sitagliptin-phosphate and Diabetes-Mellitus

Diabetic retinopathy (DR), one of the leading causes of preventable blindness, is associated with many systemic factors that contribute to the development and progression of this microvascular complication of diabetes. While the duration of diabetes is the major risk factor for the development of DR, the main modifiable systemic risk factors for development and progression of DR are hyperglycemia, hypertension, and dyslipidemia. This review article looks at the evidence that control of these systemic factors has significant benefits in delaying the onset and progression of DR.

Topics: Blood Glucose; Blood Pressure; Diabetes Mellitus; Diabetic Retinopathy; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemic Agents; Renin-Angiotensin System; Risk Factors; Sitagliptin Phosphate; Thiazolidinediones; Vision Disorders

Topics: Acarbose; Biguanides; Blood Glucose Self-Monitoring; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Routes; Drug Design; Drug Therapy, Combination; Education, Medical, Continuing; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Incretins; Insulin; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

With vildagliptin and sitagliptin on the market for the treatment of type 2 diabetes, dipeptidyl peptidase 4 (DPP4, EC 3.4.14.5) research has entered a new era. Scientists aim to uncover the broader pharmacological profile of DPP4 inhibitors and search for therapeutic opportunities outside diabetes. During the pre-clinical and clinical evaluation of vildagliptin and sitagliptin, there has been a growing awareness of the presence of other DPP4-like peptidases in various cells and tissues. This fuelled the development of more inhibitors with defined selectivity for DPP2, 8 and 9 that were used to investigate the expression, distribution and regulation of these peptidases. In turn, these studies increased the insights in the role of DPP4 in the body's response to various insults.

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Hypoxia; Neoplasms; Nitriles; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

Topics: Animals; Diabetes Mellitus; Exenatide; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Diabetes mellitus is a chronic metabolic disease which has an adverse impact on the quality of patient's life, so patients often need to receive treatment for a long time. Selection of medications with high therapeutics effects and low cost is very important for patients to take medicine for a longer period of time. Sitagliptin is a drug which is widely used in clinics and can effectively control blood glucose level. This article explores the pharmacoeconomic value of Sitagliptin in the treatment of diabetes mellitus.. A total of 100 patients with diabetes mellitus treated were recruited in this study. The patients were randomly divided into 4 groups with 25 cases in each group. Patients in group A were treated with pioglitazone, group B with Sitagliptin, group C with metformin and group D with glimepiride. The cost of the drugs, the treatment results and adverse effects were compared.. Compared with group A, C and D, the cost-effectiveness ratio of group B was low (p<0.05), and the therapeutic effect was high (p<0.05). In addition, the incidence of adverse reactions in group B was lower than that in group A, C and D (p<0.05). There was no significant difference in the levels of FPG, 2hPG and HbAlc in patients among the four groups before treatment (p>0.05). After treatment, the levels of FPG, 2hPG and HbAlc in group B were significantly lower than those in groups A, C and D (p<0.05). Finally, there was no significant difference in waist circumference and BMI among the four groups before treatment (p>0.05). After treatment, the waist circumference and BMI in group B were lower than those in groups A, C and D (p<0.05).. The application of Sitagliptin in the treatment of diabetic patients can effectively enhance the therapeutic effect. The cost effectiveness is satisfactory, and the blood glucose level can be maintained at a stable state.

Topics: Adult; Aged; Aged, 80 and over; Cost-Benefit Analysis; Diabetes Mellitus; Economics, Pharmaceutical; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Sitagliptin Phosphate; Sulfonylurea Compounds

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan-Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91-1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02-1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Drug Monitoring; Female; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Outcome and Process Assessment, Health Care; Proportional Hazards Models; Risk Assessment; Risk Factors; Sitagliptin Phosphate

Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A

Topics: Adult; Blood Glucose; Diabetes Mellitus; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Male; Pancreatectomy; Sitagliptin Phosphate; Transplantation, Autologous

Osteoporosis is the most important metabolic bone disease in patients with diabetes mellitus. Several studies have documented that metformin is osteogenic in vitro. In contrast, others showed no effect of metformin on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Incretin hormones have received much attention because of their beneficial effects beyond glycemia, including on bone health. The study evaluated the anti-osteoporotic effect of metformin and sitagliptin in postmenopausal diabetic women. Forty postmenopausal diabetic women were randomly divided into two equal groups. Group 1 received metformin (Glucophage(®) 500 mg) 1 tablet twice daily, and group 2 received sitagliptin (Januvia(®) 100 mg) 1 tablet/day, for 12 weeks. Fasting blood and urine samples were collected for measurement of serum total alkaline phosphatase (ALP), osteocalcin, and urinary deoxypyridinoline (DPD). Laboratory tests were measured at baseline, after 4 and 8 weeks, and at the end of the study. Bone mineral density of the anterior posterior lumbar spine was measured by dual energy X-ray absorptiometry at baseline and after 12 weeks of the intervention. In the metformin-treated group, the mean values for all markers of bone turnover at 12 weeks of treatment were not significantly different from baseline. In group 2, the mean serum total ALP was significantly decreased, serum osteocalcin levels were non-significantly decreased gradually by 10% at 12 weeks, while urinary DPD decreased significantly and was then maintained at 28% decrease at 12 weeks. In conclusion, metformin is neither osteogenic nor has anti-osteoporotic effect, while sitagliptin could positively regulate bone metabolism.

