Sitagliptin Group Research Articles

Decreased hepatic glucose production in obese rats by dipeptidyl peptidase-IV inhibitor sitagliptin.

Dipeptidyl peptidase-IV (DPP-4) inhibitors are now used to improve postprandial glycemic control in type 2 diabetes. However, their effects on hepatic glucose production (HGP) in obesity are not clear. This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity. Sprague Dawley male rats were divided into four groups, each on a different diet: general rat chow, n = 10 (G); G + sitagliptin, n = 10; high fat chow (obesity), n = 10 (55% fat calories, HFO); HFO + sitagliptin, n = 10. After 10 weeks, the rats were fasted overnight and glucose metabolism was determined using 3-(3)H-glucose and (14)C-glycerol as tracers. Glycerol rate of appearance (P < 0.00001), plasma glycerol (P < 0.05) and free fatty acid (FFA) (P < 0.05) concentrations, and HGP (P < 0.05) were decreased in HFO + sitagliptin group compared with HFO group, but there was no significant difference between G and G + sitagliptin groups (P > 0.05). Gluconeogenesis in HFO group was five times of that in G rats (P < 0.01), but was significantly declined in HFO + sitagliptin group (P < 0.0001). Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability, which was a result of reduced glycerol release from adipose tissues. The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity, thereby delaying or preventing the development of diabetes.

Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial.

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.

Effects of Miglitol, Acarbose, and Sitagliptin on Plasma Insulin and Gut Peptides in Type 2 Diabetes Mellitus: A Crossover Study.

IntroductionBoth dipeptidyl peptidase-4 inhibitors and α-glucosidase inhibitors (α-GI) have been reported to change the incretin and insulin secretion. To examine the effects of acarbose, miglitol, and sitagliptin on glucose metabolism and secretion of gut peptides, we conducted a crossover study in patients with type 2 diabetes mellitus (T2DM).MethodsEleven Japanese patients with T2DM underwent four meal tolerance tests with single administration of acarbose, miglitol, sitagliptin, or nothing. Fasting and postprandial plasma levels of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured.ResultsEarly-phase insulin secretion was reduced following acarbose and miglitol, and the areas under the curve (AUC) of insulin at 180 min following acarbose and miglitol were significantly lower than sitagliptin. AUC of plasma glucose at 180 min after acarbose, miglitol, and sitagliptin tended to be lower than in controls, and plasma glucose levels at 30–60 min following miglitol were significantly lower than in controls. Plasma glucagon, ghrelin, and des-acyl ghrelin levels did not differ among the four conditions. Postprandial plasma active GLP-1 levels and AUC of GLP-1 increased significantly in both the sitagliptin and miglitol groups compared to control. Postprandial plasma total GIP levels increased following sitagliptin but decreased after acarbose and miglitol. Changes in incretin levels tended to be greater with miglitol than acarbose.ConclusionThese results showed that sitagliptin and α-GIs, miglitol more so than acarbose, improved hyperglycemia in patients with T2DM after single administration, and had different effects on insulin and incretin secretion.Trial registration: UMIN-CTR number, UMIN000009981.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0113-3) contains supplementary material, which is available to authorized users.

Effect of sitagliptin on lipopolysaccharide-induced changes in the mass and function of islet β cells

