Abstract and Introduction
Abstract
Objective: To examine the efficacy and safety of once-daily oral sitagliptin as monotherapy in patients with type 2 diabetes.
Research Design and Methods: In a randomized, double-blind, placebo-controlled study, 741 patients (baseline HbA1c [A1C] 8.0%) were randomized to sitagliptin 100 or 200 mg or placebo for 24 weeks.
Results: Sitagliptin 100 and 200 mg produced significant (P < 0.001) placebo-subtracted reductions in A1C (-0.79 and -0.94%, respectively) and fasting plasma glucose (-1.0 mmol/l [-17.1 mg/dl] and -1.2 mmol/l [-21.3 mg/dl], respectively). Patients with baseline A1C ≥9% had greater reductions in placebo-subtracted A1C with sitagliptin 100 and 200 mg (-1.52 and -1.50%, respectively) than those with baseline A1C <8% (-0.57 and -0.65%) or ≥8 to <9.0% (-0.80 and -1.13%, respectively). In a meal tolerance test, sitagliptin 100 and 200 mg significantly decreased 2-h postprandial glucose (PPG) (placebo-subtracted PPG -2.6 mmol/l [-46.7 mg/dl] and -3.0 mmol/l [-54.1 mg/dl], respectively). Results for the above key efficacy parameters were not significantly different between sitagliptin doses. Homeostasis model assessment of ß-cell function and proinsulin-to-insulin ratio improved with sitagliptin. The incidence of hypoglycemia was similar, and overall gastrointestinal adverse experiences were slightly higher with sitagliptin. No meaningful body weight changes from baseline were observed with sitagliptin 100 (-0.2 kg) or 200 mg (-0.1 kg). The body weight change with placebo (-1.1 kg) was significantly (P < 0.01) different from that observed with sitagliptin.
Conclusions: In this 24-week study, once-daily sitagliptin monotherapy improved glycemic control in the fasting and postprandial states, improved measures of ß-cell function, and was well tolerated in patients with type 2 diabetes.
Introduction
Treatments that mimic or enhance the incretin axis are therapeutic approaches for managing type 2 diabetes. In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and, in turn, stimulate insulin and suppress glucagon release (both in a glucose-dependent manner), delay gastric emptying, and increase satiety. These incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents (OHAs). By slowing incretin degradation, DPP-4 inhibitors enhance meal-stimulated active GLP-1 and GIP levels by two- to threefold. Studies in animal models of, and in patients with, type 2 diabetes demonstrated that treatment with DPP-4 inhibitors improves measures of ß-cell function. In rodent models of type 2 diabetes, both GLP-1 and DPP-4 inhibitors led to ß-cell neogenesis and survival. Long-term studies are required to determine whether these ß-cell effects occur in patients with type 2 diabetes.
Sitagliptin, a once-daily, oral, potent, and highly selective DPP-4 inhibitor, inhibits plasma DPP-4 activity ≥80% over 24 h with single doses of ≥100 mg. In patients with type 2 diabetes, ≥80% inhibition of plasma DPP-4 activity with single doses of sitagliptin produced two- to threefold increases in active GLP-1 and GIP levels, increased insulin and C-peptide levels, reduced plasma glucagon levels, and reduced glycemic excursion following an oral glucose tolerance test. Two 12-week studies in patients with type 2 diabetes demonstrated that sitagliptin dose-dependently reduced HbA1c (A1C) and fasting plasma glucose (FPG), with a neutral effect on body weight and incidences of hypoglycemia and gastrointestinal adverse experiences similar to placebo.
Sitagliptin 100 mg q.d. was the most effective dose and was selected for continued development. In the present study, we tested once-daily sitagliptin 100 and 200 mg as monotherapy to explore tolerability and potential dose-dependent efficacy in patients with inadequately controlled type 2 diabetes.