Sitagliptin added to treatment with ongoing pioglitazone for up to 52 weeks improves glycemic control in Japanese patients with type 2 diabetes

Aims/Introduction:  Patients with type 2 diabetes mellitus often require treatment with more than one oral antihyperglycemic agent to achieve their glycemic goal. The present study was carried out to assess the efficacy and safety of sitagliptin as add‐on therapy in Japanese patients with type 2 diabetes mellitus inadequately controlled (HbA1c ≥ 6.9% and <10.4%) on pioglitazone monotherapy (15–45 mg/day).Materials and Methods:  In the initial 12‐week, double‐blind treatment period, patients were randomized (1:1) to sitagliptin 50 mg/day (n = 66) or placebo (n = 68), followed by a 40‐week open‐label treatment period in which all patients received sitagliptin 50 mg/day that could have been increased to 100 mg/day for patients meeting predefined glycemic parameters.Results:  After 12 weeks, mean changes from baseline in HbA1c (the primary end‐point), fasting plasma glucose and 2‐h post‐meal glucose were −0.8%, −0.9 mmol/L and −2.7 mmol/L, respectively, in the sitagliptin group compared with placebo (all P < 0.001). The incidence of adverse experiences during the double‐blind treatment period was similar in both treatment groups, and the incidences of hypoglycemia and gastrointestinal adverse experiences were low. In the open‐label period, improvements in glycemic parameters with sitagliptin treatment were maintained and sitagliptin was generally well tolerated.Conclusions:  Sitagliptin as add‐on therapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus inadequately controlled on pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. {"type":"clinical-trial","attrs":{"text":"NCT00372060","term_id":"NCT00372060"}}NCT00372060). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00120.x, 2011)     

Short‐ and long‐term effect of sitagliptin after near normalization of glycemic control with insulin in poorly controlled Japanese type 2 diabetic patients

Aims/Introduction

The aim of the present study was to examine the short‐ and long‐term effect of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin in poorly controlled type 2 diabetic patients.

Materials and Methods

We consecutively enrolled a total of 30 type 2 diabetic patients whose glycated hemoglobin levels (National Glycohemoglobin Standardization Program) were ≥7.4%, stopped all oral antidiabetic drugs and started insulin therapy. When fasting plasma glucose levels became <140 mg/dL, we carried out the first oral glucose tolerance test (OGTT). After 1‐week sitagliptin treatment (50 mg/day), the second OGTT was carried out. Furthermore, we evaluated the long‐term efficacy of sitagliptin on glucose tolerance after near normalization of glycemic control with insulin.

Results

After 1‐week sitagliptin treatment, the area under the curve of insulin was markedly increased, and the area under the curve of glucagon and glucose was markedly decreased. Duration of diabetes and insulin secretory capacity were correlated with the effect of sitagliptin. Furthermore, interestingly, near normalization of glycemic control with insulin therapy for 1–2 weeks brought out the long‐term effectiveness of sitagliptin on glucose tolerance for 24 weeks, which was not observed with other antidiabetic drugs.

Conclusions

These findings suggest that near normalization of glycemic control with insulin improves the clinical response to sitagliptin in poorly controlled type 2 diabetic patients.     

Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients

Introduction

Anagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase‐4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients.

Materials and Methods

The study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase‐4 inhibitors for ≥8 weeks and had a low‐density lipoprotein cholesterol (LDL‐C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks.

Results

There was no significant difference in percentage change in LDL‐C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL‐C levels, one of the secondary end‐points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B‐100 levels, and the percentage change in LDL‐C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B‐100 levels in the ANA group.

Conclusions

The LDL‐C‐lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL‐C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B‐100 synthesis.     

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug‐naïve Japanese patients with type 2 diabetes mellitus: A pilot study

Aims/Introduction

Dipeptidyl peptidase-4 inhibitors and glinides are effective in reducing postprandial hyperglycemia. However, little information is available on the comparative effects of the two drugs on the levels of postprandial glucose. The aim of the present study was to compare the effects of sitagliptin and nateglinide on meal tolerance tests in drug-naïve patients with type 2 diabetes mellitus.

Materials and Methods

The study participants were 19 patients with type 2 diabetes mellitus, which was inadequately controlled by diet and exercise. An open-label, prospective, cross-over trial was carried out to compare the effects of single-dose sitagliptin and nateglinide on the postprandial glucose level and its related hormones during meal tests.

Results

The change in area under the curve (AUC) of glucose from 0 to 180 min (AUC_{0–180 min}) during the meal test by nateglinide was similar to that by sitagliptin. As expected, the change in active glucagon like peptide-1 was significantly higher after a single-dose of sitagliptin than nateglinide. Then, insulin secretion relative to glucose elevation (ISG) (ΔISG_{0–180 min}: ΔAUC_{0–180 min} insulin/AUC_{0–180 min} glucose) was significantly enhanced by nateglinide compared with sitagliptin. Conversely, glucagon level (ΔAUC_{0–180 min} glucagon) was increased by administration of nateglinide, whereas the glucagon level was reduced by administration of sitagliptin.