Topics: Absorptiometry, Photon; Aged; Alkaline Phosphatase; Amino Acids; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Lumbar Vertebrae; Metformin; Middle Aged; Osteocalcin; Osteogenesis; Osteoporosis, Postmenopausal; Postmenopause; Pyrazines; Sitagliptin Phosphate; Triazoles

New-onset diabetes after transplantation (NODAT) is a common complication after renal transplantation. There are limited available oral drugs to treat hyperglycaemia in this population owing to reduced renal function, potential interactions with immunosuppressive drugs and adverse effects such as hypoglycaemic events that may increase the cardiovascular risk. This study was initiated to investigate efficacy and safety of sitagliptin treatment that may represent a novel alternative in renal transplant recipients.. Nineteen long-term stable renal transplant recipients with NODAT were included in a controlled, cross-over study and randomized to first receive either sitagliptin 50-100 mg/day or a sitagliptin-free period of 4 weeks. Median age (interquartile range, IQR) was 67 (62-72) years (12 males/7 females), all studied 1 (1-3) year after transplantation. The immunosuppressive regimen was a triple calcineurin inhibitor-based therapy. Oral glucose tolerance test (OGTT) with insulin and C-peptide responses and laser Doppler (LD) flowmetry assessment of endothelial function were performed at baseline and after each treatment period. Home measurements of plasma glucose were performed daily during the study.. The median (IQR) first- and second-phase insulin secretion responses increased significantly by 56.3% (45.2-112.6%, P = 0.005) and 39.3% (26.5-81.0%, P = 0.006), respectively, following sitagliptin treatment as compared with no sitagliptin treatment. Fasting and 2-h plasma glucose concentrations fell significantly {0.9 mmol/L [0.5-1.7 mmol/L (16.2 mg/dL), P = 0.003] and 2.9 mmol/L [0.5-6.4 mmol/L (52.3 mg/dL), P = 0.004], respectively}, as did also home measurements of plasma glucose. Endothelial function and plasma markers of cardiovascular risk were unaffected. No serious adverse events were observed. Two mild and asymptomatic hypoglycaemic episodes were observed in combination with glipizide.. Sitagliptin increases insulin secretion and reduces fasting and postprandial plasma glucose in renal transplant recipients with NODAT. The short-term treatment was well tolerated, and sitagliptin seems safe in this population.

Topics: Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postprandial Period; Prospective Studies; Pyrazines; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

The aim of this study was to evaluate the effectiveness of sitagliptin, alone or in combination with metformin, in kidney transplant patients with newly diagnosed new-onset diabetes mellitus after transplant who had inadequate glycemic control, compared with a group of patients receiving insulin glargine with special emphasis on weight gain.. Newly diagnosed renal transplant patients with new-onset diabetes mellitus after a transplant was defined by a blood glucose ≥ 11.1 mmol/L after an oral glucose tolerance test were examined. They were treated with standard immunosuppression composed of triple therapy with tacrolimus or cyclosporine, mycophenolate mofetil or azathioprine, and prednisone. They had stable graft function for more than 6 months after the transplant.. Patients with new-onset diabetes mellitus after transplant (n=28) whose glycemia was not controlled adequately with oral hypoglycemic agents (either alone or in combination) received oral sitagliptin 100 mg once daily in addition to existing therapy for 12 weeks. Patients who received insulin glargine as add-on therapy (n=17) served as the control group. Data analyses included glycated hemoglobin, fasting plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia. We found significant reductions in glycated hemoglobin and fasting plasma glucose values after 12 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. While the addition of stagliptin resulted in a small weight loss (0.4 kg), the addition of insulin glargine resulted in a weight gain (0.8 kg). The overall incidence of adverse experiences was low and generally mild in both groups.. In a group of renal transplant recipients with new-onset diabetes mellitus after a transplant in whom glycemia was not controlled adequately by oral hypoglycemic agents, the addition of sitagliptin helped to achieve glycemic control similar to insulin glargine but with a marginal weight advantage.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Kidney Transplantation; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Weight Gain; Weight Loss

Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of diabetes. The frequencies of known serious side effects might differ among DPP-4 inhibitors, therefore a large sample size is needed to study them in prospective clinical trials. We examined the adverse events that occurred during the administration of a DPP-4 inhibitor in patients with diabetes using FDA Adverse Event Reporting System (FAERS) data.. We used FAERS data reported between January 2013 and March 2022 in patients with diabetes who received a DPP-4 inhibitor. Statistical analyses were conducted to calculate reporting odds ratio (ROR) and adjusted ROR (aROR) controlling for differences in patient background.. The 9 target DPP-4 inhibitors were sitagliptin (N = 26,843), vildagliptin (N = 4767), alogliptin (N = 2085), linagliptin (N = 7969), saxagliptin (N = 3334), teneligliptin (N = 461), anagliptin (N = 102), trelagliptin (N = 17), and omarigliptin (N = 12). Compared with sitagliptin, aROR of acute kidney injury was significantly < 1.000 for alogliptin (0.247 [95% confidence interval (CI) 0.150-0.408], p < 0.001) but aROR of pemphigoid was significantly > 1.000 for alogliptin (3.082 [95% CI 2.156-4.406], p < 0.001). Similar statistical analyses were conducted for other adverse events and the types of adverse events with aROR of significantly < 1.000 or > 1.000 differed depending on the type of DPP-4 inhibitor.. Although it is impossible to select a DPP-4 inhibitor with aROR of < 1.000 of all occurrences of adverse events, these results may be used for drug selection when the patient has adverse events that need to be avoided. We provided the sample code of software R that can reproduce the results.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Prospective Studies; Sitagliptin Phosphate

