linagliptin and Diabetes-Mellitus

The aim of the present study was to investigate the effect of linagliptin on microalbuminuria in patients with diabetic nephropathy (DN). The present double-blind randomized placebo-controlled clinical trial was performed on 92 patients with DN who were divided into two groups. The intervention and control groups received linagliptin 5 mg and placebo for 24 weeks, respectively. Blood pressure, lipid profile, liver enzymes, fasting plasma glucose (FPG), and urine albumin-creatinine ratio (UACR) were assessed and recorded before, 12 weeks, and 24 weeks after the beginning of the intervention. The mean value of UACR decrease was significant over time in both groups, with higher decrease in linagliptin group, however, the differences between two groups were not, statistically significant (P > 0.05). However, the percentage of improvement in microalbuminuria (UACR < 30 mg/g) in the linagliptin group was significantly higher than that of the control group during 24 weeks of intervention (68.3% vs. 25%; P-value < 0.001). There was no statistically significant difference in the mean value of the UACR and other parameters between linagliptin treated and placebo treated patients with diabetic nephropathy. Further studies, with longer periods of follow-up are suggested to examine these patients' renal outcomes.

Topics: Albuminuria; Diabetes Mellitus; Diabetic Nephropathies; Humans; Kidney; Linagliptin

A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-l) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2° amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-l). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H

Topics: Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Discovery; Humans; Hypoglycemic Agents; Insulin; Molecular Structure; Piperazines; Pyridazines; Structure-Activity Relationship; Triazoles

Studies on the drug saxagliptin (marketed in Japan since 2013) suggest favorable efficacy in hemodialysis patients, but included small sample sizes. Noting that some hemodialysis patients at our medical institution had been switched to saxagliptin 2.5 mg from treatment with other dipeptidyl peptidase-4 inhibitors, we decided to evaluate the effects of switching to saxagliptin on blood glucose control in these patients. The study included 11 patients. Before switching drugs, six of the patients used teneligliptin 20 mg and five used linagliptin 5 mg. Mean glycated albumin (GA) from before to 4 months after switching tended to increase in the previous users of teneligliptin 20 mg (18.4±3.0% to 19.5±2.7%) and tended to decrease in the previous users of linagliptin 5 mg (18.8±3.3% to 17.7±1.4%). Lack of a substantial change in GA when the previous users of teneligliptin 20 mg and linagliptin 5 mg were switched to saxagliptin 2.5 mg indicates that these three agents might have comparable antihyperglycemic profiles when used in patients on hemodialysis. Future research following from this pilot study must evaluate the risk of cardiac failure and incidences of adverse events in a larger population, to investigate the long-term efficacy and safety of switching to saxagliptin.

Topics: Adamantane; Aged; Aged, 80 and over; Blood Glucose; Cost Savings; Diabetes Mellitus; Dipeptides; Drug Substitution; Female; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Linagliptin; Male; Middle Aged; Pilot Projects; Pyrazoles; Renal Dialysis; Serum Albumin; Thiazolidines

Topics: Adult; Behcet Syndrome; Diabetes Mellitus; Drug Eruptions; Female; Follow-Up Studies; Glucocorticoids; Humans; Hypoglycemic Agents; Japan; Linagliptin; Risk Assessment; Withholding Treatment

Numerous patients develop diabetes in response to glucocorticoid therapy. This study explored the efficacy, safety, and preventive potential of the dipeptidyl peptidase-4 inhibitor, linagliptin (TRADJENTA®), in the development of glucocorticoid-induced diabetes mellitus.. Four of five patients developed glucocorticoid-induced diabetes mellitus within 1 week of glucocorticoid treatment. For 12 weeks, two of the four patients with glucocorticoid-induced diabetes mellitus required orally administered medications, but no patients required insulin. Blood glucose levels before breakfast and lunch tended to decrease with time; the median glucose levels before breakfast were 93 and 79.5 mg/dL at 1 and 3 weeks, respectively. Two patients experienced mild hypoglycemia around 2 weeks. Glucose levels after lunch remained high throughout all 4 weeks despite decreasing the glucocorticoid dosage.. Linagliptin may be insufficient to prevent the development of glucocorticoid-induced diabetes mellitus but has the potential to reduce the requirement for insulin injection therapy. Treatment of glucocorticoid-induced diabetes mellitus was continued for at least 1 month and fasting hypoglycemia in early morning should be monitored after 2 weeks.. This trial was registered 02 November 2014 with UMIN Clinical Trials Registry (no. 000015588 ).

