Sulfonylurea-based Therapy Research Articles

Effect of Long-term Incretin-Based Therapies on Ischemic Heart Diseases in Patients with Type 2 Diabetes Mellitus: A Network Meta-analysis

Patients with type 2 diabetes mellitus (T2DM) experience many cardiovascular complications. Several studies have demonstrated the cardioprotective effects of incretin-based therapies; however, there are few studies on the effects of long-term incretin-based therapies on cardiovascular events. Therefore, the present study conducted a systematic review and network meta-analysis to evaluate the effects of long-term incretin-based therapies on ischaemic diseases. We searched PubMed, CENTRAL, and Clinicaltrial.gov to retrieve randomised control trials reported until December 2016 and enrolled only RCTs with more than a 1-year follow-up. The network meta-analysis was performed using R Software with a GeMTC package. A total of 40 trials were included. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 agonists were associated with a lower risk of myocardial infarction (MI) than were sulfonylureas (odds ratio [95% credible interval] 0.41 [0.24–0.71] and 0.48 [0.27–0.91], respectively). These results suggested that patients with T2DM receiving long-term incretin-based therapies have a lower risk of MI than do those receiving sulfonylurea-based therapy. These findings highlight the risks of cardiovascular events in patients who receive long-term incretin-based therapies, and may provide evidence for the selection of antidiabetic therapy in the future.

The Real-Life Effectiveness and Care Patterns of Diabetes Management Study for Balkan Region (Slovenia, Croatia, Serbia, Bulgaria): A Multicenter, Observational, Cross-Sectional Study.

IntroductionRecent large randomized controlled trials highlighted the clinical significance of hypoglycemic episodes in the treatment of diabetes. The present survey was conducted to provide information from real-life practice on the incidence of hypoglycemia in type 2 diabetic patients treated with sulfonylureas.MethodsThis multicenter, observational, cross-sectional study collected data on incidence of side effects of sulfonylurea-based therapy in type 2 diabetic patients in four countries of the Balkan region (Slovenia, Croatia, Serbia, Bulgaria) from October 2014 to June 2015.ResultsOf the 608 who participated in the study, 573 patients (mean age 67.2 years, mean body mass index 29.9 kg/m2) met the inclusion/exclusion criteria. More than 90% of the patients were treated with the newer generation sulfonylureas—gliclazide or glimepiride—either as monotherapy or as dual therapy in combination with metformin. In total, 210 patients (36.6%) reported hypoglycemic episode(s) in the last 6 months. Mild episodes were reported by 132 patients (62.8%), moderate by 66 (31.2%), severe by 8 patients (4.0%), and very severe by 4 patients (2%), respectively. Overall, 171 patients (28.2%) reported body weight increase during the previous year. The mean reported body weight gain in this group of patients was 4.2 kg (SD 2.7, median 3). Among them, 68.1% gained less than 5 kg, 25.0% gained 5–9 kg, and the rest gained more than 10 kg.ConclusionAlthough newer generation sulfonylureas are generally considered safe in terms of hypoglycemia, our data indicates their use is associated with substantial risk of hypoglycemia and weight gain. Clinicians should be mindful of these findings when prescribing SUs and inform patients about the risk of hypoglycemia.FundingMerck Sharp & Dohme.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0288-x) contains supplementary material, which is available to authorized users.

A higher body mass index attenuates the long-term HbA1c-lowering effects of liraglutide in type 2 diabetes patients treated using sulfonylurea-based therapy.

To identify the attenuating factor of glycated hemoglobin (HbA1c)-lowering effects of liraglutide in type 2 diabetes (T2D) patients over the long term. Forty-six T2D patients received liraglutide-glimepiride combination therapy. Clinical characteristics were compared between the following two subgroups: the relapse group (≥0.4% increase in HbA1c in 48weeks compared to 12weeks) and non-relapse group (remaining patients). A glucagon-loading test was performed to evaluate baseline endogenous insulin secretion. In the relapse group, significantly reduced HbA1c, as observed at 12weeks, tended to increase at 24 and 48weeks. In the non-relapse group, reduced HbA1c was maintained for 48weeks. Body weight was decreased at 12weeks and then recovered at 48weeks in both groups. Baseline BMI was significantly higher in the relapse group than in the non-relapse group. Age, HbA1c, duration of diabetes, fasting C-peptide, daily glimepiride dose and the duration of glimepiride treatment were comparable between both groups. Multiple logistic regression analysis revealed that baseline BMI was independently associated with the relapse group. A higher BMI is the leading factor for attenuating long-term glycemic control by liraglutide in T2D patients undergoing sulfonylurea-based therapy.

Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea.

We analyzed the changes of glycemic control over 12months and the factors influencing blood glucose in 162 Japanese patients with type2 diabetes having inadequate glycemic control despite sulfonylurea-based therapy who received add-on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4weeks of treatment, and this improvement was maintained for 1year, although HbA1c was slightly higher in week52 than in week24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks24 and 52 (n=57) with the others (n=105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P<0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24weeks of treatment and those receiving a higher dose of glibenclamide.