In coronavirus disease 2019 (Covid-19), SARS-CoV-2 may use dipeptidyl peptidase 4 (DPP4) as an entry-point in different tissues expressing these receptors. DPP4 inhibitors (DPP4Is), also named gliptins, like sitagliptin, have anti-inflammatory and antioxidant effects, thereby lessen inflammatory and oxidative stress in diabetic Covid-19 patients. Therefore, the present study aimed to illustrate the potential beneficial effect of sitagliptin in managing Covid-19 in non-diabetic patients.. A total number of 89 patients with Covid-19 were recruited from a single center at the time of diagnosis. The recruited patients were assigned according to the standard therapy for Covid-19 and our interventional therapy into two groups; Group A: Covid-19 patients on the standard therapy (n=40) and Group B: Covid-19 patients on the standard therapy plus sitagliptin (n=49). The duration of this interventional study was 28 days according to the guideline in managing patients with Covid-19. Routine laboratory investigations, serological tests, Complete Blood Count (CBC), C-reactive Protein (CRP), D-dimer, lactate dehydrogenase (LDH), and serum ferritin were measured to observed Covid-19 severity and complications. Lung Computed Tomography (CT) and clinical scores were evaluated.. The present study illustrated that sitagliptin as an add-on to standard therapy improved clinical outcomes, radiological scores, and inflammatory biomarkers than standard therapy alone in non-diabetic patients with Covid-19 (P<0.01).. Sitagliptin as an add-on to standard therapy in managing non-diabetic Covid-19 patients may have a robust beneficial effect by modulating inflammatory cytokines with subsequent good clinical outcomes.

Topics: COVID-19 Drug Treatment; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; SARS-CoV-2; Sitagliptin Phosphate

Autoimmune-led challenge resulting in β-cell loss is responsible for the development of type 1 diabetes (T1D). Melatonin, a pineal hormone or sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has increased β-cell mass in various diabetic models and has immunoregulatory property. Both β-cell regenerative capacity and melatonin secretion decrease with ageing. Thus, we aimed to investigate the therapeutic potential of melatonin combined with sitagliptin on β-cell regeneration under glucotoxic stress, in the streptozotocin-induced young and old diabetic mouse models, and euglycemic humanized islet transplant mouse model. Our results suggest that combination therapy of sitagliptin and melatonin show an additive effect in inducing mouse β-cell regeneration under glucotoxic stress, and in the human islet transplant mouse model. Further, in the young diabetic mouse model, the monotherapies induce β-cell transdifferentiation and reduce β-cell apoptosis whereas, in the old diabetic mouse model, melatonin and sitagliptin induce β-cell proliferation and β-cell transdifferentiation, and it also reduces β-cell apoptosis. Further, in both the models, combination therapy reduces fasting blood glucose levels, increases plasma insulin levels and glucose tolerance and promotes β-cell proliferation, β-cell transdifferentiation, and reduces β-cell apoptosis. It can be concluded that combination therapy is superior to monotherapies in ameliorating diabetic manifestations, and it can be used as a future therapy for β-cell regeneration in diabetes patients.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hypoglycemic Agents; Melatonin; Mice; Pyrazines; Sitagliptin Phosphate; Triazoles

Chiral drugs are of great significance in drug development and life science because one pair of enantiomers has a different combination mode with target biological active sites, leading to a vast difference in physical activity. Metal-organic framework (MOF)-based chiral hybrid materials with specific chiral sites have excellent applications in the highly effective sensing of drug enantiomers. Sitagliptin and clonidine are effective curing drugs for controlling diabetes and hypertension, while insulin and norepinephrine are the biomarkers of these two diseases. Excessive use of sitagliptin and clonidine can cause side effects such as stomach pain, nausea, and headaches. Herein, through post-synthetic strategy, MOF-based chiral hybrid material

Topics: Biomarkers; Carnitine; Clonidine; Diabetes Mellitus; Europium; Humans; Hypertension; Insulins; Metal-Organic Frameworks; Norepinephrine; Sitagliptin Phosphate

Synaptic dysfunction and neuronal damage have been extensively associated with diabetic retinopathy (DR). Our group evidenced that chronic hyperglycemia reduces the retinal expression of presynaptic proteins, which are crucial for proper synaptic function. The aim of the study was to explore the effect of topically administered sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4, on the retinal expression patterns of an experimental model of DR. Transcriptome analysis was performed, comparing the retinas of 10 diabetic (db/db) mice randomly treated with sitagliptin eye drops (10 mg/mL) twice daily and the retinas of 10 additional db/db mice that received vehicle eye drops. Ten non-diabetic mice (db/+) were used as a control group. The Gene Ontology (GO) and Reactome databases were used to perform the gene set enrichment analysis (GSEA) in order to explore the most enriched biological pathways among the groups. The most differentiated genes of these pathways were validated through quantitative RT-PCR. Transcriptome analysis revealed that sitagliptin eye drops have a significant effect on retinal expression patterns and that neurotransmission is the most enriched biological process. Our study evidenced enriched pathways that contain genes involved in membrane trafficking, transmission across chemical synapses, vesicle-mediated transport, neurotransmitter receptors and postsynaptic signal transmission with negative regulation of signaling as a consequence of neuroprotector treatment with sitagliptin. This improves the modulation of the macromolecule biosynthetic process with positive regulation of cell communication, which provides beneficial effects for the neuronal metabolism. This study suggests that topical administration of sitagliptin ameliorates the abnormalities on presynaptic and postsynaptic signal transmission during experimental DR and that this improvement is one of the main mechanisms behind the previously demonstrated beneficial effects.