Topics: Age Factors; Aged; Diabetes Mellitus; Drug Monitoring; Female; Glomerular Filtration Rate; Glucocorticoids; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Medication Therapy Management; Outcome Assessment, Health Care; Pilot Projects; Risk Factors

Topics: Aged; Diabetes Mellitus; Drug Eruptions; Female; Humans; Hypoglycemic Agents; Linagliptin; Pemphigoid, Bullous

The dipeptidyl peptidase-4 (DPP-4) inhibitors are among the newer, yet more established, classes of diabetes medications.. To compare adherence, persistence, and health care costs among patients taking DPP-4 inhibitors.. Claims were extracted from Humana Medicare Advantage Prescription Drug (MAPD) or commercial plans for patients aged > 18 years with ≥ 1 prescription filled for a DPP-4 inhibitor between July 1, 2011, and March 31, 2013. The first prescription claim for a DPP-4 inhibitor established the index date and index medication; 12-month pre-index and post-index data were analyzed. The Diabetes Complications Severity Index (DCSI) was used to assess a level of baseline diabetes-related comorbidities. Adherence (proportion of days covered [PDC] ≥ 80%) and persistence (< 31-day gap) measures were compared before and after, adjusting for DCSI, pre-index insulin, age, and gender. Post-index costs (in 2013 U.S. dollars) were compared using general linear modeling (GLM) to adjust for pre-index costs, DCSI, pre-index insulin, age, and gender.. Based on study criteria, 22,860 patients with MAPD coverage (17,292 sitagliptin, 4,282 saxagliptin, and 1,286 linagliptin) and 3,229 patients with commercial coverage (2,368 sitagliptin, 643 saxagliptin, and 218 linagliptin) were included. For MAPD patients, the mean age was 70-72 years, and females represented 50%-52% of patients. For commercial patients, mean age was 55-56 years, and females represented 44% of patients. Clinical indicators for patients on linagliptin showed a higher comorbidity level than sitagliptin or saxagliptin cohorts (MAPD DCSI 3.0 vs 2.4 and 2.2, P < 0.001; commercial DCSI 1.2 vs. 0.9 and 0.9, P < 0.001); a higher use of pre-index insulin (MAPD 22% vs. 15% and 14%, P < 0.001; commercial 18% vs. 11% and 10%, P = 0.003); and higher mean pre-index costs (MAPD $14,448 vs. $11,818 and $10,399, P < 0.001; commercial $13,868 vs. $9,357 and $8,223, P = 0.016). For the MAPD cohort, the unadjusted PDC was lower for linagliptin patients (67%) compared with saxagliptin (72%) or sitagliptin (72%) patients (P < 0.001). Significant differences were still seen when adjusted for covariates. Linagliptin patients were more likely to be nonpersistent (73%) than those on saxagliptin (65%) or sitagliptin (67%; P < 0.01 for adjusted and unadjusted comparisons). For the commercial population, there were no significant differences in mean PDC between the 3 groups (linagliptin 70%, saxagliptin 72%, and sitagliptin 74%; P = 0.096). Dichotomized comparisons of nonpersistence were significantly different (linagliptin 65%, saxagliptin 62%, and sitagliptin 57%; P = 0.010), although upon adjustment using a Cox proportional hazard model, no significant differences were found. When controlling for other factors, post-index adjusted health care costs were similar between the medication cohorts (MAPD: sitagliptin = $13,913, saxagliptin = $13,651, and linagliptin = $13,859; commercial: sitagliptin = $11,677, saxagliptin = $12,059, and linagliptin = $11,163; all P > 0.25).. For MAPD and commercial populations, baseline patient demographics were similar between the 3 DPP-4 inhibitor groups, but the linagliptin group may have had more complex patients (higher pre-index costs, higher DCSI, and more use of insulin). For the MAPD population, patients on linagliptin were less adherent and persistent than patients taking sitagliptin or saxagliptin for all unadjusted and adjusted comparisons. For the commercial population, which was notably smaller, these differences were in the same direction, but not all were statistically significant. When controlling for baseline factors, 12-month post-index direct medical health care costs were similar between index DPP-4 inhibitors.. No external funding was provided for this research. The project was done as part of internal work by Humana employees. Rascati received no compensation. None of the authors have any financial disclosures or conflicts of interests to report. Worley and Everhart are employees of Comprehensive Health Insights, a subsidiary of Humana, and Meah is an employee of Humana. Discussion of the adherence and persistence data was presented as a poster at the Academy of Managed Care Pharmacy Nexus Conference, October 2015. Cost data were presented as a poster at the International Society for Pharmacoeconomics and Outcomes Research 18th Annual European Congress, November 2015. Study concept and design were contributed by Rascati, Worley, and Meah, along with Everhart. Rascati took the lead in data collection, assisted by Meah, and data interpretation was performed by all the authors. The manuscript was written primarily by Rascati, along with Worley, Everhart, and Meah, and revised by Rascati, Everhart, and Worley, with assistance from Meah.

