sitagliptin-phosphate and Body-Weight

The emergence of genetically-modified human proteins and glucagon-like peptide-1 (GLP-1) receptor agonists have presented a promising strategy for effectively managing diabetes. Due to the scarcity of clinical trials focusing on the safety and efficacy of semaglutide as an adjunctive treatment for patients with type 2 diabetes who had inadequate glycemic control with metformin, we conducted a systematic review and meta-analysis. This was necessary to fill the gap and provide a comprehensive assessment of semaglutide compared to sitagliptin, a commonly prescribed DPP-4 inhibitor, in this patient population.. A comprehensive and systematic search was carried out on reputable databases including PubMed, the Cochrane Library, and Elsevier's ScienceDirect to identify relevant studies that compared the efficacy of once-weekly Semaglutide with once-daily Sitagliptin in individuals diagnosed with type 2 diabetes mellitus. The analysis of the gathered data was performed utilizing the random-effects model, which considers both within-study and between-study variations.. The meta-analysis incorporated three randomized controlled trials (RCTs), encompassing 2401 participants, with a balanced distribution across the treatment groups. The primary focus of the study revolved around evaluating changes in HbA1C, blood pressure, pulse rate, body weight, waist circumference, and BMI. The findings revealed that once-weekly Semaglutide showed substantially improved HbA1C (WMD: -0.98; 95% CI: -1.28, -0.69, p-value: < 0.0001; I2: 100%), systolic (WMD: -3.73; 95% CI: -5.42, -2.04, p-value: <0.0001; I2: 100%) and diastolic blood pressures (WMD: -0.66; 95% CI: -1.02, -0.29, p-value: 0.0005; I2: 100%), and body weight (WMD: -3.17; 95% CI: -3.84, -2.49, p-value: <0.00001; I2: 100%) compared to once-daily Sitagliptin. However, there was an observed increase in pulse rate (WMD: 3.33; 95% CI: 1.61, 5.06, p-value: <0.00001; I2: 100%) associated with Semaglutide treatment. Regarding secondary outcomes, there was an elevated risk of total adverse events and premature treatment discontinuation with Semaglutide. The risk of serious, severe, moderate, and mild adverse events did not significantly differ between the two treatments.. In conclusion, the administration of once-weekly Semaglutide exhibited a substantial reduction in HbA1c, average systolic blood pressure (SBP), mean diastolic blood pressure (DBP), body weight, waist circumference, body mass index (BMI), and a rise in pulse rate, as opposed to the once-daily administration of Sitagliptin.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Sitagliptin Phosphate

The purpose of this study was to assess the efficacy and hypoglycemic risk of sitagliptin versus that of GLP-1 receptor agonists in the management of obese/overweight patients with T2DM.. EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched; randomized controlled trials comparing the efficacy of sitagliptin versus that of GLP-1 receptor agonists in obese/overweight patients with T2DM were included. The mean BMI of participants for each study was ≥30 kg/m. We conducted a meta-analysis according to the methods specified in the Cochrane Handbook for Systematic Reviews of Interventions. RevMan 5.1 software was used to perform the meta-analysis. The Cochrane Q test and I statistics were used to estimate the heterogeneity among studies. The results are expressed as the mean difference (MD) or risk ratio (RR) with 95% confidence intervals.. A total of 8 eligible studies were included in our meta-analysis. Compared with GLP-1 receptor agonists, sitagliptin was less effective at reducing HbA1c (0.42 [0.27, 0.56]), FPG (0.78 [0.36, 1.19]), PPG (2.61 [1.35, 3.87]), and body weight (1.42 [0.71, 2.14]). Conversely, there were no significant differences in SBP reduction (0.38 [-1.14, 1.89]), DBP reduction (-0.30 [-1.00, 0.39]), and hypoglycemic risk (1.09 [0.50, 2.35]).. For obese/overweight patients, sitagliptin may exert a less potent effect on HbA1C, FPG, PPG, and weight reduction than GLP-1 receptor agonists, but these drugs had a similar efficacy in reducing blood pressure; furthermore, there was no significant difference in hypoglycemic risk.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Obesity; Sitagliptin Phosphate

Glucagon-like peptide-1 (GLP-1) receptor agonists are highly potent antihyperglycemic drugs that impose low risk of hypoglycemia and also result in body weight reduction. Currently, all approved members of the class require administration by injection. Areas covered: This manuscript reviews oral semaglutide-an experimental GLP-1 receptor agonist in phase-3 clinical development. Available pharmacological and clinical data of the drug are reviewed, and important end-points described. Expert opinion: Oral peptide delivery has become possible with the discovery of absorption enhancers. The clinical development program of once-daily oral semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators (sitagliptin, liraglutide, and empagliflozin). Safety and tolerability of oral semaglutide is in line with injectable members of the class. Delayed gastric emptying, local increase in pH, and enhanced absorption do not seem to affect the exposure of a number of other oral drugs that have been tested (metformin, digoxin, oral contraceptive ethinylestradiol/levonorgestrel, lisinopril, warfarin, furosemide and rosuvastatin). Clinical questions for further investigation include the effectiveness and safety of oral semaglutide in cardiovascular indications.

Topics: Benzhydryl Compounds; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Sitagliptin Phosphate

Diabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes. New medication-therapy regimens such as those containing linagliptin alone or in combination with other medications (within the category of DDP-4 inhibitors) must be evaluated in terms of efficacy and compared with other currently used drugs and then enter the medication list of the country. Hence, this study aimed to compare the clinical efficacy of the two drugs, i.e. linagliptin and sitagliptin, in patients with type 2 diabetes.. A systematic review was conducted to identify all clinical trials published by 2015 which compared the two drugs in patients with type 2 diabetes. Using keywords such as "linagliptin", "type 2 diabetes mellitus", "sitagliptin" and related combinations, we searched databases including Scopus, PubMed, and Web of Science. The quality of the selected studies was evaluated using the Jadad score. Considering primary and secondary outcomes extracted from the reviewed studies, a network meta-analysis was used to conduct a systematic comparison between the two studied drugs.. This network meta-analysis included 32 studies (Linagliptin vs PLB: n = 8, Sitagliptin vs PLB: n = 13, Linagliptin + MET vs PLB + MET: n = 4, and Sitagliptin + MET vs PLB + MET: n = 7) and a total of 13,747 patients. The results showed no significant difference between linagliptin and sitagliptin in terms of key efficacy and safety outcomes such as HbA1c changes from baseline, body weight change from baseline, percentage of patients achieving HbA1c <7, and percentage of patients experiencing hypoglycemic events (p > 0.05). The results showed that the efficacy of the two drug regimens was the same.. Based on the results, there was no significant difference between the two drugs, i.e. linagliptin and sitagliptin, in terms of efficacy; in other words, the efficacy of the two drugs was the same. Therefore, the use of these two drugs depends on their availability and cost. Graphical abstract of the network meta-analysis performed to evaluate the alternatives under the study.

Topics: Aged; Aged, 80 and over; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Network Meta-Analysis; Sitagliptin Phosphate; Treatment Outcome

A meta-analysis was conducted to assess the clinical efficacy and safety of dulaglutide in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, Cochrane Library and www. clinicaltrials. gov (up to February 15(th), 2015) were searched. Randomized controlled trials comparing dulaglutide to other drugs for T2DM were collected. Twelve RCTs were included, and the overall bias was low. As the monotherapy, compared with control (placebo, metformin and liraglutide), dulaglutide resulted in a significant reduction in HbA1c (WMD, -0.68%; 95% CI, -0.95 to -0.40), FPG (WMD, -0.90 mmol/L; 95% CI, -1.28 to -0.52), a similar risk of hypoglycemia (7.8% vs. 10.6%), less body weight loss (WMD, 0.51 kg; 95% CI, 0.27 to 0.75). As an add-on intervention with oral antihyperglycemic medication (OAM) and insulin, compared with control (placebo, sitagliptin, exenatide, liraglutide and glargine), dulaglutide lowered HbA1c (WMD, -0.51%; 95% CI, -0.68 to -0.35) and body weight significantly (WMD, -1.30 kg, 95% CI, -1.85 to -1.02) notably, and elicited a similar reduction in FPG (WMD, -0.19 mmol/L; 95% CI, -1.20 to 0.82), an similar incidence of hypoglycemia (24.5% vs. 24.5%). This meta-analysis revealed the use of dulaglutide as a monotherapy or an add-on to OAM and lispro appeared to be effective and safe for adults with T2DM.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Insulin Glargine; Liraglutide; Metformin; Patient Safety; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sitagliptin Phosphate; Treatment Outcome; Venoms

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endpoint Determination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pyrazines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Thiophenes; Triazoles; Young Adult

Incretin-based therapies which include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are recommended by several practice guidelines as second-line agents for add-on therapy to metformin in patients with type 2 diabetes (T2DM) who do not achieve glycemic control with metformin plus lifestyle interventions alone. The purpose of this study is to perform a systematic review with meta-analysis of existing head to head studies to compare the efficacy and safety of GLP-1 analogues with DPP-4 inhibitors.. We performed a systematic review and meta-analysis of head-to-head studies to compare GLP-1 analogues with DPP-4 inhibitors in the management of type 2 diabetes. A random effects model was selected to perform the meta-analyses, results were expressed as weighted mean differences for continuous outcomes and relative risks for dichotomous outcomes, both with 95% confidence intervals, and with I2 values and P values as markers of heterogeneity.. Four head-to-head randomized controlled studies with 1755 patients were included. Compared to sitagliptin, GLP-1 analogues are more effective in reducing HbA1C (weight mean difference -0.41%, 95% CI -0.51 to -0.31) and body weight (weight mean difference -1.55 kg, 95% CI -1.98 to -1.12). Conversely, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events compared to sitagliptin: nausea (relative risk 3.14, 95% CI 2.15 to 4.59), vomiting (relative risk 2.60, 95% CI 1.48 to 4.56), diarrhea (relative risk 1.82, 95% CI 1.24 to 2.69), and constipation (relative risk 2.50, 95% CI 1.33 to 4.70).. The result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parameters, however, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events and a similar incidence of hypoglycemia compared to sitagliptin.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Lipids; Pyrazines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Treatment Outcome; Triazoles

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

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are oral incretin-based glucose-lowering agents with proven efficacy and safety in the management of type 2 diabetes mellitus (T2DM). In addition, preclinical data and mechanistic studies suggest a possible additional non-glycemic beneficial action on blood vessels and the heart, via both glucagon-like peptide-1-dependent and glucagon-like peptide-1-independent effects. As a matter of fact, DPP-4 inhibitors improve several cardiovascular risk factors: they improve glucose control (mainly by reducing the risk of postprandial hyperglycemia) and are weight neutral; may lower blood pressure somewhat; improve postprandial (and even fasting) lipemia; reduce inflammatory markers; diminish oxidative stress; improve endothelial function; and reduce platelet aggregation in patients with T2DM. In addition, positive effects on the myocardium have been described in patients with ischemic heart disease. Results of post hoc analyses of phase 2/3 controlled trials suggest a possible cardioprotective effect with a trend (sometimes significant) toward lower incidence of major cardiovascular events with sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin compared with placebo or other active glucose-lowering agents. However, the definite relationship between DPP-4 inhibition and better cardiovascular outcomes remains to be proven. Major prospective clinical trials involving various DPP-4 inhibitors with predefined cardiovascular outcomes are under way in patients with T2DM and a high-risk cardiovascular profile: the Sitagliptin Cardiovascular Outcome Study (TECOS) on sitagliptin, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial on saxagliptin, the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE) trial on alogliptin, and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) on linagliptin. If these trials confirm that a DPP-4 inhibitor can reduce the cardiovascular burden of T2DM, it would be major progress that would dramatically influence the management of the disease.

Topics: Adamantane; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular System; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Lipids; Nitriles; Pyrazines; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Triazoles; Vildagliptin

Sitagliptin has been widely used in the treatment of type 2 diabetes mellitus (T2DM); however, the therapeutic efficacy of sitagliptin remains inconclusive in randomized controlled studies on T2DM in which metformin has served as a control.. The present meta-analysis aimed to compare the therapeutic efficacy of sitagliptin and metformin in the treatment of T2DM.. We searched the following databases (Medline, Embase, Cochrane databases, Chinese Medical Journal Database, and the Chinese National Knowledge Infrastructure from inception until April 2013), and identified randomized controlled trials (RCTs) involving sitagliptin and metformin for T2DM. Two independent authors determined whether or not these trials met the inclusion criteria. Then, the variance of results from each study was calculated, and I(2) was employed for evaluation of heterogeneity.. One hundred and twenty-one studies were identified, of which seven were included for further analysis. For T2DM, the therapeutic efficacy of sitagliptin and metformin was comparable in reducing HbA1c (P = 0.148, standard mean difference [SMD] = 0.13, 95% confidence interval [CI] = -0.05, 0.30), decreasing BMI (P = 0.063, SMD = 0.26, 95% CI = -0.01, 0.54), and improving the homeostasis model assessment (HOMA)-β (P = 0.285, SMD = -0.05, 95% CI = -0.15, 0.04), but sitagliptin was inferior to metformin in improving HOMA-IR (P = 0.003, SMD = 0.16, 95% CI = 0.06, 0.27).. Sitagliptin is similar to metformin in reducing HbA1c, decreasing body weight, and improving the function of beta cells, but is inferior to metformin in improving insulin sensitivity. More RCTs with large sample sizes are required to provide evidence for the rational application of sitagliptin.

Topics: Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Metformin; Pyrazines; Sitagliptin Phosphate; Triazoles

During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin.. Studies having a duration of 16-30 weeks were identified from PubMed.. A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists.. Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

To describe the efficacy and safety of the glucagon-like peptide 1 (GLP-1) analogues exenatide and liraglutide, and the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and sitagliptin, registered in the Netherlands for treatment of type 2 diabetes mellitus (DM2).. Literature study.. The Medline database was searched up to and including August 2009 for systematic reviews and randomised trials with a minimum duration of 12 weeks in patients with DM2. Two authors independently selected the studies based on the title, abstract and, if necessary, the full text.. In addition to 1 systematic review on GLP-1 analogues and 1 review on DPP-4 inhibitors, 10 studies on DPP-4 inhibitors and 16 studies on GLP-1 analogues were included. According to these studies, the DPP-4 inhibitors sitagliptin and vildagliptin gave a mean HbA1c reduction of 0.7% and 0.6% respectively. GLP-1 analogues led to a mean HbA1c reduction of 1%, which is comparable to insulin therapy. Sitagliptin was associated with a slight increase in the number of upper respiratory tract infections. In a large number of patients, GLP-1 analogues were associated with gastrointestinal complaints. DPP-4 inhibitors were associated with a small weight gain, compared with weight loss in patients treated with GLP-1 analogues. Data on microvascular and macrovascular complications, as well as data on mortality, are not yet available in either group.. GLP-1 analogues regulate blood glucose levels as effectively as the current glucose-lowering agents; DPP-4 inhibitors are less effective. GLP-1 analogues lead to a clear weight reduction while DPP-4 inhibitors cause slight weight gain. Data on efficacy and safety in the longer term are not yet available.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Vildagliptin

In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a 'new drugs update' to the 2008 guideline.. To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones.. The following databases were searched: MEDLINE (1990-April 2008), EMBASE (1990-April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000-April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers' websites.. Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (RevMan) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model.. Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) -0.70 to -0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between 386 pounds and 460 pounds. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around 437 pounds and 482 pounds, respectively. Exenatide was more expensive, with an annual cost of around 830 pounds. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around 468 pounds for the representative patient, whereas the glargine and detemir regimens were more expensive, at around 634 pounds and 716 pounds, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around 1800 pounds. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between 2700 pounds and 2600 pounds.. The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios.. Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.

Topics: Adamantane; Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Nitriles; Peptides; Pyrazines; Pyrrolidines; Quality of Life; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; State Medicine; Thiazolidinediones; Triazoles; United Kingdom; Venoms; Vildagliptin

The prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. Clinical therapies for type 2 diabetes mellitus (T2DM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative T2DM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (GLP-1) and have been shown to lower glycated hemoglobin (A1C) levels in patients with T2DM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endogenous GLP-1 levels by inhibiting the enzymatic degradation of GLP-1. Clinical studies in patients with T2DM have shown that DPP-4 inhibitors reduce elevated A1C, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. Collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with T2DM.

Topics: Adamantane; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fasting; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Nitriles; Peptides; Postprandial Period; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Sitagliptin and vildagliptin represent a new class of anti-diabetic agents that enhance the action of incretin hormones through inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme that normally inactivates incretin hormones. Because of their distinct mechanism of action, DPP-4 inhibitors can be used as add-on therapy to other classes of drugs for treatment of type 2 diabetes. The objective of this review is to critically evaluate clinical trials of sitagliptin and vildagliptin in combination with pioglitazone. The addition of either sitagliptin or vildagliptin to ongoing pioglitazone therapy is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.7% compared with placebo and 1% compared with baseline after 24 weeks. When started concomitantly in drug-naïve patients, the combination of pioglitazone 30 mg and vildagliptin 100 mg qd reduces HbA1c by 1.9% after 24 weeks, compared with 1.1% with pioglitazone monotherapy. In general, the addition of DPP-4 inhibitors to pioglitazone was well tolerated, did not increase the incidence of hypoglycemia, and did not substantially worsen the weight-gain induced by pioglitazone. The combination of sitagliptpin or vildagliptin with pioglitazone can be a useful therapeutic approach in patients with type 2 diabetes who cannot tolerate metformin or a sulfonylurea.

