0.0001), 1.14 +/- 0.24% (P < 0.0001), and 1.51 +/- 0.31% (P = 0.0137). Weight dropped from 81 +/- 0.7 to 80.2 +/- 0.7 kg (P < 0.0001), and eating from fear of hypoglycemia from 157 to 97 (P < 0.001). The daily number of meals decreased from 2.9 +/- 0.4 to 2.4 +/- 0.4 (P < 0.001). No serious adverse reactions occurred during the study.. Repaglinide is an effective oral hypoglycemic agent taken either as monotherapy or combination therapy. There is less eating to avoid hypoglycemia, fewer meals consumed, and weight loss.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Carbamates; Diabetes Mellitus, Type 2; Diet; Feeding Behavior; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Stereoisomerism; Treatment Outcome

To compare the efficacy of nateglinide with repaglinide in the treatment of type 2 diabetes mellitus.. Forty-six type 2 diabetic patients were randomly treated with repaglinide (group A, 1.0 mg tid, n=23) or nateglinide (group B, 90.0 mg tid, n=23). The trial consisted of a 4-week equilibrated period followed by 12 weeks of treatment course.. In group A, the fasting blood glucose (FBG) and 30-, 60-, 120- min postprandial blood glucose (PBG), as well as hemoglobin A1c were decreased significantly (P<0.05). In group B, the 60-min and 120-min PBG decreased remarkably (P<0.05), but FBG, 30-min PBG and A1c decreased with no statistical significance (P>0.05). After 12 weeks treatment, the 30-, 60-, 120-min postprandial insulin level, area under the curve of insulin and C peptide (0 to 120 min) increased in both groups (P<0.05). No significant difference was found between the effects of repaglinide and nateglinide on early phase insulin secretion.. The glucose lowering effect of repaglinide at a dosing level of 1.0 mg tid was better than that of nateglinide 90 mg tid on fasting blood glucose and A1c during 12 weeks treatment period, yet the insulinotropic effects of the two drugs were similar.

Topics: Adult; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal.. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart.. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses.. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Piperidines; Postprandial Period

Topics: Adult; Blood Glucose; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin, Isophane; Male; Patient Dropouts; Piperidines

Aim our study is to compare the effects of repaglinide vs glimepiride administration on cardiovascular risk factors after meal test. Thus, after 2 weeks washout period, a 3-month randomised, cross-over parallel group trial of repaglinide (1 mg x 2/day) vs glimepiride (2 mg/day) in 14 patients with type 2 diabetes "naive" on diet treatment was made. Both treatments significantly declined plasma glucose, total-cholesterol, LDL-cholesterol, triglycerides, PAI-1, PAP levels and increased HDL-cholesterol. Lowering in plasma PAI-1 and PAP levels was significantly greater in repaglinide group. Furthermore, repaglinide administration resulted in a significant decrease in fasting plasma free fatty acids, fibrinogen, thrombin-antithrombin complex and reaction product of malondialdehyde with thiobarbituric acid (TBARS) levels, in absence of significant difference in fasting plasma insulin levels. Decrease in plasma TBARS levels correlated with the decrease in Plasminogen Activator Inhibitor-1 (r = 0.72; P < 0.003) and free fatty acids concentrations (r = 0.62; P < 0.01). Analysis of the insulin and glucose concentrations throughout the meal test revealed that AUC for glucose (758 +/- 19 vs 780 +/- 28 mg/Lxmin; P = 0.02) was significantly lower after repaglinide than glimepiride administration despite similar AUC for insulin (2327 +/- 269 vs 2148 +/- 292 mU/Lxmin; P = 0.105). At time 120' of meal test, repaglinide vs glimepiride administration was associated with a significant decline in plasma triglycerides, free fatty acids, fibrinogen, Plasminogen Activator Inhibitor-1, plasmin-alpha(2)-antiplasmin complex, thrombin-antithrombin complex, TBARS levels and increase in plasma HDL-cholesterol levels. In repaglinide group a negative correlation between insulin secretion during 1st phase of meal-test and plasma TBARS levels (r = -0.55; P < 0.03) at time 120' was found. Such correlation was lost after adjusting for changes in postprandial hyperglycaemia (r = -0.48; P < 0.09). In conclusion, our results support the hypothesis that repaglinide is more efficient than glimepiride on controlling for postprandial glucose excursion and may have beneficial effect on reducing cardiovascular risk factors.

Topics: Aged; Aged, 80 and over; Area Under Curve; Blood Glucose; Carbamates; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Thiobarbituric Acid Reactive Substances

First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes.. We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2-9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses.. Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA(1c) did not reach statistical significance (P = 0.07). AUC(ins,0-12 min) during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 +/- 6.0 pmol/l/pulse vs. placebo, 31.4 +/- 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 +/- 2.4 pmol/l/min vs. placebo, 12.6 +/- 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment.. Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered.

Topics: Administration, Oral; Adult; Aged; Blood Glucose; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines; Secretory Rate

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24-85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA(1c) > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA(1c) values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA(1c) values at the end of treatment were -1.76% for repaglinide/pioglitazone, -0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were -82 mg/dl for combination therapy, -34 mg/dl for repaglinide, -18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA(1c) reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Lipids; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones

To compare the effect of Repaglinide vs Glimepiride on glucose- and meal-induced insulin secretion and on meal-test induced postprandial glucose excursions.. After 2 weeks washout period, a 3-Month randomised, cross-over parallel group trial of R (1 mg x 2/die) vs G (2 mg/die) in 14 patients with type 2 diabetes "naive" in diet treatment was made.. Both R and G significantly but similarly lowered fasting glucose levels and improved fasting plasma insulin levels vs baseline. Hyperglycemic clamp showed that both 1st (129.15 +/- 23.6 vs 106.90 +/- 18.6 pmol/L; p=0.01) and 2nd phase (189.42 +/- 34.4 vs 144.21 +/- 37.3 pmol/L; p=0.003) B-cell response to glucose as well as area under the curve (52.07 +/- 10.86 vs 39.54 +/- 10.27 micromol/L x 120'; p=0.005) were greater in R than G groups. Insulin action (4.0 +/- 1.1 vs 3.2 +/- 0.9 mg x Kg x 60'/microU/mL; p=0.046) was also improved by R than G administration. In the meal test, R therapy produced a more rapId induction of insulin secretion during the first part. In fact, the mean rise in insulin secretion peaked at 45 min in R (p=0.001 vs G) and at 60 min in G (p=0.001 vs R). Consequently, glucose spike at 60 min was higher in G group compared to glucose spike at 45 min in R group (p=0.002).. Our study demonstrates that R is more efficient that G on improving glucose- and meal- induced insulin secretion as well as on controlling for postprandial glucose excursion.

Topics: Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Middle Aged; Piperidines; Postprandial Period; Sulfonylurea Compounds; Time Factors; Triglycerides

A total of 385 drug-therapy naïve patients, with inadequately controlled type 2 diabetes, were randomised into a multinational, parallel-group study to compare two strategies for dose titration of the oral hypoglycaemic agent repaglinide. Patients were allocated to either a fasting blood glucose (FBG) monitoring group with titration target 4.4-6.1 mmol/l or to a post-prandial blood glucose (PPBG) monitoring group with titration target 4.4-8.0 mmol/l. An initial titration period of up to 8 weeks was followed by a 12-week treatment period. Glycaemic control and hypoglycaemic outcomes were compared for the respective groups. HbA(1c) decreased significantly more in the FBG monitoring group by a mean of 1.38% compared to the PPBG group by a mean of 1.22% (P=0.03). The glycaemic control targets were met by fewer patients in the FBG group than in the PPBG group (57% versus 86% (P<0.001)) despite a higher mean dose of repaglinide in the FBG group. The within-patient blood glucose variability was significantly lower in the FBG group than in the PPBG group (P<0.001). In conclusion, repaglinide lowered the HbA(1c) effectively and safely in both groups and self-monitored FBG is a suitable parameter for titration of repaglinide. Whether a lower PPBG target might be as good a guide as FBG for titration of repaglinide should be addressed in a future study.

Topics: Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Piperidines; Postprandial Period; Safety

This 24-week, randomized, multicentre, open-label, parallel-group clinical trial compared efficacy and safety of repaglinide monotherapy, rosiglitazone monotherapy, and combination therapy (repaglinide plus rosiglitazone) in Type 2 diabetes after unsatisfactory response to sulphonylurea or metformin monotherapy.. Enrolled patients (n = 252) were adults having Type 2 diabetes for at least 1 year, with HbA(1c) values > 7.0% after previous monotherapy (sulphonylurea or metformin, >/= 50% maximal dose). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, rosiglitazone, or repaglinide/rosiglitazone. Study treatments were initiated with a 12-week dose optimization period (doses optimized according to labelling), followed by a 12-week maintenance period. Efficacy endpoints were changes in HbA(1c) values (primary) or fasting plasma glucose values (secondary).. Baseline HbA(1c) values were comparable (9.3% for repaglinide, 9.0% for rosiglitazone, 9.1% for combination). Mean changes in HbA(1c) values at the end of treatment were greater for repaglinide/rosiglitazone therapy (-1.43%) than for repaglinide (-0.17%) or rosiglitazone (-0.56%) monotherapy. Reductions of fasting plasma glucose values were also greater for combination therapy (-5.2 mmol/l, -94 mg/dl) than for repaglinide monotherapy (-3.0 mmol/l, -54 mg/dl) or rosiglitazone monotherapy (-3.7 mmol/l, -67 mg/dl). Minor hypoglycaemic events occurred in 9% of combination therapy patients, vs. 6% for repaglinide and 2% for rosiglitazone. Individual weight gains for combination therapy were correlated to HbA(1c) response.. The combination therapy regimen was well tolerated. In patients previously showing unsatisfactory response to oral monotherapy, glycaemic reductions were greater for the repaglinide/rosiglitazone combination regimen than for use of either repaglinide or rosiglitazone alone.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Rosiglitazone; Thiazolidinediones; Treatment Outcome; Weight Gain

A randomized, parallel-group, open-label, multicenter 16-week clinical trial compared efficacy and safety of repaglinide monotherapy and nateglinide monotherapy in type 2 diabetic patients previously treated with diet and exercise.. Enrolled patients (n = 150) had received treatment with diet and exercise in the previous 3 months with HbA(1c) >7 and < or =12%. Patients were randomized to receive monotherapy with repaglinide (n = 76) (0.5 mg/meal, maximum dose 4 mg/meal) or nateglinide (n = 74) (60 mg/meal, maximum dose 120 mg/meal) for 16 weeks. Primary and secondary efficacy end points were changes in HbA(1c) and fasting plasma glucose (FPG) values from baseline, respectively. Postprandial glucose, insulin, and glucagon were assessed after a liquid test meal (baseline, week 16). Safety was assessed by incidence of adverse events or hypoglycemia.. Mean baseline HbA(1c) values were similar in both groups (8.9%). Final HbA(1c) values were lower for repaglinide monotherapy than nateglinide monotherapy (7.3 vs. 7.9%). Mean final reductions of HbA(1c) were significantly greater for repaglinide monotherapy than nateglinide monotherapy (-1.57 vs. -1.04%; P = 0.002). Mean changes in FPG also demonstrated significantly greater efficacy for repaglinide than nateglinide (-57 vs. -18 mg/dl; P < 0.001). HbA(1c) values <7% were achieved by 54% of repaglinide-treated patients versus 42% for nateglinide. Median final doses were 6.0 mg/day for repaglinide and 360 mg/day for nateglinide. There were 7% of subjects treated with repaglinide (five subjects with one episode each) who had minor hypoglycemic episodes (blood glucose <50 mg/dl) versus 0 patients for nateglinide. Mean weight gain at the end of the study was 1.8 kg in the repaglinide group as compared with 0.7 kg for the nateglinide group.. In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA(1c) and FPG values after 16 weeks of therapy.

Topics: Biomarkers; Body Mass Index; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Piperidines; Time Factors

Postprandial hyperglycemia may be a risk factor for cardiovascular disease. We compared the effects of two insulin secretagogues, repaglinide and glyburide, known to have different efficacy on postprandial hyperglycemia, on carotid intima-media thickness (CIMT) and markers of systemic vascular inflammation in type 2 diabetic patients.. We performed a randomized, single-blind trial on 175 drug-naive patients with type 2 diabetes mellitus (93 men and 82 women), 35 to 70 years of age, selected from a population of 401 patients who participated in an epidemiological analysis assessing the relation of postprandial hyperglycemia to surrogate measures of atherosclerosis. Eighty-eight patients were randomly assigned to receive repaglinide and 87 patients to glyburide, with a titration period of 6 to 8 weeks for optimization of drug dosage and a subsequent 12-month treatment period. The effects of repaglinide (1.5 to 12 mg/d) and glyburide (5 to 20 mg/d) on CIMT were compared by using blinded, serial assessments of the far wall. After 12 months, postprandial glucose peak was 148+/-28 mg/dL in the repaglinide group and 180+/-32 mg/dL in the glyburide group (P<0.01). HbA(1c) showed a similar decrease in both groups (-0.9%). CIMT regression, defined as a decrease of >0.020 mm, was observed in 52% of diabetics receiving repaglinide and in 18% of those receiving glyburide (P<0.01). Interleukin-6 (P=0.04) and C-reactive protein (P=0.02) decreased more in the repaglinide group than in the glyburide group. The reduction in CIMT was associated with changes in postprandial but not fasting hyperglycemia.. Reduction of postprandial hyperglycemia in type 2 diabetic patients is associated with CIMT regression.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Carbamates; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation; Insulin; Lipids; Male; Middle Aged; Piperidines; Postprandial Period; Single-Blind Method; Tunica Intima; Tunica Media; Ultrasonography

The effects of a combination of repaglinide and metformin on the insulin secretion pattern and insulin sensitivity were studied in a fixed-dose, open-label, placebo-controlled cross-over study. Eleven patients with T2 DM were allocated in random order to treatment with placebo or repaglinide (1 mg pre-meal 3 x/day) in combination with metformin (2550 mg/day) for one-week periods of each. At the end of each period a hyperglycaemic (HC) and a euglycaemic clamp (EC) were performed. Both early (0 - 10 min) and late (25 - 180 min) phases of insulin secretion were significantly increased during HC with repaglinide compared to placebo (263.3 +/- 133.1 vs. 443.6 +/- 138.5 pmol/l/10 min, p = 0.008 and 18 750.9 +/- 5936.4 vs. 34 508.65 +/- 9234.0 pmol/l/25 - 180 min; p = 0.008). The C-peptide concentrations under steady-state conditions were lower in EC with placebo than with repaglinide (p = 0.014). When euglycaemia was achieved in EC, the C-peptide concentrations decreased from hyperglycaemic to normoglycaemic values in the presence of repaglinide but remained higher than after placebo. The insulin sensitivity index (ISI) was increased by 35 % after 1 week of combination therapy with repaglinide plus metformin (1.11 +/- 0.03 x 10 (2) vs. 0.83 +/- 0.21 x 10 (2) mg x kg (-1) body weight x min (-1) x pmol (-1) x l, respectively; p = 0.033). Repaglinide increased early and late phases of insulin responses in HC, without markedly enhancing insulin secretion in euglycaemia. Repaglinide in combination with metformin produced a significant enhancement of ISI, suggesting a synergistic effect on insulin sensitivity.

Topics: Adult; Aged; C-Peptide; Carbamates; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Female; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Metformin; Middle Aged; Piperidines; Placebos; Time Factors

This study was designed to compare the effects of repaglinide plus acarbose combination treatment to repaglinide alone on postprandial glucose, serum insulin, C-peptide and proinsulin concentrations. A total of 40 patients with Type 2 diabetes (T2DM) (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) were included in this single-centre, controlled, randomised, single-dose, cross-over study. On two consecutive days, patients either received 2 mg repaglinide 15 min before breakfast followed by 100 mg acarbose with breakfast or repaglinide alone. Two fasting (7.30 h, 8.00 h) and five postprandial blood samples (from 8.30 h to 12.00 h) were taken for blood glucose, serum insulin, C-peptide and proinsulin determination. Repaglinide plus acarbose treatment significantly reduced the mean increase in postprandial blood glucose levels (24.2+/-18.2 mg/dl) compared to repaglinide alone (51.1+/-29.0 mg/dl; p<0.001). Serum insulin, C-peptide and proinsulin levels [mean area under the curve (AUC7.30-12.00h)] were significantly lower than those observed with repaglinide monotherapy (e.g. insulin: 1089.2+/-604.5 hr x pmol/l and 1596.8+/-1080.6 hr x pmol/l, resp., p<0.001), suggesting that acarbose modifies the rapid insulin release induced by repaglinide. Prandial treatment with a combination of acarbose and repaglinide results in an additive glucose lowering effect and modified insulin secretion compared to repaglinide alone. Postprandial hyperglycaemia is not abolished by rapid stimulation of insulin release induced by repaglinide. Additional reduction of postprandial blood glucose by acarbose modifies the stimulation of insulin release.

Topics: Acarbose; Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Food; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male; Middle Aged; Piperidines; Proinsulin

To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health.. Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim.. Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI.. Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).

Topics: Administration, Oral; Adult; Aged; Brachial Artery; Carbamates; Combined Modality Therapy; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Vasodilation

Diabetes and its treatment can cause problems for the Muslim population. The aim of this study was to evaluate the effect of different therapy models on clinical and metabolic status in type 2 diabetic patients during Ramadan.. Fifty-two type 2 diabetic patients were included to this study. Twelve of patients were on diabetic diet only before and during Ramadan (Group 1). Forty of patients had had sulfonylurea (Glimepiride 23 patients, gliclazide 17 patients) before Ramadan. Thirteen of these patients were on a single dose sulfonylurea (Glimepiride 8 patients, gliclazide 5 patients) (Group 2) and 27 were on Repaglinide 2 x 2 mg (Group 3) during Ramadan. Beta-hydroxybutyric acid, glucose, fructosamine, HbA1c, lipid levels and body weight were measured before and after Ramadan.. Body weight, fasting plasma glucose, fructosamine, HbA1c, total cholesterol were not changed in groups during the study. Triglyceride level decreased after Ramadan in groups 2 (p = 0.002) and 3 (p = 0.024). HDL-cholesterol level increased in group 3 (p = 0.022). Fasting capillary beta-hydroxybutyric acid level increased in group 1 (p = 0.034) and didn't change in groups 2 and 3 during the Ramadan. Only one hypoglycemic event occurred at day 6 of Ramadan in patients in group 2 (the patient was on 3 mg glimepiride).. Our results conclude that Ramadan fasting affects metabolic parameters in type 2 diabetes and hypoglycemia should be kept in mind especially in patients using sulfonylurea treatment. Ramadan fasting is not advised for type 2 diabetics while taking medical therapy. If the patient wants Ramadan fasting, these patients using Repaglinide can reduce the frequency of hypoglycemia.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; Carbamates; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fasting; Humans; Hypoglycemic Agents; Islam; Middle Aged; Piperidines; Postprandial Period; Sulfonylurea Compounds; Triglycerides

Repaglinide is an oral anti-diabetic agent that has a short duration of action, and is suitable for preventing post-prandial rises in glucose levels. Targeting post-prandial glucose levels may lead to lower HbA(1c) levels and rates of hypoglycaemia than targeting pre-prandial glucose levels.. In 42 centres, 193 drug-naive (n = 122) or metformin-treated (n = 71) individuals with Type 2 diabetes were randomly allocated to a 40-day period of repaglinide dose-titration (starting at 0.5 mg three times daily) based on either self-measured pre-prandial or post-prandial glucose levels. They were followed for a further 12 weeks and HbA(1c) and hypoglycaemia rates were recorded.. Repaglinide reduced HbA(1c) by 1.25 and 1.07% in the post-prandial and pre-prandial groups, respectively (P for difference = 0.6), and achieved target glucose levels in 80.7 and 66.7%, respectively (P = 0.16). The effect of titration strategy differed by baseline drug therapy, and was more effective in the metformin-treated individuals who experienced a HbA(1c) fall of 0.6 vs. 1.10% with pre-prandial vs. post-prandial titration (P for metformin-allocated group interaction = 0.043). The rate of hypoglycaemia did not differ by group.. In drug-naive individuals with Type 2 diabetes, similar HbA(1c) levels are achieved with repaglinide when dosing is adjusted according to either post-prandial or pre-prandial levels. Conversely, in metformin-treated individuals, repaglinide dosing according to post-prandial levels may lead to better glycaemic control than dosing according to pre-prandial levels.

Topics: Adult; Aged; Blood Glucose; Blood Specimen Collection; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Postprandial Period

The effect of repaglinide on insulin secretion and oxidative stress was evaluated in type 2 diabetic patients in a randomized, controlled, open-label trial. Forty-six patients were treated for 2 months with repaglinide, added to either diet (n=21) or metformin (n=25). A control group of 29 patients, matched for age, weight and glycaemic control, on either diet (n=13) or metformin (n=16) was also followed-up. Phases of insulin secretion (first-FPIS and second-SPIS) ware studied during IVGTT. Total serum antioxidant capacity and serum superoxide dismutase (SOD) activity were measured to assess oxidative stress. HbA(1c) decreased significantly in the repaglinide-treated group (P=0.01), the difference being significant compared with the control group (P=0.01). FPIS increased significantly after repaglinide (P<0.001). The area under the curve (AUC) for FPIS increased significantly (P<0.001), while the AUC for SPIS and for total insulin secretion did not change. Insulin secretion remained unchanged after 2 months in the control group. There was a significant increase after repaglinide in total serum antioxidant capacity (P<0.05) and serum SOD activity (P<0.0004); the difference compared to the control group being significant (P<0.002). Our results demonstrate the physiological effect of repaglinide on endogenous insulin secretion in a controlled, randomized, open-label study-there is a rise only in FPIS, which is the main beta-cell defect in type 2 diabetes mellitus. This improvement in glycaemic control was accompanied by a beneficial effect on oxidative stress in diabetes mellitus.

Topics: Carbamates; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Oxidative Stress; Piperidines; Superoxide Dismutase; Treatment Outcome

To evaluate the influence of renal impairment on the safety and efficacy of repaglinide in type 2 diabetic patients.. This multinational, open-label study comprised a 6-week run-in period, continuing prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and a 3-month maintenance period. Patients with normal renal function (n = 151) and various degrees of renal impairment (n = 130) were treated with repaglinide (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were performed at baseline (end of run-in) and at the end of study treatment.. The type and severity of adverse events during repaglinide treatment were similar to the run-in period. The number of patients with adverse events was not significantly related to renal function during run-in or repaglinide treatment. Percentage of patients with hypoglycemic episodes increased significantly (P = 0.007) with increasing severity of renal impairment during run-in but not during repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood glucose) with repaglinide was unchanged from that on previous antidiabetic medication. Final repaglinide dose tended to be lower for patients with severe and extreme renal impairment than for patients with less severe renal impairment or normal renal function (P = 0.032).. Repaglinide has a good safety and efficacy profile in type 2 diabetic patients complicated by renal impairment and is an appropriate treatment choice, even for individuals with more severe degrees of renal impairment.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Piperidines; Severity of Illness Index

Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control.. In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy).. This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI]) and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment.. One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepiride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months.. Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded.

Topics: Blood Glucose; Blood Pressure; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Homocysteine; Humans; Hypoglycemic Agents; Lipoprotein(a); Male; Middle Aged; Piperidines; Plasminogen Activator Inhibitor 1; Risk Factors; Sulfonylurea Compounds; Time Factors; Treatment Outcome

To compare glycaemic control and cardiovascular risk profile in patients with type 2 diabetes following 12 months' treatment with either repaglinide or metformin.. This was an open uncontrolled randomised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents. Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period (to optimise dosage: repaglinide, 2-4 mg/day; metformin, 1500-2500 mg/day) followed by a 12-month treatment period. Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period.. Mean (S.D.) final drug doses were 3 (+/-1) mg/day in the repaglinide group and 2000 (+/-500) mg/day in the metformin group. Significant improvements in glycaemic control [glycated haemoglobin, fasting and 2-h postprandial plasma glucose (PPG)] were demonstrated in both treatment groups. The decrease in PPG was significantly greater in the repaglinide group (P<0.05). During the treatment period, fasting plasma insulin (FPI) decreased significantly in both groups, more so with metformin (P<0.05). Two-hour postprandial plasma insulin (PPI) levels decreased only in the metformin group (P<0.05). Significant improvements between baseline and final visit were demonstrated in one or both groups in the following cardiovascular risk factors: total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, plasminogen activator inhibitor, lipoprotein(a) and homocysteine. No changes were observed in high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein B, fibrinogen, body mass index (BMI) or blood pressure.. The use of repaglinide or metformin in drug therapy-nai;ve patients with type 2 diabetes over a 12-month period is associated with improvements in both glycaemic control and cardiovascular risk profile. The latter cannot necessarily be attributed to the pharmacotherapy per se, but provides reassurance in the context of initiating oral hypoglycaemic drug therapy with these agents.

Topics: Blood Glucose; Carbamates; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Lipoproteins; Male; Metformin; Middle Aged; Piperidines; Prospective Studies; Risk Factors; Triglycerides

This prospective, 16-week, randomised, double-blind, parallel-group study assessed the differential impact of the prandial glucose regulating oral hypoglycaemic drug, repaglinide, and placebo upon perceptions of quality of life (QoL) and treatment satisfaction in pharmacotherapy-naive patients with Type 2 diabetes. In addition, the study assessed whether these outcomes were influenced by the patients' level of glycaemic control. A total of 253 patients were randomised in a 2:1 ratio of repaglinide: placebo, with doses taken flexibly with main meals (2-4 per day), whenever they were eaten. Repaglinide was initiated at 0.5 mg per meal, increased to 1 mg after 4 weeks if fasting plasma glucose exceeded 7.8 mmol/l. QoL and treatment satisfaction outcomes were compared using generic and disease-specific self-assessment measures, previously applied in diabetes: the WHO Wellbeing Questionnaire (WHO-WBQ), WHO Diabetes Treatment Satisfaction Questionnaire (WHO-DTSQ) and EuroQoL EQ-5D. Over the trial period, repaglinide-treated patients reported a significant 9% improvement in (WHO-DTSQ) treatment satisfaction score (p < 0.05). No significant increase was associated with placebo. The correlation between decrease in glycated haemoglobin (HbA1c) and increase in treatment satisfaction (WHO-DTSQ) was -0.22 (p < 0.01). Scores obtained with the other measures did not change significantly during the trial in either group, but the cohort exhibited only a slight reduction in wellbeing (WHO-WBQ) and health status (EQ-5D) at baseline compared with the background population. In conclusion, flexible mealtime dosing with oral medication appears to be well accepted by pharmacotherapy-naïve patients with Type 2 diabetes. The results suggest that repaglinide provides a higher level of treatment satisfaction than placebo, and this may in part relate to improved glycaemic control.

Topics: Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Health Status; Health Status Indicators; Humans; Hypoglycemic Agents; Patient Satisfaction; Piperidines; Prospective Studies; Quality of Life; Surveys and Questionnaires; Translating

An open-label, parallel-group, randomized, multicenter trial was conducted to compare efficacy and safety of repaglinide versus nateglinide, when used in a combination regimen with metformin for treatment of type 2 diabetes.. Enrolled patients (n = 192) had HbA(1c) >7% and < or =12% during previous treatment with a sulfonylurea, metformin, or low-dose Glucovance (glyburide < or =2.5 mg, metformin < or =500 mg). After a 4-week metformin run-in therapy period (doses escalated to 1,000 mg b.i.d.), patients were randomized to addition of repaglinide (n = 96) (1 mg/meal, maximum 4 mg/meal) or nateglinide (n = 96) (120 mg/meal, reduced to 60 mg if needed) to the regimen for 16 weeks. Glucose, insulin, and glucagon were assessed after a liquid test meal at baseline and week 16.. Final HbA(1c) values were lower for repaglinide/metformin treatment than for nateglinide/metformin (7.1 vs. 7.5%). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA(1c) (-1.28 vs. -0.67%; P < 0.001) and of fasting plasma glucose (FPG) (-39 vs. -21 mg/dl; P = 0.002). Self-monitoring of blood glucose profiles were significantly lower for repaglinide/metformin before breakfast, before lunch, and at 2:00 A.M. Changes in the area under the curve of postprandial glucose, insulin, or glucagon peaks after a test meal were not significantly different for the two treatment groups during this study. Median final doses were 5.0 mg/day for repaglinide and 360 mg/day for nateglinide. Safety assessments were comparable for the two regimens.. The addition of repaglinide to metformin therapy resulted in reductions of HbA(1c) and FPG values that were significantly greater than the reductions observed for addition of nateglinide.

Topics: Area Under Curve; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Nateglinide; Phenylalanine; Piperidines; Postprandial Period; Safety

The effect of acute repaglinide administration (2 mg) on postprandial glycaemia and lipaemia has been examined in 20 subjects with type 2 diabetes mellitus. Each subject received in the morning, after a 12 to 14 h fast, a standard mixed meal (total energy 783 kcal), preceded by one tablet of 2 mg repaglinide or placebo. Chylomicrons and chylomicron-deficient plasma were prepared by ultracentrifugation. Triglyceride levels in CM fraction (CM-triglycerides) in total plasma as well as in CM-deficient plasma (non-CM-triglycerides) were determined. A significant reduction in postprandial glycaemia was observed after repaglinide administration compared to placebo ( p < 0.001). Plasma concentrations of total triglycerides, CM-triglycerides, non-CM-triglycerides, free fatty acids and the other plasma lipids measured, were not significantly different between the two phases of the study. It is concluded that, in contrast to sulphonylureas, acute repaglinide administration does not improve postprandial lipaemia in patients with type 2 diabetes.