Topics: Adamantane; Aged; Aged, 80 and over; Diabetes Mellitus; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Health Care Costs; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Male; Managed Care Programs; Medication Adherence; Middle Aged; Sitagliptin Phosphate

It is now clear that insulin signaling has important roles in regulation of neuronal functions in the brain. Dysregulation of brain insulin signaling has been linked to neurodegenerative disease, particularly Alzheimer's disease (AD). In this regard, there is evidence that improvement of neuronal insulin signaling has neuroprotective activity against amyloid β (Aβ)-induced neurotoxicity for patients with AD. Linagliptin is an inhibitor of dipeptidylpeptidase-4 (DPP-4), which improves impaired insulin secretion and insulin downstream signaling in the in peripheral tissues. However, whether the protective effects of linagliptin involved in Aβ-mediated neurotoxicity have not yet been investigated.. In the present study, we evaluated the mechanisms by which linagliptin protects against Aβ-induced impaired insulin signaling and cytotoxicity in cultured SK-N-MC human neuronal cells.. Our results showed that Aβ impairs insulin signaling and causes cell death. However, linagliptin significantly protected against Aβ-induced cytotoxicity, and prevented the activation of glycogen synthase kinase 3β (GSK3β) and tau hyperphosphorylation by restoring insulin downstream signaling. Furthermore, linagliptin alleviated Aβ-induced mitochondrial dysfunction and intracellular ROS generation, which may be due to the activation of 5' AMP-activated protein kinase (AMPK)-Sirt1 signaling. This upregulation of Sirt1 expression was also observed in diabetic patients with AD coadministration of linagliptin.. Taken together, our findings suggest linagliptin can restore the impaired insulin signaling caused by Aβ in neuronal cells, suggesting DPP-4 inhibitors may have therapeutic potential for reducing Aβ-induced impairment of insulin signaling and neurotoxicity in AD pathogenesis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; AMP-Activated Protein Kinases; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Chromones; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Insulin-Like Growth Factor I; Linagliptin; Male; Membrane Potential, Mitochondrial; Morpholines; Neuroblastoma; Peptide Fragments; Reactive Oxygen Species; RNA, Messenger; Sirtuin 1; Superoxide Dismutase; Superoxide Dismutase-1

Topics: Adamantane; Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Nitriles; Purines; Pyrrolidines; Quinazolines; Renal Dialysis; Vildagliptin

Since its foundation in 1965, the European Association for the Study of Diabetes (EASD) has been organizing an annual meeting, which has become the largest international annual conference on diabetes research worldwide. This year, the 50th edition was held in Vienna, Austria, from September 15 to 19. A total of 1,332 abstracts were accepted for inclusion and the program comprised 6 parallel tracks, which included stimulating symposia, keynote lectures and debates covering basic and clinical science. The EASD meeting is known for bringing researchers and clinicians of the highest caliber together, and this year was no exception.

Topics: Animals; Benzhydryl Compounds; Canagliflozin; Diabetes Mellitus; Diabetic Nephropathies; Glucosides; Humans; Linagliptin

Topics: Adamantane; Diabetes Mellitus; Dipeptides; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Linagliptin; Pancreatitis; Purines; Pyrazines; Quinazolines; Sitagliptin Phosphate; Triazoles; United States

Antidiabetic effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are exerted by potentiation of the biological activity of incretin hormones like glucagon-like peptide (GLP)-1. BI 1356 [proposed trade name Ondero; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel competitive, selective, potent, and long-acting DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes. The effect of 1 to 2 months of chronic dosing of BI 1356 in two different animal models was investigated. The first is a primarily genetic model (Zucker diabetic fatty rats), and the second is a nongenetic model (mice with diabetes induced by a combination of high-fat diet and low-dose streptozotocin). BI 1356 was shown to lower HbA1c after multiple dosing in both models. The improvement of glycemic control achieved in disease models of different etiology suggests that BI 1356 would also be efficacious in treating a broad spectrum of type 2 diabetic patients. In addition, multiple dosing of BI 1356 leads to a sustained increase in basal levels of active GLP-1 in the systemic circulation, with expected long-term benefits on pancreatic alpha- and beta-cells. The effects on HbA1c and GLP-1 were superior to the short-acting DPP-4 inhibitor vildagliptin, demonstrating the potential of BI 1356 as a once daily treatment for type 2 diabetes at low therapeutic doses.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Female; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Linagliptin; Male; Mice; Purines; Quinazolines; Rats; Rats, Zucker; Tumor Cells, Cultured