Topics: Adamantane; Blood Glucose; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Edema; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Nitriles; Pioglitazone; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles; Vildagliptin

Exenatide is an incretin mimetic, while sitagliptin and vildagliptin are incretin enhancers used as adjunctive therapy in patients with type 2 diabetes failing oral agents. Sitagliptin and vildagliptin can also be used as monotherapy in patients with type 2 diabetes uncontrolled by diet.. To provide a critical review of clinical trials of exenatide, sitagliptin and vildagliptin.. Review of Phase III clinical trials based on Medline search published up to April 2008.. The use of exenatide is associated with reduction in average hemoglobin A1c (HbA1c) levels of approximately 0.8% compared with baseline. The corresponding reduction with either sitagliptin or vildagliptin is 0.7%. The actions of incretin-based drugs predominantly target postprandial hyperglycemia. Treatment-related hypoglycemia is generally mild, and mainly occurs when used with sulfonylureas (SUs). Exenatide treatment leads to a mild weight loss of around 2 kg after 30 weeks, whereas sitagliptin and vildagliptin have generally neutral effect on weight. Sitagliptin and vildagliptin are well tolerated in trials lasting up to 52 weeks. Meanwhile, 5 - 10% of patients cannot tolerate exenatide due to adverse effects, mainly nausea and vomiting. The three drugs are limited by the lack of long-term safety and efficacy data, as well as by their high cost.. Exenatide, sitagliptin and vildagliptin are useful add-on therapy for type 2 diabetes that is suboptimally controlled on oral agents, particularly when there is concern about weight gain and hypoglycemia, or when postprandial hyperglycemia is the major cause of inadequate glycemic control. Sitagliptin and vildagliptin may be used as monotherapy in patients who cannot tolerate metformin or SU, and sitagliptin may be used as alternative to metformin in renal insufficiency.

Topics: Adamantane; Body Weight; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Nausea; Nitriles; Peptides; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Vomiting

Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.

Topics: Adamantane; Animals; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Lipid Metabolism; Metformin; Nitriles; Pioglitazone; Protease Inhibitors; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Substrate Specificity; Thiazolidinediones; Triazoles; Vildagliptin

Glucagon-like peptide-1 (GLP-1)-based therapy is a novel treatment for type 2 diabetes. It is executed either by GLP-1 mimetics or by dipeptidyl peptidase-IV inhibitors. In type 2 diabetes, the two strategies reduce hemoglobin A(1c) by 0.6% to 1.1% from baseline levels of 7.7% to 8.5%. They are efficient both in monotherapy and in combination with metformin or thiazolidinediones. Both treatments are well tolerated with low risk of hypoglycemia.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Islets of Langerhans; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, that also enhances GLP-1 activity - to determine the independent effects of each treatment.. A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (-390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg/d) as a weight-neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x-ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal-Wallis test or Pearson's chi-squared test.. Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA-IR).. Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.

Topics: Adult; Appetite; Body Fat Distribution; Body Weight; Caloric Restriction; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Eating; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Prediabetic State; Sitagliptin Phosphate; Weight Loss

This study aimed to compare 12.5 mg empagliflozin effectiveness and safety vs. 50 mg sitagliptin twice daily as an add-on triple medication in Egyptians with type 2 diabetes.. Patients with hemoglobin A1c (HbA1c) between 53 and 86 mmol/mol after receiving open-label either sitagliptin 50 mg (n = 85) or empagliflozin 12.5 mg (n = 85) twice daily for 12 weeks were afterward taken into account for the administration of open-label empagliflozin 12.5 mg (n = 40) and sitagliptin 50 mg (n = 28) respectively twice daily for another 12 weeks of treatment as an added-on triple therapy. Both groups of patients kept taking metformin and empagliflozin 12.5 mg or sitagliptin 50 mg twice daily as prescribed. The HbA1c change from baseline after 12 weeks of triple-added-on therapy was the main endpoint.. The sitagliptin group receiving empagliflozin saw a substantial drop in HbA1c, fasting and postprandial plasma glucose levels, body weight, and blood pressure compared to the starting point. As opposed to that, adding sitagliptin to the empagliflozin group non-significantly reduced HbA1c, fasting, and postprandial plasma glucose levels, and systolic blood pressure from baseline but significantly reduced body weight and diastolic blood pressure. Comparing the two groups, adding empagliflozin significantly reduced HbA1c, fasting, and postprandial plasma glucose levels (p < 0.001 for all except fasting plasma glucose level, p = 0.002). While the patient's weight and blood pressure were not significantly affected.. Empagliflozin was superior to sitagliptin in relation to glycemic control, weight, and systolic/diastolic blood pressure reduction.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Egypt; Glycated Hemoglobin; Humans; Metformin; Sitagliptin Phosphate

The aim of this study is to investigate whether sitagliptin can be used as an initial drug for T2DM and to evaluate its effects on metabolic parameters in relation to its glycemic efficacies. The subjects received 25-50 mg/day sitagliptin monotherapy (n=69). At 3 months, they were divided into three groups (n=23 each) according to the novel parameter called "A1c index" which is designed to assess glycemic efficacy. The metabolic parameters were compared between good-responders and poor-responders. These two groups acted as a control each other. In the overall subjects, efficient reductions of HbA1c (10.16-8.22%) were observed with few adverse events. Significant correlations were seen between the A1c index and changes of (∆)nonHDL-C (R=0.250) or ∆LDL-C (R=0.368). At baseline, T-C, nonHDL-C and BMI levels were significantly lower in good-responders than poor-responders. At 3 months, in good-responders, HbA1c levels effectively decreased (11.03-7.00%). Indexes for insulin sensitivity/resistance [HOMA-R and 20/(C-peptide x FBG)] and beta-cell function (HOMA-B and CPR-index) ameliorated. T-C, nonHDL-C and LDL-C significantly decreased, while BMI increased. However, in poor-responders, no changes in these parameters were noted. Collectively, these results suggest that 1) Sitagliptin can be used as a first-line drug for T2DM and its glycemic efficacy is linked to some atherogenic lipids. 2) Those with lower T-C, nonHDL-C and BMI appear to respond better with this drug. 3) Good glycemic efficacy of sitagliptin is medicated through reduced insulin resistance as well as enhanced beta-cell functions. Body weight increased, while some atherogenic cholesterol decreased in good-responders.

Topics: Adult; Aged; Atherosclerosis; Blood Glucose; Body Weight; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Sitagliptin Phosphate; Treatment Outcome

Preclinical data suggest that treatment with either glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors could change the intestinal microbiome and thereby contribute to their beneficial (cardio)metabolic effects. Therefore, our study aimed to investigate the effects of these agents on microbiota composition in adults with type 2 diabetes (T2D).. Liraglutide decreased HbA. These data suggest that the beneficial effects of liraglutide and sitagliptin on glucose metabolism, body weight and bile acids, when used as add-on therapies to metformin or sulphonylureas, are not linked to changes in the intestinal microbiota (NCT01744236).

Topics: Adult; Aged; Bile Acids and Salts; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastrointestinal Microbiome; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Middle Aged; RNA, Ribosomal, 16S; Sitagliptin Phosphate; Sulfonylurea Compounds

To investigate the effect of antidiabetic agents on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM), 75 patients with T2DM and NAFLD under inadequate glycemic control by metformin were randomized (1:1:1) to receive add-on liraglutide, sitagliptin, or insulin glargine in this 26-week trial. The primary endpoint was the change in intrahepatic lipid (IHL) from baseline to week 26 as quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). Secondary endpoints included changes in abdominal adiposity (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]), glycated hemoglobin, and body weight from baseline to week 26. We analysed data from intent-to-treat population. MRI-PDFF, VAT, and weight decreased significantly with liraglutide (15.4% ± 5.6% to 12.5% ± 6.4%, P < 0.001; 171.4 ± 27.8 to 150.5 ± 30.8, P = 0.003; 86.6 ± 12.9 kg to 82.9 ± 11.1 kg, P = 0.005, respectively) and sitagliptin (15.5% ± 5.6% to 11.7% ± 5.0%, P = 0.001; 153.4 ± 31.5 to 139.8 ± 27.3, P = 0.027; 88.2 ± 13.6 kg to 86.5 ± 13.2 kg, P = 0.005, respectively). No significant change in MRI-PDFF, VAT, or body weight was observed with insulin glargine. SAT decreased significantly in the liraglutide group (239.9 ± 69.0 to 211.3 ± 76.1; P = 0.020) but not in the sitagliptin and insulin glargine groups. Changes from baseline in MRI-PDFF, VAT, and body weight were significantly greater with liraglutide than insulin glargine but did not differ significantly between liraglutide and sitagliptin. Conclusion: Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight, IHL, and VAT in addition to improving glycemic control in patients with T2DM and NAFLD.

Topics: Adult; Aged; Blood Glucose; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin Glargine; Linear Models; Lipid Metabolism; Liraglutide; Male; Metformin; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Prognosis; Prospective Studies; Sitagliptin Phosphate; Treatment Outcome

To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM).. This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported.. Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC. Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Topics: Adolescent; Age Factors; Age of Onset; Blood Glucose; Body Weight; Child; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Sitagliptin Phosphate

The efficacy and safety of semaglutide vs comparators in non-elderly (<65 years) and elderly (≥65 years) patients with type 2 diabetes (T2D) across the SUSTAIN 1-5 trials were evaluated. Patients were randomized to once-weekly subcutaneous semaglutide (0.5 or 1.0 mg) vs placebo, sitagliptin, exenatide or insulin. The primary objective was change in HbA1c and secondary objectives were changes in body weight and safety. Mean HbA1c decreased from baseline by 1.2%-1.5% and 1.5%-1.9% vs 0%-0.9% (non-elderly, n = 3045) and by 1.3%-1.5% and 1.2%-1.8% vs 0.2%-1.0% (elderly, n = 854) with semaglutide 0.5 and 1.0 mg vs comparators. Similar reductions from baseline in mean body weight with semaglutide occurred in both age groups. Similar proportions of patients experienced adverse events; premature treatment discontinuations were higher in elderly vs non-elderly patients. No increased risk of severe or blood glucose-confirmed hypoglycaemia was seen with semaglutide vs comparators between age groups. Semaglutide had a comparable efficacy and safety profile in non-elderly and elderly patients across the SUSTAIN 1-5 trials, making it an effective treatment option for elderly patients with T2D.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Sitagliptin Phosphate; Treatment Outcome

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of β-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on β-cell function.

Topics: Adult; Aged; Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Glucosides; Humans; Japan; Male; Middle Aged; Sitagliptin Phosphate; Thiophenes

Diabetes therapies that provide durable glycaemic control for people with type 2 diabetes mellitus (T2DM) are needed. We present efficacy results of albiglutide, a glucagon-like peptide-1 receptor agonist, in people with T2DM over a 3-year period.. Five of the 8 HARMONY phase 3 trials, comparing albiglutide with other therapies or placebo across a spectrum of clinical care, lasted for a preplanned 3years. Participants with uncontrolled hyperglycaemia who met predetermined criteria could receive rescue medication. The ability to remain on study medication without needing additional rescue was an efficacy measure. Glycaemic measures and body weight were analysed in 2 populations: those who remained rescue-free and all participants.. Participants (n=3132) were randomised to albiglutide or comparator. A greater proportion of participants who received albiglutide remained rescue-free (55-71%) compared with placebo (35-51%; p<0.001 to p=0.002). The proportion of rescue-free participants with albiglutide did not differ from glimepiride or insulin glargine, was higher than with sitagliptin (p=0.013), and lower than with pioglitazone (p=0.045). At 3years, albiglutide was associated with clinically significant reductions in hyperglycaemia (eg, rescue-free participants: HbA1c -0.52% [SE0.11] to -0.98% [0.12]; -5.7mmol/mol [1.2] to -10.7mmol/mol [1.3] and all participants: HbA1c -0.29% [0.11] to-0.92% [0.13]; -3.2mmol/mol [1.2] to -10.1mmol/mol [1.4]). Albiglutide was also associated with modest reductions in body weight vs pioglitazone, glimepiride, and insulin glargine, which were associated with weight gain.. These 3-year efficacy data support long-term use of albiglutide in the management of people with T2DM. ClinicalTrials.gov NCT00849056, NCT00849017, NCT00838903, NCT00838916, NCT00839527.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Glargine; Male; Pioglitazone; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Early initiation of combination therapy using antihyperglycemic agents is recommended for treating type 2 diabetes (T2D). The present multicenter double-blind randomized parallel-group study examined the efficacy and safety of a sitagliptin and metformin fixed-dose combination (Sita/Met) compared with glimepiride in T2D patients as initial treatment.. Type 2 diabetes patients (aged ≥18 years) were randomized to Sita/Met or glimepiride for 30 weeks after a wash-off run-in period. The primary endpoint was change from baseline (CFB) in HbA1c. Secondary endpoints included the proportion of patients achieving target goal (HbA1c < 7.0 % [53 mmol/mol]) and CFB in fasting plasma glucose (FPG). Safety assessments comprised weight gain from baseline and the incidence of adverse events (AEs).. In total, 292 patients were randomized to Sita/Met (n = 147) or glimepiride (n = 145). After 30 weeks, Sita/Met demonstrated superiority over glimepiride in reducing HbA1c (-1.49 % vs -0.71 %, respectively; between-group difference - 0.78 %; P < 0.001). A significantly higher proportion of patients achieved the target goal with Sita/Met (81.2 %) than with glimepiride (40.1 %; P < 0.001). Greater reduction in FPG occurred with Sita/Met than with glimepiride (least-squares mean difference - 23.5 mg/dL; P < 0.001). Both drugs were generally well tolerated. Hypoglycemia events and weight gain were significantly lower in patients with Sita/Met than with glimepiride (5.5 % vs 20.1 % and -0.83 vs +0.90 kg, respectively; both P < 0.001). No serious drug-related AEs or deaths were reported.. Compared with glimepiride, Sita/Met as an initial treatment led to significantly greater improvements in glycemic control and body weight changes, with a lower incidence of hypoglycemia, over 30 weeks.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Dyspepsia; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infections; Male; Metformin; Middle Aged; Nausea; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America.. Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]).. Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports.. Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis-related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America.. Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America.. NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Latin America; Male; Metformin; Middle Aged; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

To compare the efficacy and safety of liraglutide versus sitagliptin as add-on to metformin after 26 weeks of treatment in Chinese patients with type 2 diabetes mellitus (T2DM).. This 26-week open-label, active comparator trial (NCT02008682) randomized patients (aged 18-80 years) with T2DM inadequately controlled with metformin [glycated haemoglobin (HbA1c) 7.0-10.0% (53-86 mmol/mol)] 1 : 1 to once-daily subcutaneously administered liraglutide 1.8 mg (n = 184) or once-daily oral sitagliptin 100 mg (n = 184), both as add-on to metformin. The primary endpoint was change in HbA1c from baseline to week 26.. Liraglutide was superior to sitagliptin in reducing HbA1c from baseline [8.1% (65 mmol/mol)] to 26 weeks, as evidenced by estimated mean HbA1c change of -1.65% (-18.07 mmol/mol) versus -0.98% (-10.72 mmol/mol), respectively [estimated treatment difference for liraglutide vs sitagliptin of -0.67% (95% CI -0.86, -0.48) or -7.35 mmol/mol (95% CI -9.43; -5.26); p < 0.0001]. More patients receiving liraglutide (76.5%) than sitagliptin (52.6%) achieved the HbA1c target of <7.0% (53 mmol/mol) at week 26 [odds ratio 3.65 (95% CI 2.18, 6.12); p < 0.0001]. Reductions in fasting plasma glucose, 7-point self-measured plasma glucose and body weight were greater with liraglutide than with sitagliptin (p < 0.0001 for all). More patients experienced nausea (14.8% vs 0.5%), diarrhoea (8.2% vs 2.2%) and decreased appetite (10.9% vs 0.5%) with liraglutide than sitagliptin. Two hypoglycaemic episodes were confirmed for liraglutide and one for sitagliptin; none were severe or nocturnal.. Liraglutide provided better glycaemic control and greater body weight reduction than sitagliptin when administered as add-on to metformin. More patients had nausea, diarrhoea and decreased appetite with liraglutide versus sitagliptin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anorexia; Asian People; Blood Glucose; Body Weight; China; Diabetes Mellitus, Type 2; Diarrhea; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Metformin; Middle Aged; Nausea; Sitagliptin Phosphate; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of titrated canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin and sitagliptin.. In this randomized, double-blind study, patients with T2DM (N = 218) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo. After 6 weeks, the canagliflozin dose was increased from 100 to 300 mg (or from placebo to matching placebo) if all of the following criteria were met: baseline estimated glomerular filtration rate ≥70 ml/min/1.73 m(2) ; fasting self-monitored blood glucose ≥5.6 mmol/l (≥100 mg/dl); and no volume depletion-related adverse events (AEs) within 2 weeks before dose increase. Endpoints included change in glycated haemoglobin (HbA1c) at week 26 (primary); proportion of patients achieving HbA1c <7.0%; and changes in fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP). Safety was assessed using AE reports.. Overall, 85.4% of patients were titrated to canagliflozin 300 mg or matching placebo (mean ± standard deviation time to titration 6.2 ± 0.8 weeks). At week 26, canagliflozin (pooled 100 and 300 mg) demonstrated superiority in HbA1c reduction versus placebo (-0.91% vs. -0.01%; p < 0.001). Canagliflozin provided significant reductions in FPG, body weight and SBP compared with placebo (p < 0.001). The overall AE incidence was 39.8 and 44.4% for canagliflozin and placebo, respectively. Canagliflozin was associated with an increased incidence of genital mycotic infections.. Titrated canagliflozin significantly improved HbA1c, FPG, body weight and SBP, and was generally well tolerated over 26 weeks in patients with T2DM as add-on to metformin and sitagliptin.