Topics: Analysis of Variance; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Kinetics; Piperidines; Postprandial Period; Triglycerides

This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)].. Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l.. Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups).. Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Hemoglobin A; Humans; Hypoglycemic Agents; Insulin, Isophane; Male; Metformin; Middle Aged; Patient Satisfaction; Piperidines; Surveys and Questionnaires; Weight Gain

To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal.. A total of 12 type 2 diabetic patients with early diabetes (mean HbA(1c) of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits.. All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by approximately 61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group.. Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved beta-cell function after a single standard meal.

Topics: Aged; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Eating; Female; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Piperidines

This study compared treatment with a prandial glucose regulator (repaglinide) and a sulphonylurea (glibenclamide) in Muslim Type 2 diabetic patients who practice Ramadan fasting. Two hundred and thirty-five patients, previously treated with a sulphonylurea, were randomised to receive either repaglinide (n=116, preprandially three-times daily) or glibenclamide (n=119, preprandially once- or twice-daily) 6 weeks before Ramadan. During Ramadan, patients changed their eating pattern to two meals daily, and the daily dose of repaglinide was redistributed to two preprandial doses. After Ramadan, patients resumed their regular meal pattern and treatment dosage for 4 weeks. During Ramadan, a statistically significant reduction in mean serum fructosamine concentration from baseline was observed in the repaglinide group (-16.9+/-4.9 micromol/l, -3.8%, P<0.05) but not the glibenclamide group (-6.9+/-4.8 micromol/l, -0.8%). Difference in change in HbA(1c) from baseline was not statistically significant between groups. The number of hypoglycaemic events with midday blood glucose <4.5 mmol/l was significantly lower in the repaglinide group (2.8%) than the glibenclamide group (7.9%) (P=0.001). Apart from hypoglycaemia, both treatments were equally well tolerated. Type 2 diabetic Muslims using prandial repaglinide showed a trend towards better glycaemic control and had a lower frequency of hypoglycaemia than patients using glibenclamide during Ramadan.

Topics: Biomarkers; Carbamates; Diabetes Mellitus, Type 2; Fasting; Feeding Behavior; Female; Fructosamine; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Islam; Malaysia; Male; Middle Aged; Piperidines; Risk Factors; Safety; Time Factors

To compare the effect on glycemic control and weight gain of repaglinide versus metformin combined with bedtime NPH insulin in patients with type 2 diabetes.. A total of 80 subjects treated with 850 or 1,000 mg t.i.d. metformin combined with bedtime NPH insulin were randomized to 13 weeks of open-label treatment with 4 mg t.i.d. repaglinide (n = 39) or metformin (dose unchanged) (n = 41). Insulin dose was titrated at the clinician's discretion, aiming for a fasting blood glucose (FBG) < or =6.0 mmol/l.. Baseline age, diabetes duration, insulin requirement, weight, BMI, FBG, and HbA(1c) (Diabetes Control and Complications Trial-aligned assay, normal range 4.6-6.2%) were similar. Glycemic control improved (nonsignificantly) with insulin/metformin by (mean) 0.4%, from 8.4 to 8.1% (P = 0.09) but deteriorated with insulin/repaglinide by (mean) 0.4%, from 8.1 to 8.6% (P = 0.03; P = 0.005 between groups). Weight gain was less with insulin/metformin: 0.9 +/- 0.4 kg (means +/- SE) (P = 0.01) versus 2.7 +/- 0.4 kg (P < 0.0001) (P = 0.002 between groups). The Diabetes Treatment Satisfaction Questionnaire score (potential range 0 [minimum] to 36 [maximum]) increased from 32.4 +/- 0.8 to 34.1 +/- 0.5 (P = 0.01) with insulin/metformin but decreased from 32.5 +/- 0.9 to 29.1 +/- 1.3 (P < 0.002) with insulin/repaglinide.. Combined with bedtime NPH insulin, metformin provides superior glycemic control to repaglinide with less weight gain and improved diabetes treatment satisfaction.

Topics: Blood Glucose; Carbamates; Creatinine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Insulin, Isophane; Male; Metformin; Middle Aged; Piperidines; Time Factors

Endothelial dysfunction may contribute to the risk of premature atherosclerosis in patients with diabetes. Endothelin (ET-1) may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion. We sought to assess the activity of endogenous ET-1 in a group of patients with type II diabetes mellitus with the use of antagonists of ET-1 receptors.. Forearm blood flow (FBF) responses (strain gauge plethysmography) to intraarterial infusion of a selective blocker of ET(A) receptors (BQ-123) and, on a different occasion, to ET-1, were measured in 15 patients with diabetes and 12 healthy controls. In addition, 5 patients with diabetes received coinfusion of BQ-123 and BQ-788 (a selective blocker of ET(B) receptors). In normal subjects, BQ-123 did not significantly modify FBF from baseline (P=0.16). In contrast, BQ-123 administration resulted in a significant vasodilator response in patients with diabetes (P<0.001). Infusion of exogenous ET-1 resulted in lower vasoconstrictor responses in patients with diabetes than in controls (P=0.001), whereas the vasoconstrictor response to norepinephrine was similar in the 2 groups (P=0.78). In patients with diabetes, the vasodilator response to selective ET(A) blockade was not significantly modified by nonselective blockade of ET-1 receptors obtained by coinfusion of BQ-123 and BQ-788.. The activity of endogenous ET-1 on ET(A) receptors is enhanced in the resistance vessels of patients with diabetes, whereas their sensitivity to exogenous ET-1 is blunted. This abnormality may participate in the pathophysiology of vascular complications associated with diabetes.

Topics: Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Forearm; Heart Rate; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Reference Values; Regional Blood Flow; Vascular Resistance; Vasomotor System

Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals.. The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA(1c) 7.3%, and BMI 32 kg/m(2)). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment.. Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA(1c) levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA(1c) levels) than the same total dose of repaglinide divided into morning and evening mealtime doses.. These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Eating; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Middle Aged; Piperidines; Postprandial Period

To develop a predictive population pharmacokinetic/ pharmacodynamic (PK/PD) model for repaglinide (REP), an oral hypoglycemic agent, using artificial neural networks (ANNs).. REP, glucose concentrations, and demographic data from a dose ranging Phase 2 trial were divided into a training set (70%) and a test set (30%). NeuroShell Predictor was used to create predictive PK and PK/PD models using population covariates: evaluate the relative significance of different covariates; and simulate the effect of covariates on the PK/PD of REP. Predictive performance was evaluated by calculating root mean square error and mean error for the training and test sets. These values were compared to naive averaging (NA) and randomly generated numbers (RN).. Covariates found to have an influence on PK of REP include dose, gender. race, age, and weight. Covariates affecting the glucose response included dose, gender, and weight. These differences are not expected to be clinically significant.. We came to the following three conclusions: 1) ANNs are more precise than NA and RN for both PK and PD; 2) the bias was acceptable for ANNs as compared with NA and RN; and 3) neural networks offer a quick and simple method for predicting, for identifying significant covariates, and for generating hypotheses.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Neural Networks, Computer; Piperidines; Predictive Value of Tests

This double-blind randomized placebo-controlled parallel group study assessed the efficacy and safety (with particular regard to body weight and hypoglycemia) of repaglinide when used in a flexible mealtime dosing regimen in a situation close to everyday clinical practice.. A total of 408 patients with type 2 diabetes considered poorly controlled by diet, but without a history of previous antidiabetic medication, were randomized to receive 0.5 mg repaglinide at mealtimes (increased to 1 mg after 4 weeks depending on blood glucose response) or placebo for 16 weeks. Patients were free to choose a flexible meal pattern, adjusting the dosing schedule from two to four preprandial doses per day in accordance with a "one meal, one dose; no meal, no dose" principle. Additional snacks were not a requirement of the treatment schedule.. Treatment with repaglinide significantly improved glycemic control with respect to baseline and placebo, reducing HbA1c by 1.14% from baseline and fasting plasma glucose by 1.8 mmol/l. Improvement in glycemic control was independent of the meal pattern adopted by patients, including those most commonly taking two or four meals daily, with no correlation between meal pattern and risk of hypoglycemia. The improvement in glycemic control was also independent of degree of obesity and age < or =65 or >65 years. There was no significant body weight increase in the repaglinide group.. Mealtime dosing with repaglinide is effective in improving overall glycemic control in type 2 diabetic patients for which control is suboptimal using diet alone. Patients are able to vary their meal pattern from a conventional regimen of three meals daily without compromising control or increasing the risk of adverse events.

Topics: Aged; Blood Glucose; Body Weight; Carbamates; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Fasting; Female; Food; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Placebos

The primary objective of this single-centre, open-label, parallel-group study was to evaluate the pharmacokinetics and safety profile of the prandial glucose regulator repaglinide, following single and multiple dosing, in patients with type 2 diabetes with and without varying degrees of renal impairment.. The study comprised three screening visits, followed by a 7-day inpatient period. Thirty-four patients, with normal renal function (n = 12), mild-to-moderate renal dysfunction (n = 12) or severe renal dysfunction (n = 10), received a single 2-mg dose of repaglinide on day 1, followed by preprandial 2-mg doses with main meals (breakfast, lunch and dinner) on each of days 2-4. A final 2-mg dose of repaglinide was administered on day 5.. Patients with mild-to-moderate renal impairment showed no significant differences in the pharmacokinetics of repaglinide, compared with patients with normal renal function. In the group of patients with severe renal dysfunction, the main pharmacokinetic finding was a longer half-life after multiple dosing. Rates of minor hypoglycaemia were similar in patients with severe, mild-to-moderate and no renal dysfunction. No major hypoglycaemic episodes occurred.. Patients with type 2 diabetes and mild or moderate impairment of renal function may be treated with repaglinide without special precautions. If repaglinide is used in patients with severely impaired renal function, dose adjustment may be necessary if indicated by blood glucose measurements.

Topics: Aged; Analysis of Variance; Area Under Curve; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Hypoglycemic Agents; Male; Metabolic Clearance Rate; Middle Aged; Piperidines; Renal Insufficiency

To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.. Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.. Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).. Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Fasting; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines

The prandial glucose regulator repaglinide has a rapid onset of action, a short half-life and is metabolised mainly by the liver. Here we report the findings of a 10-week, double-blind, parallel, placebo controlled, randomised trial with repaglinide in 25 diet-treated, sulphonylurea-naïve patients with Type 2 diabetes. Repaglinide was titrated, based on capillary blood glucose, from 0.5 mg to a maximum of 4 mg, preprandially with breakfast and dinner. After 10 weeks, repaglinide was associated with a decrease in HbA(1c) of 2.3%Hb relative to the placebo group (P=0.018). This reflected a 30% decrease within the repaglinide group from a mean HbA(1c) of 7.0 to 4.9%Hb (P<0.002). Repaglinide was also associated with a decrease in fructosamine, by 0.88 mmol/l, relative to placebo (P<0.001), with a 20% decrease (from 3.80 to 3.04 mmol/l) within the repaglinide group (P<0.001). Fasting and postprandial blood glucose concentrations decreased in association with repaglinide by 3.6 and 6.4 mmol/l, respectively, relative to placebo (P<0.001 in each case). Within the repaglinide group fasting and postprandial blood glucose decreased by 3.9 and 6.2 mmol/l, respectively (P<0.001 in each case). The number of patients reporting hypoglycaemia in the repaglinide group was similar to placebo (15 vs. 20, respectively; NS). Test meal assessments confirmed that repaglinide effectively controls glucose levels by stimulating mealtime insulin secretion. Fasting serum insulin concentration was not raised compared to baseline or placebo during repaglinide therapy, albeit that fasting glucose levels were decreased by repaglinide. Twice-daily meal-related insulin secretagogue therapy with repaglinide, a new short and rapid-acting prandial glucose regulator, is capable of improving all measures of glycaemic control without increased hypoglycaemia or fasting hyperinsulinaemia.

Topics: Area Under Curve; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Fasting; Fructosamine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Piperidines; Placebos; Postprandial Period; Time Factors

In this 24-week multicenter, double-blind, randomized, fixed-dose trial, 361 patients having type 2 diabetes received daily preprandial treatment with placebo (n = 75), repaglinide 1 mg (n = 140), or repaglinide 4 mg (n = 146). By a last-observation carried-forward calculation, repaglinide 1 mg or 4 mg treatment decreased mean fasting plasma glucose (FPG) values (by -47 mg/dL or -49 mg/dL) while the placebo group had increased FPG values (by 19 mg/dL). For the repaglinide treatment groups at the end of the study, changes in HbA1c from baseline values ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no events of severe hypoglycemia. Nearly all hypoglycemic symptom episodes had blood glucose levels above 45 mg/dL. Repaglinide was well tolerated in a preprandial fixed-dose regimen of 1 mg or 4 mg, assigned without adjustment for clinical parameters.

Topics: Adult; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Fasting; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Patient Dropouts; Piperidines; Time Factors; Treatment Outcome

To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.. A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations.. During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate.. A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

Topics: Administration, Oral; Area Under Curve; Blood Glucose; C-Peptide; Carbamates; Cohort Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Eating; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines

This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone.. Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured.. The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups.. Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Carbamates; Chromans; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

Repaglinide is a newly developed oral blood glucose-lowering agent that exerts its effect by stimulating insulin secretion. This multicenter study was designed to compare the efficacy and safety of this drug with glyburide in a 1-year randomized double-blind study of outpatients with type 2 diabetes.. A total of 424 subjects (154 women, 270 men) participated and had the following characteristics: age, 61 +/- 9 years; duration of diabetes. 8 years (range 0.5-35); BMI, 28.3 +/- 3.5 kg/m2; HbA1c, 7.1 +/- 1.4%; and fasting plasma glucose, 10.8 +/- 3.1 mmol/l. The majority of the subjects (91%) were previously treated with sulfonylurea, alone or in combination with metformin. The patients were randomized to a 2:1 ratio of repaglinide (0.5-4 mg t.i.d.) or glyburide (1.75-10.5 mg daily) treatment. The study protocol included a screening visit to assess patient eligibility; a titration period of 6-8 weeks, during which the dosages of repaglinide and glyburide were optimized; and a subsequent 12-month treatment period on fixed, optimal dosages.. The trial was completed by 320 subjects, 211 (74%) in the repaglinide and 109 (78%) in the glyburide group. HbA1c initially decreased in both groups and then increased during the second half-year of the maintenance period to a similar extent in the repaglinide and glyburide subjects (0.58 and 0.45% vs. at screening, respectively). In the small group of subjects who previously controlled their condition with diet only (n = 37), a sustained improvement of metabolic control could be observed with both drugs, which was slightly better with glyburide than with repaglinide (theta HbA1c -2.4 vs. -1.0%; P < 0.05). The same trends were seen with fasting plasma glucose. There were no changes in serum lipids. Over the course of the study, 15% of the repaglinide-treated and 13% of glyburide-treated subjects withdrew due to adverse events, mostly hyperglycemia. No differences in adverse events between both drugs were reported. There were no differences in incidences of hypoglycemia.. Repaglinide is a safe and efficacious oral blood glucose-lowering agent, with a potency similar to that of glyburide. Its rapid onset of action and hepatic clearance allows meal-related administration, including in subjects with impaired kidney function.

Topics: Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines

This study was designed to compare diurnal blood glucose excursions and the effects of accidental dietary noncompliance in type 2 diabetic patients who are well-controlled on either repaglinide or glyburide treatment.. This single-center double-blind randomized study comprised type 2 diabetic patients whose mean fasting blood glucose value after repaglinide/glyburide titration and stabilization was in the range of 90-140 mg/dl. The study consisted of an initial screening day, a titration period of 3 weeks, a 1-week stabilization period, a study period, and an end-of-study day. During the 3-day study period, half the patients of each group received two meals on the first day and three meals on the next 2 days, and in the other half, this sequence was reversed. Repaglinide was administered preprandially with each meal, and glyburide was administered as recommended in current labeling, i.e., either one or two daily doses before breakfast and dinner, regardless of whether lunch had been omitted. The diurnal blood glucose excursions on a day in which three meals were eaten were compared between the two groups, and the minimum blood glucose concentration (BGmin) measurements were compared between lunch and dinner on days with three and two meals.. Of the 83 randomized patients, 43 entered into the 3-day study period and completed the trial. The results showed no significant differences between the repaglinide and glyburide groups in average blood glucose excursions from fasting blood glucose (P = 0.44). The influence on the mean BGmin of omitting a meal differed significantly between the repaglinide and glyburide groups (P = 0.014). In the latter group, BGmin decreased from 77 to 61 mg/dl as a result of omitting lunch, whereas in the repaglinide group, BGmin was unchanged for the two-meal day (78 mg/dl) and the three-meal day (76 mg/dl). All hypoglycemic events (n = 6) occurred in the glyburide group on the two-meal day, in connection with omitting lunch. No hypoglycemic events were recorded in the repaglinide group.. These results suggest that treatment with repaglinide in well-controlled type 2 diabetic patients who miss or delay a meal is superior to treatment with longer-acting sulfonylurea drugs (such as glyburide) with respect to the risk of hypoglycemic episodes.

Topics: Adult; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Drug Administration Schedule; Eating; Energy Intake; Fasting; Glyburide; Humans; Hypoglycemic Agents; Middle Aged; Piperidines

To compare the effect of repaglinide in combination with metformin with monotherapy of each drug on glycemic control in patients with type 2 diabetes.. A total of 83 patients with type 2 diabetes who had inadequate glycemic control (HbA1c > 7.1%) when receiving the antidiabetic agent metformin were enrolled in this multicenter, double-blind trial. Subjects were randomized to continue with their prestudy dose of metformin (n = 27), to continue with their prestudy dose of metformin with the addition of repaglinide (n = 27), or to receive repaglinide alone (n = 29). For patients receiving repaglinide, the optimal dose was determined during a 4- to 8-week titration and continued for a 3-month maintenance period.. In subjects receiving combined therapy, HbA1c was reduced by 1.4 +/- 0.2%, from 8.3 to 6.9% (P = 0.0016) and fasting plasma glucose by 2.2 mmol/l (P = 0.0003). No significant changes were observed in subjects treated with either repaglinide or metformin monotherapy in HbA1c (0.4 and 0.3% decrease, respectively) or fasting plasma glucose (0.5 mmol/l increase and 0.3 mmol/l decrease respectively). Subjects receiving repaglinide either alone or in combination with metformin, had an increase in fasting levels of insulin between baseline and the end of the trial of 4.04 +/- 1.56 and 4.23 +/- 1.50 mU/l, respectively (P < 0.02). Gastrointestinal adverse events were common in the metformin group. An increase in body weight occurred in the repaglinide and combined therapy groups (2.4 +/- 0.5 and 3.0 +/- 0.5 kg, respectively; P < 0.05).. Combined metformin and repaglinide therapy resulted in superior glycemic control compared with repaglinide or metformin monotherapy in patients with type 2 diabetes whose glycemia had not been well controlled on metformin alone. Repaglinide monotherapy was as effective as metformin monotherapy.

Topics: Australia; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Triglycerides

This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naïve patients suggest that patients given repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiv

Topics: Adult; Aged; Blood Glucose; C-Peptide; Carbamates; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Fibrinogen; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Prospective Studies; Triglycerides; United States; United States Food and Drug Administration

To compare the efficacy and safety of repaglinide, a novel oral prandial glucose regulator, with that of glibenclamide, an oral hypoglycaemic agent, in the treatment of patients with type 2 diabetes.. This was a 14-week, double-blind, parallel-group trail in which a total of 195 type 2 diabetic patients treated with oral hypoglycaemic agents were randomized to receive either repaglinide, administered preprandially three times daily, or glibenclamide, given preprandially once or twice daily, as per manufacturer's recommendations.. By the end of the study, the 2-h postprandial blood glucose values were lower in the repaglinide group than in the glibenclamide group, with the difference approaching statistical significance (repaglinide, 8.1 (0.6) mol x l(-1) vs glibenclamide, 9.1 (0.6)mmol x l(-1); P = 0.07). There was no statistically significant difference in the mean blood glucose level at the end of the study between the two groups (repaglinide, 7.1 (0.5) mmol x l(-1) vs glibenclamide, 7.4 (0.5) mmol x l(-1); P = 0.42), and baseline HbA1c values had decreased to the same degree in both the repaglinide [7.8% (0.1%) to 7.5% 0.1%)] and the glibenclamide groups [8.0 (0.1%) to 7.6 (0.1%)]. There are no significant differences between the repaglinide and glibenclamide treatment groups in the levels of fasting blood glucose, fructosamine, fasting C-peptide, insulin and proinsulin. Neither treatment group showed any clinically significant changes in blood lipid profiles. Repaglinide and glibenclamide were both well tolerated. No significant differences were observed between the two treatment groups with respect to adverse events, including hypoglycaemic episodes and weight change. No accumulation of repaglinide was apparent during the maintenance period.. Repaglinide is as well tolerated as glibenclamide and is equally effective in the management of type 2 diabetes. Repaglinide may, however, offer an improvement in postprandial blood glucose control compared with glibenclamide, thereby helping to reduce the relative long-term risk of diabetic complications.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glyburide; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Sulfonylurea Compounds

Repaglinide is a novel, rapid-acting prandial glucose regulator. To investigate the effect of repaglinide, 1 mg before each meal, in maintaining glycaemic control in Type 2 diabetic patients who either miss a meal or have an extra meal, 25 patients were randomized to either a fixed-meal regimen of three meals/day or one of two mixed-meal regimens consisting of repeating patterns of two, three or four meals/day over a 20-day period. On the 21st day each patient received three meals. Overall glycaemic control was assessed by weekly serum fructosamine concentrations and 13-point and 37-point serum glucose profiles. Mean fructosamine concentrations decreased significantly to normal values during the treatment period (from 3.10 to 2.68 mg/dl on the fixed-meal regimen and from 3.37 to 2.85 mg/dl on the mixed-meal regimens; P < 0.05), with no statistically significant difference in glucose control between the fixed-meal and mixed-meal regimen groups. Fasting serum glucose levels decreased slightly in both groups, but were not altered by the number of meals consumed. Similarly, serum glucose profiles were not altered significantly by the number of meals consumed. Repaglinide was well tolerated, and no hypoglycaemic events were reported. Serum cholesterol levels were significantly reduced (P < 0.05) in both the fixed-meal and mixed-meal groups, as were triglyceride levels in the mixed-meal group (P < 0.05). It was concluded that meal-associated treatment with repaglinide was well tolerated irrespective of the number of meals consumed/day. Thus, since missing or postponing a meal is a realistic scenario for many individuals, repaglinide offers an oral anti-diabetic treatment which can be adjusted to suit each individual's lifestyle.

Topics: Aged; Area Under Curve; Blood Glucose; Carbamates; Cholesterol; Diabetes Mellitus, Type 2; Eating; Female; Fructosamine; Humans; Hypoglycemic Agents; Indicators and Reagents; Male; Middle Aged; Nitroblue Tetrazolium; Piperidines; Prospective Studies; Triglycerides

Results are presented of a double-blind, Australian multicentre study of the efficacy and safety of adjunctive repaglinide in patients with Type 2 diabetes who were controlled inadequately on metformin monotherapy. Patients had to have been on metformin for at least 6 months and to have glycated haemoglobin (HbA1c) levels of more than 7.1%. Patients were randomized to one of three treatment regimens: metformin plus placebo (MET, n = 27), repaglinide plus placebo (REP, n = 29) and metformin plus repaglinide (MET/REP, n = 27). The metformin dose remained unchanged from the prestudy dose, whereas repaglinide was titrated from 0.5 mg to 4.0 mg preprandially, depending on fasting capillary blood glucose concentration. Maintenance treatment was continued for 3 months. In the MET and REP groups, the HbA1c level decreased from 8.6% to 8.3% and from 8.6% to 8.2%, respectively; in the MET/REP group, HbA1c decreased from 8.3% to 6.9% (p < 0.001 vs. baseline; p < 0.05 vs. each monotherapy group). Overall, 59% of patients in the MET/REP group achieved a HbA1c level of less than 7.1% by the end of the study, compared with 20% and 22% in the MET and REP groups, respectively. No serious adverse events occurred that were considered to be related to study medication. Mild symptoms of hypoglycaemia were seen in the REP and MET/REP groups, in many cases during the titration phase. The combination of repaglinide with metformin was safe and well tolerated and produced a greater improvement in glycaemic control than that seen by the sum of the changes with the two agents alone.

Topics: Australia; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes.. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean).. Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events.. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Topics: Adult; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Ethnicity; Fasting; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Placebos; United States

Abnormal gastric slow-wave frequencies have been observed in diabetic gastroparesis. To evaluate the effect of cisapride on gastric dysrhythmia and emptying of indigestible solids, 20 type-II diabetic patients with symptoms suggestive of gastroparesis were enrolled in this study.. Cutaneous electrogastrography, gastric emptying of radiopaque markers, and evaluation of upper gastrointestinal symptoms were performed before and after administration of an 8-week course of cisapride.. The fasting-state percentages of dominant frequency in normal and tachygastric ranges improved significantly after an 8-week course of cisapride treatment (P < 0.01 and P < 0.05, respectively). The post-meal percentages of dominant frequency in the tachygastric range also improved significantly after cisapride treatment (P < 0.05). The upper gastrointestinal symptoms score decreased significantly, and gastric emptying of radiopaque markers also increased significantly after 8 weeks of cisapride treatment (P < 0.01).. In conclusion, this study showed that cisapride can improve gastric dysrhythmia during both fasting and post-meal phases in patients with diabetic gastroparesis. In addition, upper GI symptoms and gastric emptying of indigestible solids may also show significant improvement after 8 weeks of cisapride treatment.

Topics: Blood Glucose; Cisapride; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Motility; Gastroparesis; Humans; Male; Middle Aged; Piperidines

The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes.. This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded.. From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated.. This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

Topics: Adult; Aged; Carbamates; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines

We investigated the role of arginine vasopressin (AVP) in the development of diabetic nephropathy and the effect of specific vasopressin V1 receptor antagonist of 1-(1-[4-(3-acetylaminopropoxy)-benzoyl]-4-piperidyl)-3, 4-dihydro-2(1H)-quinolinone (CAS 131631-89-5, OPC-21268) on albuminuria in patients with non-insulin dependent diabetes mellitus. Basal levels of AVP in diabetic patients showing microalbuminuria were significantly high compared to diabetics without any complications, suggesting that in those patients abnormally high amounts of AVP seem to be secreted. Three-week treatment with OPC-21268 demonstrated that albuminuria significantly decreased without affecting renal function. Increased secretion of AVP may induce proliferation of renal mesangial cells and modify blood flows in the glomerular capillaries. The present data suggest that OPC-21268 may be useful for preventing the development of diabetic nephropathy, although its long-term effects should be examined. In conclusion, AVP may play a crucial role in the pathophysiology of diabetic nephropathy and that OPC-21268 seems to prevent further progression of nephropathy in non-insulin dependent diabetes mellitus.

Topics: Albuminuria; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Heart Rate; Humans; Male; Middle Aged; Piperidines; Quinolones; Saline Solution, Hypertonic

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.

Topics: Administration, Oral; Biological Availability; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Intestinal Absorption; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Reference Values; Stereoisomerism

We have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they received either repaglinide or glibenclamide twice daily. While glibenclamide had a greater effect on fasting blood glucose (10.4 to 8.6 mmol.l-1), repaglinide significantly lowered postprandial blood glucose (13.8 to 12.2 mmol.l-1). Glycosylated haemoglobin remained unchanged in both groups, and serum fructosamine showed a tendency to fall. With both treatments total cholesterol was significantly decreased after 12 weeks, while HDL-cholesterol and triglycerides did not change. Fasting plasma insulin in the repaglinide group decreased from 80 (median value) to 67 pmol.l-1; it did not change in the glibenclamide group. Two patients in the repaglinide group did not complete the study, one for personal reasons, and one because of a rise in blood glucose. No abnormal findings attributable to repaglinide were observed in clinical and laboratory examinations, and no hypoglycaemic symptoms caused by it were observed.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Fructosamine; Gliclazide; Glyburide; Glycated Hemoglobin; Hexosamines; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Piperidines; Tolbutamide

To investigate the role of motilin in diabetic gastroparesis, we evaluated gastric emptying and plasma concentrations of motilin in diabetic patients. Gastric emptying of radiopaque marker was significantly delayed in the diabetics with autonomic neuropathy (n = 14) compared with the healthy controls (n = 6) (p < 0.01). Mean plasma motilin concentrations were significantly higher in the diabetics with autonomic neuropathy compared with the healthy controls (p < 0.01). A positive correlation was observed between gastric emptying and plasma motilin concentrations in the healthy controls (r = 0.955, p < 0.01), whereas these values were inversely correlated in the diabetics (r = 0.620, p < 0.01). Oral administration of cisapride (15 mg/day.14 day) significantly accelerated gastric emptying without an effect on plasma motilin concentration (p = 0.03). These observations suggest that gastric emptying in the diabetics with autonomic neuropathy is delayed despite elevated levels of motilin, and that cisapride accelerates gastric emptying, independent of the plasma motilin concentration.

Topics: Autonomic Nervous System Diseases; Cisapride; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Female; Gastric Emptying; Humans; Male; Middle Aged; Motilin; Piperidines; Serotonin Antagonists; Stomach Diseases

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Electromyography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Degeneration; Neurologic Examination; Peripheral Nerves; Piperidines; Sensory Thresholds; Synaptic Transmission; Thiazoles

Type 2 diabetes (T2D) is a progressive condition, and sequential additions of therapy are usually required to maintain glycemic control. The options for glucose lowering therapies have increased considerably in recent years. Fixed-dose combinations such as alogliptin with pioglitazone provide a convenient choice which can improve medication adherence.. The authors performed a literature search to identify publications describing the efficacy and safety of alogliptin and pioglitazone when used separately and in combinations.. Pioglitazone activates peroxisome proliferator-activated receptor-gamma which improves insulin sensitivity and helps to preserve β-cell function with a durable improvement in glycemic control. Pioglitazone can retard the progression of atherosclerosis and reduce cardiovascular events, but it is associated with adverse events including weight gain, fluid retention, and increased risk of fractures. Alogliptin improves glycemic control and appears neutral in terms of cardiovascular events. It does not appear to increase the adverse events associated with pioglitazone and use of the combination may permit the use of lower doses of pioglitazone with reduced adverse effects. There are no cardiovascular outcome studies with the combination but the cardiovascular benefits of pioglitazone and additional glucose lowering effects of alogliptin provide a useful combination with convenient once daily dosing.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.