Long-term Safety and Tolerability of Colesevelam HCl in Subjects with Type 2 Diabetes

The bile acid sequestrant, colesevelam hydrochloride, is approved for glycemic control in adults with type 2 diabetes. In three double-masked, placebo-controlled studies, colesevelam hydrochloride 3.75 g/day demonstrated its glycemic-lowering properties when added to existing metformin-, insulin-, or sulfonylurea-based therapy in adults with inadequately controlled type 2 diabetes. This was a 52-week open-label extension study conducted at 63 sites in the United States and one site in Mexico to further evaluate the safety and tolerability of colesevelam hydrochloride in subjects with type 2 diabetes. All subjects who completed the three double-masked, placebo-controlled studies were eligible to enroll in this open-label extension. In total, 509 subjects enrolled and received open-label colesevelam hydrochloride 3.75 g/day for 52 weeks. Safety and tolerability of colesevelam hydrochloride was evaluated by the incidence and severity of adverse events. In total, 360 subjects (70.7%) completed the extension. Of the safety population, 361 subjects (70.9%) experienced an adverse event, most (88.1%) being mild or moderate in severity. Fifty-six adverse events (11.0%) were drug-related; the most frequent drug-related adverse events were constipation and dyspepsia. Thirty-five subjects (6.9%) discontinued due to an adverse event. Fifty-four subjects (10.6%) experienced a serious adverse event; only one was considered drug-related (diverticulitis). Seventeen subjects (3.3%) experienced hypoglycemia; most episodes were mild or moderate in severity. Glycemic improvements with colesevelam hydrochloride were seen without change in weight over 52 weeks (0.2 kg mean reduction from baseline). Colesevelam hydrochloride was safe and well-tolerated as long-term therapy for patients with type 2 diabetes.

Concomitant Reduction in Low-Density Lipoprotein Cholesterol and Glycated Hemoglobin With Colesevelam Hydrochloride in Patients With Type 2 Diabetes: A Pooled Analysis

Colesevelam hydrochloride (COL), a bile acid sequestrant indicated as an adjunct to diet and exercise for reducing low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia, was shown in a pilot study to reduce both glycated hemoglobin (HbA1c) and LDL-C in patients with type 2 diabetes mellitus (T2DM). Three double-blind, placebo-controlled trials in T2DM have now independently confirmed the HbA1c and LDL-C reductions with COL. In each of the primary studies, a significant mean treatment difference in HbA1c (-0.54%, -0.50%, and -0.54%) and LDL-C (-15.9%, -12.8%, and -16.7%) resulted from the addition of 3.75 grams/day of COL to existing metformin, insulin, or sulfonylurea-based therapy, respectively, in patients with T2DM inadequately controlled on their current antidiabetic regimen. Here we report the results of a pooled analysis of data for the 1018 patients included in the three primary studies. By study end, HbA1c, fasting plasma glucose (FPG), LDL-C, total cholesterol (TC), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) were significantly reduced with COL versus placebo. Triglyceride (TG) and ApoA-I were significantly increased in the COL group relative to placebo. HDL-C did not change in either group, and the between-group treatment difference was small and not significant. Results of this pooled analysis are consistent with results reported previously in each of the primary COL studies and indicate that the HbA1c and LDL-C-lowering effects of COL are consistent, occurring regardless of whether COL is added to metformin, insulin, or sulfonylurea-based therapy. In conclusion, COL represents a novel therapeutic option by significantly lowering both LDL-C and HbA1c in patients with T2DM, two important treatment goals to forestall vascular complications.

Colesevelam HCl Improves Glycemic Control and Reduces LDL Cholesterol in Patients With Inadequately Controlled Type 2 Diabetes on Sulfonylurea-Based Therapy

OBJECTIVE—Hyperglycemia is a risk factor for microvascular complications and may increase the risk of cardiovascular disease in patients with type 2 diabetes. This study tested the LDL cholesterol–lowering agent colesevelam HCl (colesevelam) as a potential novel treatment for improving glycemic control in patients with type 2 diabetes on sulfonylurea-based therapy.RESEARCH DESIGN AND METHODS—A 26-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was carried out between August 2004 and August 2006 to evaluate the efficacy and safety of colesevelam for reducing A1C in adults with type 2 diabetes whose glycemic control was inadequate (A1C 7.5–9.5%) with existing sulfonylurea monotherapy or sulfonylurea in combination with additional oral antidiabetes agents. In total, 461 patients were randomized (230 given colesevelam 3.75 g/day and 231 given placebo). The primary efficacy measurement was mean placebo-corrected change in A1C from baseline to week 26 in the intent-to-treat population (last observation carried forward).RESULTS—The least squares (LS) mean change in A1C from baseline to week 26 was −0.32% in the colesevelam group and +0.23% in the placebo group, resulting in a treatment difference of −0.54% (P < 0.001). The LS mean percent change in LDL cholesterol from baseline to week 26 was −16.1% in the colesevelam group and +0.6% in the placebo group, resulting in a treatment difference of −16.7% (P < 0.001). Furthermore, significant reductions in fasting plasma glucose, fructosamine, total cholesterol, non–HDL cholesterol, and apolipoprotein B were demonstrated in the colesevelam relative to placebo group at week 26.CONCLUSIONS—Colesevelam improved glycemic control and reduced LDL cholesterol levels in patients with type 2 diabetes receiving sulfonylurea-based therapy.