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Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

ABSTRACT: To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes.This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at the final visit.At week 26, mean change in A1C was significantly greater (P < 0.001) for 12.5 mg (-0.56%) and 25 mg (-0.59%) alogliptin than placebo (-0.02%). Reductions in fasting plasma glucose were also greater (P < 0.001) in alogliptin-treated patients than in those receiving placebo. Overall, incidences of adverse events (67.4-70.3%) and hypoglycemia (1.5-3.0%) were similar across treatment groups.Alogliptin monotherapy was well tolerated and significantly improved glycemic control in patients with type 2 diabetes, without raising the incidence of hypoglycemia.

SUBMITTER: DeFronzo RA

PROVIDER: S-EPMC2584188 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

DeFronzo Ralph A RA Fleck Penny R PR Wilson Craig A CA Mekki Qais Q

Diabetes care 20080922 12

<h4>Objective</h4>To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes.<h4>Research design and methods</h4>This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at ...[more]

PMID: 18809631

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Project description:Background: As a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, TQ-F3083 represents a promising new drug for type 2 diabetes mellitus (T2DM). This phase I, first-in-human study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of TQ-F3083 in healthy Chinese adults. Methods: Sixty healthy participants total were enrolled in the single-ascending dose, multiple-dose, and food-effect studies. Safety endpoints included adverse events (AEs), vital signs, 12-lead electrocardiogram, abdominal ultrasound, chest X-ray, physical examination, and clinical laboratory tests. Blood, urine, and feces samples were collected for pharmacokinetic analyses. Pharmacodynamic parameters were evaluated based on DPP-4 activity and the active glucagon-like peptide-1 concentration. Results: In total, 22 treatment-related AEs, mostly grade 1 or 2, were reported in 14 individuals. No deaths, serious AEs, or grade ≥4 AEs occurred, and no dose-dependent AEs were demonstrated. For pharmacokinetic characteristics, dose linearity was analyzed using power model. The slopes (90% CIs) were 1.08 (1.02-1.13) and 1.05 (0.99-1.11) for AUC0-t and AUC0-∞, suggesting liner pharmacokinetic characteristic after oral dose TQ-F3083 from 2 to 160 mg. The accumulation factor was 1.39 after multiple dose for 7 days. Decreased plasma exposure (84.87% decrease in Cmax, 49.23% in AUC0-t, and 47.77% in AUC0-∞) was observed with administration after a high-fat and high-calorie standardized breakfast. The 0-72 h TQ-F3083 excretion recovery percentages were 7.84% in urine and 5.76% in feces. Over 80% DPP-4 inhibition for 24 h was observed in the 20-160 mg cohorts, and the model-estimated 50% effective concentration was 1.10 ng/ml. The concentration of active glucagon-like peptide-1 increased after TQ-F3083 administration, but no obvious dose dependency was observed. Conclusion: TQ-F3083 was well tolerated in healthy Chinese adults, and the pharmacokinetic and pharmacodynamic characteristics support further evaluation of TQ-F3083 in a trial in T2DM patients.

Project description:Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%-0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.

Dataset Information

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

Publications

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

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