Topics: Adiponectin; Adipose Tissue; Animals; Anthraquinones; Anti-Inflammatory Agents; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin; Male; Muscle, Skeletal; Piperidines; Rats, Sprague-Dawley

Skeletal muscle insulin resistance is a hallmark of individuals with type 2 diabetes mellitus (T2D). In healthy individuals insulin stimulates vasodilation, which is markedly blunted in T2D; however, the mechanism(s) remain incompletely understood. Investigations in rodents indicate augmented endothelin-1 (ET-1) action as a major contributor. Human studies have been limited to young obese participants and focused exclusively on the ET-1 A (ETA) receptor. Herein, we have hypothesized that ETA receptor antagonism would improve insulin-stimulated vasodilation and glucose uptake in T2D, with further improvements observed during concurrent ETA + ET-1 B (ETB) antagonism. Arterial pressure (arterial line), leg blood flow (LBF; Doppler), and leg glucose uptake (LGU) were measured at rest, during hyperinsulinemia alone, and hyperinsulinemia with (1) femoral artery infusion of BQ-123, the selective ETA receptor antagonist (n = 10 control, n = 9 T2D) and then (2) addition of BQ-788 (selective ETB antagonist) for blockade of ETA and ETB receptors (n = 7 each). The LBF responses to hyperinsulinemia alone tended to be lower in T2D (controls: ∆161 ± 160 mL/minute; T2D: ∆58 ± 43 mL/minute, P = .08). BQ-123 during hyperinsulinemia augmented LBF to a greater extent in T2D (% change: controls: 14 ± 23%; T2D: 38 ± 21%, P = .029). LGU following BQ-123 increased similarly between groups (P = .85). Concurrent ETA + ETB antagonism did not further increase LBF or LGU in either group. Collectively, these findings suggest that during hyperinsulinemia ETA receptor activation restrains vasodilation more in T2D than controls while limiting glucose uptake similarly in both groups, with no further effect of ETB receptors (NCT04907838).

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Female; Glucose; Humans; Hyperinsulinism; Leg; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Regional Blood Flow; Vasodilation

Three drugs are discussed in this article: finerenone, difelikefalin, and avacopan. Finerenone (Kerendia™) is FDA-indicated to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end stage kidney disease (ESKD), cardiovascular (CV) death, non-fatal myocardial infarction (MI), and hospitalization for heart failure (HF) in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Difelikefalin (Korsuva™) is FDA-indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD). Avacopan (Tavneos™) is FDA-indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids.

Topics: Aniline Compounds; Diabetes Mellitus, Type 2; Humans; Naphthyridines; Nipecotic Acids; Piperidines

Diabetes, a common endocrine and metabolic disease in clinical practice, generally manifests a certain defect in insulin secretion due to several factors, thereafter leading to a metabolic disorder such as hyperglycemia. This study was conducted to explore the clinical effects of repaglinide combined with exercise rehabilitation on improving the blood glucose of patients with diabetes.. In this retrospective study, 100 patients with diabetes treated in our hospital from January 2018 to January 2020 were assessed for eligibility and recruited. They were assigned at a ratio of 1 : 1 to receive either repaglinide (control group) or repaglinide plus exercise rehabilitation (experimental group). Outcome measures include fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, time to normal blood glucose, blood glucose fluctuation, insulin dosage, adverse reactions, and blood glucose adequate rate.. All eligible patients showed similar pretreatment fasting blood glucose, glycosylated hemoglobin, and 2 h postprandial blood glucose (. Repaglinide plus exercise rehabilitation results in effective blood glucose control and reduced incidence of adverse reactions and yields a promising efficacy, so it is worthy of clinical promotion and application.

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines; Retrospective Studies

SCO-267 is a potent full agonist of G-protein-coupled receptor 40. As a promising therapeutic agent for type 2 diabetes mellitus, it is necessary to elucidate its metabolite profiles during the stage of drug development for safety considerations.. The in vitro metabolism was investigated by incubating SCO-267 (5 μM) with liver microsomes and hepatocytes (rat and human). For in vivo metabolism, SCO-267 (10 mg/kg) was orally administered to rats and plasma samples were collected. The metabolites were identified via measurements of accurate mass, elemental composition and product ions using liquid chromatography coupled to hybrid quadrupole Orbitrap high-resolution mass spectrometry (LC-Orbitrap-MS).. A total of 19 metabolites were structurally identified. M2 (hydroxyl-SCO-267), M15 (SCO-267-acyl-glucuronide), M16 (desmethyl-SCO-267) and M17 (desneopentyl-SCO-267) were verified with reference standards. M2, M11, M16 and M17 were the major metabolites originating from hydroxylation, O-demethylation and N-dealkylation, respectively. Phenotyping study with recombinant human P450 enzymes demonstrated that hydroxylation (M2 and M11) was mainly catalyzed by CYP2C8 and 3A4; demethylation (M16) was mainly catalyzed by CYP2D6, and less catalyzed by CYP2C8 and 3A4; and N-dealkylation (M17) was exclusively triggered by CYP3A4.. Hydroxylation, O-demethylation, N-dealkylation and acyl glucuronidation were the major metabolic pathways of SCO-267. This study is the first to discover the metabolic fates of SCO-267, which provides a basis for safety assessment of this drug candidate.

Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Liquid; Cytochrome P-450 CYP2C8; Diabetes Mellitus, Type 2; Microsomes, Liver; Piperidines; Pyridines; Rats; Tandem Mass Spectrometry

Serious hypoglycemia is a major adverse event associated with insulin secretagogues. Previous studies have suggested a potential relationship between angiotensin-converting enzyme inhibitors (ACEIs) used with sulfonylureas and serious hypoglycemia, and widely used drug compendia warn of this potential drug-drug interaction. We investigated the association between serious hypoglycemia and concomitant use of ACEIs in patients receiving insulin secretagogues, using the self-controlled case series design and Medicaid claims data from 5 US states linked to Medicare claims from 1999-2011. The exposure of interest was active prescription for ACEIs during insulin secretagogue or metformin (negative control object drug) episodes. The outcome was hospital presentation for serious hypoglycemia, identified by discharge diagnosis codes in inpatient and emergency department claims (positive predictive value ~ 78-89%). We calculated confounder-adjusted rate ratios (RRs) and 95% confidence internals (CIs) of outcome occurrence during ACEI-exposed vs. ACEI-unexposed time using conditional Poisson regression. The RRs for ACEIs were not statistically elevated during observation time of glipizide (RR, 1.06; CI, 0.98-1.15), glyburide (RR, 1.05; CI, 0.96-1.15), repaglinide (RR, 1.15; CI, 0.94-1.41), or metformin (RR, 1.02; CI, 0.97-1.06); but was modestly elevated with glimepiride (RR, 1.23; CI, 1.11-1.37) and modestly reduced with nateglinide (RR, 0.73; CI, 0.56-0.96). The overall pattern of results do not suggest that ACEIs used with insulin secretagogues were associated with increased rates of serious hypoglycemia, with the possible exception of glimepiride.

Topics: Administrative Claims, Healthcare; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Carbamates; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Female; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Medicaid; Metformin; Middle Aged; Nateglinide; Pharmacoepidemiology; Piperidines; Secretagogues; Sulfonylurea Compounds; United States

Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context.. In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters.. Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022. These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Topics: Adamantane; China; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance; Drug Therapy, Combination; Humans; Linagliptin; Metformin; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil; Vildagliptin

Patients with type 2 diabetes (T2D) may experience frequent body weight changes over time. The prognostic impact of these weight changes (gains or losses) requires further study.. To study the associations between changes in body weight (intentional or unintentional) with subsequent outcomes.. The EXAMINE trial included 5380 patients with T2D and a recent acute coronary syndrome, who were randomized to alogliptin or placebo. Time-updated Cox models and mixed effects models were used to test the associations between changes in body weight and subsequent outcomes over a median follow-up of 1.6 (1.0-2.1) years.. During the post-randomization follow-up period, 1044 patients (19.4%) experienced a weight loss ≥ 5% of baseline weight, 2677 (49.8%) had a stable weight, and 1659 (30.8%) had a ≥ 5 % weight gain. Patients with weight loss were more frequently women and had more co-morbid conditions. In contrast, patients who gained ≥ 5% weight were more frequently men with less co-morbid conditions. A weight loss ≥ 5% was independently associated with a higher risk of subsequent adverse outcomes, including all-cause mortality: adjusted HR (95% CI) = 1.79 (1.33-2.42), P < 0.001. Similar associations were found for cardiovascular mortality, the composite of cardiovascular mortality or heart failure hospitalization, and the primary outcome. A weight gain ≥ 5% was independently associated with an increase in the risk of subsequent cardiovascular mortality or heart failure hospitalization only: adjusted HR (95% CI) = 1.34 (1.02-1.76), P = 0.033.. In patients with T2D who had a recent ACS/MI, a ≥ 5% loss of body weight was associated with a higher risk of subsequent cardiovascular events and mortality.

Topics: Acute Coronary Syndrome; Aged; Body Mass Index; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Uracil; Weight Gain; Weight Loss

We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.

Topics: Animals; Blood-Retinal Barrier; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Female; Humans; Male; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retina

Low bioavailability of anti-diabetic drugs results in the partial absorption of the drug as they are mainly absorbed from the stomach and the lower part of the GIT. Drug bioavailability of anti-diabetic drugs can be significantly increased by prolonging gastric retention time through gastro-retentive dosage form such as floating microspheres.. The study was aimed to develop and characterize resin based floating microspheres of Repaglinide and Metformin for superior and prolonged maintenance of normoglycaemia in type-2 diabetes mellitus.. Repaglinide and metformin were complexed with amberlite resin; later resin complexed drug was encapsulated in Ethylcellulose floating microspheres. Floating microspheres were characterized for morphology, particle size, IR spectroscopy, DSC, in vitro release and buoyancy studies. Further, floating microspheres were tested for in vivo blood glucose reduction potential in Streptozocin- induced diabetic mice.. Floating microspheres had a spherical shape and slightly rough surface with the entrapment efficiency in a range of 49-78% for metformin and 52-73% for repaglinide. DSC studies revealed that no chemical interaction took place between polymer and drugs. Floating microspheres showed good buoyancy behavior (P<0.05) and prolonged drug release as compared to plain drug (P<0.05). The blood glucose lowering effect of floating microspheres on Streptozocin induced diabetic rats was significantly greater (P<0.05) and prolonged (˃12h) and normoglycaemia was maintained for 6hr.. Floating microspheres containing drug resin complex were able to prolong drug release in an efficient way for a sustained period of time; as a result, profound therapeutic response was obtained.

Topics: Animals; Carbamates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Metformin; Mice; Microspheres; Piperidines; Rats; Resins, Synthetic

Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.. We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.. Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.. Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Japan; Piperidines; Prospective Studies; Registries; Uracil

α-Amylase and α-glucosidase are important therapeutic targets for the management of type 2 diabetes mellitus. The inhibition of these enzymes decreases postprandial hyperglycemia. In the present study, compounds found in commercially available herbs and spices were tested for their ability to inhibit α-amylase and α-glucosidase. These compounds were acetyleugenol, apigenin, cinnamic acid, eriodictyol, myrcene, piperine, and rosmarinic acid.. The enzyme inhibitory nature of the compounds was evaluated using in silico docking analysis with Maestro software and was further confirmed by in vitro α-amylase and α-glucosidase biochemical assays.. The relationships between the in silico and in vitro results were well correlated; a more negative docking score was associated with a higher in vitro inhibitory activity. There was no significant (P > .05) difference between the inhibition constant (K. Several of the herbal compounds studied could regulate postprandial hyperglycemia. Using herbal plants has several advantages including low cost, natural origin, and easy cultivation. These compounds can easily be consumed as teas or as herbs and spices to flavor food.. 背景: α-淀粉酶和α-葡萄糖苷酶是2型糖尿病治疗的重要靶点。抑制这些酶可以降低餐后高血糖。在本研究中, 测试了在市售草药和香料中发现的化合物对α-淀粉酶和α-葡萄糖苷酶的抑制能力。这些化合物是乙酰亮酚、芹菜素、肉桂酸、芥子醇、月桂烯、胡椒碱和迷迭香酸。 方法: 用Maestro软件进行电子对接分析, 并通过体外α-淀粉酶和α-葡萄糖苷酶生化测定进一步证实化合物的抑酶活性。 结果: 体内和体外结果之间有很好的相关性；对接得分越低, 体外抑制活性越高。广泛应用的α-葡萄糖苷酶和α-淀粉酶抑制剂阿卡波糖与芹菜素、芥子醇和胡椒碱的抑制常数(Ki)值无显著性差异(P>0.05)。对于α-淀粉酶, 阿卡波糖的Ki值与芹菜素、肉桂酸、迷迭香酸无显著差异(P>0.05)。另外采用了硫代罗丹明B(SRB)比色法检测中药复方对C2C12和HepG2细胞活力的影响。乙酰亮酚、肉桂酸、月桂烯、胡椒碱和迷迭香酸的IC50值与阿卡波糖相似(P>0.05)。 结论: 所研究的几种中草药化合物具有调节餐后高血糖的作用。使用中草药植物具有成本低、来源天然、易于栽培等优点。这些化合物可以很容易地作为茶或草药和香料食用并为食物调味。.

Topics: Acarbose; Alkaloids; alpha-Amylases; alpha-Glucosidases; Apigenin; Benzodioxoles; Chemical Phenomena; Computer Simulation; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Flavanones; Glycoside Hydrolase Inhibitors; Hep G2 Cells; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Piperidines; Plants, Medicinal; Polyunsaturated Alkamides; Spices

Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.

Topics: Aged; Blood Glucose; Carbamates; Clopidogrel; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Renal Insufficiency

Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.

Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Administration, Oral; Animals; Caco-2 Cells; Citrus paradisi; Citrus sinensis; Diabetes Mellitus, Type 2; Food-Drug Interactions; Fruit and Vegetable Juices; Half-Life; HEK293 Cells; Humans; Intestinal Absorption; Male; Malus; Organic Anion Transporters; Piperidines; Rats; Terfenadine; Uracil

To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.. This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.. Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).. In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Topics: Aged; Benzamides; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycoside Hydrolase Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mortality; Nateglinide; Piperidines; Proportional Hazards Models; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones

Diabetic bone defects may exhibit impaired endochondral ossification (ECO) leading to delayed bone repair. AdipoRon, a receptor agonist of adiponectin polymers, can ameliorate diabetes and related complications, as well as overcome the disadvantages of the unstable structure of artificial adiponectin polymers. Here, the effects of AdipoRon on the survival and differentiation of chondrocytes in a diabetic environment were explored focusing on related mechanisms in gene and protein levels. In vivo, AdipoRon was applied to diet-induced-obesity (DIO) mice, a model of obesity and type 2 diabetes, with femoral fracture. Sequential histological evaluations and micro-CT were examined for further verification. We found that AdipoRon could ameliorate cell viability, apoptosis, and reactive oxygen species (ROS) production and promote mRNA expression of chondrogenic markers and cartilaginous matrix production of ATDC5 cells in high glucose medium via activating ERK1/2 pathway. Additionally, DIO mice with intragastric AdipoRon administration had more neocartilage and accelerated new bone formation. These data suggest that AdipoRon could stimulate bone regeneration via ECO in diabetes.

Topics: Animals; Apoptosis; Bone and Bones; Bone Regeneration; Cartilage; Cell Differentiation; Cell Line; Chondrocytes; Chondrogenesis; Diabetes Mellitus, Type 2; Fracture Healing; Fractures, Bone; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Osteogenesis; Piperidines

ur preclinical findings replicated women's hypersensitivity to type-2 diabetes mellitus (T2DM)-evoked cardiac dysfunction along with demonstrating estrogen (E2)-dependent disruption of the cardiac adiponectin (APN)-connexin43 (Cx43) signaling. Whether the latter molecular anomaly underlies this women's cardiovascular health problem remains unknown. We hypothesized that restoration of the disrupted APN-Cx43 signaling alleviates this sex/E2-dependent cardiac dysfunction in diabetic female rats. To test this hypothesis, we administered the adiponectin receptor 1 (AdipoR1) agonist AdipoRon (30 mg/kg/d for 10 days) to female sham operated (SO) and ovariectomized (OVX) rats, which exhibited and lacked the T2DM left ventricular (LV) dysfunction, respectively, when fed high-fat diet and received low dose streptozotocin regimen; nondiabetic control SO and OVX rats received control diet and vehicle for streptozotocin. In T2DM SO rats, LV dysfunction, AdipoRon mitigated: (1) LV hypertrophy, (2) reductions in fractional shortening, LV developed pressure, dP/dtmax, dP/dtmin, and Tau. In LV tissues of the same rats, AdipoRon reversed reduction in Cx43 and elevations in TNFα, heme-oxygenase 1 (HO-1), and circulating cardiovascular risk factor asymmetric dimethylarginine. The findings also revealed ovarian hormones independent effects of AdipoRon, which included dampening of the pro-oxidant enzyme HO-1. These novel findings yield new insight into a causal role for compromised APN-Cx43 signaling in the E2-dependent hypersensitivity to T2DM-evoked cardiac inflammation and dysfunction. Equally important, the findings identify restoration of Cx43 signaling as a viable therapeutic modality for alleviating this women's cardiovascular health-related problem.

Topics: Adiponectin; Animals; Arginine; Connexin 43; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Estradiol; Estrogen Receptor alpha; Female; Heme Oxygenase (Decyclizing); Hypertrophy, Left Ventricular; Ovariectomy; Piperidines; Rats, Wistar; Receptors, Adiponectin; Receptors, G-Protein-Coupled; Signal Transduction; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Topics: Adamantane; Adult; Age Factors; Aged; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Piperidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Uracil; Vildagliptin; Young Adult

An orally active synthetic adiponectin receptor agonist, AdipoRon has been suggested to ameliorate insulin resistance, and glucose tolerance. However, the chronic effect of AdipoRon in the vascular dysfunction in type 2 diabetes has not been studied yet. Thus, in this study, we examined whether AdipoRon improves vascular function in type 2 diabetes.. Type 2 diabetic (db-/db-) mice were treated with AdipoRon (10 mg/kg/everyday, by oral gavage) for 2 weeks. Body weight and blood glucose levels were recorded every other day during the experimental period. Diameter of mesenteric arteries was measured. And western blot analysis was performed with mesenteric arteries.. Pressure-induced myogenic response was significantly increased while endothelium-dependent relaxation was reduced in the mesenteric arteries of db-/db- mice. Treatment of AdipoRon normalized potentiated myogenic response, whereas endothelium-dependent relaxation was not affected by treatment of AdipoRon. The expression levels of AdiR1, AdiR2, APPL1, and APPL 2 were increased in the mesenteric arteries of db-/db- mice and treatment of AdipoRon did not affect them. Interestingly, AdipoRon treatment increased the phospho-AMPK and decreased MYPT1 phosphorylation in db-/db- mice while there was no change in the level of eNOS phosphorylation.. The treatment of AdipoRon improves vascular function in the mesenteric arteries of db-/db- mice through endothelium-independent mechanism. We suggest that MLCP activation through reduced phosphorylation of MYPT1 might be the dominant mechanism in the AdipoRon-induced vascular effect.

Topics: Adaptor Proteins, Signal Transducing; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelium, Vascular; Insulin Resistance; Male; Mesenteric Arteries; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type III; Phosphorylation; Piperidines; Receptors, Adiponectin

Acarbose and repaglinide are two safe and effective antidiabetic agents that are especially in wide use in Asian and Middle Eastern countries. These two prandial agents share some outstanding qualities that their newer counterparts do not. While globally available in generic versions, both are oral and cheap. There is a paucity of data regarding their comparative efficacy. Herein, a head-to-head comparison of the efficacy of the two in treatment of postprandial hyperglycemia of newly-diagnosed type 2 diabetes was investigated.. One hundred and sixty-four newly-diagnosed type 2 diabetes patients with fasting plasma glucose levels of <7.2 mmol/L (130 mg/dL) but 2-hour postprandial glucose (2hPPG) levels of >10 mmol/L (180 mg/dL) were consecutively alternated between acarbose- and repaglinide-treatment for 6 months.. Per protocol analysis, 67% of acarbose-treated patients versus 85% of repaglinide-treated patients achieved 2hPPG levels of <10 mmol/L (180 mg/dL) (P = 0.05). Treatment adherence rates were 52.4% and 72%, respectively (P < 0.02). Thirteen of the repaglinide-treated and 2 of acarbose-treated patients reported at least one episode of hypoglycemia (P < 0.03). Fasting plasma glucose, 2hPPG, glycated hemoglobin and basal insulin requirement decreased more significantly with repaglinde than acarbose (P, <0.05, <0.04, <0.04 and <0.03, respectively). Weight increased with repaglinide and decreased with acarbose (P = 0.03). There were no significant changes in LDL levels with either treatment (P = 0.58), but triglycerides decreased more significantly with acarbose treatment (P = 0.03) CONCLUSIONS: Significantly higher rates of treatment-adherence and at-target glycemic levels were seen with repaglinide treatment. Weight decreased with acarbose and increased with repaglinide treatment. Hypoglycemic episodes were much less frequent with acarbose treatment.

Topics: Acarbose; Adult; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Iran; Male; Middle Aged; Piperidines

High blood glucose and the consequential ischemia-reperfusion (I/R) injury damage vessels of the retina, deteriorating its function, which can be clearly visualized by electroretinography (ERG). The aim of the present study was to evaluate the possible retinoprotective effects of systemic BGP-15, an emerging drug candidate, in an insulin resistant animal model, the Goto-Kakizaki rat, and compare these results with well-known anti-diabetics such as glibenclamide, metformin, and pioglitazone, which even led to some novel conclusions about these well-known agents. Experiments were carried out on diseased animal model (Goto-Kakizaki rats). The used methods include weight measurement, glucose-related measurements-like fasting blood sugar analysis, oral glucose tolerance test, hyperinsulinemic euglycemic glucose clamp (HEGC), and calculations of different indices from HEGC results-electroretinography and Western Blot. Beside its apparent insulin sensitization, BGP-15 was also able to counteract the retina-damaging effect of Type II diabetes comparable to the aforementioned anti-diabetics. The mechanism of retinoprotective action may include sirtuin 1 (SIRT1) and matrix metalloproteinase 9 (MMP9) enzymes, as BGP-15 was able to elevate SIRT1 and decrease MMP9 expression in the eye. Based on our results, this emerging hydroximic acid derivative might be a future target of pharmacological developments as a potential drug against the harmful consequences of diabetes, such as diabetic retinopathy.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Glyburide; Humans; Hydroxamic Acids; Hypoglycemic Agents; Insulin; Male; Metformin; Molecular Structure; Oximes; Pioglitazone; Piperidines; Protective Agents; Rats; Rats, Wistar; Retina

The purpose of this study was to evaluate and compare the effects on laboratory parameters among monotherapy with five DPP-4 inhibitors in patients with type 2 diabetes mellitus (DM).. We identified cohorts of new sitagliptin users (n = 879), vildagliptin users (n = 253), teneligliptin users (n = 260), alogliptin users (n = 237), and linagliptin users (n = 180) in patients with type 2 DM. We used a multivariate regression model to evaluate and compare the effects of the drugs on laboratory parameters including HbA1c concentration and serum concentrations of creatinine, estimated glomerular filtration rate, high density lipoprotein, total cholesterol, triglyceride, aspartate aminotransferase, and alanine aminotransferase among the five DPP-4 inhibitors up to 12 months.. Our study showed a favorable effect on HbA1c concentration and a slightly unfavorable effect on serum creatinine concentration in users of the five DPP-4 inhibitors, a favorable effect on lipid metabolism in sitagliptin, vildagliptin, and alogliptin users, and a favorable effect on hepatic parameters in sitagliptin, alogliptin, and linagliptin users, in comparison of the baseline and exposure periods. However, there was no significant difference in mean change in the concentration of any laboratory parameter among the five groups of DPP-4 inhibitor users.. In this study, we showed the effect of five DPP-4 inhibitors on glycemic, renal, and lipid metabolism, and hepatic parameters. DPP-4 inhibitors are well-tolerated hypoglycemic drugs.

Topics: Aged; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Linagliptin; Lipid Metabolism; Lipoproteins, HDL; Male; Middle Aged; Piperidines; Pyrazoles; Sitagliptin Phosphate; Thiazolidines; Triglycerides; Uracil; Vildagliptin

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Pemphigoid, Bullous; Piperidines; Uracil

Since the obtaining of data on the effect of Alogliptin towards the lipid profile, body weight and blood pressure (BP) of patients, the additional analysis of the results of the ENTIRE study, completed in the Russian Federation in 2018, was conducted.. Assess the dynamics of HbA1c, body weight, fats indices, blood pressure (BP), and characterize the profile of the patient who received the maximum clinical benefit on treatment of Alogliptin therapy in the ENTIRE study.. A prospective non-interventional observational study that included patients aged 18 years and older with first-onset type 2 diabetes mellitus (T2DM) or patients with T2DM who did not achieve their glycemic targets during the previous therapy.. A decrease in glycated hemoglobin (HbA1c) by more than 0.5% was detected in 73.5% of patients. The most significant absolute decrease of HbA1c was noticed in patients with initially higher values. Younger patients with a shorter duration of T2DM showed the more often compensation of carbohydrate metabolism. The average loss of weight was -2.6±4.2 kg. 76.6% of patients showed the loss of weight. The most significant decrease in body weight was noticed in patients with a large initial body mass index and a shorter duration of the disease. 74.7% of patients showed a decrease of the level of low-density lipoproteins (LDL). The most significant absolute decrease in LDL was noticed in patients with initially higher values and more often in younger people with a shorter duration of T2DM. The average decrease in systolic blood pressure (BP) was 5.9±0.3 mm Hg; the average decrease in diastolic blood pressure (BP) was 2.7±0.2 mm Hg. 59% of patients showed decrease of blood pressure during the group analyzing. The most frequent BP reduction was observed in younger patients with shorter duration of T2DM. At the same time, a more significant absolute decrease in blood pressure was noticed in patients with initially higher indicators, and an increase, on the contrary, was observed in patients with initially lower indicators.. The intensification of Alogliptin therapy allowed to achieve the compensation of carbohydrate metabolism, moderate decrease of body weight, blood pressure and LDL indices within the majority of patients with T2DM. The most frequent achievement of HbA1c targets was noticed in young patients with a shorter duration of T2DM.

Topics: Diabetes Mellitus, Type 2; Humans; Piperidines; Prospective Studies; Uracil

Chronic inflammation is associated with the production of high levels of proinflammatory cytokines via the JAK-STAT and NF-κB signalling pathways which are known to be inhibited by tofacitinib and aspirin respectively. High levels of these cytokines increase the synthesis of suppressors of cytokines (SOCS), which at high levels inhibit insulin signalling leading to insulin resistance. The effects of tofacitinib and aspirin on the degree of insulin resistance in type 2 diabetic rats were determined.. Rats were induced with type 2 diabetes (T2D) by administration of 10% fructose solution (ad libitum) followed by streptozotocin injection (40 mg/kg BW) and treated with different doses of tofacitinib (10 and 20 mg/kg BW), aspirin (100 and 200 mg/kg BW) and combination of the two drugs at both doses for 9 weeks.. Results showed that separate treatment with 10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin significantly (P < 0.05) decreased tumour necrosis factor-α (TNF-α), interleukin 6 (IL-6) and serum amyloid A when compared to diabetic untreated rats. However, the combined therapy (10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin) significantly decreased the levels of TNF-α, IL-6, serum amyloid A, HOMA-IR, blood glucose level and SOC-3 gene expression but significantly (P < 0.05) improved glucose homoestasis, insulin secretion, HOMA-β and GLUT-4 gene expression when compared to diabetic untreated rat.. It was concluded that simultaneous inhibition of the JAK-STAT and NF-κB signalling pathways with tofacitinib and aspirin respectively, could mitigate insulin resistance and hyperglycemia in T2D.

Topics: Animals; Aspirin; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Interleukin-6; Janus Kinases; Male; NF-kappa B; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Serum Amyloid A Protein; Signal Transduction; STAT Transcription Factors; Tumor Necrosis Factor-alpha

The aim of this study was to investigate whether daily glycemic profiles and treatment satisfaction would be changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily in type 2 diabetic patients. Twenty adult Japanese type 2 diabetic patients in whom once-daily 25-mg alogliptin plus twice-daily 250-mg metformin were switched to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily participated. Before and one month after the switch, participants were asked to perform one day of seven-point self-monitoring of blood glucose (SMBG), to wear a sensor of flash glucose monitoring for up to 14 days, and to respond to a questionnaire for treatment satisfaction. As a result, the SMBG profiles were significantly changed after the switch (p = 0.021); blood glucose levels 2 hours after breakfast were significantly elevated (p = 0.022), whereas those 2 hours after lunch were significantly reduced (p = 0.036). The flash glucose monitoring also demonstrated a significant change of daily glucose profiles (p < 0.001). The risk of glucose levels <80 mg/dL were decreased from evening to morning, while the risk of glucose levels ≥140 mg/dL were increased. Mean 24-hour glucose values were increased by 5 mg/dL on average (p < 0.001). Treatment satisfaction was significantly improved after the switch (p < 0.001). In conclusion, daily glycemic profiles were significantly changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the once-daily fixed-dose combination in Japanese type 2 diabetic patients. Treatment satisfaction was significantly improved after the switch.

