Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Objective: The efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy were assessed in patients with type 2 diabetes and inadequate glycemic control (glycosylated hemoglobin [HbA(1c)] >= 7% and <= 10%) while receiving a stable dose of ploglitazone. Methods: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in patients aged >= 18 years (Clinical-Trials. gov NCT00086502). At screening, all patients began a diet/exercise program that continued throughout the study period. Patients taking antihyperglycemic therapy other than ploglitazone underwent a washout of this therapy and entered an 8- to 14-week open-label ploglitazone dose-titration/stabilization period. Patients with an HbA(1c) >= 7% and <= 10% at the end of this period entered a 2-week, single-blind, placebo run-in period (total duration of run-in period, up to 21 weeks). Patients who had been receiving ploglitazone monotherapy (30 or 45 mg/d) and had an HbA(1c) >= 7% and ! 10% entered the 2-week, single-blind, placebo run-in period directly. Thus, at the time of randomization, all patients were receiving ongoing pioglitazone (30 or 45 mg/d). Patients were randomized in a 1:1 ratio to receive sitagliptin 100 mg once daily or placebo for 24 weeks. The primary efficacy end point was the change from baseline in HbA(1c) at week 24. Secondary efficacy end points included the change from baseline in fasting plasma glucose (FPG), insulin, and proinsulin; the Homeostasis Model Assessment P-cell function and insulin-resistance indexes; the proinsulin/insulin ratio; the Quantitative Insulin Sensitivity Check Index; the percent changes from baseline in selected lipid parameters; the proportion of patients meeting the American Diabetes Association HbA(1c) goal of < 7.0%; the proportion of patients requiring metformin rescue therapy; and the time to the initiation of rescue therapy. Results: One hundred seventy-five patients were randomized to receive sitagliptin, and 178 were randomized to receive placebo. The mean (SD) baseline HbA(1c) value was 8.1% (0.8) in the sitagliptin group and 8.0% (0.8) in the placebo group. After 24 weeks, sitagliptin added to ploglitazone therapy was associated with significant reductions compared with placebo in HbA(1c) (between-treatment difference in least squares [LS] mean change from baseline: -0.70%; 95% CI, -0.85 to -0.54; P < 0.001) and FPG (-17.7 mg/dL; 95% CI, -24.3 to -11.0; P < 0.001). Mean HbA(1c) values at end point were 7.2% (0.9) and 7.8% (1.1) in the respective treatment groups, and the proportions of patients reaching a target HbA(1c) of < 7.0% were 45.4% and 23.0% (P < 0.001). Significant reductions in fasting serum proinsulin levels and the proinsulin/insulin ratio were seen with sitagliptin treatment compared with placebo (both, P < 0.01). Sitagliptin was generally well tolerated, with no increased risk of hypoglycemia compared with placebo (2 vs 0 patients, respectively). The number of patients discontinuing the study due to clinical adverse experiences (10 [5.7%] vs 2 [1.1%]) and the incidence of abdominal pain (3.4% vs 0%) were significantly greater in the sitagliptin group compared with the placebo group (both, P < 0.05). The LS mean change in body weight from baseline did not differ significantly between sitagliptin or placebo added to ploglitazone therapy (between-treatment difference in LS mean change from baseline: 0.2 kg; 95% CI, -0.5 to 1.0). Conclusion: In this 24-week study, sitagliptin 100 mg once daily added to ongoing pioglitazone therapy was effective and well tolerated in these patients with type 2 diabetes who had not achieved adequate glycemic control with pioglitazone alone.