Conclusions

The effects of sitagliptin on postprandial glucose levels were similar to those of nateglinide in drug-naïve type 2 diabetes patients. However, the induced changes in insulin, active glucagon-like peptide-1 and glucagon during meal loading suggest that reduction of postprandial hyperglycemia was achieved by the unique effect of each drug.     

Sitagliptin added to voglibose monotherapy improves glycemic control in patients with type 2 diabetes

Aims/Introduction

Type 2 diabetes mellitus is a progressive disease that frequently requires patients to use more than one oral antihyperglycemic agent to achieve adequate glycemic control. The present multicenter, randomized study assessed the efficacy and safety of the addition of sitagliptin to ongoing voglibose monotherapy (0.2–0.3 mg three times daily) in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control (glycated hemoglobin ≥6.9% and <10.5%).

Materials and Methods

The present study had an initial 12‐week, double‐blind treatment period in which patients were randomized (1:1) to sitagliptin 50 mg/day (n = 70) or placebo (n = 63), followed by a 40‐week, open‐label treatment period during which all patients received sitagliptin 50 mg/day, that could have been increased to 100 mg/day for patients meeting predefined glycemic criteria.

Results

After 12 weeks, treatment with sitagliptin resulted in placebo‐subtracted mean changes from baseline in glycated hemoglobin (the primary end‐point), fasting plasma glucose and 2‐h postmeal glucose of –0.9%, –22.5 mg/dL and –51.3 mg/dL, respectively (all, P < 0.001). During the double‐blind period, adverse experiences were reported with similar frequency in both treatment groups, and the occurrences of hypoglycemia and gastrointestinal adverse experiences were low. In the open‐label period, sustained improvements in glycemic parameters were observed with sitagliptin treatment, and sitagliptin was generally well tolerated.

Conclusions

Sitagliptin added on to ongoing voglibose monotherapy provided significant improvements in glycemic parameters and was well tolerated in Japanese patients with type 2 diabetes mellitus who had inadequate glycemic control. This trial was registered with ClinicalTrails.gov (no. NCT00837577).     

Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus

Aim

To confirm the efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy.

Materials and Methods

In an initial 12‐week, double‐blind, placebo controlled, parallel‐group study, patients (n = 204) were randomized to teneligliptin 20 mg or placebo once daily added to their stable pioglitazone therapy. This was followed by a 40‐week, open‐label period during which all patients received teneligliptin once daily. The primary end‐point was the change in hemoglobin A1c (HbA_1c) from baseline to week 12.

Results

Patients in the teneligliptin group showed significantly greater reductions in HbA_1c compared with the placebo group at week 12 (P < 0.001). The changes in HbA_1c from baseline to week 12 were −0.9 ± 0.0% (least‐squares mean ± standard error) in the teneligliptin group and −0.2 ± 0.0% in the placebo group. The change in fasting plasma glucose from baseline to week 12 was greater in the teneligliptin group than in the placebo group (P < 0.001). The blood glucose lowering effects of teneligliptin were sustained throughout the 40‐week open‐label period. Adverse events and adverse drug reactions occurred slightly more frequently in the teneligliptin group than in the placebo group, although the incidence of hypoglycemia was low. Bodyweight was unchanged in the double‐blind period, but was slightly increased in the open‐label period.

Conclusions

Add‐on therapy with teneligliptin was effective and generally well tolerated throughout the study period in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. NCT01026194).     

Dipeptidyl peptidase 4 inhibitors linked bullous pemphigoid in patients with type 2 diabetes mellitus: A series of 13 cases

BackgroundDipeptidyl peptidase 4 (DPP4) inhibitors have increasingly been linked to bullous pemphigoid, but there is paucity of data from India where about 1.85 million patients have been estimated to use these drugs.MethodsIn 30,000 patients with T2DM seen by us in two tertiary care centres since 2015, we detected 13 cases of bullous pemphigoid linked to DPP4 inhibitors. We used WHO-UMC (World Health Organisation-Uppsala Monitoring Centre) causality assessment system for assessment.ResultsLesions of bullous pemphigoid appeared at varied intervals (within 1 weeks–2 years) after start of DPP4 inhibitors. Implicated drugs were Linagliptin (n, 8), Vildagliptin (n, 4) and Sitagliptin (n, 1). Mostly, lesions were seen after 60 years age, and over trunk and extremities. Skin biopsy was compatible with bullous pemphigoid in two patients. Lesions regressed within a month of stopping DPP4 inhibitors in 9 patients while delayed regression up to 6 months in 4 patients. Overall, skin lesions remitted in all patients and did not recur.ConclusionAny new bullous lesion appearing while patient is on DPP4 inhibitors should be considered as bullous pemphigoid and should necessitate prompt withdrawal of the drug.     