Topics: Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Drug Substitution; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Metformin; Middle Aged; Patient Satisfaction; Piperidines; Prospective Studies; Treatment Outcome; Uracil

The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM).. Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM.. After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%).. Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM.. Registration Number for Clinical Trial: UMIN000007722.

Topics: Aged; Arterial Pressure; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Prospective Studies; Time Factors; Treatment Outcome; Uracil; Vascular Stiffness

Several insulin secretagogues are widely used to treat diabetes; however, few outcome-based comparative studies have clarified which one of these should be used when indicated. We investigated mortality and cardiovascular event risk associated with optimal forms of insulin secretagogues.. In this cohort study using real-world data from the diabetes database of Taiwan's National Health Insurance program, patients with diabetes were enrolled if their initial treatment was glimepiride, gliclazide, glipizide, glyburide, or repaglinide from 1999 to 2013. Each group was propensity score-matched to the glimepiride group before comparison. Primary outcomes were all-cause mortality and the combined cardiovascular event risk of acute myocardial infarction and ischemic stroke. Hazard ratios were calculated by Cox proportional hazard regression models.. There were 66,790, 97,426, 38,806, 92,970, and 11,468 participants in the glimepiride, gliclazide, glipizide, glyburide, and repaglinide groups, respectively. The median follow-up time was 8 years. Glimepiride was associated with the best clinical outcome, showing the lowest mortality and lowest cardiovascular event risk of the five insulin secretagogues. Using patients on glimepiride as the reference group, the adjusted hazard ratios of all-cause mortality and cardiovascular event risk were 1.52 (p < 0.001) and 1.22 (p = 0.005) for gliclazide, 1.42 (p < 0.001) and 1.19 (p = 0.073) for glipizide, 1.43 (p < 0.001) and 1.32 (p < 0.001) for glyburide, and 1.88 (p < 0.001) and 1.69 (p = 0.001) for repaglinide.. For patients with diabetes taking an insulin secretagogue, glimepiride was associated with the best clinical outcome, showing the lowest mortality and cardiovascular event risk.

Topics: Aged; Carbamates; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Follow-Up Studies; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Mortality; Piperidines; Secretagogues; Sulfonylurea Compounds; Taiwan

Objective Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely consistent, and there are no related studies in a Chinese population, suggesting the need for further exploration. The current study investigated the associations of the ABCC8 rs1801261 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efficacy in Chinese Han T2DM patients. Methods A total of 234 T2DM patients and 105 healthy subjects were genotyped for ABCC8 rs1801261 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. A total of 70 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take 3 mg repaglinide per day (1 mg each time before meals) for 8 consecutive weeks. The pharmacodynamic parameters of repaglinide and biochemical indicators were then determined before and after repaglinide treatment. Results The frequency of ABCC8 rs1801261 allele was higher in T2DM patients than in the control subjects (22.6% vs.11.0%, p<0.01). After repaglinide treatment, T2DM patients carrying genotype CT showed a significantly attenuated efficacy on FPG (p<0.01) and HbA1c (p<0.01) compared with those with genotype CC. Conclusion These results suggested that the ABCC8 rs1801261 polymorphism might influence T2DM susceptibility and the therapeutic effect of repaglinide in Chinese Han T2DM patients. This study was registered in the Chinese Clinical Trial Register on May 14, 2013 (No. ChiCTR-CCC13003536).

Topics: Alleles; Asian People; Carbamates; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Sulfonylurea Receptors

To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application.. Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR.. Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P＜0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P＜0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P＜0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P＜0.05) in DM + H group (P＜0.05).. Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Male; Mice; Pancreas; Piperidines; Random Allocation; Receptor, Insulin; Spleen

One adverse effect of methylprednisolone (MP) pulse therapy is an acute dose-dependent increase in the blood glucose level. Five patients with thyroid ophthalmopathy but normal glucose tolerance received MP pulse therapy (3 cycles, 3 days/week) and were assessed by continuous glucose monitoring. Steroid therapy increased the mean sensor glucose level, and all patients developed steroid-induced diabetes. The patients were treated alternately with mitiglinide (30 mg/day) and repaglinide (1.5 mg/day) during the second or third MP pulse therapy. The sensor glucose levels before lunch and dinner were more favorable during treatment with repaglinide than during treatment with mitiglinide. Repaglinide may be more clinically appropriate than mitiglinide.

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Graves Ophthalmopathy; Humans; Hyperglycemia; Hypoglycemic Agents; Isoindoles; Male; Methylprednisolone; Middle Aged; Piperidines; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A

Topics: Adamantane; Algorithms; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Monitoring; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Ligands; Liraglutide; Models, Molecular; Molecular Targeted Therapy; Nitriles; Peptides; Piperidines; Pyrrolidines; Reproducibility of Results; Sitagliptin Phosphate; Uracil; Venoms; Vildagliptin

In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015.. We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE.. Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset.. Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Topics: Adamantane; Administration, Oral; Adverse Drug Reaction Reporting Systems; Aged; Bayes Theorem; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Humans; Linagliptin; Male; Middle Aged; Piperidines; Practice Guidelines as Topic; Sitagliptin Phosphate; United States; United States Food and Drug Administration; Uracil

Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.

Topics: Amides; Animals; Caco-2 Cells; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; Molecular Structure; Piperidines; Receptors, G-Protein-Coupled; Spiro Compounds; Structure-Activity Relationship

Imigliptin is a novel DPP-4 inhibitor, designed to treat type 2 diabetes mellitus (T2DM). A selective and sensitive method was developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify imigliptin, its five metabolites, and alogliptin in human plasma and urine. Solid-phase extraction (SPE) and direct dilution were used to extract imigliptin, its five metabolites, alogliptin from plasma and urine, respectively. The extracts were injected onto a SymmetryShield RP

Topics: Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Imidazoles; Limit of Detection; Linear Models; Piperidines; Pyridines; Reproducibility of Results; Tandem Mass Spectrometry; Uracil

Insulinotropic oral antidiabetics (OAD) such as sulfonylureas and (SU) glinides are among the frequently prescribed OAD. Side effects are the potential to induce hypoglycemias and weight gain. The aim was to assess the self-managing skills in case of a hypoglycemic event in an elderly type 2 diabetic patient population. In a 2-year period, 160 hospitalized patients (mean age 77.4 years) under insulinotrophic OAD were interviewed using a standardized questionnaire. Additionally, possible dementia was evaluated by using the Mini-Mental State Examination (MMSE) and the Clock-Drawing Test (CDT). The mean HbA1c was 7.6%. MMSE and CDT did intraindividually correlate well and 23.8% of the patients had moderate dementia (10 - 20 points MMSE), 13.1% had severe dementia (0 - 10 points MMSE) at the time of the survey. When under treatment with a sulfonylurea, only 16.0% of patients were aware of the potential hypoglycemia-inducing side effect. Moreover, only 11.8% of patients treated with a combination of a sulfonylurea and insulin knew this side effect of the OAD. The awareness of the side effects of repaglinide was 21.6% (without insulin therapy) versus 21.4% in the insulin-comedicated group. Only 42.6% of patients treated with sulfonylureas or repaglinide knew how to act in the case of hypoglycemia. Even under comedication with insulin, only in 41.2% of the respondents in the comedicated group knew how to take action if they were to experience hypoglycemia. Our findings raise concerns and demonstrate, that the self-managing skills in an elderly patient group are not good, which may become an increasing problem in an ageing population. The prescription or the re-prescription of insulinotropic OAD needs to be adapted to the current cognitive situation and re-evaluated regularly.

Topics: Aged; Aged, 80 and over; Aging; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Self-Management; Sulfonylurea Compounds

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.

Topics: Animals; Cecum; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Heart Diseases; Humans; Linagliptin; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Pyrrolidines; Sepsis; Signal Transduction

To study the effects of adiponin receptor agonist (AdipoRon) on renal injury in type 2 diabetic mice.. The experiment was carried out on 40 SPF C57/BL6 male mice and they were randomly divided into normal control group (. Compared with DM mice, blood glucose and TNF-α levels in DM + H mice and DM + L mice were significantly reduced (. Mice treated with AdipoRon have lower blood glucose and TNF-α levels, and higher protein expression levels of INSR, IRS-1, and higher mRNA expression levels of PDX-1 and insulin, and the content of p-IRS-1. All of these indicate that AdipoRon has a certain effects on renal injury in type 2 diabetic mice.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Kidney; Male; Mice; Piperidines

Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used E

Topics: Biostatistics; Computer Simulation; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Meta-Analysis as Topic; Models, Statistical; Network Meta-Analysis; Nonlinear Dynamics; Piperidines; Randomized Controlled Trials as Topic; Uracil

The aim of this study was to determine the similarities and differences of type 2 diabetes mellitus (T2DM) treatment patterns in daily practice in 5 European countries and whether these reflect differences in guidelines.. Prescriptions for drugs used in diabetes treatment during a 5-year study period were obtained from electronic databases. Patients initiating T2DM treatment during the study period were included. An SAS analysis tool was developed to create episodes of use of drug classes, which resulted in treatment patterns.. A total of 253,530 patients initiating T2DM treatment during the study period were included; 52% to 55% were male, and the mean age ranged from 62 to 67 years. Metformin was the most common initial treatment in all countries. After initial therapy, most patients in the Netherlands, Spain, and the United Kingdom switched to a combination of metformin + a sulfonylurea derivative (SU). In Italy, metformin in combination with an SU was outnumbered by "other treatment," mainly because of repaglinide use. In France, treatments including dipeptidyl peptidase-4 inhibitors were most frequent as second- and fourth-line treatment. Metformin monotherapy was again most commonly observed as the third line of treatment in all countries. Fourth treatment was a combination of metformin + an SU in the Netherlands and Spain; in the United Kingdom and France, dipeptidyl peptidase-4 inhibitors were the most frequently used fourth line of treatment.. This study provides a comprehensive overview of T2DM treatment patterns among patients initiating T2DM treatment in 5 European countries. There were differences, especially regarding the uptake of newer incretin-based treatments, which are usually prescribed as a second and/or third treatment in agreement with local guidelines. These variations reflect the differences between the national guidelines of these countries.

Topics: Aged; Carbamates; Databases, Factual; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Drug Utilization; Europe; Female; Humans; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Piperidines; Sulfonylurea Compounds

Saxagliptin statistically significantly increased the risk of hospitalization for heart failure compared with placebo in the clinical trial of SAVOR-TIMI 53. Neither the reason why only saxagliptin among several dipeptidyl peptidase-4 (DPP-4) inhibitors increased the risk, nor the clinical implication of the result has been explained.. To evaluate the risk of hospitalization for heart failure associated with DPP-4 inhibitors by using an alternative measure to the hazard ratio.. We used the difference in restricted mean survival time (RMST) between DPP-4 inhibitors and placebo to evaluate the risk of cardiovascular events, including hospitalization for heart failure associated with DPP-4 inhibitors. Three randomized clinical trials with cardiovascular events as a primary end point-EXAMINE (alogliptin), SAVOR-TIMI 53 (saxagliptin), and TECOS (sitagliptin)-were reevaluated by estimating the RMSTs for the DPP-4 inhibitors and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information.. The differences of RMSTs (DPP-4 inhibitors minus placebo) for hospitalization for heart failure were -4 days [-6, -2] in the SAVOR-TIMI 53 (720 days follow-up), -3 days [-9, 3] in the EXAMINE (900 days follow-up), and 1 day [-5, 7] in the TECOS (1440 days follow-up). There were no substantial differences in the risk of other cardiovascular outcomes between DPP-4 inhibitors and placebo.. There are no substantial clinically relevant differences in the risk of cardiovascular events, including hospitalization for heart failure, between 3 of the DPP-4 inhibitors and placebo.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Hospitalization; Humans; Piperidines; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk; Sitagliptin Phosphate; Uracil

To explore the intervention effects of oral active AdipoRon on liver oxidative stress in type 2 diabetic mice, which provides basic data for clinical application.. The blood glucose of DM group was obviously higher than that of NC group (. Oral active Adi-poRon which reduced the blood glucose levels of mice had a certain intervention effect on liver tissue oxidative stress in type 2 diabetes mice.

Topics: Animals; Blood Glucose; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Liver; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Oxidative Stress; Piperidines; Receptors, Adiponectin; Superoxide Dismutase

Patients with type 2 diabetes are at high risk for developing coronary artery disease (CAD). Noninvasive anatomic assessment by coronary computed tomography angiography (CCTA) is being increasingly used for detecting or excluding CAD. Recently, fractional flow reserve (FFR) using routinely acquired CCTA datasets (FFR. This study will be a prospective, non-randomized, multicenter trial performed in Japan. Patients with type 2 diabetes who have intermediate coronary artery stenosis (diameter stenosis <70%) as evaluated by CCTA will be treated with 25mg/day of alogliptin. After 48 weeks' treatment, CCTA will be repeated. The primary endpoint will be changes in FFR. This study will be the first multicenter trial to evaluate the effects of alogliptin on coronary atherosclerosis using the newly developed FFR

Topics: Aged; Carotid Intima-Media Thickness; Computed Tomography Angiography; Coronary Angiography; Coronary Stenosis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractional Flow Reserve, Myocardial; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Plaque, Atherosclerotic; Prospective Studies; Uracil

We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.

Topics: Adipose Tissue; Aged; Dexamethasone; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glucocorticoids; Glucose; Humans; Insulin Resistance; Lipolysis; Male; Middle Aged; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

Increasing evidence suggests that certain newer anti-diabetic drugs are associated with an increased risk of hospitalized heart failure (HHF). However, the potential risks associated with the use of sulfonylurea and glinide have not been carefully evaluated.. A retrospective cohort study using the Taiwan National Health Insurance claims database was conducted to examine the risks of HHF among newly diagnosed type 2 diabetic patients who initiated glinide, sulfonylurea, or acarbose therapy during 2006-2012. The outcome of interest was hospitalization due to heart failure after treatment initiation, defined by ICD-9-CM code. A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) using acarbose as the reference group.. A total of 25,638 glinide, 272,140 sulfonylurea, and 29,376 acarbose initiators were included in the analysis. Patients who initiated glinide had the highest crude HHF incidence. In the analysis adjusted for baseline differences, a significantly higher risk of HHF was found for glinide (adjusted HR, 1.53; 95% CI, 1.24-1.88), but not for sulfonylurea (adjusted HR, 0.94; 95% CI, 0.80-1.11), as compared with acarbose. The elevated risk remained consistent across different subgroups of patients as well as several sensitivity analyses including exploring the impact of potential unmeasured confounding.. These findings indicated that, as compared with acarbose, glinide may be associated with a higher risk of HHF for type 2 diabetic patients. Further researchis needed to fully evaluate the risks and benefits of glinide therapy relative to other oral anti-diabetic agents.

Topics: Acarbose; Administration, Oral; Age Factors; Aged; Carbamates; Cohort Studies; Confidence Intervals; Databases, Factual; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Heart Failure; Hospital Mortality; Hospitalization; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Piperidines; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sex Factors; Sulfonylurea Compounds; Survival Rate; Taiwan

Even though ellagic acid has previously been valued in many models of cancer, so far its full mechanistic effect as a natural antiapoptotic agent in the prevention of type 2 diabetes complications has not been completely elucidated, which was the goal of this study. We fed albino rats a high-fat fructose diet (HFFD) for 2 months to induce insulin resistance/type 2 diabetes and then treated the rats with ellagic acid (10 mg/kg body weight, orally) and/or repaglinide (0.5 mg/kg body weight, orally) for 2 weeks. At the serum level, ellagic acid challenged the consequences of HFFD, significantly improving the glucose/insulin balance, liver enzymes, lipid profile, inflammatory cytokines, redox level, adipokines, ammonia, and manganese. At the tissue level (liver, pancreas, adipose tissue, and brain), ellagic acid significantly enhanced insulin signaling, autophosphorylation, adiponectin receptors, glucose transporters, inflammatory mediators, and apoptotic markers. Remarkably, combined treatment with both ellagic acid and repaglinide had a more pronounced effect than treatment with either alone. These outcomes give new insight into the promising molecular mechanisms by which ellagic acid modulates numerous factors induced in the progression of diabetes.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers; Brain; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Ellagic Acid; Hyperglycemia; Hypoglycemic Agents; Inflammation Mediators; Insulin Resistance; Intra-Abdominal Fat; Liver; Male; Neurons; Oxidative Stress; Pancreas; Piperidines; Rats, Wistar

Fotagliptin is a novel dipeptidyl peptidase IV inhibitor under clinical development for the treatment of Type II diabetes mellitus. The objective of this study was to develop and validate a specific and sensitive ultra-performance liquid chromatography (UPLC)-MS/MS method for simultaneous determination of fotagliptin and its two major metabolites in human plasma and urine. Methodology & results: After being pretreated using an automatized procedure, the plasma and urine samples were separated and detected using a UPLC-ESI-MS/MS method, which was validated following the international guidelines.. A selective and sensitive UPLC-MS/MS method was first developed and validated for quantifying fotagliptin and its metabolite in human plasma and urine. The method was successfully applied to support the clinical study of fotagliptin in Chinese healthy subjects.

Topics: Automation; Calibration; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Humans; Linear Models; Piperidines; Protease Inhibitors; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Triazines

Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues-glipizide, glyburide, glimepiride, repaglinide, and nateglinide-to cause serious hypoglycemia.. We screened 400 drugs frequently coprescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug-drug interaction potential based on the pharmacokinetics of each secretagogue-precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug-drug interaction.. We predicted 34 pharmacokinetic drug-drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue-precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening.. The self-controlled case series design has the potential to be widely applicable to screening for drug-drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug-drug interactions in this case.

Topics: Area Under Curve; Carbamates; Cyclohexanes; Databases, Factual; Diabetes Mellitus, Type 2; Drug Interactions; Glipizide; Glyburide; Humans; Hypoglycemia; Hypoglycemic Agents; Medical Informatics; Nateglinide; Pharmacoepidemiology; Phenylalanine; Piperidines; Sulfonylurea Compounds

To observe the effect of AdipoRon for the treatment of type 2 diabetes (T2DM)in mice and its effect on the liver.. Forty male C57/BL6 mice (SPF) were randomly divided to normal control (NC) group and the experimental group. To establish the T2DM mice model, mice in the experimental group were fed with high fat and high glucose, combined with intraperitoneal injection of streptozotocin (STZ) in small doses, and mice were further subdivided into model control (DM) group, model control with low AdipoRon (DM+L) group and model control with high AdipoRon (DM+H) group (. Compared with mice in the DM group, levels of ALT, AST, ALP, triglyceride (TG), glucose (GLU) reduced in DM+L and DM+H group (. The serum indexes such as levels of ALT, AST, ALP, TG, Glu, G-6-P and PEPCK were all reduced in DM mice treated with AdipoRon, indicating the obvious protecting effect of AdipoRon on the liver in DM mice.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Liver; Male; Mice; Mice, Inbred C57BL; Piperidines

Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.

Topics: Animals; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Down-Regulation; Drug Inverse Agonism; Eating; Endocannabinoids; Endoplasmic Reticulum Stress; Humans; Inflammation; Insulin Resistance; Mitochondria; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction

The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure.. Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5-400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments.. A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively.. The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.

Topics: Adolescent; Adult; Aged; Biological Availability; Body Weight; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Kidney; Kidney Function Tests; Male; Middle Aged; Models, Biological; Piperidines; Tissue Distribution; Uracil; Young Adult

Topics: Acute Coronary Syndrome; Angina, Unstable; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Peptides; Piperidines; Uracil

Previous pharmacogenomic studies of oral anti-diabetic drugs have primarily focused on the effect of a single site. This study aimed to examine the joint effects of multiple loci on repaglinide or rosiglitazone efficacy in newly diagnosed type 2 diabetes mellitus (T2DM) patients. A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks. The reductions in fasting glucose (ΔFPG), 2h glucose (Δ2hPG) and glycated hemoglobin (ΔHbA1c) levels were significantly associated with genetic score that was constructed using the sum of the effect alleles both in the repaglinide (P = 0.0011, 0.0002 and 0.0067, respectively) and rosiglitazone cohorts (P = 0.0002, 0.0014 and 0.0164, respectively) after adjusting for age, gender, body mass index and dosage. Survival analyses showed a trend towards a greater attainment rate of target HbA1c level in individuals with a high genetic score in the repaglinide cohort and rosiglitazone cohort (Plog-rank = 0.0815 and 0.0867, respectively) when the attainment of treatment targets were defined as more than 20% decrease of FPG, 2hPG, and HbA1c levels after treatment. In conclusion, we identified the joint effects of several T2DM-related loci on the efficacy of oral anti-diabetic drugs; moreover, we built a model to predict the drug efficacy.

Topics: Administration, Oral; Adult; Alleles; Asian People; Blood Glucose; Body Mass Index; Carbamates; China; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Genetic Loci; Genotype; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linear Models; Male; Middle Aged; Piperidines; Polymorphism, Single Nucleotide; Rosiglitazone; Thiazolidinediones

The aim of the present study was to evaluate the long-term efficacy and safety of adding repaglinide in patients with type 2 diabetes mellitus whose blood glucose levels were not sufficiently controlled by treatment with a dipeptidyl peptidase-4 inhibitor, sitagliptin, in addition to diet and exercise therapies.. This was a multicenter, uncontrolled, dose-titration study with a treatment period of 52 weeks. The primary end-point was the change in glycated hemoglobin levels from baseline.. The glycated hemoglobin level was 7.43 ± 0.57% (mean ± standard deviation) at baseline, and decreased to 6.93 ± 0.91% at the end of the study. The mean changes in glycated hemoglobin levels at 4 weeks and at the end of the study were -0.44 ± 0.28% and -0.50 ± 0.82%, respectively. The glycated hemoglobin-lowering effect was maintained for 52 weeks. The rate of adverse events was 86.0% (86/100), and there were 352 adverse events. The rate of adverse drug reactions was 21.0% (21/100). Hypoglycemia was reported in 5.0% (5/100) of patients, but there was no incidence of 'major hypoglycemia'.. Combination therapy with repaglinide and sitagliptin was considered effective for a long term without clinical safety problems in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Sitagliptin Phosphate

Trelagliptin (SYR-472), a novel dipeptidyl peptidase-4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients. In this study, we characterized in vitro properties of trelagliptin, which exhibited approximately 4- and 12-fold more potent inhibition against human dipeptidyl peptidase-4 than alogliptin and sitagliptin, respectively, and >10,000-fold selectivity over related proteases including dipeptidyl peptidase-8 and dipeptidyl peptidase-9. Kinetic analysis revealed reversible, competitive and slow-binding inhibition of dipeptidyl peptidase-4 by trelagliptin (t1/2 for dissociation ≈ 30 minutes). X-ray diffraction data indicated a non-covalent interaction between dipeptidyl peptidase and trelagliptin. Taken together, potent dipeptidyl peptidase inhibition may partially contribute to sustained efficacy of trelagliptin.

Topics: Animals; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Humans; Male; Piperidines; Rats, Sprague-Dawley; Sitagliptin Phosphate; Substrate Specificity; Time Factors; Uracil

Effects of a synthetic biguanide derivative N-[imino(1-piperidinyl)methyl] guanidine (NIPMG) on free radical homeostasis, aconitase activity, and citrate concentration were studied in the liver and blood serum of rats with type 2 diabetes mellitus. Analysis of biochemiluminescence parameters showed that administration of this agent (10 mg/kg body weight) to animals with diabetes reduced the intensity of free radical processes in study tissues relative to the increased values in untreated diabetic animals. Under these conditions, aconitase activity, a principal target of ROS effects, and citrate level in the liver and blood serum of rats approached the control levels. The results show that NIPMG can positively regulate free radical homeostasis and reduce the intensity of oxidative stress in type 2 diabetes mellitus, which was accompanied by normalization of the studied parameters.

Topics: Aconitate Hydratase; Animals; Citrates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Hypoglycemic Agents; Liver; Male; Methylguanidine; Piperidines; Rats; Reactive Oxygen Species

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Hypoglycemic Agents; Piperidines; Risk Factors; Sitagliptin Phosphate; Uracil

The majority of people with type 2 diabetes mellitus (T2DM) will develop chronic kidney disease in their lifetime. Because most dipeptidyl peptidase (DPP)-4 inhibitors require dose adjustment in patients with T2DM and renal impairment, we aimed to understand how these treatments are prescribed in UK clinical practice, and to determine whether recommended dose adjustments are being made at initial prescription.. This retrospective, descriptive cohort study analyzed data from the Clinical Practice Research Datalink (CPRD). Patients of interest were those with T2DM and renal impairment initiated on a DPP-4 inhibitor between 2014 and 2015. Patients under 40 years of age and with type 1 diabetes were excluded. Descriptive statistics were calculated for baseline demographic and clinical characteristics, and the study protocol was approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research.. A total of 3425 patients diagnosed with T2DM and renal impairment and initiated on a DPP-4 inhibitor were identified. The percentages of patients prescribed the high dose of saxagliptin, alogliptin,sitagliptin, and vildagliptin were 48%, 43%, 41%, and 27%, respectively, which is not recommended given their renal dysfunction. These are conservative estimates, as they do not include patients with severe renal impairment on sitagliptin and alogliptin, whose doses should be further reduced. No patients were prescribed an inappropriately high dose of linagliptin, as there is no requirement for dose adjustment in patients with renal impairment.. In this study, a considerable number of patients with T2DM and renal impairment were prescribed an inappropriately high dose of saxagliptin, alogliptin, sitagliptin, or vildagliptin for their level of renal impairment at treatment initiation. This prescribing could have been due to the complexity of different dosing requirements, or a lack of awareness of the need for dose adjustment of most DPP-4 inhibitors in patients with renal impairment. Linagliptin may be used in patients with moderate or severe renal impairment without dose adjustment.

Topics: Adamantane; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; General Practice; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Nitriles; Piperidines; Pyrrolidines; Retrospective Studies; Sitagliptin Phosphate; Uracil; Vildagliptin

To observe the effect of alogliptin combined with metformin on pulmonary function in obese patients with type 2 diabetes inadequately controlled by metformin monotherapy (500 mg, bid po, for at least 3 months), and evaluate its efficacy and safety.. After a 2-week screening period, adult patients (aged 36-72 years) entered a 4-week run-in/stabilization period. Then, patients were randomly assigned to either the intervention group (n = 55) or the control group (n = 50) for 26 weeks. The patients in the control group were given metformin (1000 mg, bid po) and the patients in the intervention group were given metformin (500 mg, bid po) combined with alogliptin (25 mg, qd po). All the patients received counseling about diet and exercise from a nutritionist during run-in and treatment periods.The primary endpoints were the between-group differences in the changes in pulmonary function parameters (vital capacity [VC]%, forced vital capacity [FVC]%, forced expiratory volume in 1 second (FEV1)%, peak expiratory force [PEF]%, maximal voluntary ventilation [MVV]%, total lung capacity [TLC%], forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC%], diffusing capacity for carbon monoxide of lung [DLCO]%, and diffusing capacity for carbon monoxide of lung/unit volume [DLCO/VA%]) between pretherapy and posttreatment. The secondary endpoints were changes from baseline to week 26 in glycosylated hemoglobinA1c (HbA1c), FPG, 2hPG, homeostasis model assessment insulin resistance (HOMA-IR), waist circumference (WC), and BMI. The tertiary endpoints were the changes from baseline to week 26 in blood-fat (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TG]). The quartus endpoints were the changes from baseline to week 26 in systolic blood pressure (SBP) and diastolic blood pressure (DBP). The 5th endpoints were the changes from baseline to week 26 in oxidative/antioxidative parameters (reactive oxygen species [ROS], malondialdehyde [MDA], superioxide dismutase [SOD], and glutathione peroxidase [GSH-Px]). In addition, safety endpoints were assessed (AEs, clinical laboratory tests, vital signs, and electrocardiographic readings).. Eighty-one patients completed our clinical trial: intervention group (n = 44) and control group (n = 37). At week 26, pulmonary function parameters (VC%, FVC%, FEV1%, PEF%, MVV%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) had increased significantly from pretherapy values in both groups (P < 0.05), and the pulmonary function tests were significantly greater (P < 0.05) in intervention group than in controls posttherapy. Pulmonary function (FVC%, FEV1%, PEF%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) was lower in the group with HbA1c levels ≥8.0 at 26 weeks, but VC%, FEV1%, MVV%, and TLC% were not significantly lower (P > 0.05). Pulmonary function parameters were positively correlated with GSH-Px and SOD and negatively correlated with ROS and MDA. Mean declines in HbA1c, FPG, 2hPG, HOMA-IR, and blood-fat (TC, HDL-C, LDL-C, and TG) were significantly greater (P < 0.05) in intervention group compared with the controls, but mean declines in BMI, WC, and BP (SBP, DBP) did not differ significantly between the 2 groups (P > 0.05). SOD and GSH-Px increased more (P < 0.05) in the intervention group, compared with the controls; ROS and MDA declined more (P < 0.05) in intervention group, as compared with the control group. The most common AEs were gastrointestinal events, headaches, skin-related AEs (mostly pruritic events), and hypoglycemia. The incidences of AEs did not differ significantly (P > 0.05) between the 2 groups except for the headache and skin-related adverse events (the incidence of headache was higher in the intervention group than in controls; P < 0.05). No patient died during the study.. In patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin monotherapy, the addition of alogliptin contributed to clinically significant increases in pulmonary function through regulating glycemia and improving the imbalance of the oxidative-related substances in the serum, without increasing the incidence of hypoglycemia, dyslipidemia, dysarteriotony, and any notable increase in body weight.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Lung; Male; Metformin; Middle Aged; Obesity; Piperidines; Respiratory Function Tests; Uracil

Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.

