A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin and metformin co-administration. Patients on an antihyperglycemic agent (N=541) underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive placebo, 100mg of sitagliptin once daily, 500mg or 1000mg of metformin twice daily, or 50mg of sitagliptin twice daily in combination with 500mg or 1000mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin co-administration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 4, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin 500mg bid, -1.1%; metformin 1000mg bid, -1.2%; sitagliptin 50mg bid with metformin 500mg bid, -1.6%; sitagliptin 50mg bid with metformin 1000mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.

Table 4: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise*  Placebo
 Sitagliptin

100 mg QD
 Metformin
500 mg bid Metformin
1000 mg bid Sitagliptin
50 mg bid +
Metformin
500 mg bid Sitagliptin
50 mg bid +
Metformin
1000 mg bid
*
Intent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy.
†
Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡
p<0.001 compared to placebo.
A1C (%) N = 165 N = 175 N = 178 N = 177 N = 183 N = 178
Baseline (mean) 8.7 8.9 8.9 8.7 8.8 8.8
Change from baseline (adjusted mean†) 0.2 -0.7 -0.8 -1.1 -1.4 -1.9
Difference from placebo (adjustedmean†)
(95% CI)  -0.8‡
(-1.1, -0.6) -1.0‡
(-1.2, -0.8) -1.3‡
(-1.5, -1.1) -1.6‡
(-1.8, -1.3) -2.1‡
(-2.3, -1.8)
Patients (%) achieving A1C <7% 15 (9%) 35 (20%) 41 (23%) 68 (38%) 79 (43%) 118 (66%)
% Patients receiving rescue medication 32 21 17 12 8 2
FPG (mg/dL)  N = 169 N = 178 N = 179 N = 179 N = 183 N = 180
Baseline (mean) 196 201 205 197 204 197
Change from baseline (adjusted mean†) 6 -17 -27 -29 -47 -64
Difference from placebo (adjustedmean†)
(95% C