Efficacy of α‐glucosidase inhibitors combined with dipeptidyl‐peptidase‐4 inhibitor (alogliptin) for glucose fluctuation in patients with type 2 diabetes mellitus by continuous glucose monitoring

Aims/Introduction

The combination therapy of dipeptidyl‐peptidase (DPP)‐4 inhibitor and α‐glucosidase inhibitors (α‐GIs) is highly effective in suppressing postprandial hyperglycemia. The aim of the present study was to compare the effects of voglibose and miglitol on glucose fluctuation, when used in combination with DPP‐4 inhibitor by using continuous glucose monitoring (CGM).

Materials and Methods

In a randomized cross‐over study, 16 patients with type 2 diabetes who presented with postprandial hyperglycemia despite alogliptin (25 mg) were treated with voglibose (0.9 mg) or miglitol (150 mg). We measured standard deviation (SD); mean amplitude of glycemic excursions (MAGE), and mean, minimum and maximum glucose measured by CGM during three phases (alogliptin monotherapy, dual therapy of alogliptin and voglibose, and dual therapy of alogliptin and miglitol). The primary outcome measure was SD between α‐GIs.

Results

SD was significantly improved by the addition of either voglibose (18.9 ± 10.1) or miglitol (19.6 ± 8.2) to alogliptin monotherapy (36.2 ± 8.7). MAGE improved significantly with the addition of either voglibose (57.5 ± 26.1, P < 0.01) or miglitol (64.6 ± 26.2, P < 0.01) to alogliptin monotherapy (101.5 ± 21.5). There was no significant difference in glucose fluctuation between α‐GIs. There were no differences between two groups in mean (132.6 ± 21.4 and 138.7 ± 25.4) and maximum (184.3 ± 48.7 and 191.9 ± 38.3). The minimum glucose under alogliptin plus voglibose (94.9 ± 20.2) was significantly lower than that under alogliptin and miglitol (105.3 ± 21.0).

Conclusions

Glucose fluctuation was improved by the addition of voglibose or miglitol to alogliptin. Glucose fluctuations and postprandial hyperglycemia were similar between α‐GIs. This trial was registered with the University Hospital Medical Information Network (no. UMIN R000010028).     

Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment

Aim: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Methods: In this multicentre, randomized, parallel‐group, double‐blind, placebo‐controlled study, patients with glycated haemoglobin (HbA1c) 7–11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end‐stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end‐point) was analysed using an analysis of covariance model with last observation carried forward methodology. Results: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was ?0.42% (95% confidence interval: ?0.71 to ?0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (?0.64 vs. ?0.05%) and severe (?0.95 vs. ?0.50%) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end‐stage renal disease on haemodialysis (?0.84 vs. ?0.87%). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. Conclusions: Saxagliptin 2.5 mg once daily is a well‐tolerated treatment option for patients with inadequately controlled T2DM and renal impairment.     

Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study

Aims/Introduction

Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon-like peptide (GLP)-1 improves fatty liver, but the effect of dipeptidyl peptidase-4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12-week treatment with sitagliptin, a dipeptidyl peptidase-4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment.

Materials and Methods

The study participants were seven type 2 diabetes patients with fatty liver who were studied at baseline and 12 weeks after sitagliptin treatment. Intrahepatic lipid (IHL) and IMCL were assessed by ¹H magnetic resonance spectroscopy. Glucose kinetics was assessed during double-tracer OGTT (U-[¹³C]-glucose orally and 6,6-[²H₂]-glucose intravenously).

Results

Sitagliptin significantly reduced glycated hemoglobin (from 7.1 ± 0.2 to 6.5 ± 0.3%, P < 0.005), but had no effects on IHL and IMCL. The glucose level diminished, whereas GLP-1 concentration increased during OGTT at the end of treatment. These changes were not accompanied by significant changes in insulin or glucagon levels. However, long-term sitagliptin treatment partially decreased the rate of appearance of oral glucose during OGTT, but did not affect endogenous glucose production or the rate of disappearance.

Conclusions

It was found that 12-week sitagliptin treatment improved glycated hemoglobin and glucose excursion during OGTT in type 2 diabetes with fatty liver, independent of changes in lipid accumulation in the liver. This trial was registered with the Japan Clinical Trials Registry (UMIN-CTR000005666).     

Sitagliptin reduces albuminuria in patients with type 2 diabetes

We investigated the inhibitory effect of sitagliptin on albuminuria in patients with type 2 diabetes. Thirty-six patients (19 men and 17 women) whose HbA1c was higher than 6.5% (NGSP) despite receiving education on diet and exercise and medical treatment for at least 6 months at our clinic were enrolled into this study and were successfully followed over 6 months of sitagliptin treatment. Sitagliptin (50 mg/day) treatment significantly lowered both systolic and diastolic blood pressures, fasting blood glucose and postprandial blood glucose, HbA1c, and glycated albumin at 3 months and 6 months. Significant reductions in highly sensitive C-reactive protein and soluble vascular cell adhesion molecule 1 were also observed at 6 months. Urinary albumin excretion (measured as urinary albumin-to-creatinine ratio (ACR: mg/g Cr)) did not change in the 6 months before sitagliptin treatment (ΔACR: 2.3 ± 19.9) and decreased in the 6 months after sitagliptin treatment (ΔACR: -20.6 ± 24.6); these differences were statistically significant. At 6 months, the ACR decreased from 11.6 ± 8.4 to 4.5 ± 5.0 in 13 patients with normoalbuminuria (ACR < 30), from 98.4 ± 79 to 24.9 ± 20 in 15 patients with microalbuminuria (30 < ACR < 300), and from 1263 ± 492 to 561 ± 89 in 8 patients with macroalbuminuria (ACR > 300). Thus, the present findings strongly suggest that sitagliptin reduces albuminuria without lowering the estimated glomerular filtration rate, most likely depending on known factors such as blood sugar reduction, blood pressure reduction, and inflammation reduction, as well as yet undetermined factors caused by an increase in active glucagon-like peptide-1.     

Efficacy and tolerability of vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus

Aim: To investigate the efficacy and tolerability of vildagliptin as add‐on therapy to metformin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled study. Patients with T2DM (N = 438) with haemoglobin A1c (HbA1c) of 7.0–10.0% and fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl) were randomized (1 : 1 : 1) to vildagliptin 50 mg bid, vildagliptin 50 mg qd or placebo in addition to metformin. Results: The treatment groups were well balanced at baseline [mean HbA1c, 8.0%, FPG, 8.8 mmol/l (158 mg/dl); body mass index, 25.5 kg/m²]. The adjusted mean change (AMΔ) in HbA1c at endpoint was ?1.05 ± 0.08%, ?0.92 ± 0.08% and ?0.54 ± 0.08% in patients receiving vildagliptin 50 mg bid, 50 mg qd and placebo, respectively. The between‐treatment difference (vildagliptin 50 mg bid–placebo) was ?0.51 ± 0.11%, p < 0.001. A greater proportion of vildagliptin‐treated patients met at least one responder criterion (82.1 and 70.7%) compared to placebo‐treated patients (60.4%). The AMΔ at endpoint for FPG with vildagliptin 50 mg bid, ?0.95 mmol/l (?17.1 mg/dl); 50 mg qd, ?0.84 mmol/l (?15.1 mg/dl) was significantly different compared with the placebo ?0.26 mmol/l (?4.68 mg/dl) (p ≤ 0.001). Adverse events (AEs) were reported as 34.2, 36.5 and 37.5% for patients receiving vildagliptin 50 mg bid, 50 mg qd or placebo, respectively. Two patients in the vildagliptin 50 mg qd and one in the placebo group reported serious AEs, which were not considered to be related to the study drug; one incidence of hypoglycaemic event was reported in the vildagliptin 50 mg bid group. Conclusion: Vildagliptin as add‐on therapy to metformin improved glycaemic control and was well tolerated in Chinese patients who were inadequately controlled by metformin only.     

Predicting efficacy of dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes: Association of glycated hemoglobin reduction with serum eicosapentaenoic acid and docosahexaenoic acid levels

This study was initiated to identify clinical and dietary parameters that predict efficacy of dipeptidyl peptidase‐4 inhibitors. A total of 72 untreated Japanese patients with type 2 diabetes who received DPP‐4 inhibitors (sitagliptin, alogliptin or vildagliptin) for 4 months were examined for changes of glycated hemoglobin (HbA_1c) and body mass index (BMI), and self‐administered 3‐day food records, as well as serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). DPP‐4 inhibitors significantly reduced HbA_1c (before initiation of DPP‐4 inhibitors 7.2 ± 0.7%, 4 months after initiation of DPP‐4 inhibitors 6.7 ± 0.6% [paired t‐test, P < 0.01 vs before]). Multiple regression analysis showed that changes of HbA_1c were significantly correlated with baseline HbA_1c, as well as estimated intake of fish. Furthermore, changes of HbA_1c were significantly correlated with serum levels of EPA (r = −0.624, P < 0.01) and DHA (r = −0.577, P < 0.01). HbA_1c reduction by DPP‐4 inhibitors is significantly correlated with estimated intake of fish and serum levels of EPA and DHA. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00214.x, 2012)