Topics: Adolescent; Animals; Carbamates; Child; Diabetes Mellitus, Type 2; Female; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Insulin; Insulin-Secreting Cells; Male; Mice; Mutation; Pedigree; Piperidines; Regulatory Factor X Transcription Factors

Topics: Adamantane; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Piperidines; Risk; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Uracil

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Structure; Piperidines; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; Spiro Compounds; Structure-Activity Relationship

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a high-throughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The K

Topics: Adenosine Triphosphatases; Alkaloids; Animals; Basal Metabolism; Benzodioxoles; Diabetes Mellitus, Type 2; High-Throughput Screening Assays; Muscle Fibers, Fast-Twitch; Obesity; Piperidines; Polyunsaturated Alkamides; Rabbits; Skeletal Muscle Myosins; Up-Regulation

We report three Caucasian patients affected by gout and type 2 diabetes, who were treated with the recombinant nonglycosylated human interleukin-1 receptor antagonist anakinra (100 mg/day subcutaneously) after an unsatisfactory or incomplete response to urate-lowering therapy, colchicine, nonsteroidal anti-inflammatory drugs, and prednisone. The remarkable clinical improvement in joint symptoms within 24 h and in glycemic control during a 6-month period gives anakinra a potential therapeutic role in the management of gout and type 2 diabetes. When anakinra was discontinued, a gout attack occurred within 3-25 days in all three patients. The contribution of anakinra in the treatment of such syndromes is encouraging, but requires further studies to establish its long-term efficacy.

Topics: Aged; Aged, 80 and over; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Blood Glucose; Carbamates; Colchicine; Diabetes Mellitus, Type 2; Febuxostat; Glycated Hemoglobin; Gout; Gout Suppressants; Humans; Hyperuricemia; Hypoglycemic Agents; Insulin; Interleukin 1 Receptor Antagonist Protein; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uric Acid

Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM).

Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Molecular Structure; Piperidines; Pyrrolidines; Structure-Activity Relationship; Sulfonamides

Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.. Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.. A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).. Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

Topics: Aged; Carbamates; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Morbidity; Myocardial Infarction; Piperidines; Registries; Retrospective Studies; Risk Factors; Stroke; Sulfonylurea Compounds; Tolbutamide

The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl-4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure. In this study, we assessed the pharmacological properties of TT01001 in both in vitro and in vivo studies. We found that TT01001 bound to mitoNEET without peroxisome proliferator-activated receptor-γ activation effect. In type II diabetes model db/db mice, TT01001 improved hyperglycemia, hyperlipidemia, and glucose intolerance, and its efficacy was equivalent to that of pioglitazone, without the pioglitazone-associated weight gain. Mitochondrial complex II + III activity of the skeletal muscle was significantly increased in db/db mice. We found that TT01001 significantly suppressed the elevated activity of the complex II + III. These results suggest that TT01001 improved type II diabetes without causing weight gain and ameliorated mitochondrial function of db/db mice. This is the first study that demonstrates the effects of a mitoNEET ligand on glucose metabolism and mitochondrial function in an animal disease model. These findings support targeting mitoNEET as a potential therapeutic approach for the treatment of type II diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Escherichia coli; Fluorescence Resonance Energy Transfer; Humans; Hypoglycemic Agents; Iron-Binding Proteins; Ligands; Male; Membrane Proteins; Mice, Inbred Strains; Mitochondria, Muscle; Mitochondrial Proteins; Piperidines; PPAR gamma; Surface Plasmon Resonance; Thiourea

To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD).. Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use.. Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63-1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome.. In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae.

Topics: Aged; Aged, 80 and over; Alberta; Blue Cross Blue Shield Insurance Plans; Carbamates; Cardiovascular Diseases; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Female; Gliclazide; Glyburide; Hospitalization; Humans; Hypoglycemic Agents; Male; Myocardial Ischemia; Piperidines; Proportional Hazards Models; Retrospective Studies; Risk; Universal Health Insurance

Topics: Asian People; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Piperidines; Uracil

Incretin therapies are effective in controlling blood glucose levels in type 2 diabetic patients by improving the survival and function of β-cells. They include dipeptidyl peptidase-4 (DPP-4) inhibitors and long-acting glucagon-like peptide-1 (GLP-1) analogs. We have previously reported that GLP-1 enhances the survival of cultured human islets by activation of the transcription factor CREB. To test the in vivo relevance of these findings, we examined the effects of alogliptin, a DPP-4 inhibitor, in Zucker Diabetic rats, a model for type 2 diabetes. The plasma levels of GLP-1 increased in alogliptin-treated diabetic rats leading to normoglycemia. Pancreatic islets of untreated diabetic rats were characterized by decreased immunostaining for insulin and PDX-1. Elevation of GLP-1 in treated diabetic rats resulted in the improved survival of β-cells. Dual immunofluorescent staining showed phosphorylation/activation of CREB in insulin-positive β-cells of islets. This led to increases in the levels of CREB targets including Bcl-2, an antiapoptotic mitochondrial protein, BIRC3, a caspase inhibitor and IRS-2, an adapter protein needed for insulin signaling. Findings from this study suggest potential activation of cytoprotective CREB by GLP-1 in pancreatic β-cells of diabetic patients undergoing incretin-based therapies.

Topics: Animals; Baculoviral IAP Repeat-Containing 3 Protein; Blood Glucose; Cyclic AMP Response Element-Binding Protein; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Inhibitor of Apoptosis Proteins; Insulin; Insulin Receptor Substrate Proteins; Insulin-Secreting Cells; Male; Piperidines; Proto-Oncogene Proteins c-bcl-2; Rats, Zucker; Triglycerides; Uracil

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Piperidines

Topics: Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil

Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Islets of Langerhans; Lipid Metabolism; Male; Pioglitazone; Piperidines; Prediabetic State; Rats; Rats, Zucker; Thiazolidinediones; Uracil

Many patients with type 2 diabetes mellitus(T2DM) do not achieve satisfactory glycemic control by monotherapy alone, and often require multiple oral hypoglycemic agents (OHAs). Combining OHAs with complementary mechanisms of action is fundamental to the management of T2DM. Fixed-dose combination therapy(FDC) offers a method of simplifying complex regimens. Efficacy and tolerability appear to be similar between FDC and treatment with individual agents. In addition, FDC can enhance adherence and improved adherence may result in improved glycemic control. Four FDC agents are available in Japan: pioglitazone-glimepiride, pioglitazone-metformin, pioglitazone-alogliptin, and voglibose-mitiglinide. In this review, the advantages and disadvantages of these four combinations are identified and discussed.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Inositol; Isoindoles; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Thiazolidinediones; Uracil

Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.

Topics: Animals; Benzoxazines; Blotting, Western; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Liver; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, CCR2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The treatment of newly diagnosed type 2 diabetes mellitus is diverse, with no clear consensus regarding the initial drug regimen or dosing to achieve optimal glycemic control.. We treated 44 consecutive patients with newly diagnosed type 2 diabetes with maximally tolerated doses of pioglitazone 45 mg/day, metformin 1000-2000 mg/day, and repaglinide 1-4 mg before meals. The doses and drugs were subsequently decreased ("subtraction therapy") to achieve optimal glycemic control and minimize side effects. Three primary outcomes were measured: the short term HbA1c response, the long term HbA1c response, and the incidence of hypoglycemia.. All 44 patients responded with a rapid, progressive decline in their HbA1c levels from 11.43±2.3% to 6.17±0.72% (101±25.1 mmol/mol to 44±7.9 mmol/mol) by three months, and remained stable thereafter. An HbA1c ≤7.0% (≤53 mmol/mol) was reached within 1-4 months in 42 of 44 patients, and in every patient by 12 months. Each patient's lowest HbA1c level, 5.65±0.6% (38±6.6 mmol/mol), was reached over 6.3±2.9 months. Patients with initial HbA1c levels >10% (>86 mmol/mol) (n=33) responded similarly as those with HbA1c levels <10% (<86 mmol/mol) (n=11). Combination drug therapy maintained HbA1c levels between 5.0 and 7.0% (31 and 53 mmol/mol) for up to 14.83 years. Only one clinically significant hypoglycemic event occurred during 261.08 person-years of follow-up.. In our experience, combination drug "subtraction therapy" was safe and effective for treating all newly diagnosed type 2 diabetic patients.

Topics: Adult; Aged; Aged, 80 and over; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Goals; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Piperidines; Thiazolidinediones; Treatment Outcome

All dipeptidyl peptidase 4 (DPP-4) inhibitors display similar glycemic efficacies, although they differ greatly in their chemical structures and pharmacological properties. This may be due to the inclusions of non- or poor-responders in the analysis, thereby masking the real effects of these drugs. The aim of this study was to identify any differences in diabetic parameters only in good responders treated with sitagliptin and alogliptin.. Treatment naïve subjects with type 2 diabetes mellitus were assigned to either sitagliptin 25-50 mg/day (n = 69) or alogliptin 12.5-25 mg/day monotherapy (n = 62) for 3 months. Only those who showed good response selected by a novel parameter called A1c index were further analysed (n = 24 for sitagliptin and n = 21 for alogliptin).. At baseline, FBG and BMI were significantly higher and CPR-index was significantly lower in alogliptin good responders. At 3 months, while similar reductions of HbA1c were observed in these two groups, decreases of fasting blood glucose (FBG) were significantly higher in alogliptin good responders. Homeostasis model assessment (HOMA)-R significantly decreased only in alogliptin good responders, while HOMA-B similarly and significantly increased in these two groups. BMI significantly increased only in sitagliptin good responders. Significant negative correlations were observed between A1c index and changes (Δ) of HOMA-B in both groups. By contrast, significant positive and negative correlations were observed between ΔFBG and ΔHOMA-R, and between ΔFBG and ΔHOMA-B, respectively, only in alogliptin good responders.. These results implicate that the effects on diabetic parameters and the glucose-lowering mechanisms of these two drugs might be different in those who have good response with these drugs. Accordingly, the choice of these drugs may be dependent on the characteristics of the patients.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Sitagliptin Phosphate; Uracil

The aims of this study were (1) to examine the renoprotective effects of alogliptin and (2) to establish urinary angiotensinogen (AGT) as a prognostic marker of renoprotective effects of alogliptin in patients with type 2 diabetes (T2D).. In 43 patients with T2D (18 women, 66.1 ± 1.71 years), 25 mg/day of alogliptin was added to the traditional hypoglycemic agents and/or nondrug treatments. Urinary concentrations of albumin (Alb) and AGT, normalized by urinary concentrations of creatinine (Cr) (UAlbCR and UAGTCR, respectively), were measured before and after the 12-week alogliptin treatment.. Alogliptin treatment tended to decrease UAlbCR (99.6 ± 26.8 versus 114.6 ± 36.0 mg/g Cr, P = 0.198). Based on % change in UAlbCR, patients were divided into two groups, responders (< -25%) and nonresponders (≥ -25%), and a logistic analysis of UAGTCR before treatment showed cutoff value of 20.8 µg/g Cr. When all patients were redivided into two groups, those with higher values of UAGTCR before the treatment (Group H, n = 20) and those with lower values (Group L), Group H showed significantly decreased UAlbCR in response to alogliptin (-14.6 ± 8.6 versus +22.8 ± 16.8%, P = 0.033).. Urinary AGT could be a prognostic marker of renoprotective effects of alogliptin in patients with T2D.

Topics: Aged; Albumins; Angiotensinogen; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Japan; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Piperidines; Prognosis; Treatment Outcome; Uracil

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil

Topics: Acute Coronary Syndrome; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Male; Piperidines; Uracil

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines; Uracil

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Fasting; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Metformin; Middle Aged; Peptides; Piperidines; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Failure; Triazoles; Venoms

In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; CHO Cells; Cricetulus; Cyclic AMP; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Obesity; Oxadiazoles; Piperidines; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Time Factors; Transfection; Weight Gain

Topics: Animals; Diabetes Mellitus, Type 2; Longevity; Obesity; Piperidines; Receptors, Adiponectin

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Angina, Unstable; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Diabetes is a major risk factor for chronic kidney disease (CKD). In this study, we examined the effects of alogliptin on blood glucose control and the renal function in type 2 diabetes CKD patients.. We recruited 36 CKD patients with type 2 diabetes. The patients were followed up for six months after adding alogliptin. Blood biochemical, urine test and office BP values were obtained six months before and after the start of treatment.. The mean HbA1c value was not decreased; however, the 1,5-AG values tended to improve (p=0.1023). The mean eGFR was unchanged. There were no significant changes in the patients with an eGFR of 60 mL/min/1.73 m2 or more (25 patients) or in the patients with an eGFR less than 60 mL/min/1.73 m2 (11 patients). A total of 15 patients were identified to have rapidly declining diabetic nephropathy, with an annual reduction in eGFR of 5 mL/min/1.73 m2 or more. The slope of the regression line for eGFR (-1.296 before starting treatment with alogliptin) was positive, increasing up to 0.08786. The eGFR values appeared to stop decreasing and positively reversed. The urinary albumin-to-creatinine ratio exhibited a downward trend. The effect on the renal function was independent of the levels of blood sugar, blood pressure and lipids.. We examined the ability of alogliptin to maintain the renal function in patients with CKD complicated by type 2 diabetes. Our study suggests that alogliptin can be safely administered in patients with CKD. However, although we expected alogliptin to demonstrate renal protective effects, were unable to detect statistically significant differences. One reason for this finding is that there are few registered cases.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; Uracil

There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Humans; Hypoglycemic Agents; Insulin; Male; Pioglitazone; Piperidines; Rats; Thiazolidinediones; Uracil

In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors ('gliptins').. The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation.. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebo-controlled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on hospitalisations for heart failure has not been reported. Neither agent improved cardiovascular outcomes. As there is no published evidence of improved outcomes with gliptins, it is unclear to us why these agents are so widely available for use. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established.

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Linagliptin; Models, Molecular; Piperidines; Protein Conformation; Purines; Quinazolines; Structure-Activity Relationship; Substrate Specificity; Uracil

Dipeptidyl peptidase-4 (DPP-4) inhibitors including alogliptin are categorised as a newer class of oral hypoglycaemic, antidiabetic drugs to suppress the degradation of incretin hormones ((glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)) by DPP-4. We have scheduled a large-scale, multicentre, prospective, observational study (Japan-Based clinical ReseArch Network for Diabetes Registry: J-BRAND Registry) to construct an extensive database over a long-term clinical course in patients with type 2 diabetes receiving oral hypoglycaemic agents (OHAs) and to evaluate the safety and efficacy of alogliptin in Japanese population.. 20,000 patients with type 2 diabetes will be registered into two groups of 10,000 each: group A patients will be treated with alogliptin, while group B patients will be treated with non-DPP-4 inhibitor OHA(s). Approximately 300 institutions nationwide will enrol and assign eligible patients equally to either group. Each patient's data will be collected every 6 months for a 3-year period, during which time treatment with OHA(s) may be changed or discontinued, as per package insert for each OHA. Primary end points are safety variables to be compared between the two groups and their subgroups, with respect to hypoglycaemia, pancreatitis, skin disorders, infections and cancer. Secondary end points are efficacy variables including from-baseline changes of A1c, fasting glucose, fasting insulin and urinary albumin, which will be compared between groups/subgroups. New onset and progression of microangiopathy will also be evaluated against OHA(s). Overall, the J-BRAND Registry will evaluate the safety and efficacy of antidiabetic OHA(s) including alogliptin, based on a large-scale database.. This study will be conducted with the highest respect for individual participants according to this protocol, the Declaration of Helsinki, the Ethical Guidelines for Clinical Research (Japan Ministry of Health, Labour and Welfare, 2008) and relevant laws/regulations. The present study will construct a valuable database of patients with type 2 diabetes treated with OHA(s) including alogliptin.. UMIN000007976.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Observational Studies as Topic; Piperidines; Prospective Studies; Registries; Uracil

Topics: Aged, 80 and over; Carbamates; Diabetes Mellitus, Type 2; Frail Elderly; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines

Type 2 diabetes is characterised by insulin resistance and deficiencywhich explains the multitude of molecules developed for its treatment.The beneficial effects of metformin and sulfamides have been demonstrated. Over the last 10 years, new molecules have appeared: acarbose, repaglinide and incretins.

Topics: Carbamates; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Piperidines

Topics: Aged; Carbamates; Diabetes Mellitus, Type 2; Humans; Male; Piperidines; Thrombocytopenia

Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L-cells located predominantly in distal regions of the gut secrete glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L-cells stimulated by the BA receptor G protein-coupled bile acid receptor 1 (GPBAR1).. A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L-cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro-RO5527239, the acute secretion effects on L-cells were addressed via different routes of administration.. GPBAR1 signalling triggers the co-secretion of PYY and GLP-1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro-RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys.. Selective GPBAR1 activation elicits a strong secretagogue effect on L-cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal-distal loop that mediates the early phase of nutrient-evoked L-cell secretion effects.

Topics: Animals; Cell Line; CHO Cells; Cricetulus; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Isonipecotic Acids; Macaca fascicularis; Male; Metabolic Detoxication, Phase II; Mice; Mice, Mutant Strains; Mice, Transgenic; Oximes; Peptide YY; Piperidines; Receptors, G-Protein-Coupled; Recombinant Proteins; Taurine

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; United States; United States Food and Drug Administration; Uracil

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Uracil

Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake.. After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group).. Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p< 0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups.. Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.

Topics: Adiponectin; Adiposity; Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Eating; Glucose Intolerance; Insulin Resistance; Insulin-Secreting Cells; Male; Piperidines; Pyrazoles; Rats; Rats, Inbred OLETF; Receptor, Cannabinoid, CB1; Rimonabant; Rosiglitazone; Thiazolidinediones

G-protein coupled receptor (GPR)55 is a novel lipid sensing receptor activated by both cannabinoid endogenous ligands (endocannabinoids) and other non-cannabinoid lipid transmitters. This study assessed the effects of various GPR55 agonists on glucose homeostasis.. Insulin secretion and changes in intracellular Ca(2) (+) and cAMP in response to glucose and a range of GPR55 agonists [endogenous ligands (OEA, PEA), chemically synthetic cannabidiol (CBD) analogues (Abn-CBD, 0-1602), an analogue of rimonabant (AM-251) and antagonist (CBD)] were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Cytotoxicity was assessed by LDH release, cellular localization by double-staining immunohistochemistry and in vivo effects assessed in mice.. The most potent and selective GPR55 agonist was the synthetic CBD analogue, Abn-CBD (pEC50 10.33), maximum stimulation of 67% at 10(-4)  mol·L(-1) (P < 0.001) in BRIN-BD11 cells. AM-251 (pEC50 7.0), OEA (pEC50 7.0), 0-1602 (pEC50 7.3) and PEA (pEC50 6.0) stimulated insulin secretion. Results were corroborated by islet studies, with no cytotoxic effects. Concentration-dependent insulin secretion by GPR55 agonists was glucose-sensitive and accompanied by elevations of [Ca(2) (+) ]i (P < 0.01-P < 0.001) and cAMP (P < 0.05-P < 0.01). GPR55 agonists exhibited insulinotropic and glucose lowering activity in vivo. GPR55 was expressed on BRIN-BD11 cells and confined to islet beta cells with no distribution on alpha cells.. These results demonstrate GPR55 is distributed in pancreatic beta cells and is a strong activator of insulin secretion, with glucose-lowering effects in vivo. Development of agents agonizing the GPR55 receptor may have therapeutic potential in the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Calcium; Cannabidiol; Cell Line; Clone Cells; Cyclic AMP; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Ethanolamines; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Oleic Acids; Palmitic Acids; Piperidines; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Resorcinols; Time Factors

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Uracil

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Topics: Adenylate Kinase; Adiponectin; Adipose Tissue, White; Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin Resistance; Liver; Longevity; Mice; Mitochondria; Muscle Fibers, Skeletal; Muscles; Obesity; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; PPAR alpha; Receptors, Adiponectin; Signal Transduction; Small Molecule Libraries; Transcription Factors; Triglycerides

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Treatment Outcome; Uracil

To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD).. We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4).. In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069).. Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.

Topics: Adamantane; Aged; Carbamates; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Ischemic Preconditioning; Male; Middle Aged; Nitriles; Piperidines; Prospective Studies; Pyrrolidines; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to be generally well tolerated. However, angioedema has been reported as one of the rare adverse events of these drugs.. We report a case in which angioedema induced by vildagliptin disappeared after changing to another DPP-4 inhibitor, alogliptin.. Our case suggests that there is a difference in the risk of angioedema among DPP-4 inhibitors. To clarify this possibility, further investigation on the risk of angioedema among DPP-4 inhibitors is warranted.

Topics: Adamantane; Aged; Angioedema; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Substitution; Humans; Male; Nitriles; Piperidines; Pyrrolidines; Uracil; Vildagliptin

The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Expression Regulation; Glucose; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Piperidines; Podocytes; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA Interference; RNA, Small Interfering

The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Discovery; Humans; Hypoglycemic Agents; Mice; Mice, Inbred C57BL; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled

The aim of the present study was to evaluate the impact of the UCP2-866 G/A polymorphism on the efficacy of repaglinide in treating patients with diabetes mellitus type 2 (T2DM). 370 patients with T2DM and 166 healthy volunteers were enrolled to identify UCP2-866 G/A genotypes. 16 patients with GG genotype, 14 with GA genotype and 11 with AA genotype of UCP2-866 G/A underwent an 8-week repaglinide treatment regimen. There were no differences in allele frequency of UCP2-866 G/A between T2DM patients and control subjects. The patient with AA genotype of UCP2-866 G/A had higher levels of fasting plasma glucose (FPG), 30-min and 2-h postload plasma glucose, glycated haemoglobin (HbA1c), and lower concentrations of 30-min and 2-h postload plasma insulin, homeostasis model assessment of beta cell function (HOMA-beta), deltaI30/deltaG30 compared with GG genotype. After repaglinide treatment for 8 consecutive weeks, we found that A allele carriers of UCP2 in the T2DM patients had smaller decrease in FPG (P < 0.05) and HbA1c (P < 0.05), and smaller increase in 30-min postload plasma insulin (P < 0.01) compared with GG genotypes. We demonstrated that UCP2-866 G/A polymorphism is associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.

Topics: Adult; Aged; Alleles; Asian People; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; DNA Primers; Female; Genotype; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Ion Channels; Male; Middle Aged; Mitochondrial Proteins; Pancreatic Function Tests; Piperidines; Polymerase Chain Reaction; Uncoupling Protein 2

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has attracted considerable attention as a potential target for the treatment of diabetes and metabolic syndrome. Herein we report the design, synthesis and efficacy evaluation of novel amide and urea 11β-HSD1 inhibitors. Structure-activity relationship studies led to the identification of 10c, which was efficacious in a diabetic ob/ob mouse model and reduced fasting and non-fasting blood glucose levels after ip dosing.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Diabetes Mellitus, Type 2; Enzyme Activation; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Mice; Mice, Obese; Molecular Structure; Piperidines; Structure-Activity Relationship; Urea

Topics: Adolescent; Adult; Advisory Committees; Aged; Anti-Obesity Agents; Bariatric Medicine; Body Mass Index; Child; Congresses as Topic; Cyclobutanes; Diabetes Mellitus, Type 2; Drug Approval; Drug Discovery; Female; History, 20th Century; History, 21st Century; Humans; Male; Middle Aged; Multicenter Studies as Topic; Obesity; Outcome Assessment, Health Care; Piperidines; Practice Guidelines as Topic; Pyrazoles; Randomized Controlled Trials as Topic; Reference Standards; Rimonabant; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration

In this paper we analyse the discrepancies that exist in the widespread prescription of metformin in patients with type 2 diabetes and the lack of guidelines concerning its prescription in the different stages of renal failure. This cross-sectional study includes 304 patients with type 2 diabetes treated with oral antidiabetic drugs (ADOs) and a glomerular filtration rate (estimated GFR) <60ml/min/1.73m2. Patients were attended in consecutive visits to primary health centres or in hospital departments of endocrinology or nephrology during 2010. We studied the frequency of metformin and other ADO prescriptions according to renal function and the department in which the patient was treated. The ADO most frequently prescribed was metformin (54.9%), followed by repaglinide (47.7%), DPP4 inhibitors (28.6%), and sulfonylureas (18.4%). However, in nephrology departments, repaglinide was more frequently prescribed than metformin (P<.001), whereas in primary health centres, the prescription of DPP4 inhibitors increased. In patients with an estimated GFR of 15-29ml/min/1.73m2, metformin (13.3%) and sulfonylureas were the least prescribed, whereas metformin was much more frequently prescribed (70.0%) when estimated GFR was 45-59ml/min/1.73m2 (P<.001). In contrast, patients with an estimated GFR of 15-29ml/min/1.73m2 were mainly prescribed repaglinide (76.7%), as opposed to patients with an estimated GFR of 45-59ml/min/1.73m2 (38.9%) (P<.001). Substantial evidence suggests that the recommendations for the use of ADO should be modified. This would lead to safely prescribing ADO in patients with an estimated GFR<60ml/min/1.73m2, and more importantly in medical practice, according to the law.

Topics: Acidosis, Lactic; Aged; Carbamates; Consensus Development Conferences as Topic; Contraindications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Management; Drug Utilization; Endocrinology; Female; Follow-Up Studies; Glomerular Filtration Rate; Hospital Departments; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Nephrology; Piperidines; Practice Guidelines as Topic; Primary Health Care; Professional Practice; Societies, Medical; Spain; Sulfonylurea Compounds

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Weight loss is often difficult to achieve in individuals with type 2 diabetes and anti-obesity drugs are often advocated to support dietary intervention. Despite the extensive use of centrally acting anti-obesity drugs, there is little evidence of how they affect dietary composition. We investigated changes in energy intake and dietary composition of macro- and micronutrients following therapy with the endocannabinoid receptor blocker, rimonabant.. 20 obese patients with type 2 diabetes were studied before and after 6 months dietary intervention with rimonabant. Dietary intervention was supervised by a diabetes dietician. Five-day food diaries were completed at baseline and at 6 months and dietary analysis was performed using computer software (Dietplan 6).. After 6 months, (compared with baseline) there were reductions in weight (107 ± 21Kg versus 112 ± 21, p < 0.001, 4% body weight reduction), and improvements in HbA1c (7.4 ± 1.7 versus 8.0 ± 1.6%, p < 0.05) and HDL cholesterol. Intake of energy (1589 ± 384 versus 2225 ± 1109 kcal, p < 0.01), carbohydrate (199 ± 74 versus 273 ± 194 g, p < 0.05), protein (78 ± 23 versus 98 ± 36 g, p < 0.05), fats (55 ± 18 versus 84 ± 39 g, p < 0.01) and several micronutrients were reduced. However, relative macronutrient composition of the diet was unchanged. Improvement in blood glucose was strongly correlated with a reduction in carbohydrate intake (r = 0.76, p < 0.001).. In obese patients with type 2 diabetes, rimonabant in combination with dietary intervention led to reduced intake of energy and most macronutrients. Despite this, macronutrient composition of the diet was unaltered. These dietary changes (especially carbohydrate restriction) were associated with weight loss and favourable metabolic effects.

Topics: Adult; Aged; Blood Glucose; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Humans; Male; Micronutrients; Middle Aged; Obesity; Piperidines; Pyrazoles; Regression Analysis; Rimonabant; Weight Loss

Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na(+) reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na(+) excretion, and renal membrane expression of the Na(+)/H(+) exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na(+) reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Kidney; Mice; Mice, Knockout; Natriuresis; Natriuretic Agents; Obesity; Peptides; Phosphorylation; Piperidines; Receptors, Glucagon; Uracil; Venoms

Mitochondrial dysfunction plays a key pathophysiological role in type 2 diabetes mellitus (T2DM). Data delineating relationships between mitochondrial and endothelial dysfunction in humans with T2DM are lacking.. In 122 human subjects (60 with T2DM, 62 without T2DM), we measured endothelial function by brachial artery ultrasound (flow mediated dilation) and digital pulse amplitude tonometery. Endothelial function in arterioles isolated from gluteal subcutaneous adipose was measured by videomicroscopy. In arterioles and mononuclear cells, we measured inner mitochondrial membrane potential (Δψ(m)), mitochondrial mass, and mitochondrial superoxide production using fluorophores. Endothelial function was impaired in T2DM subjects versus control subjects. Δψ(m) magnitude was larger and mitochondrial mass was lower in arterioles and mononuclear cells in T2DM. Mononuclear mitochondrial mass correlated with flow-mediated dilation and pulse amplitude tonometery (ρ=0.38 and 0.33, P=0.001 and 0.02, respectively), and mononuclear mitochondrial superoxide production inversely correlated with flow-mediated dilation (ρ=-0.58, P=0.03). Low doses of 2 different mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenyl hydrazone and 2,4-dinitrophenol) that reduce Δψ(m) magnitude and a mitochondrial-targeted antioxidant (MitoTEMPOL) improved endothelial function and reduced mitochondrial superoxide levels in T2DM arterioles.. Mitochondrial dysfunction may play a central role in the impairment of endothelial dysfunction in T2DM.