Topics: Animals; Diabetes Mellitus; Diabetic Retinopathy; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Profiling; Mice; Models, Theoretical; Neuroprotective Agents; Sitagliptin Phosphate; Transcriptome

Diabetes mellitus (DM), one of the commonest worldwide metabolic conditions, is believed to be associated with an imbalance between oxidants and antioxidants. Sitagliptin is an oral anti-hyperglycaemic drug that blocks dipeptidyl peptidase 4 (DPP4). Rutin is a polyphenolic natural flavonoid which has antioxidant and anti-proliferative activity. The aim of the present work is to elucidate the concomitant effect of sitagliptin and rutin on the deleterious alterations in the liver of experimentally induced diabetes in rats.. Fifty adult male albino rats, weighing 170-200 g were used. Rats were randomly divided into five groups (n = 10): group 1 (control group), the other four groups (groups II, III, IV and V) received a single i.p. injection of streptozotocin, 65 mg/kg body weight to induce diabetes; group II (diabetic), group III (diabetic and rutin administered), group IV (diabetic and sitagliptin administered), and group V (diabetic with sitagliptin and rutin concomitantly administered). Haematoxylin and eosin, Masson trichrome, periodic acid Schiff, immune-histochemistry: a-smooth muscle actin (a-SMA), histomorphometric analysis, liver enzymes and oxidants/anti-oxidants; malondialdehyde/glutathione and were done.. Distorted hepatic architecture, dilatation, congestion of sinusoids and central veins as well as cytoplasmic vacuolations were remarkable changes in the diabetic group. There was extravasation of blood, diffuse fibrous tissue formation, increase in the mean values of liver enzymes, oxidative markers and a-SMA expression in the same group. The aforementioned changes were ameliorated in groups III and IV. Concomitant administration of sitagliptin and rutin resulted in marked enhancement of these hepatic alterations.. Combination of sitagliptin and rutin has an ameliorating effect on the hepatic deterioration induced by diabetes, which is better than either sitagliptin or rutin alone.

Topics: Actins; Animals; Diabetes Mellitus; Liver; Male; Muscle, Smooth; Rats; Rutin; Sitagliptin Phosphate; Streptozocin

γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

Topics: Animals; Apoptosis; Blood Glucose; Cell Proliferation; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Drug Therapy, Combination; GABA Agents; gamma-Aminobutyric Acid; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Mice, Inbred NOD; Middle Aged; Sitagliptin Phosphate

Sitagliptin increases the levels of incretin hormones and stimulates a decrease in blood glucose levels, by blocking the DPP4 enzyme. We have very limited information about impact of sitagliptin on male genital system and relationship between sitagliptin/diabetes/ER. Fucoidan can be effective in blood glucose homeostasis. We goal to explain of the effect of sitagliptin and introduce an approach of fucoidan treatment in experimental diabetes in male rats. Fifty-eight Wistar albino rats were divided into C-control group and D-diabetes group: 60 mg/kg streptozotocin intraperitoneal (i.p.); DS group: STZ + 10 mg/kg sitagliptin intragastric (i.g.); DF group: STZ + 100 mg/kg fucoidan i.p.; and DSF group: STZ + 10 mg/kg sitagliptin + 100 mg/kg fucoidan. A significant decrease was detected when DS, DF and DSF groups compared to group D in blood glucose levels, basement membrane thickness and also apoptotic cell/tubule index, pJNK, caspase 3, caspase 12, GRP78, CHOP and DPP4. Sitagliptin and fucoidan have been found to be effective in blood glucose homeostasis and reducing the expression of certain proteins that lead to apoptosis and especially the proteins in the ER stress pathway. Therefore, we think that both sitagliptin and fucoidan can be effective in preventing or eliminating histopathological damages in diabetic testicular tissues, and their treatment effects can be used more.