Topics: Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Hypovolemia; Male; Metformin; Middle Aged; Mycoses; Reproductive Tract Infections; Sitagliptin Phosphate; Treatment Failure; Treatment Outcome; Urinary Tract Infections

To confirm superiority on glycaemic control by switching from sitagliptin to liraglutide 1.8 mg/d versus continued sitagliptin.. A randomized, multicentre, double-blind, double-dummy, active-controlled trial across 86 office- or hospital-based sites in North America, Europe and Asia. Subjects with type 2 diabetes who had inadequate glycaemic control (glycated haemoglobin [HbA1c] 7.5-9.5% on sitagliptin (100 mg/d) and metformin (≥1500 mg daily) for ≥90 days were randomized to either switch to liraglutide (n = 203) or continue sitagliptin (n = 204), both with metformin. The primary endpoint was change in HbA1c from baseline to week 26. Change in body weight was a confirmatory secondary endpoint.. Greater reduction in mean HbA1c was achieved with liraglutide than with continued sitagliptin [-1.14% vs. -0.54%; estimated mean treatment difference (ETD): -0.61% (95% CI -0.82 to -0.40; p < 0.0001)], confirming superiority of switching to liraglutide. Body weight was reduced more with liraglutide [-3.31 kg vs. -1.64 kg; ETD: -1.67 kg (95% CI -2.34 to -0.99; p < 0.0001)]. Nausea was more common with liraglutide [44 subjects (21.8%)] than with continued sitagliptin [16 (7.8%)]. Three subjects (1.5%) taking sitagliptin reported a confirmed hypoglycaemic episode.. Subjects insufficiently controlled with sitagliptin who switch to liraglutide can obtain clinically relevant reductions in glycaemia and body weight, without compromising safety. A switch from sitagliptin to liraglutide provides an option for improved management of type 2 diabetes while still allowing patients to remain on dual therapy.

Topics: Adult; Aged; Aged, 80 and over; Asia; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Substitution; Drug Therapy, Combination; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Male; Metformin; Middle Aged; Nausea; North America; Sitagliptin Phosphate; Treatment Outcome

To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks.. Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c <0% and body weight <0 kg, and attainment of HbA1c <7.0% and body weight reduction ≥5% at Week 52 were evaluated. Safety was assessed based on adverse event reports.. Canagliflozin provided reductions in HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c <7.0% and body weight reduction ≥5% with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (18.9%, 18.3%, and 5.7%, respectively). Canagliflozin was generally well tolerated.. A greater proportion of patients with T2DM achieved reductions in both HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks.. www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Racial Groups; Sitagliptin Phosphate; Sulfonylurea Compounds; Weight Loss; Young Adult

To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.. A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored.. Ertugliflozin (1-25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) -0.45% (1 mg) to -0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (-0.76%; p = 0.0001)], FPG (LSM -1.17 to -1.90 mmol/l; p < 0.0001) and body weight (-1.15 to -2.15%; p < 0.0001). The LSM SBP decreased by -3.4 to -4.0 mmHg from baseline with ertugliflozin 5-25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo.. Ertugliflozin (1-25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Genital Diseases, Female; Genital Diseases, Male; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mycoses; Sitagliptin Phosphate; Sodium-Glucose Transport Proteins; Urinary Tract Infections

The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone.. This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an active-controlled, double-blind treatment period in which patients ≥ 65 and ≤ 85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks. The main outcome measures were change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight; and the incidence of symptomatic hypoglycemia.. The mean baseline HbA1c was 7.8% in both the sitagliptin group (n = 197) and the glimepiride group (n = 191). After 30 weeks, the least squares (LS) mean change in HbA1c baseline was -0.32% with sitagliptin and -0.51 % with glimepiride, for a between-group difference (95% CI) of 0.19% (0.03-0.34). This result met the pre-specified criterion for declaring non-inferiority, which required that the upper 95% confidence limit lie below 0.4%. The LS mean change in FPG from baseline was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with glimepiride, for a between-group difference (95% CI) of 6.7 mg/dL (0.7-12.7). The percentages of patients with adverse events of symptomatic hypoglycemia were 0.8% in the sitagliptin group and 4.7% in the glimepiride group (between-treatment difference = -3.9%, p = 0.009). The LS mean change in body weight from baseline was 0.4 kg with sitagliptin and 1.1 kg with glimepiride, for a between-group difference of -0.7 kg (p = 0.011).. In elderly patients with T2DM and inadequate glycemic control with diet and exercise alone, sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride. Compared with glimepiride, sitagliptin had a lower risk of hypoglycemia. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful.. ClinicalTrials.gov NCT01189890.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome

Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for treatment of type 2 diabetes mellitus (T2DM). The long-term efficacy and safety of canagliflozin monotherapy were evaluated over 52 weeks in patients with T2DM inadequately controlled with diet and exercise.. This randomized, double-blind, Phase 3 study included a placebo-controlled, 26-week core period (canagliflozin 100 or 300 mg vs placebo) and an active-controlled, 26-week extension (blinded switch of placebo-treated patients to sitagliptin 100 mg [placebo/sitagliptin]).. ClinicalTrials.gov, NCT01081834.. Efficacy endpoints assessed at 52 weeks included changes in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and systolic blood pressure (BP); and percentage changes in body weight and fasting plasma lipids. Adverse events (AEs) were recorded throughout the study. Efficacy data are reported for canagliflozin 100 and 300 mg (placebo/sitagliptin group was used to maintain the double-blind and to serve as a control group for safety purposes; not as an efficacy comparator); safety data are reported for canagliflozin 100 and 300 mg and placebo/sitagliptin.. Efficacy analyses included 451 patients who were randomized and dosed, entered the extension, and did not receive rescue therapy during the core period. Safety analyses included 584 patients who were randomized and dosed. At Week 52, canagliflozin 100 and 300 mg provided dose-related decreases from baseline in HbA1c of -0.81% and -1.11%. Canagliflozin 100 and 300 mg decreased FPG (-1.5 and -2.2 mmol/L [-27.4 and -39.1 mg/dL]), body weight (-3.3% and -4.4%), and systolic BP (-1.4 and -3.9 mmHg); decreased triglycerides and increased HDL-C and LDL-C were also seen. Over 52 weeks, overall AE rates were 67.2%, 66.0%, and 64.1% with canagliflozin 100 and 300 mg and placebo/sitagliptin; rates of serious AEs and AE-related discontinuations were low across groups. Compared with placebo/sitagliptin, canagliflozin was associated with higher rates of genital mycotic infections and AEs related to osmotic diuresis; these led to few discontinuations. Rates of volume depletion AEs and documented hypoglycemia were low across groups.. Canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks.

Topics: Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Exercise; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Placebos; Pyrazines; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Treatment Outcome; Triazoles; Triglycerides; Weight Loss

To assess the efficacy and safety of dapagliflozin as add-on therapy in patients with type 2 diabetes who were inadequately controlled with a dipeptidyl peptidase-4 inhibitor with or without metformin.. In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study with a 24-week blinded extension period, 432 patients were randomized to receive dapagliflozin 10 mg/day or placebo added to sitagliptin (100 mg/day) ± metformin (≥1,500 mg/day).. Baseline HbA1c and FPG levels were 7.9% (63.0 mmol/mol) and 162.2 mg/dL (9.0 mmol/L) for the dapagliflozin group and 8.0% (64.0 mmol/mol) and 163 mg/dL (9.0 mmol/L) for placebo. At week 24, dapagliflozin significantly reduced mean HbA1c levels (-0.5% [-4.9 mmol/mol]) versus placebo (0.0% [+0.4 mmol/mol]). Dapagliflozin reduced body weight versus placebo (-2.1 and -0.3 kg) and reduced HbA1c levels in patients with baseline values ≥8.0% (-0.8% [8.7 mmol/mol] and 0.0% [0.3 mmol/mol]) and fasting plasma glucose levels (-24.1 mg/dL [-1.3 mmol/L] and 3.8 mg/dL [0.2 mmol/L]). Similar results were observed when data were stratified by background therapy. Glycemic and weight benefits observed at week 24 were maintained through week 48. Changes from baseline in systolic blood pressure at week 8 were not significantly different between treatment groups. Over 48 weeks, fewer patients receiving dapagliflozin were discontinued or rescued for failing to achieve glycemic targets compared with placebo. Adverse events were balanced between groups, and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%).. These results suggest that in patients with type 2 diabetes, inadequately controlled on sitagliptin with or without metformin, add-on treatment with dapagliflozin provides additional clinical benefit and is well tolerated.

Topics: Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Urinary Tract Infections; Weight Loss

The dipeptidyl-peptidase-IV (DPP-4) inhibitors, including sitagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM). Adiponectin, an adipocyte-derived circulating protein, has anti-atherosclerotic and anti-diabetic properties and is effectively elevated in bloodstream by thiazolidinediones, an insulin sensitizer. However, the effect of sitagliptin treatment on serum adiponectin level in T2DM has not fully elucidated in Japanese T2DM patients. The aim of the present study was to examine the effect of sitagliptin treatment on serum adiponectin levels in T2DM subjects.. Twenty-six consecutive Japanese T2DM outpatients were recruited between April 2011 and March 2013, and randomized into the control (conventional treatment, n = 10) group and sitagliptin treatment group (n = 16). Serum adiponectin was measured by enzyme-linked immunosorbent assay.. Indices of glycemic control, such as hemoglobin A1c, glycated albumin, and 1.5-anhydro-D-glucitol, were significantly improved after the three-month treatment in both the control and sitagliptin groups. Serum adiponectin level was significantly increased in sitagliptin group from 6.7 ± 0.8 to 7.4 ± 1.0 μg/mL without change of body mass index (p = 0.034), while serum adiponectin level was not altered in the control group (p = 0.601).. In Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight.. UMIN000004721.

Topics: Adiponectin; Aged; Asian People; Biomarkers; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo.. Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue.. Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA1c compared with placebo (-0.9% [-9.8 mmol/mol]; P < 0.0001), sitagliptin (-0.4% [-4.4 mmol/mol]; P = 0.0001), and glimepiride (-0.3% [-3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide -1.21 kg (95% CI -1.68 to -0.74), placebo -1.00 kg (95% CI -1.81 to -0.20), sitagliptin -0.86 kg (95% CI -1.32 to -0.39), glimepiride 1.17 kg (95% CI 0.70-1.63). The difference between albiglutide and glimepiride was statistically significant (P < 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6-10.9%) and nausea (albiglutide 10.3%, other groups 6.2-10.9%) were generally the most frequently reported gastrointestinal events.. Added to metformin, albiglutide was well tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome; Triazoles

Type 2 diabetes mellitus (T2DM) is primarily a self-managed disease in which self-care behaviors play an important role in achieving optimal outcomes. Because self-care does not result in immediate tangible or noticeable benefits, adherence to such a regimen can be confusing, difficult, and frustrating. People are more likely to adhere to treatment regimens that offer benefits from the patient perspective, such as convenience, avoidance of hypoglycemic episodes, and weight loss, compared with regimens that do not. In this study, we explored the impact of the average weight loss amount demonstrated with canagliflozin treatment on improvement in 3 patient-relevant outcomes that have been linked to performance of healthy behaviors and better outcomes in T2DM: weight-related quality of life, as measured by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, and satisfaction with physical health and emotional health, as measured by the Current Health Satisfaction Questionnaire (CHES-Q), using data from a previously reported study. Weight loss of an amount demonstrated in clinical trials of canagliflozin was associated with improvements in weight-related quality of life and satisfaction with physical and emotional health, concepts shown to be important to the persistent and consistent performance of healthy behaviors.

Topics: Adult; Age Factors; Aged; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Health Behavior; Humans; Hypoglycemic Agents; Male; Middle Aged; Personal Satisfaction; Pyrazines; Quality of Life; Self Efficacy; Sex Factors; Sexual Behavior; Sitagliptin Phosphate; Thiophenes; Triazoles; Weight Loss

Glucose fluctuation often remains to be corrected under basal-supported oral therapy. We investigated the efficacy of adding once-daily rapid-acting insulin in Japanese diabetes patients treated with basal-supported oral therapy.. In this 8-week, parallel-group, randomized, open-label trial, 62 Japanese adults with type 2 diabetes treated with insulin glargine and 50 mg of sitagliptin were randomized into the following two arms: the single-bolus group, in which once-daily insulin glulisine was initiated at a main meal at a fifth (i.e., 20%) the dose of insulin glargine, and the control group, in which the dose of sitagliptin was maximized to 100 mg. The primary end point was the change of glycemic fluctuation assessed with the M-value.. Baseline hemoglobin A1c levels, mean blood glucose profiles, and M-value were 7.2 ± 0.6%, 9.3 ± 1.7 mmol/L, and 21 ± 13 units, respectively. At the end of the study, the single-bolus group had a greater reduction of M-value than the control group (P=0.02); the difference was 6.5 units (95% confidence interval, 1.1-11.9 units). The single-bolus group also had a greater reduction of mean blood glucose levels (P=0.01). There were no significant differences in the incidence of hypoglycemia or the weight change between the two groups (P>0.05).. Adding once-daily insulin glulisine was more effective in controlling the glycemic fluctuation in Japanese type 2 diabetes patients treated with insulin glargine together with sitagliptin.

Topics: Adult; Asian People; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Japan; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

To evaluate attainment of diabetes-related quality measures with canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg in patients with type 2 diabetes mellitus.. This post hoc analysis used pooled data from two 52-week, randomized, double-blind, phase 3 clinical trials that evaluated the comparative efficacy of canagliflozin and sitagliptin. One trial evaluated patients on metformin at baseline with add-on canagliflozin 100 mg, canagliflozin 300 mg, or sitagliptin 100 mg; the other trial evaluated patients on metformin and a sulfonylurea at baseline with add-on canagliflozin 300 mg or sitagliptin 100 mg.. Individual diabetes-related quality measures, including glycated hemoglobin (A1C), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), body mass index (BMI), and change in body weight, were assessed.. At baseline, the proportions of patients meeting criteria for all quality measures were similar between groups. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 100 mg demonstrated either comparable or superior glycemic control. Additionally, canagliflozin 100 mg versus sitagliptin 100 mg demonstrated superior attainment of BP, BMI, and weight-related quality measures; no difference was seen with respect to LDL-C. At 52 weeks, compared with sitagliptin 100-mg treatment, canagliflozin 300 mg demonstrated superior glycemic control at all thresholds of A1C, and superior BP, BMI, and weight-related quality measures; there was no difference in LDL-C quality measure attainment.. We evaluated the comparative efficacy of canagliflozin 100 mg, canagliflozin 300 mg, and sitagliptin 100 mg on quality measure attainment after 52 weeks of treatment. Compared with sitagliptin 100 mg, canagliflozin 100 mg demonstrated comparable or superior attainment of diabetes-related quality measures. Compared with sitagliptin 100 mg, canagliflozin 300 mg demonstrated superior diabetes-related quality measure attainment, including glycemic, BP, and weight-related quality measures; there was no difference in LDL-C quality measure attainment between either dosage of canagliflozin and the 100-mg dosage of sitagliptin.

Topics: Blood Pressure; Body Mass Index; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Thiophenes; Treatment Outcome; Triazoles

Sitagliptin has been proven to be effective and safe as add-on to insulin in adult patients with type 2 diabetes and absolute insulin deficiency. Recently, it has been suggested to extend the use of dipeptidyl-peptidase-4 inhibitors to type 1 diabetes. The aim of this study was to evaluate and compare the effects of a long-term, fixed-dose combination of sitagliptin and metformin as add-on to insulin on body mass index, fasting plasma glucose, fructosamine, HbA(1c), lipids, and daily dose of insulin in both type 1 diabetes and insulin-treated type 2 diabetes.. We recruited 25 patients with type 1 diabetes (mean age 51 ± 10 years, mean disease duration 26 ± 13 years) and 31 insulin-treated type 2 diabetic patients (mean age 66 ± 8 years, mean disease duration 19 ± 9 years), who received sitagliptin with metformin as a fixed-dose combination (50/1000 mg once or twice daily) or sitagliptin (100 mg once daily, if intolerant to metformin) in addition to ongoing insulin therapy for 46 ± 19 weeks and 56 ± 14 weeks, respectively.. After 21 ± 9 weeks, patients with type 1 diabetes had a significantly lower body mass index, fasting plasma glucose, fructosamine, HbA(1c), and daily insulin requirement. After 49 ± 17 weeks, they maintained their weight loss and total daily insulin dose and showed a significant reduction in low-density lipoprotein cholesterol levels, whereas their HbA(1c) had returned to baseline values. In patients with type 2 diabetes, long-term treatment remained weight-neutral but had persistent beneficial effects on short-term, intermediate-term, and long-term biomarkers of metabolic control, as well as on low-density lipoprotein cholesterol levels and insulin requirement.. Clinical outcomes differed according to type of diabetes in terms of quality and over time. In type 2 diabetes, the combination therapy significantly improved metabolic control and the lipid profile, and decreased insulin requirements, even in the absence of clinically significant weight loss. In type 1 diabetes, the combined therapy only temporarily improved metabolic control, but significantly decreased body weight, low-density lipoprotein cholesterol levels, and insulin requirements.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Body Weight; Cholesterol, LDL; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles

The efficacy and safety of insulin degludec (IDeg), a new basal insulin with an ultra-long duration of action, was compared to sitagliptin (Sita) in a 26-week, open-label trial.. Insulin-naïve subjects with type 2 diabetes [n = 458, age: 56 years, diabetes duration: 7.7 years, glycosylated haemoglobin (HbA1c): 8.9% (74 mmol/mol)] were randomized (1 : 1) to once-daily IDeg or Sita (100 mg orally) as add-on to stable treatment with 1 or 2 oral antidiabetic drugs (OADs).. Superiority of IDeg to Sita in improving HbA1c and fasting plasma glucose (FPG) was confirmed [estimated treatment difference (ETD) IDeg-Sita for HbA1c: -0.43%-points [95% confidence interval (CI): -0.61; -0.24, p < 0.0001] and for FPG: -2.17 mmol/l (95% CI: -2.59; -1.74, p < 0.0001)]. HbA1c < 7% (<53 mmol/mol) was achieved by 41% (IDeg) versus 28% (Sita) of patients, estimated odds ratio IDeg/Sita: 1.60 (95% CI: 1.04; 2.47, p = 0.034). There was no statistically significant difference in the rate of nocturnal confirmed hypoglycaemia between IDeg and Sita [0.52 vs. 0.30 episodes/patient-year, estimated rate ratio (ERR): IDeg/Sita: 1.93 (95% CI: 0.90; 4.10, p = 0.09)]. Rates of overall confirmed hypoglycaemia were higher with IDeg than with Sita [3.1 vs. 1.3 episodes/patient-year, ERR IDeg/Sita: 3.81 (95% CI: 2.40; 6.05, p < 0.0001)]. IDeg was associated with a greater change in body weight than Sita [ETD IDeg-Sita: 2.75 kg (95% CI: 1.97; 3.54, p < 0.0001)]. The overall rates of adverse events were low and similar for both groups.. In patients unable to achieve good glycaemic control on OAD(s), treatment intensification with IDeg offers an effective, well-tolerated alternative to the addition of a second or third OAD.

Topics: Administration, Oral; Argentina; Blood Glucose; Body Weight; Canada; Diabetes Mellitus, Type 2; Drug Administration Schedule; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; India; Insulin, Long-Acting; Male; Mexico; Middle Aged; Pyrazines; Sitagliptin Phosphate; South Africa; Treatment Outcome; Triazoles; Turkey; United States

Therapies for type 2 diabetes mellitus that leverage the glucagon-like peptide-1 (GLP-1) receptor signaling pathway have been shown to reduce rates of hyperglycemia and have beneficial effects on body weight. This post hoc analysis compared the effects of 2 GLP-1 receptor- based therapies, exenatide once weekly (EQW), a GLP-1 receptor agonist, and sitagliptin (sita), a dipeptidyl peptidase-4 inhibitor, on glucose control across the range of baseline glycated hemoglobin (HbA1c) levels specified in the American Association of Clinical Endocrinologists and American College of Endocrinology treatment algorithm.. Data from patients treated with either EQW or sita for 26 weeks in 2 randomized, double-blind, comparator-controlled clinical trials were pooled and analyzed. Glycemic endpoints and cardiovascular risk factors were evaluated in subgroups and the overall population.. Analysis included 737 patients on background therapies of diet and exercise and/or metformin. While both agents reduced HbA1c and fasting blood glucose (FBG) levels from baseline, significantly greater reductions in HbA1c and FBG levels occurred with EQW compared with sita across all baseline HbA1c level strata, and significantly more patients in the EQW group achieved goal HbA1c levels compared with the sita group. Patients treated with EQW also experienced significantly greater reductions in body weight and cholesterol levels compared with patients treated with sita. The incidences of the most common adverse events of nausea and diarrhea were higher in the EQW group compared with the sita group, and incidences of these adverse events decreased over time. Both groups experienced a low incidence of minor hypoglycemic events.. Significantly greater improvements in HbA1c and FBG levels were observed in EQW- compared with sita-treated patients across all baseline HbA1c level strata. Additionally, greater reductions in body weight and some cardiovascular risk factors were observed with EQW treatment compared with sita treatment. Both EQW and sita were generally well tolerated; sita-treated patients experienced fewer adverse events than EQW-treated patients.. www.ClinicalTrials.gov identifiers: NCT00637273, NCT00676338.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Pyrazines; Retrospective Studies; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.. This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N = 1,284) with type 2 diabetes aged ≥ 18 and ≤ 80 years who had inadequate glycaemic control (HbA1c ≥ 7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.. At week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (-0.79%, -0.94%, -0.17%, respectively; p < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (-0.73%, -0.88%,-0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (-0.12, 0.12) and -0.15% (-0.27, -0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: -3.7%, -4.2%, -1.2%, respectively; p < 0.001) and sitagliptin (week 52: -3.8%, -4.2%, -1.3%, respectively; p < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.. Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.. ClinicalTrials.gov NCT01106677 FUNDING: This study was supported by Janssen Research & Development, LLC.

Topics: Adolescent; Aged; Aged, 80 and over; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Thiophenes; Treatment Outcome; Triazoles

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antihyperglycemic drugs that block degradation ofincretin hormones.. To assess the effects oftreatment with DPP-4 inhibitors on glucoregulation and body weight in obese patients with type 2 diabetes mellitus.. The study included 9 females and 9 males with type 2 diabetes (n=18), BMI=31.24 +/- 2,26 kg/m2, mean age 58 +/- 6,8 years. The patients have been thoroughly evaluated before treatment, and 6 months after treatment with DPP-4 inhibitor (sitagliptin) in combination with metformin.. After 6 months of treatment with DPP-4 inhibitors in combination with metformin HbAlc (-1,49%)., FBG (-3.75 mmol/L) and PBG (-5.79 mmol/L) significantly reduced (p=0.000). Mean body weight also significantly reduced (-12.5%; p=0.000). Reduction of mean fasting insulin was 5.46 mIU/L or 27% (p=0.000). Mean HOMA-IR change was -1.64 (p=0.000). Also there was significant decreasing of systolic blood pressure (p=0.001), cholesterol (p=0.004), triglycerides (p=0.001), LDL (p=0.002) and increasing of HDL (p=0.002). Hypoglycaemia was not registered in any of the patients.. These results show that in obese patients with type 2 diabetes, DPP-4 inhibitors treatment in combination with metformin was associated with improvements in glycaemic control, and a reduction in body weight.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Obesity; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Triglycerides

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

Topics: Aged; Asian People; Body Mass Index; Body Weight; C-Peptide; Demography; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Male; Pyrazines; ROC Curve; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control.. Patients (n = 426) were randomized 1:1 to sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1) renal status (moderate or severe renal insufficiency); 2) history of cardiovascular disease; and 3) history of heart failure.. At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (-0.8 vs. -0.6%; between-group difference -0.11%; 95% CI -0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (-0.6 kg) versus an increase (1.2 kg) with glipizide (difference, -1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments.. In patients with T2DM and chronic renal insufficiency, sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.

Topics: Body Weight; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hypoglycemic Agents; Male; Pyrazines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles

Individuals requiring insulin therapy for type 2 diabetes often require escalation of their regimen to achieve glycaemic control. Optimal management strategies for uncontrolled type 2 diabetes would improve glycaemic control without hypoglycaemia and weight gain. This study compared the efficacy and tolerability of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, and an up to 20% increase in insulin dose in patients with uncontrolled type 2 diabetes on insulin therapy.. We conducted a 24-week, randomized, active-competitor, parallel-group study in subjects with uncontrolled type 2 diabetes [haemoglobin A1c (HbA1c) = 7.5-11%] currently using insulin therapy. Subjects were randomly assigned to either the sitagliptin adding (100 mg daily, n = 70) or an insulin-increasing arm (≥ 10% at week 12 and ≥ 10% at week 24, n = 70) while continuing other medications.. Average baseline HbA1c was 9.2% in both groups. HbA1c decreased more at 24 weeks in the sitagliptin adding than the insulin-increasing arm (-0.6 ± 0.1% vs. -0.2 ± 0.1%, p < 0.01). Insulin was increased by 25% at 24 weeks in the insulin-increasing group. Hypoglycaemic events were less common and less severe in sitagliptin adding arm than insulin-increasing arm (7.0 vs. 14.3 events per patient-year, p < 0.05). Weight was stable in the sitagliptin adding subjects (68.6 ± 11.6 vs. 68.1 ± 11.4 kg) but increased in the insulin-increasing subjects (66.2 ± 10.6 vs. 67.4 ± 9.7 kg, p < 0.05). Other adverse events occurred at similar rates in both arms.. Compared to a 25% increase in insulin dose, adding sitagliptin to an insulin-based regimen was more effective at lowering HbA1c and associated with less hypoglycaemia and weight gain over 24 weeks.. NCT01100125.

Topics: Adult; Aged; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles; Waist Circumference

In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin.. In this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35-70 years with glycated haemoglobin A(1c) (HbA(1c)) of 7-11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25-45 kg/m(2) were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0-5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA(1c) from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT00751114.. 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA(1c) was greater for patients on insulin glargine (n=227; -1·72%, SE 0·06) than for those on sitagliptin (n=253; -1·13%, SE 0·06) with a mean difference of -0·59% (95% CI -0·77 to -0·42, p<0·0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4·21 [SE 0·54] vs 0·50 [SE 0·09] events per patient-year; p<0·0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event.. Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease.. Sanofi.

Topics: Adult; Aged; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

To compare the efficacy and safety of sitagliptin and glimepiride in treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin alone.. In an 18 week, randomized parallel group interventional trial, 50 subjects who were only on metformin as antidiabetic agent, with inadequate glycemic control, were randomized to either sitagliptin 50/100mg or glimepiride 1/2 mg per day. Dose of drugs was adjusted after 4 weeks if glycemic control was not reached.. At 18 weeks both groups (sitagliptin and glimepiride) produced significant (P < 0.001) reduction in HbA1C (-0.636% and -1.172% respectively), with 12% patients in sitagliptin group and 36% patients in glimepiride group achieving target HbA1C. Reduction was also significant (P < 0.001) in both groups in FPG (-15.49 mg and -29.84 mg respectively) and 2HPPG (-34.28 mg and -44.83 mg respectively). Sitagliptin group showed net decrease in bodyweight by 0.102 kg whereas glimepiride group showed net increase in body weight by 0.493 kg. Incidence of hypoglycemia was 4% in sitagliptin group and 8% in glimepiride group.. In this study addition of sitagliptin and glimepiride to metformin monotherapy, produced significant improvement in glycemic control. Benefits were more with glimepiride in comparison to sitagliptin. Sitagliptin was well tolerated, with lower risk of hypoglycemia than glimepiride, and produced weight loss as compared to weight gain with glimepiride.

Topics: Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Metformin; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Time Factors; Treatment Outcome; Triazoles

To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes.. In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged.. Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA(1c)) by -0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, -0.2%, P = 0.006; 1.8 mg/day, -0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, -0.8 mmol/L, P = 0.0004; 1.8 mg/day, -1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, -1.6 kg; 1.8 mg/day, -2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA(1c) <7% (from ∼30% to ∼50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3-4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA(1c) (baseline 8.3 and 8.4%, respectively) by -0.9 and -1.3%, respectively; FPG by -1.3 and -1.7 mmol/L, respectively; and weight by -2.6 and -3.1 kg, respectively, with 9-10% of participants reporting minor hypoglycemia.. Glycemic control, weight, and treatment satisfaction improved after switching from sitagliptin to liraglutide, albeit with a transient increase in gastrointestinal reactions.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Liraglutide; Metformin; Nausea; Patient Satisfaction; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

To assess change in patient-reported outcomes in subjects with type 2 diabetes treated with exenatide once weekly compared with those treated with sitagliptin or pioglitazone.. In this 26-week randomized, multicenter, double-dummy study, 491 subjects received 2 mg of exenatide once weekly or maximum daily doses of sitagliptin (100 mg) or pioglitazone (45 mg) on a background of metformin. Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction were assessed at baseline and week 26. Mean group changes from baseline to week 26 were estimated by ANCOVA.. Weight-related quality of life total scores improved significantly in the exenatide once weekly and sitagliptin arms only; the exenatide once weekly group experienced significantly greater improvement than the pioglitazone group in weight-related quality of life total scores and in several domain scores. Health utility scores improved significantly for exenatide once weekly and sitagliptin groups (P < 0.05) with no significant difference between the exenatide once weekly group and either comparison group. All groups experienced significant improvements on the psychological well-being global scale and all six domain scores, with no significant difference between the exenatide once weekly group and either comparator. All groups experienced significant improvements in total diabetes treatment satisfaction scores. The exenatide once weekly group experienced greater improvement than the sitagliptin group in treatment satisfaction total scores.. In combination with clinical outcomes from this study, these results indicate it is possible for patients treated with metformin to initiate exenatide therapy with potential benefits in both clinical and patient-reported outcomes.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Health Status; Humans; Hypoglycemic Agents; Male; Mental Health; Middle Aged; Patient Satisfaction; Peptides; Pioglitazone; Pyrazines; Quality of Life; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles; Venoms

Sitagliptin is not associated with weight gain and has neutral effects on body weight. It is unclear whether sitagliptin treatment alters serum ghrelin levels in people with type 2 diabetes.. Forty-four subjects with type 2 diabetes were randomly assigned to receive sitagliptin or medical nutrition therapy (MNT) for 12 weeks. Changes in anthropometric variables, glycemic control, insulin resistance, lipid parameters, and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment.. Significant decreases in body weight and body mass index were observed over the entire study period in both treatment groups. Glycosylated hemoglobin and postprandial plasma glucose levels were statistically significant decreased in the groups receiving sitagliptin compared with baseline values (p=0.021 and p=0.021, respectively), while they were unchanged in the groups receiving MNT. There was a significant decrease in total ghrelin in the groups receiving sitagliptin (p=0.04) compared with baseline values but not in the groups receiving MNT (p=0.46) at the end of the 12 weeks.. In this study of patients with type 2 diabetes, treatment with sitagliptin was associated with a significant decrease in serum ghrelin levels. These results suggest that the neutral effect of sitagliptin on weight might be associated with the suppression of fasting serum ghrelin levels.

Topics: Aged; Analysis of Variance; Biomarkers; Blood Glucose; Body Mass Index; Body Weight; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Female; Ghrelin; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles; Turkey

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, beta-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA(1c), FPG, and PPG and a significant increase of homeostasis model assessment beta-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-alpha with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-alpha values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-alpha decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA(1c), FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if si

Topics: Adiponectin; Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Diet; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Pioglitazone; Pyrazines; Resistin; Sitagliptin Phosphate; Thiazolidinediones; Triazoles; Tumor Necrosis Factor-alpha

The purpose of this study was to evaluate the efficacy and safety of sitagliptin as an add-on to metformin therapy in patients with moderately severe (hemoglobin A(1c) >or= 8.0% and or= 6 weeks of stable metformin monotherapy (>or= 1500 mg/day), patients were randomized to either the addition of sitagliptin 100 mg once daily or placebo to ongoing metformin for 30 weeks.. The primary efficacy endpoint was reduction in hemoglobin A(1c) (HbA(1c)) measured after 18 weeks of sitagliptin treatment. Key secondary endpoints included reduction in fasting plasma glucose (FPG) and 2-hour (2-h) postprandial plasma glucose (PPG) at 18 weeks, and HbA(1c) at 30 weeks. The proportion of patients meeting the goal of HbA(1c) < 7.0% was also analyzed.. Sitagliptin significantly reduced HbA(1c), FPG, and 2-h PPG, compared with placebo (all p < 0.001). The net improvement in HbA(1c) was - 1.0% at both 18 and 30 weeks, and a significantly greater proportion of patients treated with sitagliptin achieved HbA(1c) < 7.0% by the end of the study (22.1% vs. 3.3%, p < 0.001). Sitagliptin was well-tolerated. Compared with placebo, sitagliptin had a neutral effect on body weight and did not significantly increase the risk of hypoglycemia or gastrointestinal adverse events.. Addition of sitagliptin 100 mg once daily to ongoing metformin therapy was well-tolerated and resulted in significant glycemic improvement in patients with moderately severe T2DM who were treated for 30 weeks.

Topics: Adult; Aged; Area Under Curve; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles

To assess the addition of sitagliptin to ongoing metformin therapy in patients with type 2 diabetes who were inadequately controlled [haemoglobin A(1c) (HbA(1c)) 7-11%] on metformin monotherapy.. Patients (n = 273) on metformin (>/=1500 mg/day) were randomized to receive the addition of once-daily placebo, sitagliptin 100 mg or rosiglitazone 8 mg in a 1 : 1 : 1 ratio for 18 weeks. The efficacy analysis was based on the all-patients-treated population using an analysis of co-variance with change in HbA(1c) from baseline as the primary endpoint.. The mean baseline HbA(1c) was 7.7% for the entire cohort. After 18 weeks, both active add-on therapies led to greater improvements in HbA(1c) from baseline: -0.73% for sitagliptin (p < 0.001 vs. placebo) and -0.79% for rosiglitazone compared with -0.22% for placebo. No difference was observed between the sitagliptin and rosiglitazone treatments (0.06% [95% confidence interval (CI): -0.14 to 0.25]). The proportion of patients achieving an HbA(1c) < 7% was greater with sitagliptin (55%) and rosiglitazone (63%) compared with placebo (38%). Body weight increased from baseline with rosiglitazone (1.5 kg) compared with body weight reduction with sitagliptin (-0.4 kg) and placebo (-0.8 kg). The difference in body weight between the sitagliptin and rosiglitazone groups was 1.9 kg (95% CI: 1.3-2.5). In a prespecified analysis, the proportion of patients experiencing a greater than 3-kg increase in body weight was 21% in the rosiglitazone group compared with 2% in both the sitagliptin and placebo groups. Both active treatments were generally well tolerated, with no increased risk of hypoglycaemia or gastrointestinal adverse events compared with placebo.. In this 18-week study, the addition of sitagliptin was effective and well tolerated in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Treatment with sitagliptin produced similar reductions in HbA(1c) compared with the addition of rosiglitazone.

Topics: Analysis of Variance; Biomarkers; Blood Glucose; Body Weight; Cholesterol, LDL; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Metformin; Middle Aged; Pyrazines; Rosiglitazone; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles; Triglycerides

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Administration, Oral; Blood Glucose; Body Weight; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycoproteins; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Pyrazines; Sitagliptin Phosphate; Triazoles

Cyclophosphamide (CYP) is a classic DNA-interacting anticancer agent with broad application in chemotherapy. However, CYP cerebral neurotoxicity is a worrisome side effect for clinicians and patients. Strategies to mitigate the underlying oxidative inflammatory cascades and neuroapoptosis induced by CYP are urgently needed. Herein, we have repurposed an antidiabetic drug, sitagliptin (STG), for a possible abrogation of CYP-induced cerebral neurotoxicity in rats. Healthy rats were administered STG (20 mg/kg body weight) for 5 days prior to neurotoxicity induced by CYP (200 mg/kg body weight, ip) on day 5 only, and rats were sacrificed after 24 h post-CYP injection. CYP caused profound increases in the cerebral levels of nitric oxide (NO), acetylcholinesterase (AChE), malondialdehyde (MDA), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS), caspase-3 and Bax protein compared to the control. Furthermore, CYP markedly depressed the activities of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), along with levels of reduced glutathione (GSH) and nuclear factor erythroid 2-related factor2 (Nrf2) compared to the control (p < 0.05). Interestingly, STG pretreatment inhibited the CYP-induced alterations in caspase-3, Bax, pro-inflammatory cytokines, NO, iNOS, AChE, NF-κB, and restored the cerebral antioxidant apparatus, including the Nrf2 and histopathological abrasions. Therefore, these findings show that STG could be repurposed to prevent CYP-induced cerebral toxicity in the brain.

Topics: Acetylcholinesterase; Animals; Antioxidants; bcl-2-Associated X Protein; Body Weight; Caspase 3; Cyclophosphamide; Hypoglycemic Agents; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Oxidation-Reduction; Oxidative Stress; Rats; Sitagliptin Phosphate

Glucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism.. Adult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses.. Dexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances.. Coadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.

Topics: Animals; Blood Glucose; Body Weight; Dexamethasone; Diabetes Mellitus, Experimental; Feeding Behavior; Glucose Tolerance Test; Hypoglycemic Agents; Male; Metformin; Rats; Rats, Wistar; Sitagliptin Phosphate

Neuropeptide Y (NPY) plays a crucial role in many neurobiological functions, such as cognition and memory. Cognitive and memory impairment have been described in diabetic patients. The metabolism of NPY is determined by the activity of proteases, primarily dipeptidyl-peptidase-IV (DPP-IV). Therefore, DPP-IV inhibitors, such as sitagliptin, may modulate the function of NPY. In this study, we investigated the effect of type 1 diabetes and sitagliptin treatment on the regulation of the mRNA encoding for NPY and its receptors (Y1, Y2, and Y5 receptors) in the hippocampus.. Type 1 diabetes was induced in male Wistar rats by i.p. injection of streptozotocin. Starting two weeks after diabetes onset, animals were treated orally with sitagliptin (5mg/kg, daily) for two weeks. The mRNA expression of Npy and its receptors (Npy1r, Npy2r, and Npy5r) in the hippocampus was evaluated using in situ hybridization with. The mRNA expression of Npy, Npy1r and Npy5r was higher in the dentate gyrus, whereas Npy2r highest level was observed in the CA3 subregion. The mRNA expression of Npy, Npy1r and Npy5r in dentate gyrus, CA1 and CA3 was not affected by diabetes and/or by sitagliptin treatment. Type 1 diabetes increased the mRNA expression of Npy2r in the CA3 subregion, which was prevented by sitagliptin treatment.. Our results show that type 1 diabetes, at early stages, induces mild changes in the NPY system in the hippocampus that were counteracted by sitagliptin treatment.

Topics: Analysis of Variance; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Hippocampus; Hypoglycemic Agents; Male; Neuropeptide Y; Oligonucleotide Probes; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

According to the data, there are 387 million people with diabetes in the world, and the number of people with diabetes is expected to reach 600 million by 2035 (Nature Reviews Endocrinology, 14, 2018, Zheng et al.). At present, there are nearly 110 million diabetic patients in China, the incidence of which is increasing (Diabetologia, 61, 2018, Ma). Islet β cell apoptosis and proliferation is an important basis for the occurrence and development of diabetes. It has been reported that enhancing the activity of incretin-cAMP signaling pathway can also promote islet β cell proliferation, reduce β cell apoptosis and promote insulin secretion (Diabetologia, 59, 2016, Iida et al.). Tibetan medicine Triphala (THL) is a traditional national medicine, it plays a good role in anti-fatigue, antioxidation, prevention and treatment of polycythemia at high altitude. Research have shown that it can reduce blood glucose in patients with diabetes and inhibit the activity of glucosidase in the intestines (The Journal of Alternative and Complementary Medicine, 23, 2017, Peterson et al.). After the diabetic Wistar rat model induced by Streptozocin (STZ) was successfully duplicated, the positive drug sitagliptin tablet and THL were given and the changes of body weight and blood glucose were measured. After 6 weeks, the expression of related factors in serum and pancreas was observed. Compared with the model group, in the treatment group, blood glucose decreased, body weight increased, incretin-cAMP signaling pathway related factors glucose-dependent insulin-promoting polypeptide (GIP), glucagon-like peptide-1 (GLP-1), GLP-1R, cAMP, P-protein kinase A (PKA), AKT were up-regulated, insulin secretion was increased, liporing protein interaction protein (TXNIP) expression was down-regulated. In addition, in the treatment group, the degree of islet atrophy was alleviated and the number of islet β cells increased. This study shows that THL may enhance the activity of incretin-cAMP signal pathway and affect the proliferation and apoptosis of islet β cells, so as to achieve the effect of anti-diabetes.

Topics: Animals; Apoptosis; Body Weight; Cell Cycle Proteins; Cell Proliferation; Cyclic AMP-Dependent Protein Kinases; Glucagon-Like Peptide 1; Incretins; Insulin; Insulin-Secreting Cells; Male; Pancreas; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Sitagliptin Phosphate

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Metformin; Sitagliptin Phosphate

We sincerely thank Dr. Sikarin Upala for his interest in our article and for sharing his experience in the treatment of nonalcoholic fatty liver disease (NAFLD). NAFLD is prevalent in patients with type 2 diabetes mellitus (T2DM), yet only preliminary evidence are available on the effect of anti-diabetic agents to NAFLD in T2DM patients. According to clinical practice guidelines for NAFLD management

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

We read with interest a recent article written by Yan et al.

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Biomarkers; Body Weight; Eating; Exenatide; Fructose; Male; Oxidative Stress; Rats; Rats, Wistar; Sitagliptin Phosphate

Topics: Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Insulin Glargine; Lipids; Liraglutide; Metformin; Non-alcoholic Fatty Liver Disease; Sitagliptin Phosphate

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Pressure; Body Weight; Cardiotonic Agents; Diastole; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Kidney; Kidney Function Tests; Male; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Rats, Wistar; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sitagliptin Phosphate; Up-Regulation; Ventricular Remodeling

Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (

Topics: Acute Disease; Animals; Blood Glucose; Body Weight; Cyclooxygenase 2; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Electrocardiography; Heart Ventricles; Insulin-Like Growth Factor I; Interleukin-6; Male; Myocardial Infarction; Neovascularization, Physiologic; Organ Size; Rats; Sitagliptin Phosphate; Vascular Endothelial Growth Factor A

two common anti-diabetic treatments used are sitagliptin and sulphonylureas however evidence examining their comparative effectiveness in older people is limited.. to evaluate effectiveness of sitagliptin vs sulphonylureas when added to metformin in older (aged ≥75) vs younger people (18-75).. retrospective cohort study.. UK Primary Care.. 2,904 individuals prescribed sitagliptin (223 aged≥75) and 13,683 prescribed sulphonylureas (1,725 aged ≥75).. multivariable regression to analyse difference in HbA1c and weight, 12 months after add-on initiation and proportion achieving different glycaemic targets.. after multivariate adjustment to remove baseline differences, the HbA1c after 12 months of treatment was on average 1 mmol/mol (95%CI -0.7 to 2.8) higher with sitagliptin vs sulphonylureas in older people though this was not statistically significant. The weight however, was significantly lower -1.4 kg (95%CI -2.1 to -0.7) with sitagliptin vs sulphonylureas. A lower proportion prescribed sitagliptin vs sulphonylureas recorded HbA1c < 48 mmol/mol by study end: Odds Ratio 0.63 (95%CI 0.42-0.95). In younger people, similar HbA1c reductions were also observed with both treatments, however weight after 12 months was even lower with sitagliptin vs sulphonylureas: -2.3 kg (95%CI -2.5 to -2.0).. similar HbA1c reduction was observed when sitagliptin or sulphonylureas were added to metformin in older and younger age-groups. Sitagliptin use led to modest comparative weight loss. There may be greater risk of over-treatment with sulphonylureas evidenced by greater proportion recording HbA1c < 48 mmol/mol by study end. This evidence supporting use of sitagliptin when add-on therapy is selected in older adults should be considered alongside the wider evidence-base and patient-preference.

Topics: Adolescent; Adult; Age Factors; Aged; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Retrospective Studies; Sitagliptin Phosphate; Sulfonylurea Compounds; Treatment Outcome; Young Adult

We aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore.. This was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m. In total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation.. Our findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Hypoglycemic Agents; Least-Squares Analysis; Male; Middle Aged; Osmosis; Retrospective Studies; Singapore; Sitagliptin Phosphate; Systole; Treatment Outcome; Young Adult

To analyze the efficacy and safety of replacing sitagliptin with canagliflozin in patients with type 2 diabetes (T2D) and poor metabolic control despite treatment with sitagliptin in combination with metformin and/or gliclazide.. In this multicentre observational, retrospective, 26-week clinical study of patients with T2D and poor glycaemic control (HbA1c: 7.5-9.5%) treated with sitagliptin in combination with metformin and/or gliclazide, sitagliptin (and gliclazide if appropriate) were replaced by canagliflozin. The main outcome of the study was the proportion of patients who achieved good glycaemic control (HbA1c<7%) by the end of the study.. In patients with T2D poorly controlled with sitagliptin, whether alone or in combination with metformin and/or gliclazide, replacing it with canagliflozin may be a simple yet effective intensification strategy. Our results, which may have important implications for clinical practice, now need to be confirmed in larger observational studies.

Topics: Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Diabetes Mellitus, Type 2; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Retrospective Studies; Sitagliptin Phosphate

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Collagen; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Fatty Acids; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Male; Metformin; Mitogen-Activated Protein Kinase 14; Myocardium; Organ Size; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger; Signal Transduction; Sitagliptin Phosphate

Chronic overnutrition leads to cardiac dysfunction and insulin (INS) resistance. Dipeptidyl peptidase-4 (DPP-4) improves glucose metabolism and insulin sensitivity in both human and animal models. In this study, we explored whether DPP-4 inhibitor sitagliptin (SIT) is involved in the protection of cardiac function and. Six-week-old C57BL6/J mice were fed a high fat and fructose Western diet with DPP-4 inhibitor SIT for 12 weeks. Cardiac function was examined by echocardiography. Body weight, plasma glucose, and insulin concentrations were measured. The contents of total S6 kinase 1 (S6K1), phosphorylation of S6K1 activation, and INS docking proteins INS receptor substrates 1 and 2 (IRS-1, IRS-2) were assayed, and histology of heart tissue was performed.. This study revealed pleiotropic protective effects of DPP-4 inhibitor SIT on cardiac function, glycemia, and

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Echocardiography; Enzyme Activation; Female; Heart; Homeostasis; Insulin; Insulin Receptor Substrate Proteins; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Obesity; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Sitagliptin Phosphate

The beneficial glycemic and food intake-suppressive effects of glucagon-like peptide-1 (GLP-1) have made this neuroendocrine system a leading target for pharmacological approaches to the treatment of diabetes and obesity. One strategy to increase the activity of endogenous GLP-1 is to prevent the rapid degradation of the hormone by the enzyme dipeptidyl peptidase-IV (DPP-IV). However, despite the expression of both DPP-IV and GLP-1 in the brain, and the clear importance of central GLP-1 receptor (GLP-1R) signaling for glycemic and energy balance control, the metabolic effects of central inhibition of DPP-IV activity are unclear. To test whether hindbrain DPP-IV inhibition suppresses blood glucose, feeding, and body weight gain, the effects of 4th intracerebroventricular (ICV) administration of the FDA-approved DPP-IV inhibitor sitagliptin were evaluated. Results indicate that hindbrain delivery of sitagliptin improves glycemic control in a GLP-1R-dependent manner, suggesting that this effect is due at least in part to increased endogenous brainstem GLP-1 activity after sitagliptin administration. Furthermore, 4th ICV injection of sitagliptin reduced 24h body weight gain and energy intake, with a selective suppression of high-fat diet, but not chow, intake. These data reveal a novel role for hindbrain GLP-1R activation in glycemic control and also demonstrate that DPP-IV inhibition in the caudal brainstem promotes negative energy balance.

Topics: Animals; Area Under Curve; Blood Glucose; Body Weight; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Eating; Energy Metabolism; Fasting; Glucose Tolerance Test; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Rhombencephalon; Sitagliptin Phosphate

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

Topics: Animals; Autophagy; Body Weight; Cells, Cultured; Diet; Drug Evaluation, Preclinical; Energy Intake; Exenatide; Fructose; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Male; Membrane Proteins; Microscopy, Electron; Peptides; Rats, Wistar; RNA, Messenger; Sitagliptin Phosphate; Venoms

The inhibitors of proline specific peptidase dipeptidyl peptidase-IV (DPP-IV, CD 26; EC 3.4.14.5) diprotin A (2 mg/kg) and sitagliptin (4 mg/kg) upon daily systemic exposure in rat pups on postnatal days 1-7 induced emotional and motivational disorders in one- and two-month-old rats. In adolescent rats, both the inhibitors produced a decreased locomotion in the automated open field test and an in- creased depression-like behavior in the Forced Swimming Test. At the same time, diprotin A increased sucrose consumption (a percent of the body weight) while sitagliptin decreased anxiety in the Elevated Plus Maze (EPM). In adult rats, diprotin A caused an increase in anxiety according to the reduced pref- erence for open arms of the maze and both the inhibitors decreased the percentage of rats entering open. arms in the EPM. Adult diprotin A-treated animals demonstrated increased aggression in social contact test. as compared to sitagliptin-treated rats. The one-and two-month-old animals in both experimental groups exhibited a decreased weight as compared to the controls. The results of the study show that diprotin A compared with sitagliptin negatively affects emotional and motivational behavior in adolescent and adult rats by increased number of indices increasing depression, anxiety, and aggression, while the main result of sitagliptin is increased depression when the animals were treated with the DPP-IV inhibitors in the first postnatal week. The findings support the hypothesis that DPPIV is involved in the genesis of emotional-motivational disorders.

Topics: Age Factors; Aggression; Animals; Animals, Newborn; Anxiety; Body Weight; Depression; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Eating; Exploratory Behavior; Hypoglycemic Agents; Locomotion; Male; Maze Learning; Mood Disorders; Oligopeptides; Rats; Rats, Wistar; Sitagliptin Phosphate; Sucrose; Swimming

This study was designed to evaluate the efficacy of sitagliptin in Taiwanese diabetic subjects with different baseline BMI status.. This was a single-center, hospital-based, retrospective chart review in subjects (n=1874) with type 2 diabetes who received sitagliptin. Subjects were classified into subgroups depending upon their baseline BMI by Taiwan national weight classification: normal (BMI<24kg/m(2)) (n=504), overweight (BMI: 24-27kg/m(2)) (n=615), and obese (BMI⩾27kg/m(2)) (n=755). Changes in HbA1c and weight were evaluated over a 12month treatment period.. For all three groups, the HbA1c levels declined over the first three months by about 8%, and subsequently plateaued for the next nine months. Obese subjects were slower in reducing HbA1c compared with normal and overweight subjects (P<0.05), but at nine months the reduction was similar across groups. Mean body weight increased over the first nine months of sitagliptin therapy in subjects with normal BMI (57.12-58.30kg), but there was no change in mean body weight in the overweight group. After three months the obese groups had significantly greater loss in body weight compared with the normal group.. Baseline BMI status may influence the reduction of HbA1c levels within the first six months of sitagliptin therapy and affect weight change after three months. Being obese was associated with an initial lag in HbA1c reduction and greater weight loss compared with normal and overweight subjects.

Topics: Aged; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Overweight; Retrospective Studies; Sitagliptin Phosphate; Taiwan

Background. Emerging evidences have shown a close interplay between obesity, diabetes, and intestinal flora disturbance. Dipeptidyl peptidase-4 inhibitor, exemplified by sitagliptin, is highly efficacious in treating type 2 diabetes (T2DM), yet little is known if sitagliptin exerts beneficial effects on microbiota associated with obesity and T2DM. We evaluated changes of gut microbiota following the induction of obesity and T2DM in a streptozotocin treated high fat/high carbohydrate fed (HF/HC-STZ) rat model and explored the effect of sitagliptin on gut microbiota for HF/HC-STZ rats. Methods. Sitagliptin was administered via oral gavage to diabetic rats. Fecal DNA extraction and 454 pyrosequencing based on analysis of 16S rRNA genes was utilized to determine the overall structure of microbiota in fecal DNA samples. Results. Results showed that, at the level of phylum, there was higher abundance of Firmicutes and Tenericutes and less abundance of Bacteroidetes in obese rats compared to their lean counterparts. At the level of genus, short-chain fatty acid- (SCFA-) producing bacteria, Blautia, Roseburia, and Clostridium, and probiotics Lactobacillus, Bifidobacterium, and so forth were identified significantly different from each other among conditions. Conclusion. Marked shifts of the gut microbiota structure were observed in the rats during development of glucose intolerance. Intestinal flora changed in the process of glucose intolerance, and treatment of sitagliptin moderately corrected the dysbiosis of microbiota in T2DM.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Complications; Disease Progression; Gastrointestinal Microbiome; Glucose Intolerance; Hypoglycemic Agents; Rats; Sitagliptin Phosphate

This study examines the association between changes in diabetes-related quality measures (QMs) (HbA1c, systolic and diastolic blood pressure [BP], low-density lipoprotein cholesterol [LDL-C], and body weight) and healthcare costs in Type 2 diabetes mellitus (T2DM) patients. It also performs an economic simulation that evaluates the cost implications of the changes in QMs and of the incidence rates (IRs) of adverse events (AEs) associated with canagliflozin (CANA) and sitagliptin (SITA) treatments in a real-world setting.. Health-insurance claims and electronic medical records from the Reliant Medical Group database (2007-2011) were used to identify adult patients with T2DM receiving metformin and sulfonylurea who did not achieve adequate glycemic control. The association between the changes in QMs and healthcare costs was evaluated using multivariate regression and non-parametric bootstrap methods. AE-related costs were taken from the literature. The cost impact of CANA and SITA outcomes was evaluated using the aforementioned costs and the changes in QMs and the IRs of AEs observed in a recent phase 3 trial comparing CANA and SITA as third oral agent (DIA3015).. Eight hundred and fifty-six T2DM patients were identified (mean age = 65.8; female 45.4%). The regression analysis found that increases of 1 percentage point in HbA1C and 1% in systolic and diastolic BP, LDL-C, or weight were associated with a per patient per year (PPPY) cost increase of $4476 (p = 0.028) and $566 (p = 0.006), a decrease of $362 (p = 0.070) and $7 (p = 0.817), and an increase of $241 (p = 0.481), respectively. The economic simulation showed that changes in QMs and IRs of AEs equivalent to those reported in DIA3015 would be associated with a reduction in PPPY healthcare costs of $6061 (p = 0.036) for CANA and $2190 (p = 0.098) for SITA.. This study suggests that integrated approaches that manage to control a combination of quality measures are most successful at reducing downstream healthcare costs.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Canagliflozin; Cholesterol, LDL; Comorbidity; Computer Simulation; Costs and Cost Analysis; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insurance Claim Review; Male; Middle Aged; Models, Econometric; Quality Indicators, Health Care; Sitagliptin Phosphate; Young Adult

In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently.. In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks.. Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001).. In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.

Topics: Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Sitagliptin Phosphate; Sulfonylurea Compounds

Shubat, probiotic fermented camel milk, has been used both as a drink with ethnic flavor and a medicine among Kazakh population for diabetic patients. Kazakh people have lower diabetic prevalence and impaired fasting glucose (IFG) than do other ethnic groups living in Xinjiang China, which might be related to the beneficial properties of shubat. We therefore prepared shubat in laboratory and tested anti-diabetic activity and evaluated its possible hypolipidemic and renoprotective effects in type 2 diabetic rats.. Type 2 diabetic rats were induced by an administration of high-glucose-fat diet for 6 weeks and an intraperitoneal injection of streptozotocin (STZ, 30mg/kg). Diabetic rats were divided randomly into four groups and treated for 28 days with sitagliptin (30mg/kg) or shubat (6.97×10(6) lactic acid bacteria+2.20×10(4) yeasts) CFU/mL, (6.97×10(7) lactic acid bacteria+2.20×10(5) yeasts) CFU/mL and (6.97×10(8) lactic acid bacteria+2.20×10(6) yeasts) CFU/mL. In addition, a normal control group and a diabetic control group were used for comparison. All drugs were given orally once daily 10mL/kg for 4 weeks. Fasting blood glucose (FBG) and body weight (BW) were measured before treatment and every week thereafter. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), serum creatinine (SCr), blood urea nitrogen (BUN), C-peptide, glycated hemoglobin (HbAlc), glucagon-like peptide-1 (GLP-1) levels and pancreas tissue sections were tested after 4 weeks.. Shubat demonstrated positive hypoglycemic activity on FBG, HbAlc, C-peptide and GLP-1 levels, high dose shubat decreased FBG (P<0.01) and HbAlc (P<0.05), increased C-peptide (P<0.05) and GLP-1 (P<0.01), decreased serum TC, TG, LDL-c (P<0.05), increased HDL-c (P<0.01), and improved the reduction of body weight as well as decreased SCr and BUN levels (P<0.01) compared to diabetic controls. Histological analysis showed shubat protected the function of islets of type 2 diabetic rats.. The results of this study indicate that shubat has significant hypoglycemic potential in T2D rats and may modulate lipid metabolism and protect renal function in the type 2 diabetic condition, which might be related to various probiotics acting through promoting the release of GLP-1 and improving the function of β-cells.

Topics: Animals; Blood Glucose; Body Weight; C-Peptide; Cholesterol; Cultured Milk Products; Diabetes Mellitus, Experimental; Diet, High-Fat; Dietary Carbohydrates; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Hypertrophy; Hypoglycemic Agents; Kidney; Male; Pancreas; Probiotics; Rats; Sitagliptin Phosphate; Streptozocin

Diabetes is a major public health problem that is rapidly increasing in prevalence. In this study, the effects of sitagliptin, a dipeptidyl peptidase-4 inhibitor, were examined on newborn diabetic rat model.. Wistar albino newborn rats were divided into control (Ctrl), sitagliptin (Sit), diabetic and diabetic+Sit groups. On the second day after the birth, 100mg/kg streptozotocin (STZ) was administered intraperitoneally in a single dose to induce type-2 diabetes in rats. The Sit and diabetic+Sit groups were administered sitagliptin (1.5mg/kg subcutaneous) as of the day 5 for 15 days. The pancreas sections were stained with insulin (INS), glucagon (GLU), somatostatin (SS), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 receptor (GLP-1R) antibodies by the streptavidin-biotin peroxidase technique. The TUNEL method for apoptosis and biochemical analysis were performed in the pancreas and serum, respectively.. Body weight and blood glucose levels showed significant differences among all groups on days 11 and 20. In diabetic rats following treatment with sitagliptin, the area percentage of INS immunopositive cells increased while the area percentage of SS immunopositive cells decreased, insignificantly. A significant increase was observed on the area percentage of GLU, GLP-1 and GLP-1R immunopositive cells in the diabetic+Sit group when compared to the diabetic group. The area percentage of apoptotic cells was the same among all groups. While serum glutathione and malondialdehyde levels demonstrated insignificant alterations, the catalase and superoxide dismutase activity significantly changed among four groups.. According to our findings, sitagliptin may be a useful therapeutic agent to a certain extent of type-2 diabetic condition.

Topics: Animals; Animals, Newborn; Apoptosis; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Islets of Langerhans; Rats; Rats, Wistar; Sitagliptin Phosphate; Somatostatin

This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect.. Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naïve outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of ≥700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for ≥700 and <700 days, respectively. The primary endpoint was ΔHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated.. Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Δbody weight value, and ΔHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin.. Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's ΔHbA1c at 3 months may be a predictor of their ΔHbA1c at 24 months.

Topics: Adult; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Retrospective Studies; Sitagliptin Phosphate; Time Factors; Treatment Outcome

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

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor-based incretin therapy intended for the treatment of type 2 diabetes mellitus (T2DM), has not been linked to adverse effects on the pancreas in prospective clinical trials or in nonclinical toxicology studies. To further assess potential pancreatic effects, sitagliptin was studied in the male Zucker diabetic fatty (ZDF) rat model of T2DM. Following 3 months of oral dosing with vehicle, or sitagliptin at doses 3- to 19-fold above the clinically therapeutic plasma concentration, which increased active plasma glucagon-like peptide-1 levels up to approximately 3-fold, or following 3 months of oral dosing with metformin, a non-incretin-based reference T2DM treatment, the pancreas of male ZDF rats was evaluated using qualitative and quantitative histopathology techniques. In the quantitative evaluation, proliferative index was calculated in exocrine pancreatic ducts and ductules using computer-based image analysis on sections stained by immunohistochemistry for cytokeratin (a cytoplasmic epithelial cell marker) and Ki-67 (a nuclear marker of recent cell division). Relative to controls, sitagliptin treatment did not alter disease progression based on detailed clinical signs and clinical pathology assessments. Sitagliptin treatment did not result in pancreatitis or any adverse effect on the pancreas based on a qualitative histopathology evaluation. Proliferative index did not increase with sitagliptin treatment based on quantitative assessment of more than 5000 sections of pancreas, where control group means ranged from 0.698-0.845% and sitagliptin-treated group means ranged from 0.679-0.701% (P = .874). Metformin treatment was similarly evaluated and found not to have adverse effects on pancreas.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Hypoglycemic Agents; Keratins; Ki-67 Antigen; Male; Metformin; Pancreas, Exocrine; Pyrazines; Rats; Rats, Zucker; Sitagliptin Phosphate; Triazoles

Dipeptidyl peptidase IV (DPP IV) modulates protein activity by removing dipeptides. DPP IV inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. DPP IV substrates not only increase insulin secretion but also affect bone metabolism. In this study, the effect of DPP IV inhibitor sitagliptin on bone was evaluated in normal and streptozotocin-induced diabetic rats. This study included 64 male Wistar rats divided into four groups (n = 16): two diabetic and two control groups. One diabetic and one control group received sitagliptin through drinking water. Tibiae were scanned every 3 wk using an in vivo μCT scanner. After 6 and 12 wk, rats were euthanized for histomorphometric analysis of bone parameters. The mechanical resistance of femora to fracture was assessed using a three-point bending test, and serum levels of bone metabolic markers were measured. Efficient DPP IV inhibition was achieved in sitagliptin-treated groups. Trabecular bone loss, the decrease in trabecular number, and the increase in trabecular spacing was attenuated through sitagliptin treatment in diabetic rats, as shown by in vivo μCT. Bone histomorphometry was in line with these results. μCT analysis furthermore showed that sitagliptin prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora during three-point bending. Finally, the serum levels of the resorption marker CTX-I were significantly lower in sitagliptin-treated diabetic animals compared with untreated diabetic animals. In conclusion, sitagliptin treatment attenuates bone loss and increases bone strength in diabetic rats probably through the reduction of bone resorption and independent of glycemic management.

Topics: Animals; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Compressive Strength; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Male; Pyrazines; Rats; Rats, Wistar; Sitagliptin Phosphate; Streptozocin; Stress, Mechanical; Triazoles

Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.. C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.. Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.. Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peptides; Sitagliptin Phosphate; Venoms

In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.. From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m(2), n = 22,015), and metabolic control (HbA(1c) ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21-26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27-40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9-1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0-1.5% with DPP-4 inhibitors.. In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.

Topics: Adamantane; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Italy; Male; Metformin; Middle Aged; Monitoring, Physiologic; Nitriles; Peptides; Pyrazines; Pyrrolidines; Registries; Sex Factors; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

L-glutamine is a non-essential amino acid. It decreased blood sugar, stimulated insulin secretion in type 2 diabetic patients. The objective of the present investigation was to evaluate L-glutamine increases glucagon like peptide-1 (GLP-1) (7-36) amide secretion in streptozotocin-nicotinamide (STZ-NTM) induced diabetic Sprague Dawley rats. Molecular docking study was performed to elucidate the molecular basis for GLP-1 receptor agonistic activity. Type 2 diabetes was induced in overnight fasted Sprague Dawley rats pre-treated with nicotinamide (100 mg/kg, i.p.) followed by 20 min after administration of streptozotocin (55 mg/kg, i.p.). The rats were divided into; I - nondiabetic, II - diabetic control, III - sitagliptin (5 mg/kg, p.o.), IV - L-glutamine (250 mg/kg, p.o.), V - L-glutamine (500 mg/kg, p.o.) and VI - L-glutamine (1000 mg/kg, p.o.). The L-glutamine and sitagliptin treatment was 8 week. Plasma glucose was estimated every week. Body weight, food and water intake were recorded daily. Glycosylated haemoglobin, lipid profile, plasma and colonic active (GLP-1) (7-36) amide, mRNA expression of proglucagon GLP-1, plasma and pancreatic insulin, histology of pancreata and biomarkers of oxidative stress (superoxidase dismutase, reduced glutathione, malondialdehyde, glutathione peroxidase, glutathione S transferase) were measured after 8 week. In acute study, the rats were divided into I - glucose (2.5 g/kg, p.o.), II - sitagliptin (5 mg/kg, p.o.), III - L-glutamine (250 mg/kg, p.o.), IV - L-glutamine (500 mg/kg, p.o.) and V - L-glutamine (1000 mg/kg, p.o.). Plasma glucose, active GLP-1 (7-36) amide concentration and insulin levels were measured after glucose loading. The docking data indicated that l-glutamine bind to the GLP-1 receptor. L-glutamine decreased plasma glucose, increased plasma and pancreatic insulin, increased plasma and colonic active GLP-1 (7-36) amide secretion as well as decreased oxidative stress in streptozotocin-nicotinamide induced diabetic rats.

Topics: Administration, Oral; Animals; Blood Glucose; Body Weight; Colon; Diabetes Mellitus, Experimental; Drinking; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Glutamine; Glycated Hemoglobin; Insulin; Lipid Metabolism; Male; Molecular Docking Simulation; Niacinamide; Oxidative Stress; Pancreas; Peptide Fragments; Protein Conformation; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles

Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinaemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance.. Male Wistar rats weighing 180-200 g, were fed either a normal diet (20% energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into three subgroups to receive vildagliptin (3 mg·kg(-1)·day(-1)), sitagliptin (30 mg·kg(-1)·day(-1)) or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function and cardiac mitochondrial function were determined.. Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction and completely restored HRV.. Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin-resistant rats.

Topics: Adamantane; Animals; Blood Glucose; Blood Pressure; Body Weight; Cardiotonic Agents; Cholesterol; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Heart; Heart Rate; Insulin; Insulin Resistance; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria, Heart; Nitriles; Obesity; Oxidative Stress; Pyrazines; Pyrrolidines; Rats, Wistar; Reactive Oxygen Species; Sitagliptin Phosphate; Triazoles; Vildagliptin

Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) increase colon cancer risk. Antidiabetic drugs stabilizing incretin hormones, such as inhibitors of dipeptidyl peptidase-4 activity (DPP4i), may affect colon carcinogenesis; however, the data remain controversial. Therefore, the authors studied whether long-term administration of the DPP4i Sitagliptin (SITA) affects 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male F344 rats fed a high-fat (HF) diet promoting colon carcinogenesis and IR, were induced with DMH (100 mg/kg × 2 times). One week later, the animals were allocated to two groups: one continuing with HF diet (controls; n = 8) and one receiving SITA (n = 8) mixed in the diet (260 ppm). Body weight, food consumption and glycemia were not affected by SITA. Fifteen weeks after DMH, the number of the precancerous lesions mucin-depleted foci (MDF) was significantly lower in rats treated with SITA [MDF/colon: 9.5 ± 0.9 and 6.4 ± 0.9 in controls (n = 8) and SITA groups (n = 8), respectively; means ± SE, p < 0.05]. Reactive oxygen species in the blood were also significantly lower in the SITA group [6.75 ± 0.69 and 5.63 ± 0.75 (H2 O2 in mM) in controls (n = 5) and SITA (n = 6), respectively; means ± SE, p < 0.05]. Rats treated with SITA had a lower DPP4 activity in the intestine but not in the plasma. Intestine growth morphometric parameters and colon proliferation, as proliferating cell nuclear antigen expression, were not affected by SITA. In conclusion, the results suggest a protective effect of DPP4i against colon carcinogenesis that could be exploited in chemoprevention trials.

Topics: 1,2-Dimethylhydrazine; Animals; Body Weight; Carcinogenesis; Colonic Neoplasms; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Intestinal Mucosa; Intestines; Male; Mucins; Pyrazines; Random Allocation; Rats; Rats, Inbred F344; Reactive Oxygen Species; Sitagliptin Phosphate; Triazoles

Previously we have reported that, cycloart-23-ene-3β, 25-diol (called as B2) and L-glutamine stimulated glucagon like peptide-1 (GLP-1) (7-36) amide secretion diabetic rats. The objective of present investigation was to investigate the concomitant administration of cycloart-23-ene-3β, 25-diol+sitagliptin and L-glutamine+sitagliptin in streptozotocin - nicotinamide induced diabetic Sprague Dawley. Type 2 diabetes was induced in overnight fasted male Sprague Dawley rats pre-treated with nicotinamide (100 mg/kg, i.p.) followed by administration of streptozotocin (55 mg/kg, i.p.) 20 min after. The rats were divided into; I- non-diabetic, II- diabetic control, III- Sitagliptin (5 mg/kg, p.o.)+cycloart-23-ene-3β, 25-diol (1 mg/kg, p.o.), IV- Sitagliptin (5 mg/kg, p.o.)+L-glutamine (1000 mg/kg, p.o.). The concomitant treatment of cycloart-23-ene-3β, 25-diol and L-glutamine with sitagliptin was 8 weeks. Plasma glucose, body weight, food and water intake were determined every week. Glycosylated haemoglobin, lipid profile, plasma and colonic active (GLP-1) (7-36) amide, plasma and pancreatic insulin, histology of pancreata and biomarkers of oxidative stress were measured after 8(th) week treatment. Concomitant administration of cycloart-23-ene-3β, 25-diol and L-glutamine with sitagliptin significantly (p<0.001) reduced plasma glucose, glyoxylated haemoglobin, lipid profile and oxidative stress parameters compared to diabetic control groups. Both concomitant treatment increased plasma and pancreatic insulin as well as plasma and colonic active (GLP-1) (7-36) amide secretion. Histological analysis by Gomori staining observed less destruction of pancreatic β cells. The result obtained from this study; it is concluded that concomitant administration of cycloart-23-ene-3β, 25-diol+sitagliptin and L-glutamine+sitagliptin showed additive antihyperglycaemic effect in diabetic rats.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Colon; Diabetes Mellitus, Experimental; Drinking Behavior; Feeding Behavior; Glucagon-Like Peptide 1; Glutamine; Glycated Hemoglobin; Insulin; Lipid Metabolism; Male; Niacinamide; Oxidative Stress; Pancreas; Pyrazines; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Staining and Labeling; Streptozocin; Triazoles; Triterpenes

The purpose of this study is to investigate the effects and the underlying mechanisms of sitagliptin pretreatment on myocardial injury and cardiac function in myocardial ischemia/reperfusion (I/R) rat model. The rat model of myocardial I/R was constructed by coronary occlusion. Rats were pretreated with sitagliptin (300 mg/kg/day) for 2 weeks, and then subjected to 30 min ischemia and 2h reperfusion. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), cardiac function and cardiomyocyte apoptosis were evaluated. The levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in heart and glucagon-like peptide-1 (GLP-1) level in plasma were measured. Western blot analysis was performed to detect the target proteins of sitagliptin. Our results showed that sitagliptin pretreatment decreased LDH and CK-MB release, and MDA level in I/R rats. More importantly, we revealed for the first time that sitagliptin pretreatment decreased cardiomyocyte apoptosis while increased the levels of GSH-Px and SOD in heart. Sitagliptin also increased GLP-1 level and enhanced cardiac function in I/R rats. Furthermore, sitagliptin pretreatment up-regulated Akt(serine473) and Bad(serine136) phosphorylation, reduced the ratio of Bax/Bcl-2, and decreased expression levels of cleaved caspase-3 and caspase-3. Interestingly, the above observed effects of sitagliptin were all abolished when co-administered with GLP-1 receptor antagonist exendin-(9-39) or PI3K inhibitor LY294002. Taken together, our data indicate that sitagliptin pretreatment could reduce myocardial injury and improve cardiac function in I/R rats by reducing apoptosis and oxidative damage. The underlying mechanism might be the activation of PI3K/Akt signaling pathway by GLP-1/GLP-1 receptor.

Topics: Animals; Apoptosis; Body Weight; Cardiotonic Agents; Creatine Kinase, MB Form; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glutathione Peroxidase; Heart; Heart Ventricles; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocytes, Cardiac; Organ Size; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Reperfusion Injury; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles

The purpose of the current study was to test the hypothesis that the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which exerts anti-hyperglycemic and anti-hypertensive effects, upregulates GLUT4 translocation, protein levels, and/or mRNA expression in heart and skeletal muscle of spontaneously hypertensive rats (SHRs). Ten days of treatment with sitagliptin (40 mg/kg twice daily) decreased plasma DPPIV activity in both young (Y, 5-week-old) and adult (A, 20-week-old) SHRs to similar extents (~85%). However, DPPIV inhibition only lowered blood pressure in Y-SHRs (119 ± 3 vs. 136 ± 4 mmHg). GLUT4 translocation, total protein levels and mRNA expression were decreased in the heart, soleus and gastrocnemius muscle of SHRs compared to age-matched Wistar Kyoto (WKY) normotensive rats. These differences were much more pronounced between A-SHRs and A-WKY rats than between Y-SHRs and Y-WKY rats. In Y-SHRs, sitagliptin normalized GLUT4 expression in the heart, soleus and gastrocnemius. In A-SHRs, sitagliptin increased GLUT4 expression to levels that were even higher than those of A-WKY rats. Sitagliptin enhanced the circulating levels of the DPPIV substrate glucagon-like peptide-1 (GLP-1) in SHRs. In addition, stimulation of the GLP-1 receptor in cardiomyocytes isolated from SHRs increased the protein level of GLUT4 by 154 ± 13%. Collectively, these results indicate that DPPIV inhibition upregulates GLUT4 in heart and skeletal muscle of SHRs. The underlying mechanism of sitagliptin-induced upregulation of GLUT4 in SHRs may be, at least partially, attributed to GLP-1.

Topics: Animals; Blood Pressure; Body Weight; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 4; Heart; Homeostasis; Intracellular Space; Male; Muscle, Skeletal; Myocytes, Cardiac; Phosphorylation; Protein Transport; Pyrazines; Rats; Rats, Inbred SHR; RNA, Messenger; Signal Transduction; Sitagliptin Phosphate; Triazoles; Up-Regulation

In previous study, we have reported cycloart-23-ene-3β, 25-diol is an active antidiabetic constituent isolated from stem bark of Pongamia pinnata (Linn.) Pierre. The objective of the present investigation was to evaluate cycloart-23-ene-3β, 25-diol stimulates glucagon like peptide-1 (GLP-1) (7-36) amide secretion in streptozotocin-nicotinamide induced diabetic Sprague Dawley rats. Molecular docking studies were performed to elucidate the molecular basis for GLP-1 receptor agonistic activity. Type 2 diabetes was induced in overnight fasted Sprague Dawley rats pre-treated with nicotinamide (100mg/kg, i.p.) followed by administration of streptozotocin (55 mg/kg, i.p.) 20 min after. The rats were divided into following groups; I- non-diabetic, II- diabetic control, III- sitagliptin (5mg/kg, p.o.), IV- cycloart-23-ene-3β, 25-diol (1mg/kg, p.o.). The cycloart-23-ene-3β, 25-diol and sitagliptin treatment was 8 week. Plasma glucose was estimated every week (week 0 to week 8). Body weight, food and water intake were recorded daily. Glycosylated haemoglobin, lipid profile, plasma and colonic active (GLP-1) (7-36) amide, mRNA expression of proglucagnon GLP-1, plasma and pancreatic insulin, histology of pancreata as well as biomarkers of oxidative stress (superoxidase dismutase, reduced glutathione, malondialdehyde, glutathione peroxidase, glutathione S transferase) were measured after 8th week treatment. In acute study, active GLP-1 (7-36) amide release, plasma glucose and insulin were measured during oral glucose tolerance test. The docking data clearly indicated cycloart-23-ene-3β, 25-diol bind to the GLP-1 receptor. It decreased plasma glucose level, increased plasma and pancreatic insulin level as well as increased plasma and colonic active GLP-1 (7-36) amide secretion in streptozotocin-nicotinamide induced diabetic Sprague Dawley rats.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Drinking; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Male; Molecular Docking Simulation; Niacinamide; Oxidative Stress; Pancreas; Peptide Fragments; Protein Conformation; Pyrazines; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Time Factors; Triazoles; Triterpenes

Few studies have investigated the factors related to improvement and maintenance of glycemic control with sitagliptin in Type 2 diabetes (T2D) patients.. To identify factors contributing to reaching and maintaining glycated hemoglobin (HbA1c) <7% with sitagliptin in Japanese T2D patients.. This study included 1327 patients who were: taking sitagliptin as monotherapy; switched to sitagliptin; or taking sitagliptin in combination therapy. At baseline and 1, 3, 6, and 12 months after starting sitagliptin, weight, body mass index (BMI), HbA1c, fasting plasma glucose (FPG), and post-prandial plasma glucose (PPG) were measured. The subjects were divided into a group that achieved HbA1c<7% at 12 months, a poor control group (HbA1c≥8% at 12 months), and a discontinued group. Multiple regression analysis was performed to identify factors contributing to long-term control and maintenance with sitagliptin treatment.. HbA1c decreased significantly from 8.0% at baseline to 7.3%, but weight was unchanged. FPG and PPG improved significantly. The HbA1c<7% group had a significantly higher age and a signifi cant ly lower BMI at baseline than the HbA1c≥8% group and the discontinued group. On multivariate regression analysis, baseline HbA1c, baseline BMI, and Δbody weight after 12 months were significantly related to HbA1c reduction. The most common adverse event was hypoglycemia, and the most common adverse event responsible for discontinuation was constipation.. HbA1c<7.0% was achieved in 31% of T2D patients who had poor control with conventional treatment. Weight management is important for maintaining good long-term control with sitagliptin.

Topics: Aged; Asian People; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Fasting; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Triazoles

Bile acid sequestrants have been shown to reduce glucose levels in patients with type 2 diabetes. We previously reported that the bile acid sequestrant colesevelam HCl (Welchol) (COL) induced the release of glucagon-like peptide (GLP)-1 and improved glycemic control in insulin-resistant rats. In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0.4% (120 mg/day) SIT alone, or with the combination (COL+SIT). After 4 wk of treatment, the glucose area under the curve (AUC) was reduced more in the COL+SIT than the COL although both groups showed decreased glucose AUC with increased AUC of bioactive GLP-1 (GLP-1A) compared with the model group. The above changes were not observed after 8 wk. Increasing the SIT dose by 50% (180 mg SIT/day) in the diet reduced the glucose AUC in the COL+SIT group even after 8 wk but still not in the SIT alone group compared with the model. It was noteworthy that, after 8 wk, insulin levels in the SIT group declined to levels similar to the model. Histological examination of the pancreatic β-cell islets showed that islet sizes were larger, proliferation enhanced, and cell apoptosis reduced in the COL+SIT but not the SIT alone group compared with the model. We hypothesize that the combination of COL with SIT extends the half life of COL-induced GLP-1A and benefits preservation of the islets that delay the development of diabetes and improve glycemic control. This study suggests that the combined therapy (COL+SIT) is more effective than either drug alone for reducing glucose levels in diabetes.

Topics: Allylamine; Animals; Anticholesteremic Agents; Apoptosis; Bile Acids and Salts; Blood Glucose; Body Weight; Cell Proliferation; Cell Size; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Diet; Drug Synergism; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; In Situ Nick-End Labeling; Insulin; Insulin-Secreting Cells; Ki-67 Antigen; Male; Postprandial Period; Pyrazines; Rats; Rats, Zucker; Receptors, G-Protein-Coupled; RNA, Messenger; Sitagliptin Phosphate; Triazoles

We examined the effects of the oral dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin on glycaemic control and pancreatic β-cell mass and morphology in a mouse model of type 2 diabetes mellitus (T2DM).. Male C57BL/6 mice (n = 12/group) aged 4 to 6 weeks and weighing >15 g received a high-fat diet throughout this 45-day study. After a 7-day handling period, baseline levels of plasma glucose, plasma insulin and glycated haemoglobin (HbA1c) were assessed. Animals were allocated to one of six groups: compound vehicle control, intraperitoneal streptozotocin (STZ, 50 mg/kg)-treated control and saxagliptin (10 mg/kg) or sitagliptin (10 mg/kg, positive control) initiated 7 days before or 1 day after STZ administration. Endpoints included changes in body weight, food and water consumption, glucose tolerance (approximately 3 weeks post-STZ), fasting glucose and HbA1c and immunohistochemical analyses of the pancreas.. Body weight, weight gain and food intake were reduced in STZ versus control mice. DPP-4 inhibitor treatment did not affect these changes, but the increase in water intake observed post-STZ administration was significantly attenuated with DPP-4 inhibitors whether initiated before or after STZ injury. Small but significant improvements in glycaemic control were observed with DPP-4 inhibitors versus the STZ control. Improved β-cell mass and morphology were observed with saxagliptin given pre- or post-STZ and sitagliptin given post-STZ.. Saxagliptin mitigated damage to β-cells and improved glycaemic control in this mouse model of T2DM.

Topics: Adamantane; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptides; Drinking; Eating; Glucose Tolerance Test; Glycated Hemoglobin; Hypoglycemic Agents; Immunohistochemistry; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Pyrazines; Sitagliptin Phosphate; Triazoles

Inhibitors of dipeptidyl peptidase-IV (DPP-IV), such as sitagliptin, increase glucagon-like peptide-1 (GLP-1) concentrations and are current treatment options for patients with type 2 diabetes mellitus. As patients with diabetes exhibit a high risk of developing severe atherosclerosis, we investigated the effect of sitagliptin on atherogenesis in Apoe (-/-) mice.. Apoe (-/-) mice were fed a high-fat diet and treated with either sitagliptin or placebo for 12 weeks. Plaque size and plaque composition were analysed using Oil Red O staining and immunohistochemistry. Furthermore, in vitro experiments with the modified Boyden chamber and with gelatine zymography were performed to analyse the effects of GLP-1 on isolated human monocyte migration and metalloproteinase-9 (MMP-9) release.. Treatment of Apoe (-/-) mice with sitagliptin significantly reduced plaque macrophage infiltration (the aortic root and aortic arch both showing a 67% decrease; p < 0.05) and plaque MMP-9 levels (aortic root showing a 69% and aortic arch a 58% reduction; both p < 0.01) compared with controls. Moreover, sitagliptin significantly increased plaque collagen content more than twofold (aortic root showing an increase of 58% and aortic arch an increase of 73%; both p < 0.05) compared with controls but did not change overall lesion size (8.1 ± 3.5% vs 5.1 ± 2.5% for sitagliptin vs controls; p=NS). In vitro, pretreatment of isolated human monocytes with GLP-1 significantly decreased cell migration induced by both monocyte chemotactic protein-1 and by the protein known as regulated on activation, normal T cell expressed and secreted (RANTES) in a concentration-dependent manner. Furthermore, GLP-1 significantly decreased MMP-9 release from isolated human monocyte-derived macrophages.. Sitagliptin reduces plaque inflammation and increases plaque stability, potentially by GLP-1-mediated inhibition of chemokine-induced monocyte migration and macrophage MMP-9 release. The effects observed may provide potential mechanisms for how DPP-IV inhibitors could modulate vascular disease in high-risk patients with type 2 diabetes mellitus.

Topics: Animals; Apolipoproteins E; Arteriosclerosis; Body Weight; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Immunohistochemistry; Lipid Metabolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Pyrazines; Sitagliptin Phosphate; Triazoles

BACKGROUND. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. AIMS. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. METHODS. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. RESULTS. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12-73.1, P = 0.04). CONCLUSIONS. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight.

Topics: Adult; Alanine Transaminase; Blood Glucose; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Drug Evaluation; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Inflammation; Liraglutide; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Odds Ratio; Pioglitazone; Platelet Count; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles

The aim of the present study was to test the effect of sitagliptin and exendin-4 upon metabolic alterations, β-cell mass decrease and hepatic steatosis induced by F (fructose) in rats. Normal adult male Wistar rats received a standard commercial diet without (C) or with 10% (w/v) F in the drinking water (F) for 3 weeks; animals from each group were randomly divided into three subgroups: untreated (C and F) and simultaneously receiving either sitagliptin (CS and FS; 115.2 mg/day per rat) or exendin-4 (CE and FE; 0.35 nmol/kg of body weight, intraperitoneally). Water and food intake, oral glucose tolerance, plasma glucose, triacylglycerol (triglyceride), insulin and fructosamine concentration, HOMA-IR [HOMA (homoeostasis model assessment) for insulin resistance], HOMA-β (HOMA for β-cell function) and liver triacylglycerol content were measured. Pancreas immunomorphometric analyses were also performed. IGT (impaired glucose tolerance), plasma triacylglycerol, fructosamine and insulin levels, HOMA-IR and HOMA-β indexes, and liver triacylglycerol content were significantly higher in F rats. Islet β-cell mass was significantly lower in these rats, due to an increase in the percentage of apoptosis. The administration of exendin-4 and sitagliptin to F animals prevented the development of all the metabolic disturbances and the changes in β-cell mass and fatty liver. Thus these compounds, useful in treating Type 2 diabetes, would also prevent/delay the progression of early metabolic and tissue markers of this disease.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Diet; Dipeptidyl-Peptidase IV Inhibitors; Drinking; Drug Evaluation, Preclinical; Eating; Exenatide; Fatty Liver; Fructose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin-Secreting Cells; Male; Metabolic Syndrome; Peptides; Pyrazines; Rats; Rats, Wistar; Sitagliptin Phosphate; Triazoles; Venoms

Adipose tissue inflammation and reduced pancreatic β-cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP IV inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high-fat (60% kcal fat) diet for 12 wk, with or without sitagliptin (4 g/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ∼25%. Sitagliptin treatment reduced body weight without changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes despite reducing the number of the very large adipocytes. Sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac2 was reduced by sitagliptin (P < 0.01), as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction (P < 0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes, including IL-6, TNFα, IL-12(p35), and IL-12(p40), 2.5- to fivefold as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35) (5-fold, P < 0.01), and IP-10 (2-fold). Collectively, the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.

Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Anti-Inflammatory Agents; Body Weight; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Flow Cytometry; Glucose; Glucose Intolerance; Glucose Tolerance Test; Immunohistochemistry; Inflammation; Insulin; Islets of Langerhans; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophil Infiltration; Pyrazines; Reverse Transcriptase Polymerase Chain Reaction; Sitagliptin Phosphate; Triazoles

this study reports on the effectiveness of sitagliptin in Asian Indian type 2 diabetes patients seen at a tertiary diabetes care center who had inadequate glycemic control with oral hypoglycemic agents either alone or in combination, compared to a group of patients who received insulin glargine.. patients with type 2 diabetes mellitus (n = 2,817) whose glycemia was not controlled adequately (glycated hemoglobin >6.5%) with oral hypoglycemic agents (either alone or in combination) received oral sitagliptin 100 mg once daily in addition to existing therapy for a period of 24 weeks. Patients who received insulin glargine as add-on therapy (n = 2,743) served as the reference group. Data analysis included glycated hemoglobin, fasting plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia.. significant reductions in glycated hemoglobin and fasting plasma glucose values were noted after 24 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. While sitagliptin addition resulted in a small weight loss (0.3 kg), insulin glargine addition resulted in a weight gain (0.7 kg). The overall incidence of adverse experiences was low and generally mild in both groups.. in a large group of Asian Indian type 2 diabetes patients seen at a tertiary diabetes center in whom glycemia was not controlled adequately by oral hypoglycemic agents (either alone or in combination), addition of sitagliptin helped to achieve glycemic control to a similar extent as insulin glargine but with a marginal weight advantage.

Topics: Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemia; India; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Statistics, Nonparametric; Triazoles; Triglycerides

The SHROB (spontaneously hypertensive rat - obese strain) is a model of prediabetes and metabolic syndrome with insulin resistance, glucose intolerance and hypertension. Inhibitors of dipeptidyl dipeptidase IV (DPP-IV) are effective hypoglycemic agents in type 2 diabetes through potentiation of incretin hormones that act in the pancreas to increase insulin and decrease glucagon release. We sought to determine whether the DPP-IV inhibitor sitagliptin might be effective in prediabetes relative to standard therapy with the sulfonylurea glyburide, by using the SHROB model. SHROB show normal fasting glucose but are insulin resistant and hyperglucagonemic. SHROB were treated for six weeks with vehicle, sitagliptin (30 mg/kg/d) or glyburide (1 mg/kg/d) and compared with untreated lean spontaneously hypertensive rats. Body weight, food intake and fasting glucose were all unchanged in all three SHROB groups, but glucagon was reduced by 33% by sitagliptin while remaining unchanged following glyburide or vehicle. In oral glucose (6 g/kg) tolerance testing, both sitagliptin and glyburide lowered plasma glucose. Both sitagliptin and glyburide shifted peak insulin secretion earlier (30 min for glyburide and 60 min for sitagliptin but 240 min for vehicle). Only sitagliptin significantly enhanced insulin secretion. Sitagliptin is effective in normalizing excess glucagon levels and delaying exaggerated insulin secretion in response to a glucose challenge in a prediabetic model.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Feeding Behavior; Glucagon; Glucagon-Like Peptide 1; Glyburide; Hypoglycemic Agents; Insulin; Insulin Secretion; Pyrazines; Rats; Sitagliptin Phosphate; Triazoles

Type 2 diabetes is associated with an increased risk of cardiac complications. Inhibitors of dipeptidylpeptidase 4 (DPP-4) are novel drugs for the treatment of patients with type 2 diabetes. The effect of DPP-4 inhibitors on myocardial metabolism has not been studied in detail. In wild-type C57Bl6-mice, 3weeks of treatment with sitagliptin had no effect on body weight and glucose tolerance nor on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoAcarboxylase (ACC), phosphofructokinase-2 (PFK2) or tuberin-2 (TSC2) in the left ventricular myocardium. However, in 10week old db/db-/- mice, a model of diabetes and obesity, sitagliptin potently reduced plasma glucose rise in peritoneal glucose tolerance tests and reduced weight increase. The myocardium of untreated db/db-/- mice exhibited a marked increase of the phosphorylation of AMPK, ACC, TSC2, expression of p53 and fatty acid translocase (FAT/CD36) membrane expression. These changes were reduced by DPP-4 inhibition. Sitagliptin showed no effect on cardiomyocyte size but prevented myocardial fibrosis in the 10week old db/db-/- mice and reduced expression of TGF-β1, markers of oxidative stress and the accumulation of advanced glycation end products in cardiomyocytes. Working heart analyses did not show an effect of sitagliptin on parameters of systolic cardiac function. In animals with diabetes and obesity, sitagliptin improved glucose tolerance, reduced weight gain, myocardial fibrosis and oxidative stress. Furthermore the study provides evidence that treatment with sitagliptin decreases elevated myocardial fatty acid uptake and oxidation in the diabetic heart. These observations show beneficial myocardial metabolic effect of DPP-4 inhibition in this mouse model of diabetes and obesity.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Body Weight; CD36 Antigens; Cell Membrane; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Glucose Tolerance Test; Glucose Transporter Type 4; Glycation End Products, Advanced; Guanine; Heart; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Phosphorylation; Protein Transport; Pyrazines; Sitagliptin Phosphate; Triazoles; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

In this study, the effects of sitagliptin analogue (SITA) or pioglitazone (PIO) treatment on glucose homeostasis and Β-cell dynamics in animal models of type 2 diabetes--Akita and db/db mice were evaluated. After 4-6 weeks of treatment, both SITA and PIO were shown to lower non-fasting glucose levels and reduced glycemic excursion in the intraperitoneal glucose tolerance test. In addition, both drugs preserved normal islet structure and the proportion of Β-cells in the islets. Compared to the controls, SITA treatment induced a higher Β-cell proliferation rate in Akita mice and a lower rate of apoptosis in db/db mice, whereas PIO treatment induced a lower rate of apoptosis in db/db mice and reduced proliferation rates in Akita mice. In conclusion, both SITA and PIO appear to exert some beneficial effects on the islet structure in addition to glycemic control via different mechanisms that involve Β-cell dynamics in Akita and db/db mice. [BMB reports 2011; 44(11): 713-718].

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Fasting; Glucose Tolerance Test; Homeostasis; Insulin-Secreting Cells; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Pioglitazone; Pyrazines; Sitagliptin Phosphate; Thiazolidinediones; Triazoles

This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0-2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Insulin; Kidney Glomerulus; Lipid Peroxidation; Lipids; Male; Obesity; Pyrazines; Rats; Rats, Zucker; Sitagliptin Phosphate; Treatment Outcome; Triazoles

In the context of a need for improved strategies to control glycemia in patients with type 2 diabetes, new information was discussed during the American Diabetes Association's annual meeting on the dipeptidyl peptidase 4 inhibitor sitagliptin. As reviewed below, clinical trials corroborated the feasibility of adding sitagliptin to ongoing metformin or pioglitazone therapy, without the risk for hypoglycemia or the negative impact on body weight observed after add-on sulfonylureas, although the neutral or beneficial effect of sitagliptin on body weight resulted from a complex interaction with baseline levels of hemoglobin A1c levels and the change brought about by treatment. New studies of sitagliptin presented during the meeting also indicated additional effects of the drug not mediated by inhibition of dipeptidyl peptidase-4, but through direct inhibition of endogenous glucose production and/or glucagon responses and improved β-cell glucose sensitivity.

Topics: Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Pyrazines; Sitagliptin Phosphate; Triazoles

Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidyl-peptidase-IV inhibitors, which increase the endogenous levels of GLP-1, on myocardial protection, are unknown. We studied whether sitagliptin (SIT) and PIO have additive effects on IS limitation in the mouse. Mice received 3-day or 14-day oral SIT (300 mg.kg(-1).day(-1)), PIO (5 mg.kg(-1).day(-1)), SIT + PIO, or vehicle. In addition, mice received intravenous H-89 [20 mg/kg, a protein kinase A (PKA) inhibitor] or vehicle 1 h before ischemia. Rats underwent 30 min myocardial ischemia and 4 h reperfusion. SIT, PIO, and SIT + PIO for 3 days significantly reduced IS (24.3 +/- 2.7, 23.0 +/- 0.8, and 14.7 +/- 0.9%) compared with controls (46.2 +/- 2.8%). H-89 completely blocked the effect of SIT and partially blocked the PIO effect. SIT, but not PIO, increased cAMP levels. PKA activity was increased by PIO and to a greater extent by SIT. PIO, but not SIT, increased cytosolic phospholipase A(2) and cyclooxygenase-2 activity. Accordingly, 6-keto-PGF(1alpha) and 15-deoxy-PGJ(2) increased by PIO but not SIT. In contrast, SIT, and to a lesser extent PIO, increased 15-epi-lipoxin A(4) levels. H-89 completely blocked the effect of SIT and PIO on 15-epi-lipoxin A(4) levels. PIO, and to a greater extent SIT, increased endothelial nitric oxide synthase and cAMP response element-binding protein phosphorylation, an effect that was blocked by H-89. With a 14-day pretreatment experiment, IS was 46.4 +/- 1.0% in the control group, 16.9 +/- 0.6% in SIT (P < 0.001), 19.1 +/- 1.1% in PIO (P = 0.014), and 12.9 +/- 0.7% in SIT + PIO (P < 0.001). We found that SIT and PIO limit IS using different pathways. The protective effect of SIT is via cAMP-dependent PKA activation, whereas PIO mediates its effects via both PKA-dependent and -independent pathways.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Culture Media; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dipeptidyl-Peptidase IV Inhibitors; Eicosanoids; Glucagon-Like Peptide 1; Hypertrophy, Left Ventricular; Hypoglycemic Agents; In Vitro Techniques; Mice; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Organ Size; Phospholipases A2; Pioglitazone; Prostaglandin-Endoperoxide Synthases; Protective Agents; Pyrazines; Sitagliptin Phosphate; Thiazolidinediones; Triazoles

1. Dipeptidyl peptidase (DPP) IV inhibitors enhance renovascular responses to angiotensin (Ang) II in spontaneously hypertensive rats (SHR), but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in metabolic syndrome, it is important to determine whether DPPIV inhibition in this setting enhances renovascular responses to AngII. 2. Six-week-old Lean-ZSF1 rats (harbouring SHR genes, but without metabolic syndrome; n = 11) and Obese-ZSF1 rats (harbouring SHR genes and expressing metabolic syndrome; n = 10) were provided food and water ad libitum, and metabolic parameters and renovascular responses to AngII were assessed when the animals were 7 and 8 weeks of age, respectively. 3. At 7 weeks of age, compared with Lean-ZSF1, Obese-ZSF1 demonstrated significant (P < 0.05) increases in bodyweight (262 +/- 8 vs 310 +/- 13 g), plasma glucose (112 +/- 4 vs 153 +/- 9 mg/dL), haemoglobin A1c (4.7 +/- 0.1 vs 5.8 +/- 0.4%), urinary glucose excretion (0.021 +/- 0.003 vs 6.70 +/- 1.80 g/kg bodyweight per 24 h) and urinary protein excretion (100 +/- 7 vs 313 +/- 77 mg/kg bodyweight per 24 h). Mean blood pressure was high (133 +/- 7 mmHg) in both strains. 4. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1 rats, renovascular responses (i.e. changes in perfusion pressure) to physiological levels of AngII (0.1 nmol/L) were 3.4 +/- 1.3 and 18.2 +/- 5.9 mmHg in untreated (n = 5) and 1 micromol/L sitagliptin-treated (n = 6) kidneys, respectively. In Obese-ZSF1 rats, renovascular responses to AngII were 5.5 +/- 1.3 and 17.8 +/- 8.2 mmHg in untreated (n = 4) and sitagliptin-treated (n = 6) kidneys, respectively. Analysis of variance revealed a significant (P = 0.0367) effect of sitagliptin on renovascular responses to AngII that was independent of strain. 5. In conclusion, sitagliptin enhances renovascular responses to AngII in rats harbouring SHR genes and this effect persists in rats with diabetic nephropathy and metabolic syndrome.

Topics: Angiotensin II; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Hypertension; Kidney; Male; Metabolic Syndrome; Proteinuria; Pyrazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Sitagliptin Phosphate; Triazoles; Vasoconstriction; Vasoconstrictor Agents

Sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, and exenatide, an injectable glucagon-like peptide-1 receptor agonist, are incretin-based therapies for the treatment of type 2 diabetes. This study examined differences in baseline characteristics between patients with type 2 diabetes initiating sitagliptin vs. exenatide treatment in clinical practice settings in the US.. The General Electric Healthcare's Clinical Data Services electronic medical records database, covering 12 million US patients of all ages from 49 states, was used to identify patients with type 2 diabetes, aged > or =30 years, who received their first sitagliptin or exenatide prescription between October 1, 2006 and June 30, 2008 (index period). Patient's medical records, including demographics, diagnoses, procedures, prescriptions, and laboratory results were extracted for the 12-month period (baseline) prior to the date of the first prescription of sitagliptin or exenatide (ie, the index date). Patient baseline profiles were stratified by mono-, dual, or triple therapy and compared between regimens with sitagliptin or exenatide.. A total of 9543 patients initiated therapy with sitagliptin (n=5589) or exenatide (n=3954) during the index period. For those initiating monotherapy, 876 patients initiated sitagliptin and 476 initiated exenatide. Compared with patients initiating exenatide at baseline, patients on sitagliptin were older (64 vs. 55 years), more likely to be men (45% vs. 35%), and less likely to be obese (60% vs. 87%), and had higher hemoglobin A(1c) (HbA(1c); 7.1% vs. 6.9%), a higher serum creatinine (1.2 mg/dL vs. 1.0 mg/dL), and a higher prevalence of pre-existing cardiovascular complications or microvascular conditions (all P<0.01 for sitagliptin vs. exenatide). For dual therapy, 1885 were prescribed sitagliptin and 1392 were prescribed exenatide. For triple therapy, 2828 were prescribed sitagliptin and 2086 were prescribed exenatide. The observed patient profile differences with dual and triple therapy were generally consistent with those observed with monotherapy.. In a clinical practice setting, there are differences in the baseline characteristics of patients with type 2 diabetes who are prescribed sitagliptin relative to those prescribed exenatide. These findings have important implications for conclusions drawn from observational studies using medical record or claim databases, as estimated clinical and health outcomes measures may be biased due to channeling of patients to different therapies based on different baseline characteristics.

Topics: Adult; Age Factors; Aged; Body Mass Index; Body Weight; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insurance Claim Review; Lipids; Male; Middle Aged; Peptides; Pyrazines; Retrospective Studies; Sex Factors; Sitagliptin Phosphate; Socioeconomic Factors; Triazoles; Venoms

The purpose of this paper is to evaluate the chronic effect of sitagliptin on metabolic profile, inflammation, and redox status in the Zucker Diabetic Fatty (ZDF) rat, an animal model of obese type 2 diabetes. Diabetic and obese ZDF (fa/fa) rats and their controls (ZDF +/+) were treated during 6 weeks with vehicle (control) and sitagliptin (10 mg/kg/bw). Glucose, HbA1c, insulin, Total-c, TGs, IL-1beta, TNF-alpha, CRPhs, and adiponectin were assessed in serum and MDA and TAS in serum, pancreas, and heart. Pancreatic histology was also evaluated. Sitagliptin in diabetic rats promoted a decrease in glucose, HbA1c, Total-c, and TGs accompanied by a partial prevention of insulinopenia, together, with a decrease in CRPhs and IL-1beta. Sitagliptin also showed a positive impact on lipid peroxidation and hypertension prevention. In conclusion, chronic sitagliptin treatment corrected the glycaemic dysmetabolism, hypertriglyceridaemia, inflammation, and hypertension, reduced the severity of the histopathological lesions of pancreatic endocrine and exocrine tissues, together with a favourable redox status, which might be a further advantage in the management of diabetes and its proatherogenic comorbidities.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glycated Hemoglobin; Insulin; Insulin Resistance; Interleukin-1beta; Lipids; Male; Oxidative Stress; Pancreas; Pyrazines; Rats; Sitagliptin Phosphate; Triazoles

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Pyrazines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Triazoles

Pharmacological approaches that enhance incretin action for the treatment of type 2 diabetes mellitus have recently been developed, i.e. injectable glucagon-like peptide-1 receptor (GLP-1R) agonists with prolonged plasma half-lives and orally available inhibitors of dipeptidyl peptidase (DPP)-4, the main enzyme responsible for the rapid degradation of circulating glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. The mechanism(s) underlying the glucose-lowering effect of these two pharmacotherapies differs and is not yet fully understood. Here we investigated whether acute GLP-1R activation (exendin-4) or DPP-4 inhibition (des-F-sitagliptin) modulates insulin action in mice using a hyperinsulinemic euglycemic clamp. A single iv bolus of des-F-sitagliptin (11 mg/kg) was administered to mice 15 min after the start of the clamp, and its effect was compared with a 50-ng bolus of exendin-4 or the same volume of saline. Despite matched levels of plasma glucose and insulin, within 15 min the glucose infusion rate required to maintain euglycemia was significantly greater after des-F-sitagliptin compared with saline or exendin-4. This difference was entirely due to enhancement of insulin-mediated suppression of endogenous glucose production by des-F-sitagliptin, with no difference in glucose disposal rate. These findings illustrate that DPP-4 inhibition modulates glucose homeostasis through pathways distinct from those used by GLP-1R agonists in mice.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucose Clamp Technique; Glucose Tolerance Test; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Dibenzothiazepines; Dietary Fats; Disease Models, Animal; Eating; Exenatide; Food Preferences; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Obesity; Peptides; Pyrazines; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Venoms

We used a mathematical model to estimate the contribution of urinary glucose excretion (UGE) to reported changes in body weight (BW) following oral antihyperglycemic agent (AHA) therapy. This modeling approach was used to gain novel insight into the mechanisms by which oral AHA affects BW.. Twenty-four hour glucose profiles were used to predict UGE before and after treatment with oral AHA. Model-predicted changes in BW due to reduced UGE were compared with reported changes in BW to quantify non-UGE-dependent effects (fluid retention, food intake, and energy expenditure).. In type 2 diabetes patients [hemoglobin A1c (HbA1c) >7.3%], the energy lost to UGE is predicted to decrease an average of 100 kcal/day for each 1% decrease in HbA1c. This effect, alone, is predicted to increase BW 1.4 kg after 6 months. Differences from this value reported for changes in BW with oral AHA therapy (+1.4 kg for pioglitazone and rosiglitazone; -0.4 kg for glyburide; -0.9 kg for sitagliptin and vildagliptin; -2.3 kg for metformin) are therefore predicted to be due to additional, non-UGE-dependent mechanisms.. Weight gain following thiazolidinedione therapy is predicted to result from both reduced UGE and non-UGE-dependent mechanisms. Reduced UGE alone is predicted to account for most of the weight gain reported following sulfonylurea therapy. Weight loss observed in response to metformin and weight maintenance observed in response to dipeptidyl peptidase-4 inhibitors may result from an increase in satiety, energy expenditure, or both.

Topics: Body Weight; Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Metformin; Models, Theoretical; Pyrazines; Sitagliptin Phosphate; Triazoles