Effect of Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients With Type 2 Diabetes

Abstract

OBJECTIVE—To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS—In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5–11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS—The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was −2.07% (S100/M2000), −1.57% (S100/M1000), −1.30% (M2000), −0.99% (M1000), and −0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was −2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS—The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.

DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials

“…The initial combination of sitagliptin (2 × 50 mg) or vildagliptin (2 × 50 mg) with metformin (low dose of 2 × 500 mg or high dose of 2 × 1000 mg) had superior efficacy compared with monotherapy treatments, with comparable overall tolerability profiles and low risk of hypoglycaemia [13][14][15][19][20][21]71]. Similar results were obtained with the initial combination of saxagliptin 5 or 10 mg plus metformin 500 mg uptitrated to 2000 mg [20,21].…”

“…As metformin is considered the first-line drug therapy for the management of T2DM [10,11], it is of interest to compare the efficacy (and safety) of aDPP-4 inhibitor with that of metformin in drug-naive T2DM patients insufficiently controlled with diet and exercise [12][13][14][15][16][17][18][19][20][21]. Overall, metformin (1000-2000 mg/day) demonstrated slightly (but significantly) greater reductions in both HbA 1c and body weight ( Table 1, Fig.…”

“…Several clinical trials have evaluated initial combinations of either metformin + gliptin [13][14][15][19][20][21]71] or TZD + gliptin [22,23,58,72] and compared the results with an initial monotherapy (Table 1). However, none of these trials evaluated an initial combination including a DPP-4 inhibitor vs another initial combination not including a gliptin in a head-to-head comparison.…”

Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy

“…DPP-4 inhibitors are small molecules that enhance the effects of GLP-1 and GIP, increasing glucose-mediated insulin secretion and suppressing glucagon secretion. [83,84]. The first oral DPP-4 inhibitor, sitagliptin, was approved by the Food and Drug Administration in October 2006 for use as monotherapy or in combination with metformin or TZDs.…”

“…Another DPP-4 inhibitor, vildagliptin, was approved in Europe in February 2008, and several other compounds are under development. In clinical trials performed to date, DPP-4 inhibitors lower HbA 1c levels by 0.6-0.9 percentage points and are weight neutral and relatively well tolerated [83,84]. They do not cause hypoglycaemia when used as monotherapy.…”