Topics: Animals; Apoptosis; Diabetes Mellitus; Male; Polysaccharides; Rats; Rats, Wistar; Sitagliptin Phosphate; Testis

Sitagliptin, a dipeptidyl peptidase-4(DPP-4) Inhibitor, has been found to have an anti-atherosclerotic effect. Since apoptosis of vascular smooth muscle cells (VSMCs) contributes to the occurrence of diabetic atherosclerosis. This study aimed to examine whether sitagliptin suppresses the atherosclerosis progression to hyperglycemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated the effect of sitagliptin on VSMCs apoptosis and its underlying mechanism. In vivo studies, eight-week-old low-dose STZ-induced diabetic apolipoprotein E (apoE)-deficient (apoE-/-) mice fed a high-fat diet were administered a DPP-4 inhibitor, sitagliptin, 200 mg/kg/day, or Lantus insulin by daily subcutaneous injection of 1 unit/mouse over a period of 12 weeks. Aortic atherosclerosis and apoptosis in the plaque were determined using dUTP-biotin nick end labeling (TUNEL) staining and immunohistochemistry. In vitro studies utilized the VSMCs for determination of glucagon-like peptide 1 receptor (GLP-1R) and DPP-4 expression and flow cytometry and Western blotting were used to determine apoptosis and protein expression, respectively. Sitagliptin significantly reduced atherosclerotic lesion area (7.00 ± 0.13 vs. 12.80 ± 2.7%, p = 0.003) and suppressed vascular smooth muscle cell apoptosis (2.30 ± 1.34 vs. 4.8 ± 1.93%, p = 0.003) compared with vehicle treatment. In addition, sitagliptin significantly increased the expression of β-catenin in the aortic tissue(0.56 ± 0.13 vs.0.17 ± 0.02, p = 0.008)compared with vehicle treatment. In cultured mouse VSMCs, sitagliptin enhanced GLP-1 activity significantly retarded oxidative stress (H

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Sitagliptin Phosphate

Topics: Cystic Fibrosis; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Humans; Sitagliptin Phosphate

Patients with SARS-CoV-2 infections experience lymphopenia and inflammatory cytokine storms in the severe stage of the disease, leading to multi-organ damage. The exact pattern of immune system changes and their condition during the disease process is unclear. The available knowledge has indicated that the NF-kappa-B pathway, which is induced by several mediators, has a significant role in cytokine storm through the various mechanisms. Therefore, identifying the state of the immune cells and the dominant mechanisms for the production of cytokines incorporated in the cytokine storm can be a critical step in the therapeutic approach. On the other hand, some studies identified a higher risk for diabetic patients. Diabetes mellitus exhibits a close association with inflammation and increases the chance of developing COVID-19. Patients with diabetes mellitus have shown to have more virus entry, impaired immunity response, less viral elimination, and dysregulated inflammatory cytokines. The parallel analysis of COVID-19 and diabetes mellitus pathogenesis has proposed that the control of the inflammation through the interfering with the critical points of major signaling pathways may provide the new therapeutic approaches. In recent years, the role of Dipeptidyl Peptidase 4 (DPP4) in chronic inflammation has been proved. Numerous immune cells express the DPP4 protein. DPP4 regulates antibody production, cytokine secretion, and immunoglobulin class switching. DPP4 inhibitors like sitagliptin reduce inflammation intensity in different states. Following the accumulating data, we hypothesize that sitagliptin might reduce COVID-19 severity. Sitagliptin, an available DPP4 inhibitor drug, showed multidimensional anti-inflammatory effects among diabetic patients. It reduces the inflammation mostly by affecting on NF-kappa-B signaling pathway. Under the fact that inflammatory mediators are active in individuals with COVID-19, blocking the predominant pathway could be helpful.

Topics: Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokines; Diabetes Complications; Diabetes Mellitus; Dipeptidyl Peptidase 4; Humans; Inflammation; Insulin Resistance; Models, Theoretical; NF-kappa B p50 Subunit; Pandemics; Pneumonia, Viral; Signal Transduction; Sitagliptin Phosphate

To analyse glucose-lowering drug utilization, focusing on the novel glucose-lowering drug groups dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors, and the financial burden they entail.. Crude reimbursed national drug utilization and expenditure data for the entire population of Hungary were obtained from the National Health Insurance Fund for the study period: 2008 to 2017. Data were analysed using the WHO's Anatomical Therapeutic Chemical Classification/defined daily dose system and were expressed in defined daily dose per 1000 inhabitants per day.. Total glucose-lowering drug consumption in Hungary showed an 18% increase over the study period, reaching 74.7 defined daily doses per 1000 inhabitants per day, while novel glucose-lowering drug use increased to 11.7 defined daily doses per 1000 inhabitants per day (16% of total glucose-lowering drug use) by 2017. Dipeptidyl-peptidase 4 inhibitor consumption grew to 7.4 defined daily doses per 1000 inhabitants per day by 2017. The most widely used dipeptidyl-peptidase 4 inhibitor was sitagliptin. Glucagon-like peptide-1 receptor agonists were used the least, but by 2017 rose to 1.5 defined daily doses per 1000 inhabitants per day, led by liraglutide. Sodium-glucose co-transporter-2 inhibitors appeared in the utilization data in 2014 and their consumption, mainly empagliflozin, reached 2.8 defined daily doses per 1000 inhabitants per day by 2017. The total expenditure on glucose-lowering drugs increased 94% between 2008 and 2017, and the total cost of novel glucose-lowering drug utilization comprised 44% of the total glucose-lowering drug expenditure in 2017.. Both the use of and the financial burden posed by novel glucose-lowering drugs in Hungary increased steadily between 2008 and 2017. This increase is expected to continue.