Objective To investigate the effect of dipeptidyl peptidase-4(DPP-4)inhibitor on lipopolysaccharide(LPS)-induced changes in the mass and function of pancreatic β-cells. Methods RINm cells were cultured and treated with LPS alone or combined with different concentrations of sitagliptin for 24 h. The proliferation of RINm cells was detected by CCK-8 assay. Apoptotic rate was determined by Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide flow cytometry. Insulin secretion was measured by enzyme-linked immunosorbent assay. The expression of IL-6 mRNA was displayed by RT-PCR. Results LPS significantly stimulated the proliferation of RINm cells(0.89±0.04 vs 1.14±0.08, P<0.01), while LPS+ sitagliptin showed no significant difference compared with LPS group. The cell apoptotic rate in LPS+ 10-1mmol/L sitagliptin group was significantly lower than that in LPS group. There were no significant differences in basal insulin secretion among all groups, but after the high/low glucose stimulation, LPS increased insulin secretion as compared with the control. The IL-6 mRNA expression in LPS+ sitagliptin group was significantly lower than that in LPS group(0.77±0.33 vs 1.30±0.41, P=0.006). Conclusions DPP-4 inhibitor has no influence on LPS-induced proliferation of pancreatic β-cell, but it can inhibit LPS-induced apoptosis and insulin secretion, and IL-6 may be involved in the process. (Chin J Endocrinol Metab, 2015, 31: 447-451) Key words: Dipeptidyl peptidase-4 inhibitor; Lipopolysaccharide; Pancreatic β-cell

Efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring: a post hoc analysis with single-day treatment

Objective: To compare the efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring (CGM) in a single-day treatment setting.Methods: This was a post hoc analysis of a randomized crossover study comparing the efficacy of sitagliptin, mitiglinide and the combination of these two drugs. Twenty-four hour CGM was performed before and after a single-day treatment with each drug alone or in combination.Results: Mean glucose levels were decreased in all groups. The average of three postprandial glucose excursions AUC (average of all three 4-h postprandial periods throughout the day) (AUCpp-average) decreased in the mitiglinide and combination treatment groups, but not in the sitagliptin group. The lowering effect on AUCpp-average was greater in patients given mitiglinide (–47 mg/dl, p < 0.001) or combination treatment (–66 mg/dl, p < 0.001) compared with sitagliptin alone (–18 mg/dl). The reduction in mean amplitude of glycemic excursion was greater with mitiglinide (–29.3 mg/dl, p < 0.001) and combination treatment (–28.3 mg/dl, p < 0.01) than with sitagliptin alone (–8.9 mg/dl).Conclusions: Mitiglinide or combination treatment resulted in lower glycemic variability and postprandial glucose excursion than sitagliptin alone; however, the results of this single-day pharmacodynamics study cannot be generalized to a clinical setting.

Fermented Berry Beverage Phenolics Reduced Fat Mass and Fasting Blood Glucose in High‐Fat Fed Mice

The objective was to determine the potential of phenolic compounds from a fermented 30:70% blueberry‐blackberry beverage to reduce obesity and hyperglycemia in three week old male diet‐induced obese C57BL/6j mice. Mice (n= 12/group) were randomized into six groups to drink: an alcohol‐free fermented beverage (AFFB) containing 65.1 ± 1.6 mg cyanidin‐3‐glucoside (C3G) equivalents/L; three doses of a phenolic extract where AFFB was eluted through Amberlite XAD‐7HP and adjusted to 6.4 (0.1x), 59.6 (1x) and 192.4 (3x) mg C3G eq./L; sitagliptin (30 mg/kg BW/d) or water as positive and negative controls, respectively. After a week, mice started on a 60% fat diet (HFD). Daily consumption of anthocyanins was 8.4, 1.1, 9.0, and 19.0 mg C3G/kg BW/d for AFFB, 0.1x, 1x, and 3x, respectively, with anthocyanins present predominantly C3G (65.8%). The BW/food intake ratio and sucrose consumption were similar (p &gt; 0.05). Mice in the 3x group had the lowest body weight gain (10.3 ± 0.3 g) and the water group the most weight gain (16.7 ± 1.2 g, p &lt; 0.05). The weight increase was attributed to a gain in fat mass (18.0 ± 0.8 % BW for 3x vs. 31.3 ± 1.1 % BW for water) which was correlated with visceral fat (0.8 ± 0.1 g for 3x vs. 2.4 ± 0.2 g for water), while absolute lean mass did not differ (p &gt; 0.05). After 3 weeks of treatment, all groups had fasting blood glucose (FBG) above 126 mg/dL. At the end of the study (week 12), FBG for 1x and 3x groups was significantly lower (168 and 184 mg/dL, respectively) than the water (222 mg/dL), and the sitagliptin group (217 mg/dL, p &lt; 0.05). Overall, phenolic compounds, mainly anthocyanins, from a fermented blueberry‐blackberry beverage reduced BW gain, fat mass accumulation, and FBG in diet‐induced obese mice.Funded by Hatch grant Division of Nutritional Sciences 20/20

A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine.

IntroductionThe objective of this study was to assess the effect of sitagliptin on insulin dose in patients with inadequately controlled type 2 diabetes who titrate basal insulin to a target fasting glucose level after initiating sitagliptin.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled, 24-week clinical trial in which treatment with sitagliptin 100 mg/day or placebo was administered concurrently with insulin glargine titration, targeting a fasting glucose of 4.0–5.6 mmol/L (72–100 mg/dL). The trial randomized 660 patients with type 2 diabetes and inadequate glycemic control on insulin, with or without metformin (≥1500 mg/day) or sulfonylurea, for ≥10 weeks. Patients could remain on metformin but not sulfonylurea after randomization.ResultsThe increase from baseline in the daily dose of insulin was less in the sitagliptin group (N = 329) compared to placebo (N = 329) (between group difference = −4.7 IU [95% confidence interval [CI] −8.3, −1.2]; p = 0.009). Patients in the sitagliptin group had lower glycated hemoglobin (HbA1c) levels after 24 weeks (between-group difference of −0.4% [95% CI −0.6, −0.3; −4.9 mmol/mol (95% CI −6.6, −3.2)]; p < 0.001), and more patients in the sitagliptin group reached the HbA1c goal of <7.0% (53 mmol/mol), with a between-group difference of 17.3% (95% CI 10.4%, 24.1%; p < 0.001). Fewer patients in the sitagliptin group experienced an adverse event of hypoglycemia (between-group difference = −15.5%, p < 0.001).ConclusionAdministration of sitagliptin prior to intensive titration of basal insulin glargine reduces the insulin dose requirement while providing superior glycemic control and less hypoglycemia, compared to an insulin-only regimen.FundingMerck & Co., Inc., Kenilworth, NJ, USA.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0105-3) contains supplementary material, which is available to authorized users.

Effects of sitagliptin on coronary atherosclerosis evaluated using integrated backscatter intravascular ultrasound in patients with type 2 diabetes: rationale and design of the TRUST study

Patients with diabetes mellitus are at high risk for developing coronary artery disease (CAD), even if they are treated with statins. Several studies have shown the beneficial effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on the cardiovascular system in an animal model. However, recent clinical trials using DPP-4 inhibitors have shown that these inhibitors fail to reduce the occurrence of cardiovascular events. Therefore, this study will be performed to evaluate the effects of sitagliptin, a DPP-4 inhibitor, on coronary atherosclerosis in patients with type 2 diabetes. This study will be a prospective, open-label, randomized multicenter trial performed in 6 centers in Japan. Stable CAD patients with type 2 diabetes who have undergone successful percutaneous coronary intervention under integrated backscatter (IB)-intravascular ultrasound (IVUS) guidance will be studied. They will be randomly assigned to either the sitagliptin group or a control group. After 48weeks' treatment, the IVUS examination will be repeated in the same coronary artery as at baseline. The primary end point will be the percentage change in plaque volume measured using grayscale IVUS from baseline to the 48-week follow-up. This study will be the first multicenter trial to evaluate the effects of a DPP-4 inhibitor on coronary atherosclerosis evaluated using IB-IVUS, and the findings will clarify the anti-atherogenic effects of sitagliptin.

Efficacy and safety of sitagliptin compared with sulfonylurea therapy in patients with type 2 diabetes showing inadequately controlled glycosylated hemoglobin with metformin monotherapy: A meta-analysis.