Topics: 2,4-Dinitrophenol; Adult; Arterioles; Brachial Artery; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Case-Control Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Humans; Male; Membrane Potential, Mitochondrial; Middle Aged; Mitochondria; Organophosphorus Compounds; Piperidines; Pulse Wave Analysis; Superoxides; Ultrasonography; Uncoupling Agents

Naringenin is a flavone flavonoid possessing antidiabetic, antioxidant and memory improving effects. Therefore, we studied the influence of naringenin against type-2 diabetes-induced memory dysfunction in rats. Type-2 diabetes was induced by high-fat diet and high-fat emulsion for two weeks and a low dose of streptozotocin (35 mg/kg). The memory deficit was assessed by using a novel object recognition paradigm. The changes in oxidative markers and cholinesterase (ChE) levels were evaluated in the hippocampal region. After confirmation of diabetes, naringenin (50mg/kg) treatment was given to animals as a preventive and in another set of experiments naringenin (25 and 50mg/kg) or pioglitazone (5mg/kg) or donepezil (3mg/kg) treatments were started after long-standing diabetes (4 weeks after confirmation). Both the treatment schedules show significant protection and improvement in cognitive behavior against diabetes-induced memory dysfunction and biochemical changes. Also, treatment with pioglitazone and donepezil improved memory performance in rats. Naringenin was found to decrease oxidative stress by depleting elevated lipid peroxide and nitric oxide and elevating reduced glutathione levels. Cholinergic function was improved by naringenin through the inhibition of elevated ChE activity. In conclusion, the present study suggests that naringenin acts as an antioxidant and ChE inhibitor against type-2 diabetes-induced memory dysfunction.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cholinesterase Inhibitors; Cholinesterases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Donepezil; Estrogen Antagonists; Fat Emulsions, Intravenous; Flavanones; Glutathione; Hypoglycemic Agents; Indans; Lipid Peroxidation; Male; Memory Disorders; Nitric Oxide; Parasympathetic Nervous System; Pioglitazone; Piperidines; Rats; Rats, Sprague-Dawley; Recognition, Psychology; Thiazolidinediones

New dipeptidyl peptidase IV inhibitors were designed based on Alogliptin using a scaffold-hopping strategy. All of the compounds constructed on a thienopyrimidine scaffold demonstrated good inhibition and selectivity for DPP-IV. Compound 10d exhibited subnanomolar (IC(50)=0.33nM) DPP-IV inhibitory activity, good in vivo efficacy and an acceptable pharmacokinetic profile. A pharmacokinetic-driven optimization of 10d may lead to a new class of clinical candidate DPP-IV inhibitors.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Drug Discovery; HEK293 Cells; Humans; Male; Piperidines; Pyrimidines; Rats; Uracil

We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.

Topics: Adamantane; Allylamine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Investigational New Drug Application; Liraglutide; Nitriles; Peptides; Piperidines; Practice Guidelines as Topic; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Triazoles; United States; United States Food and Drug Administration; Uracil; Venoms; Vildagliptin

Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression.. Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot.. WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists.. This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.

Topics: Animals; Benzoxazines; Cannabinoids; Cardiotonic Agents; Coronary Vessels; Diabetes Mellitus, Type 2; Heart; Heart Rate; Indoles; Male; Morpholines; Myocardial Ischemia; Myocardial Reperfusion Injury; Naphthalenes; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

A 3-amino-4-substituted pyrrolidine series of dipeptidyl peptidase IV (DPP-4) inhibitors was rapidly developed into a candidate series by identification of a polar valerolactam replacement for the lipophilic 2,4,5-trifluorophenyl pharmacophore. The addition of a gem-difluoro substituent to the lactam improved overall DPP-4 inhibition and an efficient asymmetric route to 3,4-diaminopyrrolidines was developed. Advanced profiling of a subset of analogs identified 5o with an acceptable human DPP-4 inhibition profile based on a rat PK/PD model and a projected human dose that was suitable for clinical development.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Models, Molecular; Piperidines

A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC(50)<50n M) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes.

Topics: Amides; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Inhibitory Concentration 50; Mice; Mice, Inbred ICR; Piperidines

To provide feedback on the initial market authorization of rimonabant, a drug to be used under strict guidelines, we conducted a study with information from the National health insurance reimbursements database for southeastern France. The aims of this study were to: (1) describe the characteristics of subjects who have had one rimonabant prescription reimbursed; (2) study the frequency of prescriptions that did not comply with reimbursement criteria; (3) study the frequency of prescriptions for patients simultaneously treated with antidepressants; and (4) analyse the factors associated with both types of prescription (patient and prescriber characteristics).. Using the database of drug reimbursements maintained by the southeastern France general health insurance fund, we studied the characteristics of outpatients with at least one reimbursement for rimonabant, compared them to the rest of the population, and analysed compliance with the indications, contraindications, and regulations for rimonabant prescription with multivariate logistic regressions.. A total of 10,510 beneficiaries (0.28%) had at least one rimonabant reimbursement. Among them, 55.7% were treated for diabetes. For at least 62.4% of rimonabant beneficiaries, the reimbursement regulations were not respected: this was significantly more frequent among women less than 57 years old, subjects with no chronic diseases, and when the prescriber was not an endocrinologist; 11.4% of rimonabant beneficiaries also received an antidepressant treatment.. Despite the specific status of rimonabant regarding its reimbursement modalities, these results suggest that some prescribers get around reimbursement instructions and that a significant percentage of prescriptions did not respect an important contraindication. Tools to follow up the prescriptions of new drugs with strict guidelines for use should be developed and physicians should be better informed and trained regarding specific prescription regulations.

Topics: Adult; Antidepressive Agents; Body Mass Index; Depressive Disorder; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Prescriptions; Feedback; Female; France; Humans; Insurance, Health, Reimbursement; Logistic Models; Male; Middle Aged; Obesity; Piperidines; Practice Guidelines as Topic; Pyrazoles; Retrospective Studies; Rimonabant

Meglitinides (repaglinide and nateglinide) are insulin secretagogues used to treat diabetes mellitus. We present a case of hypersensitivity reaction to repaglinide in a 61-year-old man who developed a maculopapular rash 5 days after treatment. Skin prick tests including repaglinide (0.5 g/mL) and patch tests (0.05% in pet and saline) were performed, and the results were negative. A blind oral challenge test with repaglinide was performed and the therapeutic dose was subsequently taken at home every 24 hours for 7 days. The result was positive with a delayed reaction at day 3. A punch biopsy of the skin lesions revealed drug-induced exanthema. The clinical manifestations, the latency period, the reappearance of cutaneous lesions after rechallenge, and the histopathology report of the skin biopsy suggest a type IV mechanism.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Erythema; Exanthema; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Patch Tests; Phenylalanine; Piperidines

1. In the present study, we investigated the associations of nicotinamide phosphoribosyltransferase (NAMPT)-3186 C/T and -948G/T polymorphisms with the risk of Type 2 diabetes mellitus (T2DM) and their impact on the efficacy of repaglinide in Chinese Han T2DM patients. 2. In all, 170 patients with T2DM and 129 healthy controls were genotyped for NAMPT-948G>T and -3186C>T polymorphisms. Thirty-five patients with different NAMPT -3186 C/T genotypes and the same organic anion-transporting polypeptide 1B1 (OATP1B1521) T/C genotype were randomly selected to undergo 8 weeks preprandial repaglinide treatment (1 mg, three times daily). Serum fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), glycated haemoglobin (HbAlc), fasting serum insulin (FINS), post-prandial serum insulin (PINS), triglyceride (TG), total cholesterol (CHO), homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) were determined before and after repaglinide treatment. 3. After repaglinide treatment for 8 consecutive weeks, there were significantly decreases in PFG, PPG, HbAlc, CHO and LDL-C, and increases in FINS, HDL-C and the HDL-C : LDL-C ratio, in T2DM patients. The elevated PINS value in patients with CT genotypes was significantly lower than that in patients with the CC and TT genotypes (P < 0.05) and there were significant differences in CHO between patients with the CT genotype and the CC or TT genotype (P < 0.05). 4. The data suggest that the NAMPT -3186C>T polymorphism is significantly associated with plasma levels of PINS and CHO in Chinese T2DM patients with repaglinide monotherapy.

Topics: Adult; Aged; Alleles; Asian People; Carbamates; Cholesterol; Control Groups; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Piperidines; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Treatment Outcome

The use of retroviral drugs in the treatment of infection by human immunodeficiency virus (HIV) is associated, especially for first generations, with side effects such as lipodystrophy, fatty liver and insulin resistance, which may trigger secondary diabetes or worsen existing diabetes. The use of Glucagon-Like Peptide-1 in obese patients with type 2 diabetes on HIV retroviral as an alternative to insulin therapy is not documented; we report the case of a 47-year-old treated with exenatide when insulin was discontinued. During the first year of treatment, exenatide, in combination with metformin and repaglinide, led to a weight loss of 14 kg and fat mass and waist circumference were respectively reduced from 31 to 25.5% and from 114 to 103 cm. Homeostatic model assessment (HOMA) was used to calculate β-cell secretion which increased from 50 to 78% and insulin sensitivity which increased from 28 to 51%, reflecting a decrease in HbA(1c) by 1.9%. Exenatide may be a new therapeutic option for HIV-infected type 2 diabetes patients undergoing retroviral therapy.

Topics: Adipose Tissue; Antiretroviral Therapy, Highly Active; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; HIV Infections; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Piperidines; Venoms; Waist Circumference; Weight Loss

Topics: Administration, Oral; Biguanides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines; Sulfonylurea Compounds

Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid and glucose metabolism. PPARgamma agonists improve insulin sensitivity and hyperglycemia and are effective in treating type 2 diabetes mellitus (T2DM), whereas PPARalpha agonists are used to treat dyslipidemia and atherosclerosis. The goal here was to examine the efficacy of a selective PPARalpha agonist {(S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP-900691} on lipid, glycemic, and inflammation indices in 14 cynomolgus monkeys with spontaneous T2DM maintained on daily insulin therapy. Monkeys were dosed orally with either vehicle (n = 7) or CP-900691 (3 mg/kg, n = 7) daily for 6 weeks. CP-900691 treatment increased plasma high-density lipoprotein cholesterol (HDLC) (33 +/- 3 to 60 +/- 4 mg/dL, p < 0.001) and apolipoprotein A1 (96 +/- 5 to 157 +/- 5 mg/dL, p < 0.001), reduced plasma triglycerides (547 +/- 102 to 356 +/- 90 mg/dL, p < 0.01), and apolipoprotein B (62 +/- 3 to 45 +/- 3 mg/dL, p < 0.01), improved the lipoprotein index (HDL to non-HDLC ratio; 0.28 +/- 0.06 to 0.79 +/- 0.16, p < 0.001), decreased body weight (p < 0.01) and C-reactive protein (CRP) (1700 +/- 382 to 304 +/- 102 ng/ml, p < 0.01), and increased adiponectin (1697 +/- 542 to 4242 +/- 1070 ng/ml, p < 0.001) compared with baseline. CP-900691 treatment reduced exogenous insulin requirements by approximately 25% (p < 0.04) while lowering plasma fructosamine from 2.87 +/- 0.09 to 2.22 +/- 0.17 mM (p < 0.05), indicative of improved glycemic control. There were no changes in any of the aforementioned parameters in the vehicle group. Because low HDLC and high triglycerides are well established risk factors for cardiovascular disease, the marked improvements in these parameters, and in glycemic control, body weight, and CRP, suggest that CP-900691 may be of benefit in diabetic and obese or hyperlipidemic populations.

Topics: Adiponectin; Animals; Area Under Curve; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glucose Tolerance Test; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Lipids; Lipoproteins; Macaca fascicularis; Piperidines; PPAR alpha; Propionates; Weight Loss

To investigate a potential association between SNP rs10494366 in the neural nitric oxide synthase adaptor protein (NOS1AP) and efficacy of repaglinide (an insulin secretagogue) in newly diagnosed Shanghai Chinese type 2 diabetes patients.. A total of 104 newly diagnosed type 2 diabetes patients (69 men, 35 women) were recruited and treated with repaglinide for 24 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 24-week treatment. Genotyping was performed by sequencing.. The baseline value of BMI, HOMA-IR, HOMA-B, and fasting insulin level were significantly different between GG, GT, and TT genotypes (P=0.024, 0.030, 0.005, and 0.007, respectively). Carriers of TT genotype were in significant insulin resistance at baseline. After 24-week repaglinide monotherapy, the Delta value of fasting insulin (P=0.019) and HOMA-IR (P=0.011) were significantly different. TT carriers had the least insulin resistance after treatment. The mixed model analysis showed that the variation had an interaction effect with repaglinide treatment only on HOMA-IR (P=0.013).. A common variant in rs10494366 is associated with repaglinide monotherapy efficacy on insulin resistance in newly diagnosed Shanghai Chinese type 2 diabetes patients.

Topics: Adaptor Proteins, Signal Transducing; Carbamates; China; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; Piperidines; Polymorphism, Single Nucleotide

Topics: Adult; Androstanols; Anesthesia, Intravenous; Cholecystectomy, Laparoscopic; Cholelithiasis; Contraindications; Diabetes Mellitus, Type 2; Fentanyl; Humans; Intraoperative Complications; Male; MELAS Syndrome; Neuromuscular Nondepolarizing Agents; Oxygen; Piperidines; Postoperative Complications; Preanesthetic Medication; Preoperative Care; Propofol; Remifentanil; Rocuronium; Succinylcholine

To investigate whether the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) rs1470579 and rs4402960 polymorphisms are associated with the development of type 2 diabetes mellitus (T2DM) and the repaglinide therapeutic efficacy in Chinese T2DM patients.. A case-control study of a total of 350 patients with T2DM and 207 healthy volunteers was conducted to identify their genotypes for the IGF2BP2 rs1470579 and rs4402960 polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-two patients were randomly selected to undergo an 8-week repaglinide treatment (3 mg/d). Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbAlc), fasting serum insulin (FINS), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), serum triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) were determined before and after repaglinide treatment.. The frequencies of the IGF2BP2 rs1470579 C allele and the rs4402960 T allele were higher in T2DM patients than in healthy controls (P<0.05 and P<0.001, respectively). The effects of the repaglinide treatment on FPG (P<0.05) and PPG (P<0.05) were reduced in patients with the rs1470579 AC+CC genotypes compared with AA genotype carriers. Patients with the rs4402960 GT+TT genotypes exhibited an enhanced effect of repaglinide treatment on PINS (P<0.01) compared with GG genotype subjects.. The IGF2BP2 rs1470579 and rs4402960 polymorphisms may be associated with the development of T2DM, and these polymorphisms may affect the therapeutic efficacy of repaglinide in Chinese T2DM patients.

Topics: Adult; Aged; Asian People; Carbamates; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Risk Factors; RNA-Binding Proteins

A growing body of evidence supports an important role for the endocannabinoid system as a regulator of appetite, body weight, and systemic metabolism, which is overactive in obesity and type 2 diabetes. While initial attempts to target this system using the cannabinoid receptor inverse agonist rimonabant were successful in producing modest weight loss and improving obesity-related metabolic complications in humans, adverse central nervous system side effects precluded introduction of this drug into clinical practice. However, new data, presented by Tam and colleagues in this issue of the JCI, demonstrate that selective blockade of peripheral cannabinoid receptors may be a novel successful therapeutic approach.

Topics: Animals; Appetite Regulation; Body Weight; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Genome-wide association studies (GWASs) identified that SLC30A8 genetic polymorphism was a risk of type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with T2DM susceptibility and repaglinide therapeutic efficacy in Chinese T2DM patients.. We conducted a case-control study of 443 T2DM patients and 229 healthy volunteers to identify SLC30A8 rs13266634 and rs16889462 genotypes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Forty-eight patients were randomly selected and underwent an 8-week repaglinide treatment (3 mg/d). Fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin (HbAlc), fasting serum insulin (FINS), postprandial serum insulin (PINS), homeostasis model assessment for insulin resistance (HOMA-IR), serum triglyceride, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c) were determined before and after repaglinide treatment.. SLC30A8 rs13266634 risk C allele frequency was higher in T2DM patients than in healthy controls (P < 0.05). There was a better repaglinide response on FINS (P < 0.05) and PINS (P < 0.01) in patients with rs13266634 CT+TT genotypes compared with CC genotype carriers. Patients with rs16889462 GA genotype showed an enhanced repaglinide efficacy on FPG (P < 0.01), PPG (P < 0.01) and HbAlc (P < 0.05) compared with GG genotype individuals.. SLC30A8 rs13266634 and rs16889462 polymorphisms were associated with repaglinide therapeutic efficacy in Chinese T2DM patients.

Topics: Adult; Aged; Base Sequence; Carbamates; Case-Control Studies; Cation Transport Proteins; China; Diabetes Mellitus, Type 2; DNA Primers; Female; Gene Frequency; Genome-Wide Association Study; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Polymerase Chain Reaction; Polymorphism, Genetic; Zinc Transporter 8

Aim of this prospective study is to evaluate the effect of repaglinide t.i.d. (three times a day) plus single-dose insulin glargine regimen in low-risk type 2 diabetic patients during Ramadan fasting. Participants had been taking the regimen for at least 3 months. Patients with a history of diabetic coma, severe hypoglycemic crisis or repeating attacks of hypoglycemia were excluded. Hypoglycemic unawareness, kidney or liver disease or HbA1c over 8% were also accepted as exclusion criteria. Eleven patients who insisted on this worship and eight non-fasting cases were involved. All were told to make home-glucose-monitorisation weekly and report any hypoglycemic event throughout Ramadan. Fasting blood glucose (FBG), post-prandial blood glucose (PBG) and fructosamine levels, body weights and blood pressures were recorded just before and after Ramadan. Seven patients in each group concluded the follow-up. Any significant change was detected in the parameters in either groups (P>0.05). Glucose control remained unchanged; fructosamine 318.14+/-65.38 versus 317.28+/-52.80 mmol/L in fasting group, 290.71+/-38.48 versus 290+/-38.56 mmol/L in non-fasting group. None of them exhibited either a major or a minor hypoglycemic event. The results of this pilot study indicated that repaglinide t.i.d. plus single-dose insulin glargine regimen was safe for low-risk type 2 diabetic patients who insisted on fasting during Ramadan.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Blood Pressure; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Female; Fructosamine; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Islam; Male; Middle Aged; Patient Selection; Piperidines; Risk Assessment; Safety; Turkey

Several combination therapies have been investigated in an effort to achieve and maintain glycemic control in patients with type 2 diabetes. In this study, we combined the novel dipeptidyl peptidase (DPP)-IV inhibitor ASP8497 with the antidiabetic drugs metformin, glibenclamide, voglibose, rosiglitazone, and insulin to examine the effects of each combination on glucose tolerance in streptozotocin-nicotinamide-induced mildly diabetic mice. Single treatments with ASP8497 (1 mg/kg), metformin (300 mg/kg), glibenclamide (3 mg/kg), voglibose (0.3 mg/kg), rosiglitazone (10 mg/kg), or insulin (0.2 IU/kg) significantly improved glucose tolerance during the liquid meal tolerance test. In addition, combination treatment with ASP8497 and each antidiabetic drug additively improved glucose tolerance. Among these, the combination of ASP8497 and glibenclamide or insulin additively ameliorated glucose tolerance with an additive increase in the plasma insulin level; however, it did not affect the fasting blood glucose lowering effects of glibenclamide or insulin. These profiles indicate that the combination of ASP8497 with existing antidiabetic drugs could be useful for correcting the postprandial hyperglycemia seen with type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred ICR; Niacinamide; Piperidines; Postprandial Period; Pyrrolidines; Streptozocin

Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) has a potent glucose-dependent insulinotropic effect and is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, the use of DPP-IV inhibitors is being actively explored as a novel approach to the treatment of type 2 diabetes. The present study investigated the antidiabetic effects of the DPP-IV inhibitor ASP8497 in streptozotocin-nicotinamide-induced mildly diabetic mice which possess aggravation of glucose tolerance due to loss of early-phase insulin secretion. ASP8497 exhibited good oral bioavailability with potent inhibition of plasma DPP-IV activity. This inhibitory activity lasted up to 24 h when administered at 5 mg/kg twice a day or 10 mg/kg once a day. A single oral administration of ASP8497 (0.3-3 mg/kg) significantly improved glucose tolerance by increasing plasma insulin and GLP-1 levels during the oral glucose or liquid meal tolerance tests. These effects were seen not only immediately, but also 8 h after administration. In contrast, ASP8497 (0.3-10 mg/kg) had no significant effect on blood glucose and plasma insulin levels under fasting conditions. Furthermore, repeated administration of ASP8497 (5 mg/kg twice a day or 10 mg/kg once a day) for 25 days significantly decreased nonfasting blood glucose and HbA(1c) levels. These results suggest that ASP8497 is a potent and long-acting DPP-IV inhibitor that improves glucose tolerance through glucose-dependent insulinotropic action via the elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic mice. It is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Fasting; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Insulin; Male; Mice; Mice, Inbred ICR; Pancreas; Piperidines; Pyrrolidines

The present study investigated the antidiabetic effects of the dipeptidyl peptidase (DPP)-IV inhibitors ASP8497 and vildagliptin, and the sulfonylureas glibenclamide and gliclazide in streptozotocin-nicotinamide-induced mildly diabetic mice. A single administration of ASP8497 and vildagliptin significantly improved glucose tolerance by increasing plasma insulin and glucagon-like peptide-1 levels. In addition, a single administration of glibenclamide and gliclazide also caused significant improvement in glucose tolerance with an accompanying increase in the plasma insulin level. Subsequently, the effects of a 1-week chronic daily dosing of DPP-IV inhibitors and sulfonylureas were investigated. All drugs significantly improved glucose tolerance on day 1 of chronic daily dosing. After 1 week of chronic daily dosing, the DPP-IV inhibitors caused a significant improvement in glucose tolerance similar to those observed on day 1 by increasing the plasma insulin and glucagon-like peptide-1 levels. In contrast, the sulfonylureas had no significant improving or insulinotropic effect. Furthermore, ASP8497 also had an antihyperglycemic effect and improved pancreatic histopathologic lesions in a 4-week chronic daily dosing study. These results suggest that chronic daily dosing of sulfonylureas had virtually no antidiabetic effects because of marked attenuation of the insulinotropic action in streptozotocin-nicotinamide-induced mildly diabetic mice. In contrast, the antidiabetic efficacy of DPP-IV inhibitors, including ASP8497, did not change even after chronic daily dosing; therefore, DPP-IV inhibitors are useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes mellitus.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gliclazide; Glucagon-Like Peptide 1; Glucose Intolerance; Glyburide; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred ICR; Niacinamide; Piperidines; Pyrrolidines; Sulfonylurea Compounds

Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Benzamides; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Drug Design; Hepatocytes; Humans; Inhibitory Concentration 50; Insulin; Microsomes; Models, Chemical; Molecular Structure; Piperidines; Solubility; Structure-Activity Relationship

A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Humans; Hypoglycemic Agents; Phenethylamines; Piperidines; Rats

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET(A) and ET(B)) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ET(B) receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ET(A) antagonist) but not by BQ-788 (ET(B) antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N(G)-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ET(A) and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ET(A), a defect in ET(B)-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Butadienes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Male; MAP Kinase Kinase Kinases; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitriles; Nitroarginine; Nitroprusside; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction; Vasoconstriction; Vasodilation

Alogliptin, a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, enhances incretin action and pioglitazone enhances hepatic and peripheral insulin actions. Here, we have evaluated the effects of combining these agents in diabetic mice.. Effects of short-term treatment with alogliptin alone (0.01%-0.1% in diet), and chronic combination treatment with alogliptin (0.03% in diet) and pioglitazone (0.0075% in diet) were evaluated in db/db mice exhibiting early stages of diabetes.. Alogliptin inhibited plasma DPP-4 activity up to 84% and increased plasma active glucagon-like peptide-1 by 4.4- to 4.9-fold. Unexpectedly, alogliptin alone lacked clear efficacy for improving glucose levels. However, alogliptin in combination with pioglitazone clearly enhanced the effects of pioglitazone alone. After 3-4 weeks of treatment, combination treatment increased plasma insulin by 3.8-fold, decreased plasma glucagon by 41%, both of which were greater than each drug alone, and increased plasma adiponectin by 2.4-fold. In addition, combination treatment decreased glycosylated haemoglobin by 2.2%, plasma glucose by 52%, plasma triglycerides by 77% and non-esterified fatty acids by 48%, all of which were greater than each drug alone. Combination treatment also increased expression of insulin and pancreatic and duodenal homeobox 1 (PDX1), maintained normal beta-cell/alpha-cell distribution in islets and restored pancreatic insulin content to levels comparable to non-diabetic mice.. These results indicate that combination treatment with alogliptin and pioglitazone at an early stage of diabetes improved metabolic profiles and indices that measure beta-cell function, and maintained islet structure in db/db mice, compared with either alogliptin or pioglitazone monotherapy.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cell Degranulation; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Eating; Glucagon; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Lipids; Male; Mice; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

Hypoglycaemia is an acute complication associated with intensive treatment of patients with diabetes mellitus. This complication poses a major challenge in diabetes management. Furthermore, severe hypoglycaemia may be life threatening. Although hypoglycaemia is more often associated with insulin treatment, oral hypoglycaemic agents have the potential to trigger hypoglycaemia.. The aim of this study was to quantify the incidence of hypoglycaemic events and to describe the pattern of these incident events during the first 9 months of treatment with four oral antidiabetic drugs, rosiglitazone, pioglitazone, nateglinide and repaglinide, prescribed in general practice in England.. We used data collected for prescription-event monitoring (PEM) studies of rosiglitazone, pioglitazone, nateglinide and repaglinide. PEM is an observational, non-interventional, incept cohort study. Observation time for each patient and incidence rate (IR) per 1000 patient-years of treatment for hypoglycaemia was calculated for each drug cohort. Smoothed hazard estimates were plotted over time. Case/non-case analysis was performed to describe and compare patients who had at least one hypoglycaemic event in the first 9 months of treatment with those who did not.. The total number of patients included in the analysis was 14,373, 12,768, 4,549 and 5,727 in rosiglitazone, pioglitazone, nateglinide and repaglinide cohorts, respectively. From these, 276 patients experienced at least one episode of hypoglycaemia. The IR was between 50% and 100% higher in patients receiving treatment with meglitinides compared with those treated with the thiazolidinediones (TZDs) [IR = 9.94, 9.64, 15.71 and 20.32 per 1,000 patient-years for rosiglitazone, pioglitazone, nateglinide and repaglinide, respectively]. The plot of the hazard function and the estimated shape parameter from the Weibull regression model showed that pioglitazone, nateglinide and repaglinide had non-constant (decreasing) hazards over time, whereas the hazard for rosiglitazone-treated patients was approximately constant over time. Nateglinide and repaglinide had similar shape hazard function, indicating a significantly higher number of hypoglycaemic episodes shortly after starting treatment. For women treated with TZDs, hypoglycaemia was reported more frequently than for men.. This analysis shows that the frequency of reported hypoglycaemia within the study cohorts was relatively low. The rates of hypoglycaemia were not equal between drug classes. Treatment with nateglinide or repaglinide was characterized by a higher incidence of hypoglycaemia at the beginning of treatment. Further investigation is necessary to assess whether women treated with TZDs are more prone to hypoglycaemia than men. Findings from this study should be taken into account with other clinical and pharmacoepidemiological studies.

Topics: Administration, Oral; Adult; Adverse Drug Reaction Reporting Systems; Carbamates; Cohort Studies; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Prescriptions; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Sex Factors; Thiazolidinediones

Loss of efficacy over time or secondary failure occurs somewhat often and remains a major concern of sulfonylurea (SU) therapy. In this study, we investigated the benefits of alogliptin, an oral, potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in a rat model exhibiting SU secondary failure.. Neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), a non-obese model of type 2 diabetes, were used in these studies. The effects of alogliptin on DPP-4 activity and glucagon-like peptide 1 (GLP-1) concentration were determined by measuring their levels in plasma. In addition, the effects of alogliptin on an oral glucose tolerance test were investigated by using an SU secondary failure model.. Alogliptin dose dependently suppressed plasma DPP-4 activity leading to an increase in the plasma active form of GLP-1 and improved glucose excursion in N-STZ-1.5 rats. Repeated administration of glibenclamide resulted in unresponsiveness or loss of glucose tolerance typical of secondary failure. In these rats, alogliptin exhibited significant improvement of glucose excursion with significant increase in insulin secretion. By contrast, glibenclamide and nateglinide had no effect on the glucose tolerance of these rats.. The above findings suggest that alogliptin was effective at improving glucose tolerance and therefore overcoming SU induced secondary failure in N-STZ-1.5 rats.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Piperidines; Rats; Sulfonylurea Compounds; Treatment Failure; Uracil

Topics: Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Drug Combinations; Drug Interactions; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Piperidines; Tablets; Treatment Outcome

The subject matter of this case report is "sudden deterioration" of glycemic control in a thus far well-complying patient with type 2 diabetes. It describes possible impacts of glucometer technical failure associated with other unfavorable circumstances. An error in displaying glycemia was discovered when analyzing data from glucometer in a computer using software (DIABASS PRO, Mediaspect GmbH, Konstanz, Germany) for data evaluation, and other possible complications (especially hypoglycemia episodes) resulting from inadequate treatment correction were thus prevented.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Carbamates; Computers; Diabetes Mellitus, Type 2; Equipment Failure; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Piperidines; Self Care; Software

A novel class of N-substituted 4-hydrazino piperidine derivatives were designed, synthesized and evaluated for DPP IV inhibition. The SAR studies on the N-substituted piperidine led to the discovery of compound 22e as a potent DPP IV inhibitor (IC(50) 88nM), which is highly selective over other peptidases. In vivo efficacy indicates that compound 22e stimulates insulin release in response to glucose load and improves glucose tolerance in n5-STZ and Zucker Diabetic Fatty (ZDF) rats.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Hydrazines; Hypoglycemic Agents; Piperidines; Rats; Rats, Zucker; Structure-Activity Relationship

The pathological development and the drug intervention of type 2 diabetes mellitus (T2DM) involve altered expression of downstream low molecular weight metabolites including lipids and amino acids, and carbohydrates such as glucose. Currently, a small number of markers used for clinical assessment of T2DM treatment may be insufficient to reflect global variations in pathophysiology. In this study, a metabonomic study was performed to determine metabolic variations associated with T2DM and the drug treatments on 74 patients who were newly diagnosed with T2DM and received a 48 week treatment of a single drug, repaglinide, metformin or rosiglitazone. Fasting overnight and 2 h postprandial blood serum of patients were collected at 24 and 48 weeks to monitor the biochemical indices (FPG, 2hPG, HbA1c, etc.). Gas chromatography/mass spectrometer coupled with multivariate statistical analysis was used to identify the alteration of global serum metabolites associated with T2DM as compared to healthy controls and responses to drug treatment. Significantly altered serum metabolites in diabetic subjects include increased valine, maltose, glutamate, urate, butanoate and long-chain fatty acid (C16:0, C18:1, C18:0, octadecanoate and arachidonate), and decreased glucuronolactone, lysine and lactate. All of the three treatments were able to down-regulate the high level of glutamate to a lower level in serum of T2DM patients, but rosiglitazone treatment was able to reverse more abnormal levels of metabolites, such as valine, lysine, glucuronolactone, C16:0, C18:1, urate, and octadecanoate, suggesting that it is more efficient to alter the metabolism of T2DM patients than the other two drugs.

Topics: Carbamates; Diabetes Mellitus, Type 2; Gas Chromatography-Mass Spectrometry; Humans; Hypoglycemic Agents; Lactic Acid; Lysine; Metabolomics; Metformin; Piperidines; Rosiglitazone; Thiazolidinediones; Uric Acid; Valine

To compare the efficacy and safety of alogliptin, a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, in elderly (> or =65) and younger (<65) patients with type 2 diabetes mellitus.. Pooled analysis of six randomized, double-blind, placebo-controlled studies of alogliptin.. Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control.. Elderly (mean age 70.0; n=455) and younger (mean age 51.8; n=1,911) patients received alogliptin 12.5 mg (n=922), alogliptin 25 mg (n=910), or placebo (n=534) for 26 weeks (12 weeks in a Phase 2 study). The studies evaluated alogliptin as monotherapy and coadministered with pioglitazone, glyburide, metformin, or insulin.. Efficacy endpoints included change from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, and lipid values. Safety variables included hypoglycemic events, adverse events, and blood pressure.. Least-squares mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients (P<.001 for both alogliptin doses vs placebo for both age groups P=.70 for 12.5 mg and .68 for 25 mg for differences between age groups). Results were similar for FPG. Incidence of hypoglycemia was 8.3% or less in all alogliptin groups (< or =10.5% for placebo), with no apparent difference between elderly and younger patients. Changes in weight were negligible in all treatment groups in both age categories. The safety profiles of alogliptin were similar in the age and dose groups.. Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies. Improvements in HbA1c were similar to those seen in younger patients, and no increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Blood Glucose; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome; Uracil; Young Adult

Repaglinide (RPG) is an oral hypoglycemic agent with excellent bioavailability (90-98%) and a short plasma half-life (2-6 h). A full dose of RPG is required before each meal; hence, therapy may become inconvenient. Thus, the aim of the present study was to design a novel delivery system to maintain peak plasma levels of RPG for the long-term management of diabetes mellitus.. Two nanoparticle formulations were prepared by combining RPG with poly (lactic-co-glycolic) acid alone or as a copolymer with methoxypolyethylene glycol (RPGNP1 and RPGNP2, respectively); both formulations were subjected to in vitro and in vivo characterization. In vivo characterization was performed in a streptozotocin (STZ)-induced diabetic male albino rats.. The mean particle size of the RPGNP1 and RPGNP2 formulations was 387.8 ± 11.9 and 310.2 ± 12.4 nm, respectively, with a zeta potential of -27.4 ± 0.7 and -15.7 ± 0.5 mV, respectively. The entrapment efficiency and drug content of RPGNP1 (58.7 ± 1.3% and 27.4 ± 2.3%, respectively) was better than that of RPGNP2 (45.8 ± 1.2% and 24.3 ± 1.1%, respectively). Blood glucose levels of RPGNP1- and RPGNP2-treated STZ-diabetic rats were reduced significantly (to normal levels) compared with untreated STZ-diabetic rats (P < 0.05), but there was no difference between the two treatment groups (P > 0.05). However, whereas RPGNP1 was effective for a period of only 24 h, RPGNP2 was effective for up to 1 week.. The results of the present study show that RPGNP2 effectively manages type 2 diabetes mellitus for up to 1 week. Surface-modified NPs could be used to improve patient compliance with drug treatment as a result of decreased dosing frequency.

Topics: Administration, Oral; Animals; Blood Glucose; Carbamates; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Compounding; Hypoglycemic Agents; Lactic Acid; Male; Nanoparticles; Particle Size; Piperidines; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Solubility

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Humans; Hypoglycemic Agents; Peptides; Piperidines; Pyrazoles; Rimonabant; Venoms

The endocannabinoid system is a physiological system, which is responsible for the control of glucose and lipid-metabolism, as well as for the regulation of the body weight. The endocannabinoid receptors are distributed both in the central and peripher nervous system. Different studies provide evidence that an hyperactive endocannabinoid system is involved in the development of different cardiovascular risk factors. The pharmacological blockade of these cannabinoid receptors may represent a new approach for cardiometabolic risk management.

Topics: Blood Glucose; Body Weight; Cannabinoid Receptor Modulators; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Europe; Humans; Insulin Resistance; Lipids; Obesity; Overweight; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus typ 2, and cardiometabolic risk factors. This article provides an review of efficacy of rimonabant the first selective blocker of the cannabinoid-1 receptor.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

The induction of conformationally restricted N-(aryl or heteroaryl)-3-azabicyclo[3.1.0]hexane derivatives at P(2) region of compounds of 2-cyanopyrrolidine class was explored to develop novel DPP-IV inhibitors. The synthesis, structure-activity relationship, and selectivity against related proteases are delineated.

Topics: Amino Acid Motifs; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Chemistry, Pharmaceutical; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Hexanes; Humans; Ligands; Models, Chemical; Molecular Conformation; Piperidines; Protease Inhibitors; Structure-Activity Relationship; T-Lymphocytes

The aim of this study was to investigate the association of KCNJ11 E23K and ABCC8 exon16-3T/C with the therapeutic effect of repaglinide in patients with type 2 diabetes.. A total of 100 Chinese patients with newly diagnosed type 2 diabetes were treated with repaglinide for 24 weeks. Arginine stimulation tests were performed to evaluate beta cell function. Gene variations were detected with PCR-restriction fragment length polymorphism. Responders were defined by a greater than 25% decrease in fasting plasma glucose or a greater than 20% decrease in hemoglobin A1c (HbA1c) values (or both) after the 24 week repaglinide treatment.. Both baseline HbA1c and the decrease of HbA1c were significantly higher in patients with E/K and K/K genotypes of the KCNJ11 E23K variant when compared with E/E homozygotes (P=0.0103 and 0.0221, respectively). The decrease in 2 h postprandial plasma glucose (2hPG) was significantly greater in E/K heterozygotes than E/E homozygotes (P=0.0367). There was a significant difference in the response rate to repaglinide treatment between the E and K alleles (68% vs 82%, P=0.0324). The changes in fasting insulin and the homeostasis model assessment of insulin resistance were significantly greater in patients with ABCC8 exon16-3 C/C versus the T/C and T/T genotypes (P=0.0372 and 0.0274, respectively).. The KCNJ11 E23K variant was associated with the therapeutic effect of repaglinide. In addition, The C/C homozygotes of the ABCC8 exon16-3T/C variant responded better to repaglinide in insulin sensitivity than the T/C and T/T genotypes.

Topics: ATP-Binding Cassette Transporters; Carbamates; Diabetes Mellitus, Type 2; DNA; Female; Gene Frequency; Genotype; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and uric acid as well and it increases HDL cholesterol; in diabetics it improves glycated hemoglobin. Sibutramine has conflicting effects on blood pressure: in some studies there was a minimal decrease, in some others a modest increase. In all the studies this drug increased pulse rate. Sibutramine is not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease. Orlistat is a pancreatic lipase inhibitor that reduces fat absorption by parti

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Economics, Pharmaceutical; Humans; Lactones; Lipase; Meta-Analysis as Topic; Obesity; Orlistat; Piperidines; Practice Guidelines as Topic; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Time Factors; Weight Loss

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Overweight; Piperidines; Pyrazoles; Rimonabant

To establish whether the effect of SLCO1B1[encoding organic anion transporting polypeptide 1B1 (OATP1B1)] c.521T-->C (p.Val174Ala) polymorphism on the pharmacokinetics of repaglinide is dose-dependent.. Twelve healthy volunteers with the SLCO1B1 c.521TT genotype (controls) and eight with the c.521CC genotype ingested a single 0.25-, 0.5-, 1- or 2-mg dose of repaglinide in a dose-escalation study with a wash-out period of > or =1 week.. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) of 0.25, 0.5, 1 or 2 mg repaglinide was 82% (95% confidence interval 47, 125), 72% (24, 138), 56% (24, 95) or 108% (59, 171) (P < or = 0.001) larger in participants with the SLCO1B1 c.521CC genotype than in those with the c.521TT genotype, respectively. Repaglinide peak plasma concentration and AUC(0-infinity) increased linearly along with repaglinide dose in both genotype groups (r > 0.88, P < 0.001). There was a tendency towards lower blood glucose concentrations after repaglinide administration in the participants with the c.521CC genotype than in those with the c.521TT genotype.. The effect of SLCO1B1 c.521T-->C polymorphism on the pharmacokinetics of repaglinide persists throughout the clinically relevant dose range.

Topics: Area Under Curve; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Female; Genotype; Humans; Hypoglycemic Agents; Liver-Specific Organic Anion Transporter 1; Male; Metabolic Clearance Rate; Organic Anion Transporters; Piperidines; Polymorphism, Single Nucleotide; Young Adult

The Tako-Tsubo syndrome (or transient left ventricular apical balloning) is a new clinical entity, very similar to acute myocardial infarction, but different by its excellent short-term prognosis. It has been reported after a physical or an emotional stress, and it is diagnosed by a coronary angiogram and a left ventriculography. We report here a case of Tako-Tsubo syndrome related to an anaphylactic shock caused by succinylcholine during general anaesthesia of a female patient, wearing an unadjustable gastric band.

Topics: Anaphylaxis; Anesthesia, General; Anesthesia, Intravenous; Diabetes Mellitus, Type 2; Female; Gastroplasty; Heart Arrest; Humans; Intraoperative Complications; Laparoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Obesity; Pelvic Floor; Piperidines; Postoperative Complications; Propofol; Pulmonary Edema; Remifentanil; Succinylcholine; Takotsubo Cardiomyopathy; Ventricular Fibrillation

Platelets are hyperactive in Type 2 diabetes mellitus (T2DM), and antiplatelet treatment with glycoprotein (GP) IIb/IIIa inhibitors provides better thrombotic protection in DM than in non-diabetic subjects.. We hypothesized that diabetic platelets are hyperprocoagulant, and that this hyperactivity can be inhibited by GPIIb/IIIa blockade.. Patients with T2DM and gender/age/body mass index-matched non-diabetic controls were recruited (n = 12 for both) to study the effect of GPIIb/IIIa blockade on platelet procoagulant activity. Platelet phosphotidylserine (PS), factor (F) Va expression, and platelet-derived microparticle (PDMP) generation were measured by whole blood flow cytometry. Platelet-dependent thrombin generation and plasma clotting time were monitored in recalcified platelet-rich plasma.. Compared to controls, basal platelet activation was similar, while thrombin receptor activating peptide stimulated activation was enhanced in patients with T2DM. Diabetic platelets also displayed more profound elevations of platelet PS exposure, FVa binding, and PDMP generation upon stimulation. These alterations resulted in a hyperprocoagulant state, as evidenced by a marked increase in the platelet procoagulant index, enhanced thrombin generation, and a shortened plasma clotting time. GPIIb/IIIa blockade by c7E3 or SR121566 decreased platelet PS exposure and FVa binding, and diminished platelet procoagulant activity in patients with T2DM.. Platelets have increased procoagulant activity in patients with T2DM. The hyperprocoagulant activity is counteracted by GPIIb/IIIa blockade.

Topics: Benzylamines; Blood Platelets; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Phosphatidylserines; Piperidines; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Thrombin; Thiazoles; Thrombophilia

1 Alpha1-Adrenoceptor (alpha1-AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD(2) (-log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective alpha1-AR competitive antagonists: 5-methylurapidil (alpha1A-), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; alpha1B-) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; alpha(1D)-). The relative abundance of mRNA for all three alpha(1)-ARs was determined. 4 The maximal contractile responses to phenylephrine were: E(max) 1.59 +/- 0.17, 1.48 +/- 0.08 and 1.55 +/- 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the alpha(1A)-AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the alpha1B-AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the alpha1D-AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of alpha(1B)-ARs and reduced both alpha1A- and alpha(1D)-ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional alpha1-AR changes.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adult; Arteries; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Humans; Imines; Kidney Failure, Chronic; Male; Middle Aged; Omentum; Phenylephrine; Piperazines; Piperidines; Receptors, Adrenergic, alpha-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasoconstriction; Vasoconstrictor Agents

The present study is designed to screen the effect of syringin, an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae), on the plasma glucose and investigate the possible mechanisms. Plasma glucose decreased in a dose-dependent manner 60 min after intravenous injection of syringin into fasting Wistar rats. In parallel to the decrease of plasma glucose, increases of plasma insulin level as well as the plasma C-peptide was also observed in rats receiving same treatment. Both the plasma glucose lowering action and the raised plasma levels of insulin and C-peptide induced by syringin were also inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), the antagonist of the muscarinic M3 receptors, but not affected by the ganglionic nicotinic antagonist, pentolinium or hexamethonium. Moreover, disruption of synaptic available acetylcholine (ACh) using an inhibitor of choline uptake, hemicholinium-3, or vesicular acetylcholine transport, vesamicol, abolished these actions of syringin. Also, physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the actions of syringin. Mediation of ACh release from the nerve terminals to enhance insulin secretion by syringin can thus be considered. The results suggest that syringin has an ability to raise the release of ACh from nerve terminals, which in turn to stimulate muscarinic M3 receptors in pancreatic cells and augment the insulin release to result in plasma glucose lowering action.

Topics: Acetylcholine; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Eleutherococcus; Glucosides; Insulin; Insulin Secretion; Male; Muscarinic Antagonists; Phenylpropionates; Phytotherapy; Piperidines; Rats; Receptor, Muscarinic M3

Dipeptidyl peptidase (DPP)-IV is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibitors are expected to become a useful new class of antidiabetic agent. This report describes the pharmacological profile of the novel DPP-IV inhibitor, ASP8497 [(2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate], both in vitro and in vivo. ASP8497 inhibited DPP-IV in plasma from mice, dogs, and humans with median inhibition concentration (IC(50)) values of 2.6 nM, 7.3 nM, and 6.2 nM, respectively. In contrast, ASP8497 did not potently inhibit human DPP8 or DPP9 activity (IC(50)=1,700 nM and 100 nM, respectively) and exhibited selectivity against several proteases, including proline-specific proteases (IC(50)>10 microM). Kinetic analysis indicated that ASP8497 is a competitive DPP-IV inhibitor. In normal mice, ASP8497 inhibited plasma DPP-IV activity even 12 h after administration. ASP8497 significantly inhibited increases in the blood glucose level during the oral glucose tolerance test (OGTT) conducted 0.5 h after administration. This was accompanied by increases in the plasma active GLP-1 and insulin levels. In addition, ASP8497 significantly inhibited increases in the blood glucose level during the OGTT conducted 8 h after administration. Furthermore, in Zucker fatty rats, ASP8497 dose dependently improved glucose tolerance with significance at doses of 1 mg/kg or higher. In contrast, ASP8497 did not cause hypoglycemia in fasted normal mice. These results indicate that ASP8497 is a potent, competitive, and selective DPP-IV inhibitor with antihyperglycemic activity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dogs; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Insulin; Male; Mice; Mice, Inbred ICR; Piperidines; Protease Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Rats, Zucker

For patients with type 2 diabetes, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) currently recommend a glycosylated hemoglobin (HbA(1c) ) target of <7%, and the British Medical Association (BMA) Quality and Outcomes Framework recommends an HbA(1c) target of >or=7.5%.. This letter presents a reanalysis of data from a previous study of the effect on glycemic control of adding repaglinide to metformin monotherapy in patients with type 2 diabetes to determine the proportion of patients achieving current ADA/EASD and BMA targets.. PubMed was searched using the terms repaglinide AND metformin AND HbA(1c) to identify published comparisons of monotherapy and combination therapy with these drugs in patients with type 2 diabetes.. In the original analysis, which employed an HbA(1c) target of <7.1%, 59%of patients treated with metformin plus repaglinide achieved their glycemic target, compared with approximately 20% of patients treated with metformin or repaglinide alone. On reanalysis of the data according to the current ADA/EASD HbA(1c) target of <7%, 56% of patients receiving metformin and repaglinide achieved that goal,compared with 19%each in the groups treated with metformin or repaglinide monotherapy. On reanalysis of the data according to the BMA Quality and Outcomes Framework HbA(1c) target of >or=7.5%, 89% of patients receiving metformin and repaglinide achieved that goal, compared with 43%and 42% of patients receiving metformin and repaglinide monotherapy, respectively.. Based on this reanalysis of earlier data in terms of currently recommended HbA(1c) targets, combination therapy with repaglinide and metformin would appear to be a good treatment option for patients with type 2 diabetes.

Topics: Biomarkers; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome

Many drugs have been reported to interact with repaglinide in patients with type 2 diabetes mellitus, resulting in hypoglycemia. However, to our knowledge, an interaction between clarithromycin and repaglinide in these patients has not been previously reported. We describe an 80-year-old man with end-stage renal disease and well-controlled type 2 diabetes (hemoglobin A1c < 7%) who was hospitalized for treatment of severe hypoglycemia. He had been receiving repaglinide 0.5 mg 3 times/day for the previous 2 years. Clarithromycin 500 mg twice/day had been started for Helicobacter pylori infection several days before admission. Within 48 hours of starting the drug, he developed severe hypoglycemia, which resolved with intravenous glucose administration. However, 48 hours later, the patient again experienced hypoglycemia and was unresponsive. Intravenous glucose administration again resolved the problem. Repaglinide was discontinued, and no further hypoglycemic episodes occurred. Clinicians should be aware of this possible clarithromycin-repaglinide interaction; in particular, in elderly patients with type 2 diabetes who are taking repaglinide and begin clarithromycin therapy, blood glucose levels should be monitored closely for potential dosage adjustment of repaglinide.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Blood Glucose; Carbamates; Clarithromycin; Diabetes Mellitus, Type 2; Drug Interactions; Helicobacter Infections; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, alogliptin dose-dependently inhibited DPP-4 activity by 28-82% and increased active GLP-1 by 3.2-6.4-fold. After 4 weeks, alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4-0.9%, plasma glucose by 7-28% and plasma triglycerides by 24-51%, increased plasma insulin by 1.5-2.0-fold, and decreased plasma glucagon by 23-26%, with neutral effects on body weight and food consumption. In addition, after drug washout, alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration-time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glucagon; Glucagon-Like Peptide 1; Insulin; Male; Mice; Mice, Obese; Piperidines; Triglycerides; Uracil

Although diabetics may be exempted from Ramadan fasting, many patients still insist on this worship. Aim of the present study is to compare the effects of glimepiride, repaglinide, and insulin glargine in type 2 diabetics during Ramadan fasting on the glucose metabolism. Patients, who were willing to fast, were treated with glimepiride (n=21), repaglinide (n=18), and insulin glargine (n=10). Sixteen non-fasting control type 2 diabetics matched for age, sex, and body mass index were also included. Fasting blood glucose (FBG), post-prandial blood glucose (PBG), HbA1c, and fructosamine as well as lipid metabolism were evaluated in pre-Ramadan, post-Ramadan, and 1-month post-Ramadan time points. There was no significant change from pre-Ramadan in FBG, PBG, and HbA1c variables in fasting diabetics at post-Ramadan and 1-month post-Ramadan. However, PBG was found higher in non-fasting control diabetics at post-Ramadan and 1-month post-Ramadan (p<0.05 and p<0.001, respectively). In fructosamine levels, a significant increase was noted both in fasting group and non-fasting group at 1-month post-Ramadan (p<0.01 for all). However, no significant difference was found in the comparison of the changes in fructosamine levels between fasting group and non-fasting group. Risk of hypoglycemia did not significantly differ between fasting and non-fasting diabetics. There was no significant difference between three drug therapies regarding glucose metabolism and rate of hypoglycemia. No adverse effects on plasma lipids were noted in fasting diabetics. In this fasting sample of patients with type 2 diabetes, glimepiride, repaglinide, and insulin glargine did not produce significant changes in glucose and lipid parameters.

Topics: Adult; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Fasting; Female; Fructosamine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Islam; Male; Middle Aged; Patient Selection; Piperidines; Sulfonylurea Compounds; Turkey

In the past few years, oral antihyperglycaemic agents have been considered as an alternative to insulin therapy in the treatment of gestational diabetes. There is still little information available on the safety of these drugs during pregnancy, but there have been several studies published regarding their use. Here we report on the case of a woman who took repaglinide up to the seventh week of pregnancy. Delivery occured with no complications and the newborn showed no malformations. Further studies are required to confirm the safety of repaglinide during pregnancy.

Topics: Adult; Carbamates; Diabetes Mellitus, Type 2; Embryonic Development; Female; Humans; Hypoglycemic Agents; Infant, Newborn; Maternal-Fetal Exchange; Piperidines; Pregnancy; Pregnancy in Diabetics

Topics: Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Topics: Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Exercise; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; PPAR gamma; Pyrazoles; Rimonabant; Weight Loss

Topics: Depression; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ET(A) and dual ET(A)+ET(B)) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease.. Seven patients (aged 58 +/- 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET(A) receptor blockade (BQ123), and during combined ET(A) (BQ123) and ET(B) receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate.. Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp.. Dual ET(A)+ET(B) receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Endothelin Receptor Antagonists; Glucose Clamp Technique; Glucose Intolerance; Heart Rate; Humans; Insulin; Insulin Resistance; Middle Aged; Obesity; Oligopeptides; Peptides, Cyclic; Piperidines

Topics: Chemotherapy, Adjuvant; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Benzazepines; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Obesity; Piperidines; Prevalence; Pyrazoles; Quinoxalines; Rimonabant; Risk Factors; Smoking; Smoking Cessation; Tobacco Use Disorder; Varenicline

Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ET(A)) and type B (ET(B)) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ET(A) and ET(B) receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary alpha(1)-AR function has not been examined. Therefore, we examined the effect of ET(A) and ET(B) receptor inhibition on coronary vasoconstriction to ET-1 and alpha(1)-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective alpha(1)-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with selective ET(A) or ET(B) receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET(B), but not ET(A), receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ET(A) receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET(B) inhibition abolished this response only in control hearts. In addition, ET(A) inhibition enhanced alpha(1)-AR-mediated vasoconstriction in T2D, but not control, hearts following l-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ET(B) receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ET(A) receptor subtype.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Obesity; Oligopeptides; Peptides, Cyclic; Phenylephrine; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic, alpha-1; Vasoconstriction

A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.

Topics: Administration, Oral; Animals; Caco-2 Cells; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Humans; Hypoglycemic Agents; Linagliptin; Macaca fascicularis; Macaca mulatta; Male; Models, Molecular; Piperidines; Purines; Quinazolines; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship

We have previously established a nonobese diabetes mouse model characterized by moderate hyperglycemic levels, like those usually occurring in human type 2 diabetes. As oxidative stress is considered a major mechanism of progressive beta-cell damage in diabetes, we tested in this model the protective effects of a new low-molecular-weight antioxidant, namely, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate dihydrochloride (IAC).. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Two weeks later, STZ-NA mice were treated for 5 weeks with different doses of IAC (15 or 30 mg/kg per day intraperitoneally) and monitored for glycemia, insulinemia, glucose tolerance, and pancreatic insulin content.. Streptozotocin-NA mice showed moderate hyperglycemia, hypoinsulinemia, glucose intolerance, growth impairment, and markedly reduced pancreatic insulin content (22% of controls). IAC-treated STZ-NA mice showed clear-cut reduction of hyperglycemia and attenuation of glucose intolerance, associated to higher residual pancreatic insulin content with respect to untreated diabetic animals. Plasma nitrotyrosine levels (an index of oxidative stress), enhanced 3-fold in diabetic mice, were significantly reduced by IAC treatment. Significant correlations were found between plasma nitrotyrosine values and either blood glucose levels or pancreatic insulin content.. In the STZ-NA diabetic mouse model, the new antioxidant, IAC, improves diabetic metabolic alterations, likely by counteracting beta-cell dysfunction and loss associated with oxidative stress.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Esters; Fatty Acids, Nonesterified; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Molecular Weight; Niacinamide; Oxidative Stress; Pancreas; Piperidines; Streptozocin; Time Factors; Tyrosine

We examined the frequency of cognitive impairment using the mini-mental-status examination (MMSE), as well as cerebral perfusion using single photon emission computed tomography (SPECT) in elderly diabetic patients. Written consent was obtained from all patients prior to their inclusion in this study. An MMSE score of 26 or less was adopted as an indication of cognitive impairment. Following an initial study, a 3-month study incorporating the use of MMSE and SPECT was performed in subjects, some of whom were taking donepezil hydrochloride. Of the 92 subjects enrolled in this study, 38% exhibited cognitive functional impairment and 18% earned MMSE scores of 23 or lower that were indicative of dementia. With regard to their cerebral blood flow pattern as determined by SPECT 217, 31.4 and 34.2% of subjects showed parieto-temporal hypoperfusion, asymmetrical hypoperfusion and fronto-temporal hypoperfusion patterns of abnormalities, respectively; 11.4% displayed unclassifiable findings and 8.5% showed no detectable abnormalities. No significant differences were seen in patients that were taking donepezil hydrochloride compared to those who were not. The incidence of cognitive functional impairment in elderly, diabetic patients was significantly elevated and was accompanied by a reduction in cerebral blood flow in the fronto-temporal region, as determined by SPECT.

Topics: Aged; Brain; Cerebrovascular Circulation; Cholinesterase Inhibitors; Cognition Disorders; Diabetes Mellitus, Type 2; Donepezil; Female; Humans; Incidence; Indans; Male; Mental Status Schedule; Piperidines; Tomography, Emission-Computed, Single-Photon

Repaglinide is a prandial glucose regulator indicated for management of type 2 diabetes. This post-marketing study used the observational cohort technique of prescription-event monitoring (PEM) to monitor safety of repaglinide prescribed in primary care in England. Patients were identified from dispensed prescriptions issued by general practitioners (GPs) between December 1998 and January 2001. Demographic and clinical event data were collected from questionnaires posted to GPs at least six months after the date of first prescription for each patient. The cohort consisted of 5731 patients [median age 60 (IQR 51-68), 49.9% male]. Event incidence densities (IDs) [no. 1st reports/1000 patient-months of exposure] were calculated for all events reported. The most frequently recorded clinical events in the first month were diarrhoea (ID(1) 10.3), malaise/lassitude (ID(1) 8.1) and nausea/vomiting (ID(1) 7.9). The most frequently reported reason for stopping was 'not effective' (647), with the most common clinical reasons being diarrhoea (60), malaise/lassitude (55) and intolerance (54). One hundred and thirteen adverse drug reactions (ADRs) were reported, with the most frequently specified being diarrhoea (10), abdominal pain (10) and nausea/vomiting (9). We concluded that repaglinide is generally well tolerated when used in general practice in England and did not identify any serious unrecognised adverse events.

Topics: Aged; Carbamates; Cause of Death; Cohort Studies; Diabetes Mellitus, Type 2; Drug Prescriptions; England; Family Practice; Female; Humans; Hypoglycemic Agents; Infant; Middle Aged; Piperidines; Pregnancy; Safety; State Medicine; Survival Analysis; Vision Disorders

Topics: Adolescent; Adult; Age Factors; Aged; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Clinical Trials, Phase III as Topic; Contraindications; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Time Factors; Triglycerides; Weight Loss

Topics: Adult; Carbamates; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Piperidines; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, First

Topics: Diabetes Mellitus, Type 2; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Ninety-eight diabetic patients (type 2) were studied together with 24 healthy normotensive controls. Microaggregates (particle scale, <25 microm) of platelets were detected by a laser scattering system. Microaggregates in the control group showed a time-dependent reversible change; however, they existed continuously in 82 of 98 diabetic patients. When platelets of diabetics were stimulated by a shear stress alone without ADP, 74 also showed spontaneous and irreversible microaggregates even though they were not observed in all control subjects. In control subjects, microaggregates were inhibited by MRS2279 (a P2Y1 antagonist), but not AR-C69931MX (a P2Y12 antagonist). However, AR-C69931MX prevented irreversible microaggregates in diabetic patients. When either aspirin or ticlopidine was administered to diabetic patients with irreversible microaggregates, both drugs significantly decreased microaggregates induced by a low dose of ADP. Ticlopidine additionally reduced the microaggregates induced by shear stress alone. In conclusion, microaggregates of platelets via P2Y12 receptors could play a key role in the hypersensitivity of platelets in diabetic patients, and the measurement of microaggregation could be a useful marker to estimate of thrombogenesis. These findings present a possible new means for patients with diabetes to prevent ischemic events.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Aged; Diabetes Mellitus, Type 2; Female; Humans; Male; Membrane Proteins; Middle Aged; Piperazines; Piperidines; Platelet Aggregation; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Reference Values

Topics: Aged; Carbamates; Chemical and Drug Induced Liver Injury; Cholestasis; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Male; Piperidines

Topics: Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Male; Middle Aged; Piperidines; Rosiglitazone; Thiazolidinediones

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoids; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

(1) There are few clinical trials comparing combination therapy with a sulphonylurea and metformin after oral antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of insulin therapy in patients in whom oral antidiabetic therapy fails is based solely on surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose glucose levels were no longer controlled by a sulphonylurea, the addition of metformin or a daily injection of insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However, metformin caused less weight gain. (4) There are no randomised controlled trials comparing the addition of insulin versus a sulphonylurea when ongoing metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus metformin, adding a daily insulin injection is more effective in lowering HbA1c levels than the addition of acarbose and as effective as adding a glitazone. The adjunction of insulin appears to have a better risk-benefit balance than an oral three-drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral antidiabetic to ongoing insulin therapy reduces HbA1c levels in patients with type 2 diabetes. The addition of metformin is also beneficial in terms of body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with metformin, have compared the addition of a bedtime injection of insulin isophane versus replacement of the oral antidiabetics by several daily insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less weight gain when the oral antidiabetics were continued and a single insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea, metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of insulin isophane. (9) Insulin isophane is the first-choice insulin for combination therapy with an oral antidiabetic. In comparative trials, when combined with an oral antidiabetic, insulin glargine was no more effective than insulin is

Topics: Acarbose; Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections; Insulin; Metformin; Piperidines; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Weight Gain

Topics: Diabetes Mellitus, Type 2; Humans; Piperidines; Pyrazoles; Rimonabant; United States; Weight Loss

Type 2 diabetes mellitus is a chronic disease with potentially devastating long-term complications. Despite the tremendous body of research and experience in the adult population, relatively little is established regarding this condition and its optimal management in children and adolescents. The pediatric community awaits results of ongoing trials as well as further study of optimal intervention in children, as they continue to extrapolate management practices from their adult counterparts.

Topics: Administration, Oral; Adolescent; Carbamates; Child; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.. Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.. BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).. ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension; Kidney Cortex; Kidney Medulla; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Piperidines; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Thromboxane A2

Type 2 diabetes mellitus is the consequence of both insulin resistance and impaired insulin secretion. In the progression from normal glucose tolerance to diabetes, postprandial glucose (PPG) levels often rise before fasting plasma glucose (FPG) levels increase above 126 mg/dL (7.0 mmol/L). Numerous epidemiologic studies have shown that impaired glucose tolerance is associated with increased risk for macrovascular disease and that isolated postchallenge hyperglycemia is an independent factor for increased mortality. Reducing the risk for microvascular complications by improving glycosylated hemoglobin (HbA(1c)) levels is well documented. Emerging data now support the relationship between glycemic control and macrovascular disease. Epidemiologic studies documenting postprandial hyperglycemia and the risk for increased mortality suggest that lowering PPG levels might be beneficial. Optimizing both FPG and PPG is important in achieving normal/near-normal glucose levels. Many patients with type 2 diabetes have difficulty attaining the recommended HbA(1c) goal despite normal/near-normal FPG levels; thus, pharmacologic treatment targeting PPG levels may prove beneficial.

Topics: Antihypertensive Agents; Blood Glucose; Blood Glucose Self-Monitoring; Carbamates; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Progression; Drug Therapy, Combination; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Metformin; Piperidines; Postprandial Period

As an example application of the CORE Diabetes Model in type 2 diabetes, we simulated the cost-effectiveness of repaglinide/metformin combination therapy versus nateglinide/metformin for treatment of individuals with type 2 diabetes with an inadequate response to sulphonylurea, metformin, or fixed dose glyburide/metformin.. The CORE Diabetes Model was used to simulate long-term outcomes for a cohort of individuals with type 2 diabetes treated with either repaglinide/metformin or nateglinide/metformin. HbA1c changes for each regimen were taken from a comparative study. At the end of the study, changes in HbA1c from baseline were -1.28% points and -0.67% points for repaglinide/metformin and nateglinide/metformin, respectively. Median final doses were 5.0 mg/day for repaglinide, 360 mg/day for nateglinide and 2000 mg/day metformin in each treatment arm. Costs were calculated as the annual costs for drugs plus costs of complications (US Medicare perspective) over a 30-year period. Life expectancy (LE) and quality-adjusted life expectancy (QALE) were calculated. Outcomes and costs were discounted at 3% annually.. With repaglinide/metformin, improved glycaemic control led to projected decreases in complication rates, improvement of LE and QALE by 0.15 and 0.14 years respectively, and total cost savings of 3,662 dollars/person over the 30-year period. Repaglinide/metformin had a 96% probability that the incremental costs per quality-adjusted life year gained would be 20,000 dollars or less, and a 66% probability that repaglinide/metformin would be cost-saving compared to nateglinide/metformin. Sensitivity analyses supported the validity and reliability of the results.. In the health economic context, repaglinide/metformin combination was dominant to nateglinide/metformin. The CORE Diabetes Model is a tool to help third-party reimbursement payers identify treatments for type 2 diabetes that are good value for money.

Topics: Carbamates; Cohort Studies; Computer Simulation; Cost of Illness; Cost-Benefit Analysis; Cyclohexanes; Decision Support Systems, Clinical; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Health Care Costs; Humans; Male; Metformin; Middle Aged; Models, Econometric; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Piperidines; Quality-Adjusted Life Years

Diabetes mellitus is a complex disorder of the energy metabolism. In the present paper, we have tried to illustrate the changes in the regulation of blood glucose levels encountered in the two main types of diabetes: Type 2 (T2DM) and Type 1 (T1DM) diabetes mellitus, compared with healthy, non-diabetic subjects. For this we used the MiniMed CGMS (Continuous Glucose Monitoring System) which allows the continuous in vivo blood glucose measurement over a 3-day period. The study group comprised 19 diabetic patients (14 T1DM and 5 T2DM cases) and 4 non-diabetic controls. The recording in normal subjects showed a glycemic variation between 46 and 118 mg/dl, suggesting the existence of a strong and efficient glycemic control mechanism. In T2DM patients, both on diet only or on oral antidiabetic treatment, the oscillation of blood glucose levels was significantly higher compared to that recorded in non-diabetic subjects. In T1DM patients with stable metabolic control blood glucose fluctuations were comparable with those recorded in long-term type 2 diabetic patients but the "mean" values of blood glucose over 72 hours were lower. The CGMS is a valuable tool in the detection of unrecognized hypoglycemic episodes and hyperglycemic postprandial peaks and allows the patient and the health care team to adjust the treatment regimen in order to improve glycemic control. From our point of view, the CGMS could offer valuable information for the knowledge of glycemic regulation in normal people and for the diabetogenic mechanisms in prediabetic IGT and IFG patients.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Carbamates; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Postprandial Period; Statistics as Topic; Treatment Outcome

Topics: Aged; Carbamates; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Piperidines

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Administration Schedule; Eating; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

To evaluate the accuracy of nocturnal continuous glucose monitoring by CGMS.. A CGMS was inserted in 14 type 2 diabetic patients on combined oral and insulin therapy at altogether 15 occasions. During the second (48 hours) and third (72 hours) night of registration each subject was observed and plasma glucose was analysed seven times during the night by venous sampling and compared to CGMS. These venous values were not used for calibration of the sensor. Pairs of data were analysed using correlation coefficient, Bland-Altman graphs and Clarke Error Grid analysis.. 32% of CGMS data did not meet the quality criteria for optimal accuracy and were excluded. A correlation coefficient of 0.80 (p < 0.0001) was seen after 48 hours and a lower coefficient of 0.33 (p = 0.0082) after 72 hours. Bland-Altman analyses demonstrated that the dispersion of the values around the mean of differences was wider after 72 hours as compared to after 48 hours. In the Clark Error Grid analysis 100% of data were within zones A and B after 48 hours, with 60% in zone A. After 72 hours only 44% were in zone A and 7% of data were in the clinically unacceptable zone D.. The MiniMed Medtronic CGMS has acceptable nocturnal accuracy after 48 hours of registration, but the accuracy thereafter deteriorates with time, implicating that the CGMS thereafter may prove less useful for nocturnal monitoring.

Topics: Administration, Oral; Aged; Body Mass Index; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Monitoring, Ambulatory; Monitoring, Physiologic; Piperidines; Regression Analysis; Reproducibility of Results; Time Factors

To assess the short-term direct medical costs and effectiveness associated with achieving recommended glycaemic goals using commonly prescribed first-line oral antihyperglycaemic medications in type 2 diabetes mellitus.. A literature-based, decision-tree model was developed to project the number of patients achieving glycosylated haemoglobin values of <7% on oral therapies and the associated costs over a 3-year timeframe. For each first-line strategy, patients could progress to combination therapy using two or more agents prior to the introduction of insulin. The overall cost of treatment included costs (2001/2002 values; US dollars) of comprehensive medical care, laboratory tests, patient education, drug therapy, home glucose monitoring and adverse events.. At 3 years, the overall cost of treatment for the various first-line strategies was 6,106 US dollars for glipizide gastrointestinal therapeutic system, 6,727 US dollars for metformin immediate release, 6,826 US dollars for metformin extended release, 7,141 US dollars for glibenclamide (glyburide)/metformin, 7,759 US dollars for rosiglitazone and 9,298 US dollars for repaglinide. Costs of comprehensive routine medical care ranged from approximately 1,538-2,128 US dollars in year 1 and from approximately 952-1,543 US dollars in subsequent years, for controlled and uncontrolled patients, respectively. Adverse events represented <1%, and drug therapies represented approximately 50%, of the overall cost, respectively. Substantial cost differences between the strategies were seen within the first year. Regardless of first-line therapy, patients progressed quickly to combination therapies, with effectiveness among the agents being similar.. Short-term costs required to provide comprehensive diabetes care and achieve glycemic goals can be substantial. The model suggests a sulphonylurea strategy may provide similar effectiveness with cost savings over other agents and should be considered when selecting an initial drug therapy in newly diagnosed patients with type 2 diabetes mellitus.

Topics: Carbamates; Cohort Studies; Decision Trees; Diabetes Mellitus, Type 2; Direct Service Costs; Drug Costs; Drug Therapy, Combination; Glipizide; Glyburide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Managed Care Programs; Markov Chains; Metformin; Models, Economic; Piperidines; Rosiglitazone; Thiazoles; Thiazolidinediones; United States

A retrospective database analysis compared costs among patients with type 2 diabetes receiving four antidiabetic regimens: (1) repaglinide monotherapy, (2) metformin monotherapy, (3) repaglinide and metformin in combination, or (4) metformin and glyburide in combination. Pharmacy, medical, and total costs were measured for each cohort over a nine-month period. Although not statistically significant, total adjusted costs were lowest for the repaglinide-metformin combination ($8,924), followed by metformin monotherapy ($9,448), metformin and glyburide ($9,576), and repaglinide monotherapy ($11,910). These results must be confirmed in larger populations, but they imply that differences in pharmacy costs of repaglinide-metformin therapy are offset by measurable medical cost savings.

Topics: Administration, Oral; Adolescent; Adult; Aged; California; Carbamates; Cohort Studies; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glyburide; Health Care Costs; Humans; Hypoglycemic Agents; Insulin; Insurance Claim Review; Male; Managed Care Programs; Metformin; Middle Aged; Piperidines; Retrospective Studies

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Piperidines; Treatment Outcome

Topics: Adiponectin; Blood Glucose; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Nateglinide; Phenylalanine; Piperidines; Proteins; Sulfonylurea Compounds

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines

Good glucose control is a prerequisite for the prevention of long-term complications in type 2 diabetics. In recent years, two new groups of substances have been approved for the oral treatment of type 2 diabetes: glinides and glitazones. The former are short-acting agents that promote insulin secretion and offer an alternative to the sulfonylureas, in particular in patients with irregular eating habits and high postprandial glucose peaks. The glitazones improve one of the disorders underlying type 2 diabetes, insulin resistance. They are used in particular in patients who are inadequately controlled with a sulfonylurea or metformin and who show insulin resistance. Both groups of substances are a useful addition to the antidiabetic drug armamentarium. Endpoint studies involving these substances have, however, not yet been performed.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Nateglinide; Phenylalanine; Pioglitazone; Piperidines; Rosiglitazone; Thiazoles; Thiazolidinediones; Treatment Outcome

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Piperidines; Thiazoles; Thiazolidinediones

Topics: Carbamates; Diabetes Mellitus, Type 2; Diet, Diabetic; Feeding Behavior; Humans; Hypoglycemic Agents; Patient Compliance; Piperidines

Topics: Carbamates; Diabetes Mellitus, Type 2; Half-Life; Humans; Hypoglycemic Agents; Insulin; Piperidines; Structure-Activity Relationship

Topics: 1-Deoxynojirimycin; Acarbose; Carbamates; Diabetes Mellitus, Type 2; Glucosamine; Humans; Hypoglycemic Agents; Imino Pyranoses; Multicenter Studies as Topic; Pioglitazone; Piperidines; Randomized Controlled Trials as Topic; Thiazoles; Thiazolidinediones

Clinical trials provide information regarding the safety and efficacy of medications used to manage type 2 diabetes but do not elucidate drug effectiveness in a typical managed care environment. The aim of this study was to characterize "real-world" drug utilization patterns from both a prescriber and a patient perspective.. We conducted a retrospective analysis of a large administrative pharmacy claims database, using data on continuously pharmacy benefit-eligible members prescribed oral hypoglycemic agents (OHAs).. The 12-month persistence rate for the OHA cohort was low, ranging from 31% for alpha-glucosidase inhibitors to 60% for metformin; compliance rates varied between 70 and 80%. During the first 12 months of therapy, 36% of the patients remaining on therapy at 12 months had one or more therapy modifications. The mean number of therapy changes increased with the length of patient follow-up, with more than half of all patients experiencing at least one therapy change over the duration of follow-up.. These findings document the wide variation in utilization patterns associated with pharmacological management of type 2 diabetes, suggesting that opportunity exists to optimize its pharmacological management.

Topics: Carbamates; Chromans; Cohort Studies; Databases as Topic; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insurance, Pharmaceutical Services; Longitudinal Studies; Managed Care Programs; Metformin; Piperidines; Retrospective Studies; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones; Time Factors; Troglitazone; United States

Repaglinide (NovoNorm) is an antidiabetic oral agent of the new glinide class with insulinotropic activity. Its action on insulin secretion is more rapid and shorter than that of sulphonylurea compounds. Thanks to these properties, repaglinide is able to better control postprandial hyperglycaemia and is associated with a lower risk of delayed hypoglycaemic episodes. It is indicated for the treatment of type 2 (non-insulin-dependent) diabetes mellitus as monotherapy, after diet failure, or in combination with metformin, when the biguanide is insufficient. NovoNorm is commercialized as tablets of 0.5, 1 and 2 mg, to be taken just before each meal. Initial dosis should be 0.5 mg before meal in diabetic patients on diet alone or 1 mg before meal in patients already receiving an hypoglycaemic agent. If necessary, the dosis should be progressively increased, depending on the individual response, up to 4 mg before meal (maximal daily dosage of 16 mg), in order to optimize blood glucose control.

Topics: Administration, Oral; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Piperidines; Postprandial Period

(1) In France, repaglinide is indicated for the treatment of type 2 diabetes, alone or in combination with metformin, when lifestyle measures are inadequate. (2) The clinical file on repaglinide contains no trials based on morbidity and mortality end points. (3) According to comparative trials versus glucose-lowering sulphonamides, the glucose-lowering effect of repaglinide seems to be equivalent to that of glibenclamide. (4) The adverse effect profile of repaglinide appears similar to that of glucose-lowering sulphonamides. Hypoglycaemia is the most frequent adverse effect. In comparative trials, hypoglycaemia was as frequent in patients on repaglinide as in those on glucose-lowering sulphonamides. (5) Drug interactions can occur between repaglinide and some enzyme inhibitors or inducers. (6) Treatment with repaglinide at the maximal dose recommended in France is nearly 4 times as costly as with glibenclamide at the maximal dose.

Topics: Anti-Infective Agents; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Sulfonamides; Treatment Outcome

Topics: Aged; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin, Isophane; Male; Middle Aged; Piperidines

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Piperidines; Postprandial Period

Topics: Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypoglycemic Agents; Piperidines

Repaglinide is a novel oral antidiabetic agent, marking the development of a new class of drugs for type 2 diabetes. This article examines repaglinide and its position in the treatment of type 2 diabetes.

Topics: Administration, Oral; Blood Glucose; Body Weight; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Piperidines; Sulfonylurea Compounds

Repaglinide is the first stimulator of insulin secretion from the new meglitinide family. Via specific binding to the ATP-sensitive potassium channel of the beta cell membrane, it stimulates the rapid release of insulin. In preclinical studies, the insulin-stimulating effect of repaglinide has been found to be 10 to 20 times more potent than that of glibenclamide. Repaglinide is rapidly absorbed and has a short action, which makes it particularly well suited for the regulation of prandial blood glucose and meal-related dose adjustment. Since repaglinide is eliminated almost exclusively by non-renal routes, it can be used without danger in patients with moderately reduced renal function. Repaglinide is a suitable agent for first-line monotherapy in patients whose glucose metabolism cannot be optimally controlled by increasing physical activity and appropriate dietary measures. Repaglinide is clearly superior to glibenclamide in reducing postprandial hyperglycemia, and has a lower hypoglycemia risk than all the sulphonylureas. The flexibility of repaglinide makes it possible for good oral meal-related treatment.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypoglycemic Agents; Obesity; Piperidines

Prandial glucose regulation has the potential for achieving good metabolic control with a low risk of hypoglycaemia and increased flexibility with regard to eating patterns. Comparative studies have suggested that the prandial glucose regulator repaglinide is at least equivalent to sulphonylureas in terms of efficacy, but incurs a lower risk of major hypoglycaemia. However, these trials employed fixed dosing and mealtime regimens, so repaglinide was not used as intended. This prospective investigation in a daily clinical setting aimed to assess the efficacy and tolerability profile of flexible prandial glucose regulation with repaglinide in Type 2 diabetes.. 5,985 patients with Type 2 diabetes in Germany were surveyed prospectively. These patients were assessed before and after a mean of 46 days treatment with repaglinide. At baseline, available data showed that 64% of patients had previously received therapy with conventional oral antidiabetic drugs, 22% were on diet alone, and 13% were naive to any treatment.. Overall, mean HbA1c decreased from 8.6 to 7.4%, fasting blood glucose from 183.9 to 134.2 mg/dl (10.2 to 7.4 mmol/l), blood glucose prior to main meals from 198.5 to 141.4 mg/dl (11 to 7.8 mmol/l), and blood glucose 2 hours after main meals from 219.3 mg/dl to 153.2 mg/dl (12.2 to 8.5 mmol/l). Subgroup analysis showed significant improvements in each of these parameters (P<0.0001) in therapy-naive patients, in patients switched from other oral antidiabetic drugs, and in patients receiving repaglinide as combination therapy. Body weight decreased slightly (1.2+/-2.7 kg). Only 49 hypoglycaemic episodes were reported, of which 38 cases were mild and no adverse sequelae to these events have been reported. Repaglinide also led to a liberating effect on lifestyle when patients were switched from other oral hypoglycaemic agents (OHAs), with 80% reporting a sense of relief at the prospect of being able to miss meals. The proportion of these patients reporting lifestyle restrictions as a result of fixed mealtimes declined from 36% to 7%. Before switching, 38% of the patients admitted to eating when not hungry for fear of hypoglycaemia, but only 10% continued this behaviour and patients took fewer supplementary snacks after switching to repaglinide.. Prandial glucose regulation with repaglinide improves metabolic control in patients with Type 2 diabetes without causing weight gain and with few hypoglycaemic episodes. This beneficial effect is seen in patients who are therapy-naive, have switched from alternative OHAs, or are in need of combination therapy. The prandial approach to treatment has a liberating effect with regard to eating behaviour that is welcomed by most patients switched from alternative therapies.

Topics: Attitude to Health; Blood Glucose; Carbamates; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Eating; Feeding Behavior; Female; Germany; Humans; Hypoglycemic Agents; Life Style; Male; Middle Aged; Piperidines; Professional Practice; Prospective Studies; Surveys and Questionnaires; Treatment Outcome; Weight Loss

Topics: Blood Glucose; C-Peptide; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Insulin; Piperidines

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 10-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T(1/2)), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T(1/2) of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.

Topics: Aged; Carbamates; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Piperidines

Topics: Carbamates; Contraindications; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines

Topics: Acarbose; Carbamates; Chromans; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

In type 2 diabetic patients, the important post-prandial hyperglycemic peak combined with the defective insulin secretion emphasizes the need for restoring a physiological insulin profile during meals, characterized by insulinemia peaking within 1 hour and returning to basal levels within 4 hours. During type 1 diabetes mellitus, short acting insulin analogs aim at counteracting on post-prandial hyperglycemic peak. During type 2 diabetes mellitus, repaglinide is the first fast-acting oral antidiabetic drug able to stimulate endogenous insulin secretion during meal by mimicking physiological insulin secretion pattern.

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Inulin; Piperidines

The natural history of type 2 diabetes involves a progressive pancreatic beta-cell dysfunction leading to quantitative, qualitative and/or temporal abnormalities in insulin secretion and insensitivity to insulin action which predominates in muscles. These abnormalities can be observed during early phases of glucose intolerance, but their determinism remains unclear. The high prevalence of type 2 diabetes, its increasing incidence among developed countries and the huge cost induced by diabetic complications explain why this disease is being viewed as a major public health issue. An earlier diagnosis by general practitioners and more intensive treatments are urged for patient and social beneficial outcome. In addition to non pharmacological (dietary, physical activity) approaches, several drugs were established as efficient therapies for type 2 diabetic patients: sulfonylureas acting by enhancing insulin secretion, metformin improving insulin resistance, or acarbose delaying carbohydrate intestinal absorption. These drugs have been used during the UKPDS trial; nevertheless, their effect was somehow limited, when considering long-term blood glucose control, risk for hypoglycemia, and/or prevention of macroangiopathy. The new generation of insulin secretion enhancers, including repaglinide, by allowing a reduction of total insulinemia, potentiating nutrient-induced insulin secretion, and minimizing risks for hypoglycemia, raises hope for a progress.

Topics: Carbamates; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Exercise; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Piperidines

In addition to dietary and lifestyle changes, standing as the cornerstone of type 2 diabetes care, pharmacological treatments, whether as single or multidrug patterns, are often necessary for an efficient blood glucose control. Besides insulin, four different oral antidiabetic drug categories are available, each of them acting through different and potentially synergistic ways. Oral antidiabetic drugs include: 1) biguanides acting through the reduction of hepatic glucose production and are most efficient in obese patients; 2) alpha-glucosidase inhibitors delaying carbohydrate intestinal absorption; 3) thiazolidinediones or "glitazones", acting as insulin sensitizers; 4) insulin secretion enhancers, mainly including sulfonylureas, which increase insulin secretion and are being credited by a long clinical usage; these are now joined by the new generation of insulin secretion enhancers, led by repaglinide, which can mimic the physiological insulin secretion profile by a specific stimulatory effect on beta-cells characterized by its fast onset and short half-life. Obviously, the combination of these different antidiabetic drugs, by targetting different synergistic and additive pathways, can help to further improve blood glucose.

Topics: Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Metformin; Piperidines

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Piperidines

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exercise; Humans; Hyperglycemia; Hypoglycemic Agents; Piperidines; Weight Loss

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Piperidines

The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic action in vivo, binding to betaTC-3 cells, insulin secretion from perifused mouse islets, and capacity to stimulate exocytosis by direct interaction with the secretory machinery in single voltage-clamped mouse beta-cells. Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l). In contrast to glibenclamide, repaglinide (in concentrations as high as 5 micromol/l) lacked the ability to enhance exocytosis in voltage-clamped beta-cells. Repaglinide was more potent than glibenclamide in stimulating insulin release from perifused mouse islets (EC50 29 vs. 80 nmol/l). The greater potency of repaglinide in vitro was paralleled by similar actions in vivo. The ED50 values for the hypoglycemic action were determined to be 10.4 and 15.6 microg/kg after intravenous and oral administration, respectively. The corresponding values for glibenclamide were 70.3 microg/kg (intravenous) and 203.2 microg/kg (oral). Further, repaglinide (1 mg/kg p.o.) was effective (P < 0.001) as an insulin-releasing agent in a rat model (low-dose streptozotocin) of type 2 diabetes. These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms.

Topics: Animals; Binding Sites; Binding, Competitive; Blood Glucose; Carbamates; Cohort Studies; Culture Techniques; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Evoked Potentials; Glucose; Glyburide; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Inbred Strains; Osmolar Concentration; Patch-Clamp Techniques; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors; Tritium

Topics: Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Fasting; Humans; Hypoglycemic Agents; Piperidines; Postprandial Period

The influence of three daily oral doses of repaglinide (1.0 microg/g body wt.) on plasma insulin and glucose concentrations, pancreatic islet insulin content and both protein biosynthesis and insulin release in isolated islets incubated for 90 min in the presence of either 2.8 or 16.7 mM D-glucose was examined in both control and hereditary diabetic Goto-Kakizaki (GK) rats. In the control rats, repaglinide lowered the plasma glucose concentration, whilst failing to affect significantly the plasma insulin concentration or insulin/glucose ratio, 24 h after the last administration of the antidiabetic agent. Despite a severe decrease of islet insulin content, the ratio between insulin release and content was not altered in islets obtained from repaglinide-treated control rats and incubated in the presence of 16.7 mM D-glucose. Also the biosynthesis of islet peptides was increased at both low and high hexose concentrations. In GK rats, repaglinide administration affected neither plasma glucose nor insulin concentration, restored a normal value for the otherwise abnormally high basal insulin output, increased the 16.7 mM/2.8 mM ratio for insulin release, and again augmented protein biosynthesis at both low and high hexose concentrations. In both control and GK rats, the stress induced by bleeding and decapitation augmented plasma glucose concentration. This effect was more pronounced in GK than in control rats and, in the diabetic animals, coincided with a severe lowering of the plasma insulin/glucose ratio, suggesting a higher adrenergic sensitivity of islet cells in the GK than in control rats. The increased secretory responsiveness to glucose and increased biosynthetic activity found in islets from GK rats after repaglinide administration, are considered favourable attributes of this meglitinide analogue in the perspective of its use as an insulinotropic agent in noninsulin-dependent diabetes.

Topics: Administration, Oral; Animals; Blood Glucose; Carbamates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Glucose; Hypoglycemic Agents; Insulin; Islets of Langerhans; Piperidines; Rats; Rats, Wistar

Topics: Aged; Carbamates; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Piperidines

Topics: Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Piperidines

Topics: Administration, Oral; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Diet, Diabetic; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Piperidines

Repaglinide (1 microg/g body wt), glibenclamide (10 microg/g) or glimepiride (10 microg/g) were administered orally to either fed or overnight fasted normal rats and hereditarily diabetic animals (GK rats). In both fed and starved normal rats, repaglinide provoked a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than those observed after administration of the hypoglycemic sulfonylureas. Likewise, in fed GK rats, the plasma insulin concentration was already increased by 30.0 +/- 1.6% 15 min after administration of repaglinide, whilst a sizeable insulinotropic action of the sulfonylureas was only recorded at much later times. Except for a lower glycemia at the 240th min of the test, there was little to distinguish, in starved GK rats, between control experiments including the oral administration of the solution of carboxymethylcellulose used as vehicle and the experiments conducted with the antidiabetic agents. Several converging observations indicated that glimepiride stimulated insulin release more promptly than glibenclamide. It is proposed that advantage can be taken from these vastly different time-courses of the hormonal and metabolic response to distinct hypoglycemic agents to optimize the control of glucose homeostasis in non-insulin-dependent diabetic subjects.

Topics: Administration, Oral; Animals; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Fasting; Female; Glyburide; Hypoglycemic Agents; Insulin; Male; Piperidines; Rats; Rats, Wistar; Sulfonylurea Compounds

Topics: Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Piperidines

Abnormal gastro-intestinal motility is a well-recognized complication of autonomic neuropathy in diabetics; delayed gastric emptying is frequently documented. Various pharmacologic agents have been used to treat this complication such as cisapride. We have evaluated the effects of cisapride on gastric emptying in nine diabetic patients with autonomic neuropathy through radio-scintigraphic method. Gastric emptying diabetic patients was significantly prolonged compared control subjects (p < 0.01). In our study cisapride increased gastric emptying, but this did not reach statistical significance. We concluded that cisapride may be considered as a good alternative in cases where limited efficacy or side effects preclude the use of metoclopramide.

Topics: Aged; Cisapride; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Humans; Male; Middle Aged; Piperidines; Radioisotopes; Sympathomimetics

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Diabetes Mellitus, Type 2; Female; Heart Failure; Heart Rate; Humans; Kidney Failure, Chronic; Piperidines; Quinolones

Author trie to prove a possible positive effect of sabeluzole in patients with diabetic polyneuropathy. All patients were examined by EMG stimulating method for n. tibialis sin., n. peroneus sin. and n. medianus dx. The distal motor latency, motor conduction velocity and sensory conduction velocity with areas of motor evoked responses were evaluated. The realised test had lower sensitivity than the originally planned one and the expected positive effect of sabeluzole was not proved by this method.

Topics: Diabetes Mellitus, Type 2; Diabetic Neuropathies; Electromyography; Humans; Piperidines; Thiazoles

The long-team effects of cisapride on gastric emptying and hormonal interaction in diabetic patients without gastrointestinal symptoms was evaluated. Gastric emptying was determined by the N-acetyl-p-amino-phenol (APAP) method before and after cisapride treatment. Gastric emptying improved significantly, from 5.95 to 8.04 micrograms/ml, after 6 weeks of treatment. Plasma concentrations of immunoreactive insulin (IRI), after 30 and 45 minutes in the gastric emptying test, increased significantly after treatment. It appeared that improvement of gastric emptying after loading with cisapride might be related to improved insulin secretion in diabetic patients without subjective symptoms of gastroparesis.

Topics: Acetaminophen; Blood Glucose; Cisapride; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Piperidines; Serotonin Antagonists