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Costs; Glucagon-Like Peptide-1 Receptor; Humans; Hungary; Hypoglycemic Agents; Retrospective Studies; Sitagliptin Phosphate

Topics: Case-Control Studies; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islets of Langerhans Transplantation; Pancreatectomy; Pancreatic Diseases; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Transplantation, Autologous; Treatment Outcome

The aim of the study to formulate and statistically optimize sitagliptin-loaded eudragit nanoparticles (SIT-NPs) and evaluate the in-vitro pharmaceutical quality and in-vivo anti-diabetic assessment.. SIT-NPs were prepared by using combination method of solvent evaporation and nano-precipitation techniques. The influence of different independent variables as eudragit RL100 concentration (%), tween 80 concentration (%) and sonication time (min) were evaluated on dependent variables like particle size (nm), drug loading (%) and in-vitro drug release (%). Further, the optimized formulation was evaluated for surface morphology, CLSM, ex-vivo permeation study and in-vivo anti-diabetic activity and stability study.. The developed SIT-NPs formulations showed particle size range (135.86-193.45 nm), drug loading (6.36-8.76%) and prolonged drug release over 24 h. The prepared SIT-NPs were found to be nearly spherical with smooth surface. The comparative in-vitro release study and CLSM study results revealed that SIT-NPopt showed significantly (p < .05) enhanced release and permeation as compared to SIT free solution (SIT-Fs). The in-vivo anti-diabetic assessment revealed that SIT-NPopt able to reduce the blood sugar level (BSL) for a prolonged period of time. Further, the stability study data showed the formulations were found stable at both temperature and having the shelf life of 488 d.. This research has shown that SIT-NPs based on experimental design offers a new and better approach to delivering SIT, thus encouraging further development of this formulation.

Topics: Administration, Oral; Animals; Diabetes Mellitus; Drug Carriers; Drug Compounding; Drug Liberation; Feasibility Studies; Hypoglycemic Agents; Nanoparticles; Particle Size; Permeability; Polymers; Rats; Rats, Wistar; Sitagliptin Phosphate

Topics: Adrenal Cortex Hormones; Aged; Autoimmune Diseases; Diabetes Complications; Diabetes Mellitus; Dyslipidemias; Female; Humans; Hypertension; Immunoglobulin G; Liver; Pancreatitis; Pioglitazone; Sitagliptin Phosphate; Thiazolidinediones

A 78-year-old man presented with cutaneous blisters of the limbs and abdominal distension. He had been treated for various diseases, including liver cirrhosis. He had begun receiving sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for diabetes mellitus three years before the hospitalization. A skin biopsy demonstrated bullous pemphigoid. Ultrasonography (US) revealed multiple liver tumors, although he had been receiving regular US studies. We stopped sitagliptin and started insulin and corticosteroids. However, his renal dysfunction progressed, and he died 14 days after the hospitalization. We should therefore be careful of various complications, including bullous pemphigoid and progression of tumors, when using DPP-4 inhibitors.

Topics: Aged; Carcinoma, Hepatocellular; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Liver Cirrhosis; Liver Neoplasms; Male; Pemphigoid, Bullous; Sitagliptin Phosphate

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

Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors.. Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group.. A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors.. Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

Topics: Adamantane; Aged; Cohort Studies; Diabetes Mellitus; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Nitriles; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Treatment Outcome; Vildagliptin

For analysis of the anti-diabetic drugs metformin and sitagliptin and the renal clearance marker creatinine in the same human dried blood spot (DBS) extract two liquid chromatography methods employing HPLC/UV and LC-ESI-MS/MS have been developed and validated. An accurate volume of 40μL blood was spotted on a sampling paper which was extracted using 90% acetonitrile with 10% formic acid. The new methods were shown to be selective, accurate and precise. The validated ranges were 0.2-5μg/mL for metformin, 1.5-15μg/mL for creatinine and 3-500ng/mL for sitagliptin. Since drug analysis in DBS determines whole blood concentrations as opposed to the typically used plasma levels the partition ratios between human plasma and blood cells, c(P)/c(BC), were elucidated in vitro to gain insight into the significance of blood cells as compartment of distribution for both compounds. The c(P)/c(BC) was found to be 4.65±0.73 for metformin and 5.58±0.98 for sitagliptin. While an accumulation of metformin in erythrocytes was already known we now present the first evidence that sitagliptin distributes into human blood cells. The analytical methods were also successfully applied to authentic capillary blood samples from two diabetic patients regularly taking a combination of metformin and sitagliptin. Both samples revealed analyte trough concentrations well above the lower limit of quantification of the respective compounds. Therefore, the present study offers a methodological basis for the DBS analysis of metformin and sitagliptin in relation to the patients' creatinine concentration.

Topics: Creatinine; Diabetes Mellitus; Dried Blood Spot Testing; Drug Stability; Humans; Hypoglycemic Agents; Linear Models; Metformin; Reproducibility of Results; Sensitivity and Specificity; Sitagliptin Phosphate

Topics: Achilles Tendon; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Magnetic Resonance Imaging; Middle Aged; Pyrazines; Sitagliptin Phosphate; Tendinopathy; Triazoles