Previous randomized controlled trials (RCTs) have reported conflicting results for the efficacy of sitagliptin and sulfonylurea therapy in patients with type 2 diabetes mellitus showing inadequate glycemic control with metformin monotherapy. To clarify these findings, a meta-analysis was conducted of the outcomes of all published RCTs comparing sitagliptin with sulfonylureas in the treatment of type 2 diabetes mellitus. Standard medical databases were searched to identify relevant English- and Chinese-language RCTs. RCT results were compared regarding the mean change in glycated hemoglobin (HbA1c) level; the proportion achieving <7% HbAlc; and a change in body weight. No significant differences were found between the metformin plus sitagliptin and metformin plus sulfonylurea groups regarding HbAlc or the proportion achieving <7% HbAlc, while the metformin plus sitagliptin group experienced fewer hypoglycemic events (P<0.00001) and a greater reduction in body weight (P<0.00001). Metformin plus sitagliptin therapy may decrease HbAlc values in patients with type 2 diabetes mellitus who are not achieving their glycemic targets with metformin monotherapy in a manner similar to metformin plus sulfonylurea therapy, whilst posing a lower risk of hypoglycemia, and yielding a more beneficial effect on body weight.

The inspection of sitagliptin to metabolic index and carotid artery IMT in metabolic syndrome patients with type 2 diabetes

Objective To evaluate the effects of sitagliptin on blood glucose, blood pressure, blood lip and carotid artery intima media thickness (IMT) in metabolic syndrome patients with type 2 diabetes. Methods The clinical data were collected for 64 cases of inpatient and outpatient patients with metabolic syndrome with type 2 diabetes. Those patients included anti-diabetes native patients and patients only used the stable metformin dose. After signed off the informed consent form, those patients were randomized to the sitagliptin treatment group or original treatment group, and the metabolic index and carotid artery intima-media thickness were evaluated after 24 weeks treatment. Results The body mass index (BMI), waist circumference (WC), fasting plasma glucose (FPG), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated hemoglobin a1c (HbA1c), and carotid artery IMT in two groups were comparable at baseline. After 12 weeks treatment, the FPG, TG, DBP, and HbA1c in the sitagliptin group were significantly better than original treatment group and the baseline, while there was no different between two groups in other index. After 24 weeks treatment, the FPG, TG, HDL-C, DBP, HbA1c, and carotid artery IMT in the sitagliptin group were significantly better than original treatment group and the baseline. Conclusions Sitagliptin presents the functions of lowering blood pressure, adjusting blood lipid, and protecting vascular endothelial in addition to lowering blood glucose. Key words: Hypoglycemic agents/therapeutic use; Diabetes mellitus, type 2/complications; Metabolic syndrome X/complications; Diabetes mellitus, type 2/drug therapy; Metabolic syndrome X/drug therapy; Carotid arteries/pathology

Beneficial Effects of Incretin-Based Therapy on Glycemic Control, Adipokines, Insulin Sensitivity Parameters and Weight Loss in Overweight or Obese Patients With Newly Diagnosed Type 2 Diabetes: A Prospective Study

Background: The aim of the study was to examine the incretin-based therapy on glycemic control, insulin sensitivity parameters, weight loss and adipokines in overweight or obese patients with newly diagnosed type 2 diabetes mellitus (T2DM). Methods: This was a 24-week prospective study of 75 enrolled overweight or obese subjects (body mass index (BMI) is greater than or equal to 25 kg/m 2 ) with newly diagnosed T2DM randomly assigned to the liraglutide, metformin, and sitagliptin groups. Outcome measures were fasting blood glucose (FBG), HbA1c, weight, BMI, waist circumstance, plasma lipids, fast insulin, fast C-peptide, HOMA-IR, HOMA-B, leptin, adiponectin, and high-sensitivity C-reactive protein (hsCRP). Results: At the endpoint of 24 weeks, administration of liraglutide, metformin or sitagliptin all resulted in significant improvements of glycemic control, weight loss and insulin sensitivity parameters. It was also demonstrated that liraglutide was superior to metformin and sitagliptin in terms of achieving target HbA1c values and sustaining weight loss after 24-week treatment, but not to the incidence of adverse events (AEs). Moreover, liraglutide administration showed beneficial effects on reducing leptin levels and L/A ratio as well as elevating adiponectin levels compared to the metformin and sitagliptin administration. Conclusion: Liraglutide treatment during 24 weeks in newly diagnosed T2DM patients led to reduction of BMI and improvement of glucose control, insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines could play an important role in GLP-1 treatment. J Endocrinol Metab. 2015;5(5):284-290 doi: http://dx.doi.org/10.14740/jem304w

Efficacy, Safety and Treatment Satisfaction of Glimepiride vs Sitagliptin in Combination with Metformin in Type 2 Diabetes Mellitus.

Metformin is a preferred drug for starting treatment in type 2 diabetes mellitus. But, eventually most of the patients need additional drug to control blood sugar level. The choice of drug depends upon several factors including patient specific criteria, economical factors and treatment satisfaction. The aim of the present study is to investigate the effects of adding sitagliptin or glimepiride on efficacy, safety and treatment satisfaction in patients with type 2 diabetes mellitus. It was a retrospective observational study on 50 patients each in sitagliptin and glimepiride group, who are receiving treatment for at least 12 weeks and are stable on respective treatment regimen. Glycated haemoglobin (HBA1c) was the primary measure of efficacy. Safety was assessed by checking weight gain/loss, hypoglycaemia episodes and other laboratory investigations. Patient satisfaction was assessed by Diabetes Treatment Satisfaction Questionnaire. The HbA1c level after 12-24 weeks of treatment was not found to be significant compared to each other or from baseline. Compared to baseline fasting plasma glucose & postprandial plasma glucose were lower in glimepiride group. Sitagliptin was associated with less episodes of hypoglycaemia. Weight gain was associated with glimepiride but it was non-significant (p=0.08). Overall treatment satisfaction score were better for sitagliptin but were not statistically significant. The efficacy of sitagliptin was comparable. Sitagliptin had superior adverse effect profile with less chances of hypoglycaemia and weight gain. Questionnaire scores were higher for sitagliptin indicating better treatment satisfaction compared to glimepiride.

Sitagliptin and cardiovascular outcomes in diabetic patients with chronic kidney disease and acute myocardial infarction: A nationwide cohort study

BackgroundThe cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear. MethodsWe analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death. ResultsPrimary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97–1.79; P=0.079) during the mean follow-up of 1.02years (SD=0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group (P=0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15–2.58; P=0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04–1.95; P=0.026). ConclusionsAmong type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization.

Clinical outcomes and health care costs combining metformin with sitagliptin or sulphonylureas or thiazolidinediones in uncontrolled type 2 diabetes patients.

ObjectivesTo compare clinical outcomes and health care costs across three cohorts of uncontrolled diabetic patients who initiated treatment with one of the following: sulphonylureas (SU), thiazolidinediones (TZD) or sitagliptin (SITA).Materials and methodsWe performed a retrospective study based on a linkage between administrative and laboratory databases maintained by three Italian local health units. The index period ranged from July 2008–June 2010. Patients were treatment-naïve to either SU, TZD, or SITA, but they were already treated with other oral hypoglycemic agents. Demographics and clinical characteristics were assessed at baseline. Adherence was measured by the medication possession ratio and adherent was defined as a patient with a medication possession ratio of 80% or greater. We used a Poisson regression model to estimate the risk ratios for disease-related hospitalizations that occurred during the 18-month follow-up period. The total annual costs included all the pharmacological treatments and the direct costs due to hospitalizations and outpatient services.ResultsWe identified 928 patients treated with SU, 330 patients treated with TZD, and 83 patients treated with SITA. SITA patients were significantly younger and with fewer previous hospital discharges. The baseline mean glycated hemoglobin level was 8.1% for SU, 8.0% for TZD, and 8.3% for SITA patients. SITA-naïve patients were more adherent than the SU- and TZD-naïve patients (79.5% versus 53.2% and 62.8%, respectively; P<0.001). The SU and TZD group showed a significant increased risk of disease-related hospitalizations compared with the SITA group (the unadjusted rate was 10.42 and 7.16 per 100 person-years versus 1.64 per 100 person-years, P=0.003; compared with SU, the adjusted incidence rate ratio for SITA was 0.21, P=0.030). The total annual costs per patient were €972 for SITA, €706 for SU, and €908 for those treated with TZD.ConclusionUncontrolled diabetic patients who initiated – as a second-line therapy in addition to metformin – treatment with SITA, compared to those who initiated treatment with SU or TZD, showed a reduced risk of disease-related hospitalizations. The total annual costs per patient were not significantly different among the three groups.

HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin.

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.

Sitagliptin Improves the Impaired Acute Insulin Response during a Meal Tolerance Test in Japanese Patients with Type 2 Diabetes Mellitus: A Small-Scale Real-World Study.

IntroductionSeveral studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors improve insulin secretion during oral glucose tolerance tests. However, the effects of DPP-4 inhibitors on impaired acute insulin responses in the postprandial state in real-world settings are unknown. Therefore, we evaluated the effects of sitagliptin on the acute insulin responses in Japanese patients with type 2 diabetes mellitus (T2DM) using meal tolerance tests.MethodsTwenty-one patients with T2DM were given a test meal (460 kcal), and plasma glucose and insulin were measured at 0, 30, 60, 120, and 180 min after the meal. The insulinogenic index of all of these patients was below 43.2. The postprandial profiles were assessed at baseline and after 3 months of treatment with 50 mg/day sitagliptin after a meal (n = 11) or were untreated (control group; n = 10). This study was a prospective, open-label, non-blinded, non-randomized, clinical study.ResultsSitagliptin significantly decreased the plasma glucose levels at 60, 120, and 180 min, and significantly increased the plasma insulin levels at 0 and 30 min. There were no significant changes in glucose or insulin in the control group. The insulinogenic index increased significantly in the sitagliptin group compared with the control group (+16.7 vs. +0.1, P < 0.005). However, homeostasis model assessment of insulin resistance and the insulin sensitivity index were not significant different between the two groups.ConclusionAdministration of sitagliptin at 50 mg/day after a meal improved the impaired acute insulin response and suppressed postprandial hyperglycemia. Whereas the study is rather small and the design is suboptimal as it is not randomized and not blinded, these results suggest that sitagliptin is effective in Japanese patients with T2DM, many of whom display impaired acute insulin responses after a meal.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-014-0071-1) contains supplementary material, which is available to authorized users.

A pilot three-month sitagliptin treatment increases serum adiponectin level in Japanese patients with type 2 diabetes mellitus--a randomized controlled trial START-J study.

BackgroundThe 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.MethodsTwenty-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.ResultsIndices 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).ConclusionIn Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight.Trial registrationUMIN000004721

Impact of Sitagliptin on Carotid Intima-Media Thickness in Patients With Coronary Artery Disease and Impaired Glucose Tolerance or Mild Diabetes Mellitus

Sitagliptin has been widely used for the treatment of diabetes and shown recently to have beneficial pleiotropic outcomes on cardiovascular systems in experimental studies. However, little is known about the influence of sitagliptin on atherosclerosis-related cardiovascular diseases in a clinical setting. This study examined the effect of sitagliptin on carotid intima-media thickness (IMT). A total of 76 patients with clinically stable and documented coronary artery disease, who were newly diagnosed with impaired glucose tolerance or mild type 2 diabetes mellitus, were allocated, randomly, to receive either sitagliptin 100mg/day or the placebo control. Common carotid IMT, glucose profiles, glycosylated hemoglobin (HbA1c), and lipid profiles were measured at baseline and repeated at 12months. Sitagliptin-treated patients showed less IMT progression than the control group (p= 0.02). In addition, the sitagliptin group showed greater reductions in body weight (2.2%), 2-hour glucose levels on the 75-g oral glucose tolerance test (17.3%), HbA1c (4.7%), and low-density lipoprotein cholesterol levels (7.9%) from that at baseline. In conclusion, treatment with sitagliptin for 12months was associated with a beneficial effect in the prevention of carotid IMT progression, compared with the diet control.

Mo1767 Genetic Deletion of IL-25 Increases Susceptibility to High-Fat Diet-Induced Metabolic Dysfunction in Mice

unknown. This study therefore evaluated the effect of the DPP-4 inhibitor, sitagliptin (STG), on diabetes-related colon carcinogenesis in mice. Materials and Methods: Six-week-old male wild-type (WT) and leptin-deficient (ob/ob) C57BL/6J mice were used in this study. The mice received 1,2-dimethlhydrazine (DMH) subcutaneously at a dose of 20 mg/kg body weight three times within a week, and chronic colitis was then induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). Sitagliptin (3 mg/kg) was administered to the mice by oral gavage every day during the entire experimental period. The mice were divided into the following three groups: WT group; obob group; and obob+STG group. The mice were sacrificed 28 days after the completion of both cycles of DSS. Results: During the DSS administration cycle, mean body weight decreased significantly in the WT group compared with the obob and obob+STG groups. The disease activity index (DAI) was also increased significantly in the WT group. However, administration of STG did not affect the DAI or body weight. The mean number of tumors was 7.8±4.5, 10.6±3.3, and 6.7±2.4 in the WT, obob, and obob+STG groups, respectively. STG significantly suppressed the occurrence of neoplasia in the obob mice. Mucosal DPP-4 activity and the mucosal concentration of GLP-2 were not significantly different in the three groups. Conclusion: Administration of STG exerts a suppressive effect on the development of colon neoplasia in a murine model of type 2 diabetes. However, STG does not affect the mucosal DPP-4 activity. Because DPP-4 mRNA/DPP-4 activity are highly expressed/detected in the small intestine andDPP-8 and 9 are expressed predominantly in the colon, DPP-4 inhibitors may suppress colon carcinogenesis independent of the GLP pathway.

Mo1991 Sitagliptin Inhibits the Development of Hepatic Steatosis by Down-Regulated Expressions of Hepatic Acetyl-CoA Carboxyrase (ACC) and Fatty Acid Synthase (Fas)

Aims; Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and a key factor of obesity-related metabolic dysfunctions featuring dyslipidemia, insulin resistance, and loss of glycemic control. Although sitagliptin (dipeptidyl peptidase-4 inhibitior) is a treatment drug used for type 2 diabetic mellitus (T2DM) patients, the role of sitagliptin in the development NAFLD has not yet been well known. It has yet to be completely understood how much dysregulated de novo lipogenesis contributes to the pathogenic development of hepatic steatosis. We investigated whether the treatment of sitagliptin is metabolically connected to hepatic steatosis. Methods: Five-week-old male ob/ob mice, which develop T2DM and NAFLD by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks (Control group; n=6) as controls, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks (Sitagliptin group; n=6). Results: Histological comparison between the liver of Control group and that of Sitagliptin group showed significantly more inhibition of hepatic steatosis than in Sitagliptin group. It was suggested that sitagliptin inhibited the development of hepatic steatosis in the mice induced by histologically. The enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) regulate the synthesis of fatty acids. Sitagliptin reduced the hepatic expressions of ACC and FAS, markedly inhibited hepatic de novo lipogenesis, and protected against hepatic steatosis in ob/ob mice. Conclusion: These findings suggested that sitagliptin has effects of downregulated hepatic ACC and FAS in lipid metabolism. Therefore, sitagliptin may serve as a potential target to treat NAFLD and T2DM.