Aim: To assess the efficacy and safety of a 24‐week treatment with sitagliptin, a highly selective once‐daily oral dipeptidyl peptidase‐4 (DPP‐4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA1c) ≥7.5% and ≤10.5%] while on glimepiride alone or in combination with metformin. Methods: After a screening, diet/exercise run‐in and drug wash‐off period, a glimepiride ± metformin dose titration/stabilization period and a 2‐week, single‐blind placebo run‐in, 441 patients (of ages 18–75 years) were randomized to receive the addition of sitagliptin 100 mg once daily or placebo in a 1 : 1 ratio for 24 weeks. Of these patients, 212 were on glimepiride (≥4 mg/day) monotherapy and 229 were on glimepiride (≥4 mg/day) plus metformin (≥1500 mg/day) combination therapy. Patients exceeding pre‐specified glycaemic thresholds during the double‐blind treatment period were provided open‐label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA1c from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2‐h post‐meal glucose and lipid measurements. Results: Mean baseline HbA1c was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA1c by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA1c by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment‐β, a marker of β‐cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2‐h post‐prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug‐related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. −0.4 kg; p < 0.001). Conclusions: Sitagliptin 100 mg once daily significantly improved glycaemic control and β‐cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.
Background: Patients with type 2 diabetes are often treated with oral antidiabetic agents plus a basal insulin. Objective: To investigate the efficacy and safety of glimepiride combined with either morning or bedtime insulin glargine or bedtime neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. Design: open-label, randomized, controlled trial. Setting: 111 centers in 13 European countries. Patients: 695 patients with type 2 diabetes who were previously treated with oral antidiabetic agents. Intervention: Randomization to treatment with morning insulin glargine, bedtime NPH insulin, or bedtime insulin glargine for 24 weeks in addition to 3 mg of glimepiride. The insulin dose was titrated by using a predefined regimen to achieve fasting blood glucose levels of 5.56 mmol/L or lower (less than or equal to100 mg/dL). Measurements: Hemoglobin A(1c) values, blood glucose levels, insulin dose, and body weight. Results: Hemoglobin A(1c) levels improved by -1.24% (two-sided 90% CI, -1,10% to -1.38%) with morning insulin glargine, by -0.96% (CI, -0.81% to -1.10%) with bedtime insulin glargine, and by -0.84% (CI, -0.69% to -0.98%) with bedtime NPH insulin. Hemoglobin A(1c) improvement was more pronounced with morning insulin glargine than with NPH insulin (0.40% [CI, 0.23% to 0.58%]; P = 0.001) or bedtime insulin glargine (0.28% [CI, 0.11% to 0.46%]; P = 0.008). Baseline to end-point fasting blood glucose levels improved similarly in all three groups. Nocturnal hypoglycemia was less frequent with morning (39 of 236 patients [17%]) and bedtime insulin glargine (52 of 227 patients [23%]) than with bedtime NPH insulin (89 of 232 patients [38%]) (P < 0.001). Conclusion: The risk for nocturnal hypoglycemia was lower with glimepiride in combination with morning and bedtime insulin glargine than with glimepiride in combination with bedtime NPH insulin in patients with type 2 diabetes. Morning insulin glargine provided better glycemic control than did bedtime insulin glargine or bedtime NPH insulin.
Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients. Diabetes 62:1289-1296, 2013
Summary Background New treatments for type 2 diabetes mellitus are needed to retain insulin–glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder. Methods In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1·2 mg [n=251] or 1·8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA1c ). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NTC00294723. Findings At 52 weeks, HbA1c decreased by 0·51% (SD 1·20%) with glimepiride, compared with 0·84% (1·23%) with liraglutide 1·2 mg (difference −0·33%; 95% CI −0·53 to −0·13, p=0·0014) and 1·14% (1·24%) with liraglutide 1·8 mg (−0·62; −0·83 to −0·42, p<0·0001). Five patients in the liraglutide 1·2 mg, and one in 1·8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so. Interpretation Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA1c , weight, hypoglycaemia, and blood pressure than does glimepiride. Funding Novo Nordisk A/S.
Summary Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion. We compared the efficacy and safety of canagliflozin, an SGLT2 inhibitor, with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Methods We undertook this 52 week, randomised, double-blind, active-controlled, phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28, 2009, and Dec 21, 2011. Patients aged 18–80 years with type 2 diabetes and glycated haemoglobin A1c (HbA1c ) of 7·0–9·5% on stable metformin were randomly assigned (1:1:1) by computer-generated random sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg, or glimepiride (up-titrated to 6 mg or 8 mg per day) orally once daily. Patients, study investigators, and local sponsor personnel were masked to treatment. The primary endpoint was change in HbA1c from baseline to week 52, with a non-inferiority margin of 0·3% for the comparison of each canagliflozin dose with glimepiride. If non-inferiority was shown, we assessed superiority on the basis of an upper bound of the 95% CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0%. Analysis was done in a modified intention-to-treat population, including all randomised patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00968812. Findings 1450 of 1452 randomised patients received at least one dose of glimepiride (n=482), canagliflozin 100 mg (n=483), or canagliflozin 300 mg (n=485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0·01% [95% CI −0·11 to 0·09]), and canagliflozin 300 mg was superior to glimepiride (–0·12% [–0·22 to −0·02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]). Interpretation Canagliflozin provides greater HbA1c reduction than does glimepiride, and is well tolerated in patients with type 2 diabetes receiving metformin. These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy. Funding Janssen Research & Development, LLC.
OBJECTIVE - Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas (hypoglycemic risk, sulfonylurea receptor selectivity, and effects on myocardial ischemic preconditioning). The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS - A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), years of age with and without a history of coronary artery disease (CAD) and not on insulin or a noninsulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models were used to compare cohorts. RESULTS - No statistically significant difference in the risk of overall mortality was observed among these agents in the entire cohort, but we did find evidence of a trend toward an increased overall mortality risk with glyburide versus glimepiride (hazard ratio 1.36[95% CI 0.96-1.91]) and glipizide versus glimepiride (1.39 [0.99-1.96]) in those with documented CAD. CONCLUSIONS - Our results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD.
Objectives The DPP-4 inhibitors are incretin-related drugs that improve hyperglycemia in a glucose-dependent manner and have been reported to exert favorable effects on atherosclerosis. However, it has not been fully elucidated whether DPP-4 inhibitors are able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of sitagliptin, a DPP-4 inhibitor, on endothelial function and glycemic metabolism compared with that of the sulfonylurea glimepiride. Materials and Methods In this multicenter, prospective, randomized parallel-group comparison study, 103 outpatients with type 2 diabetes (aged 59.9 +/- 9.9 years with HbA1c levels of 7.5 +/- 0.4%) with dietary cure only and/or current metformin treatment were enrolled and randomly assigned to receive sitagliptin or glimepiride therapy once daily for 26 weeks. Flow-mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force 1 Monitor), and serum metabolic markers were assessed before and after the treatment. Results During the study period, no statistically significant change in %FMD was seen in both groups (sitagliptin, 5.6 to 5.6%; glimepiride, 5.6 to 6.0%). Secretory units of islets in transplantation, TNF-alpha, adiponectin and biological antioxidant potential significantly improved in the sitagliptin group, and superoxide dismutase also tended to improve in the sitagliptin group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different. Conclusions Regardless of glycemic improvement, early sitagliptin therapy did not affect endothelial function but may provide favorable effects on beta-cell function and on inflammatory and oxidative stress in patients with type 2 diabetes without advanced atherosclerosis.
Aims To evaluate the safety and efficacy of once‐weekly dulaglutide 1.5 mg, a long‐acting glucagon‐like peptide‐1 receptor agonist, compared with placebo in patients with type 2 diabetes (T2D) on glimepiride monotherapy. Methods This phase III, randomized (4 : 1; dulaglutide:placebo), double‐blind, placebo‐controlled, 24‐week study compared the safety and efficacy of once‐weekly dulaglutide 1.5 mg with placebo in sulphonylurea‐treated (≥half‐maximal dose, stable ≥3 months) patients (N = 300) with T2D and inadequate glycaemic control [glycated haemoglobin (HbA1c) ≥7.5 and ≤9.5% (≥58 mmol/mol and ≤80 mmol/mol)]. Analysis was carried out according to intention‐to‐treat. Results At baseline, the mean participant age was 58 years; mean HbA1c was 8.4% (68 mmol/mol) and mean weight was 85.5 kg. Dulaglutide 1.5 mg was superior to placebo at 24 weeks for HbA1c reduction from baseline with a between‐group HbA1c difference of −1.3% [95% confidence interval (CI) −1.6, −1.0] or ‐14 mmol/mol (95% CI −17, −11); p < 0.001. A greater proportion of participants in the dulaglutide group reached an HbA1c level of <7.0% (53 mmol/mol) compared with placebo (55.3% vs 18.9%; p < 0.001). Dulaglutide significantly decreased fasting serum glucose from baseline compared with placebo (between‐group difference −1.86 mmol/l (95% CI −2.58, −1.14) or −33.54 mg/dl (95% CI −46.55, −20.53); p < 0.001. Weight was decreased significantly from baseline in the dulaglutide group (p < 0.001); the between‐group difference was not significant. The most common treatment‐emergent adverse events for dulaglutide 1.5 mg were gastrointestinal: nausea (10.5%), diarrhoea (8.4%) and eructation (5.9%). Total hypoglycaemia was higher with dulaglutide 1.5 mg vs placebo (2.37 and 0.07 events/participant/year, respectively; p = 0.025). No severe hypoglycaemia was reported. Conclusions Once‐weekly dulaglutide 1.5 mg had a favourable benefit/risk profile when added to glimepiride monotherapy.
Background: In a previous single-center, open-label randomized 3-month study of triple oral antidiabetes drug (OAD) therapy, we investigated factors affecting the glycemic control afforded by sitagliptin, high-dose metformin, and low-dose glimepiride. Patients were prospectively assigned to either Group 1 (50% reduction in metformin) or Group 2 (discontinuation of glimepiride) and compared. The results showed that the glycated hemoglobin (HbA1c) levels of patients in Group 2 deteriorated more than those in Group 1, whereas HbA1c levels were maintained in some patients in both groups. Materials and Methods: To determine the factors associated with maintenance of HbA1c under this triple OAD regimen, data from the prospective study were further analyzed. Results: In both Groups 1 and 2, the baseline HbA1c level was higher in patients with HbA1c ≥7.0% after 3 months of treatment than those with an HbA1c level of <7.0%. A generalized linear model revealed that high-dose metformin was associated with a deterioration of HbA1c levels in Group 2. Conclusions: Together, the findings indicate that glimepiride and high-dose metformin are important for sustained glycemic control in triple OAD therapy with sitagliptin, metformin, and sulfonylurea.
Drug-free microparticles were prepared using a spray congealing process with the intention of studying the influence of processing parameters. By varying the atomizing pressure and liquid feed rate, microparticles with median sizes ( d (0.5)) from 58 to 278 μm were produced, with total process yields ranging from 81% to 96%. An increased liquid feed rate was found to increase microparticle size, and higher atomizing pressures were found to decrease microparticle size. Greater change in microparticle size was achieved by varying atomizing pressure, which can be considered a dominant process parameter regarding microparticle size. In addition, microparticles with glimepiride, a model poorly water-soluble drug, were prepared by spray congealing using three different hydrophilic meltable carriers: Gelucire ® 50/13, poloxamer 188, and PEG 6000. Spherical microparticles with relatively smooth surfaces were obtained, with no drug crystals evident on the surfaces of drug-loaded microparticles. XRPD showed no change in crystallinity of the drug due to the technological process of microparticle production. All glimepiride-loaded microparticles showed enhanced solubility compared to pure drug; however, Gelucire ® 50/13 as a carrier represents the most promising approach to the dissolution rate enhancement of glimepiride. The influence of storage (30 °C/65% RH for 30 days) on the morphology of glimepiride/Gelucire ® 50/13 microparticles was studied, and the formation of leaf-like structures was observed (a “blooming” effect).