To investigate the chronic effect of sitagliptin (7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-(3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate, SIT) on metabolism and cardiac function in genetic diabetic Akita mice, 10 weeks old Akita mice were either exposed for 4 months to a high fat and high cholesterol (HF-HC) diet, with or without 10mg/kg/day SIT, or were fed for 3 months with the same diet with or without 50mg/kg/day SIT. SIT treatment of Akita mice at either a low or high dose did not affect body or liver weight. A significant increase in subcutaneous and gonadal fat mass was only observed for the 50mg/kg/day dose of SIT. Furthermore, only the 50mg/kg/day SIT dose resulted in an improvement of glycemic control, as evidenced by a decrease in fasting blood HbA1c levels and an increase in plasma adiponectin levels. Echocardiographic analysis revealed that Akita mice kept on the HF-HC diet with 10mg/kg/day of SIT for 4 months showed an increase in ejection fraction and fractional shortening, whereas the higher dose (50mg/kg/day) had no effect on these parameters, but instead induced left ventricular (LV) hypertrophy as evidenced by an enlarged LV internal diameter, volume and mass. Thus, in the diabetic Akita mouse SIT is cardioprotective at a low dose (10mg/kg/day), whereas improvement of glycemic control requires a higher dose (50mg/kg/day) which, however, induces LV hypertrophy. This mouse model may thus be useful to study the safety of anti-diabetic drugs.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Heart; Heart Function Tests; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myocardium; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Adolescent; Adult; Diabetes Mellitus; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glyburide; Humans; Hypoglycemic Agents; Mutation; Potassium Channels, Inwardly Rectifying; Pyrazines; Sitagliptin Phosphate; Time Factors; Triazoles

Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients.. In Taiwan National Health Insurance research database, a study of the beneficiaries aged ≥ 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes.. A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence.. The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed.

Topics: Diabetes Mellitus; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Morbidity; Population Surveillance; Propensity Score; Pyrazines; Retrospective Studies; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Taiwan; Triazoles

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

Topics: Diabetes Mellitus; Female; Glucagon; Humans; Hyperglycemia; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles; Werner Syndrome

A novel data-mining method was developed to gauge the experiences of the diabetes mellitus drug Januvia. Self-organizing maps were used to analyze forum posts numerically to infer user opinion of drug Januvia. Graph theory was used to discover influential users. The result is a word list compilation correlating positive and negative word cluster groups and a web of influential users on Januvia. The implications could open new research avenues into rapid data collection, feedback, and analysis that would enable improved solutions for public health.

Topics: Data Mining; Diabetes Mellitus; Humans; Hypoglycemic Agents; Pyrazines; Sitagliptin Phosphate; Social Media; Treatment Outcome; Triazoles

Dipeptidyl peptidase-4 (DPP-4) inhibitors and other incretin-related drugs have attracted attention as antidiabetic agents, but they are expensive. The Japanese government has adopted a policy of reducing healthcare costs, and medical institutions must provide medical care while considering economic efficiency. This study was a comparative survey of the usage, treatment effectiveness, and cost of DPP-4 inhibitors. The subjects were patients prescribed DPP-4 inhibitors (sitagliptin, vildagliptin, and alogliptin) at Gifu Municipal Hospital between February 2010 and August 2011. HbA1c: Japan Diabetes Society values (%) and concomitant antidiabetic agents were surveyed for 12 weeks after the start of DPP-4 inhibitors. A cost-effectiveness analysis showed that the cost required for a 0.1% decrease in HbA1c for 12 weeks was the lowest with vildagliptin (2,478 yen; decrease in HbA1c: 0.75% +/- 0.85%). In a cost analysis with a virtual cohort of 1000 patients, the number of patients who achieved the treatment target (HbA1c 6.5%) was estimated with respect to a virtual cohort created based on the HbA1c level (7.59 +/- 1.13%) at baseline of 307 patients, in cases assuming the use of each DPP-4 inhibitor. In addition, the incremental cost-effectiveness ratio (ICER) was obtained with sitagliptin 50 mg as the reference. The number of patients achieving the treatment target was the highest with vildagliptin 100 mg (413 of 1000 patients), and the estimated ICER of 28,359 yen was the lowest. Robustness was also confirmed with a sensitivity analysis. These results suggest that vildagliptin provides a superior cost-benefit.

Topics: Adamantane; Clinical Trials as Topic; Cohort Studies; Cost-Benefit Analysis; Costs and Cost Analysis; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Nitriles; Piperidines; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

We evaluated the association between self-monitoring of blood glucose (SMBG) use and sitagliptin or sitagliptin/metformin (SSMT) adherence. SSMT was chosen as these medications have little risk of hypoglycemia and are believed to not require SMBG data for titration.. This was an observational study using data extracted from a large United States insurance claims database (i3 InVision™ Data Mart, Ingenix, Inc.). Data were extracted on noninsulin-using patients initiating SSMT for each 12-month period pre- and post-SSMT initiation. Logistic regression was used to assess the relationship between SMBG use and the likelihood of being medication adherent (defined as a medication possession ratio of ≥75%) while controlling for covariates.. This analysis included 7,306 patients (57.6% male; mean age 54.2 years). Mean pre-SSMT hemoglobin A1c (HbA1c) was 8.0%. In the post-SSMT initiation period, 58% of patients were adherent with SSMT. Older age, male gender, prior use of oral diabetes medication, and lower HbA1c were associated with improved SSMT adherence. SMBG use was associated with improved adherence [odds ratio (OR) ranged from 1.198 to 1.338; p < .05] compared with patients with no SMBG use pre- or post-SSMT initiation. For patients who began SMBG after starting SSMT, greater SMBG use was associated with better adherence (OR 1.449 for higher vs 1.246 for lower strip use; p < .05).. This study demonstrated that SMBG is associated with improved SSMT adherence. This relationship is strengthened with greater SMBG use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Child; Computer Simulation; Diabetes Mellitus; Drug Therapy, Combination; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Logistic Models; Male; Medication Adherence; Metformin; Middle Aged; Odds Ratio; Predictive Value of Tests; Pyrazines; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles; United States; Young Adult

Topics: Blood Glucose; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles; Werner Syndrome

Chronic exposure to high glucose and fatty acid levels caused by dietary sugar and fat intake induces β cell apoptosis, leading to the exacerbation of type 2 diabetes. Oleic acid and linoleic acid are two major dietary fatty acids, but their effects in diabetes are unclear. We challenged β cell-specific glucokinase haploinsufficient (Gck(+/-)) mice with a diet containing sucrose and oleic acid (SO) or sucrose and linoleic acid (SL) and analyzed β cell apoptosis. In Gck(+/-) but not wild-type mice, SL significantly decreased the β cell mass and β cell proportion in islet cells arising from increased apoptosis to a greater degree than did SO. The mRNA expression of SREBP-1c was significantly higher, and that of E-cadherin was significantly lower in the islets of Gck(+/-) mice fed SL compared with mice fed SO. We next evaluated monotherapy with desfluorositagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in these mouse groups. DPP-4 inhibitor protected against β cell apoptosis, restored the β cell mass, and normalized islet morphology in Gck(+/-) mice fed SL. DPP-4 inhibition normalized the changes in the islet expression of SREBP-1c and E-cadherin mRNA induced by the SL diet. Furthermore, linoleic acid induced β cell apoptosis to a greater degree in the presence of high glucose levels than in the presence of low glucose levels in vitro in islets and MIN6 cells, whereas a GLP-1 receptor agonist prevented apoptosis. In conclusion, SL exacerbated β cell apoptosis in diabetic Gck(+/-) mice but not in euglycemic wild-type mice, and DPP-4 inhibition protected against these effects.

Topics: Administration, Oral; Animals; Apoptosis; Arachidonic Acid; Diabetes Mellitus; Dietary Carbohydrates; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Haploinsufficiency; Insulin-Secreting Cells; Linoleic Acid; Male; Mice; Pyrazines; Receptors, Glucagon; Signal Transduction; Sitagliptin Phosphate; Sucrose; Triazoles

To describe 2.5 years of exposure to sitagliptin on glycemic control, immunosuppressive therapy, and adverse events following solid organ transplantation.. A 63-year-old Caucasian male received an orthotopic heart transplantation in June of 2006 secondary to idiopathic nonischemic cardiomyopathy. He was diagnosed with new-onset diabetes mellitus after transplantation (NODAT). Sitagliptin monotherapy was initiated in August 2007 and continued for 2.5 years.. Hemoglobin A(1c) increased from 5.8% to 6.1%, but the recommended glycemic target of <7% was maintained over time and improvements in fasting home blood glucose monitoring values were achieved. Tacrolimus concentrations were not altered. Only minor dose adjustments to tacrolimus and mycophenolate mofetil were required. Maintenance corticosteroid dose remained unchanged and there was no evidence of biopsy-proven acute rejection. No adverse events were reported.. This case report demonstrates that long-term sitagliptin treatment for NODAT may be effective, safe, and well tolerated in solid organ transplant recipients.

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Male; Middle Aged; Organ Transplantation; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney Transplantation; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Blood Glucose; Comorbidity; Diabetes Complications; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Female; Hepatitis C, Chronic; Humans; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Topics: Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Pyrazines; Sitagliptin Phosphate; Triazoles; Weight Gain

Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.

Topics: Binding Sites; Chemistry, Pharmaceutical; Crystallography, X-Ray; Cytochrome P-450 CYP3A; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Inhibitory Concentration 50; Models, Chemical; Molecular Structure; Piperazine; Piperazines; Pyrazines; Sitagliptin Phosphate; Structure-Activity Relationship; Triazoles

Topics: Diabetes Mellitus; Diabetic Angiopathies; Exenatide; Heart Diseases; Humans; Hypoglycemic Agents; Metformin; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Amyloid; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Diabetes mellitus is a frequent comorbidity of cancer patients. The growing epidemic of diabetes is anticipated to have tremendous impact on health care. Diabetes may negatively impact both cancer risk and outcomes of treatment. Oncology nurses are ideally positioned to identify patients at risk for complications that arise from cancer treatment in the setting of pre-existing diabetes. Additionally, oncology nurses may be the first to identify underlying hyperglycemia/hidden diabetes in a patient undergoing cancer treatment. Strategies for assessment and treatment will be discussed, along with specific strategies for managing hyperglycemia, potential renal toxicity, and peripheral neuropathy. Guidelines for aggressive treatment of hyperglycemia to minimize risks of complications will be reviewed. The role of interdisciplinary care, utilizing current evidence, is crucial to supporting patients and their families as they manage the challenges of facing two life-limiting diseases. Whole-person assessment and individualized treatment plans are key to maximizing quality of life for patients with cancer and diabetes.

Topics: Ambulatory Care; Amyloid; Comorbidity; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Inpatients; Insulin; Islet Amyloid Polypeptide; Neoplasms; Peptides; Practice Guidelines as Topic; Pyrazines; Quality of Life; Risk Factors; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms