See online appendix for list of Sitagliptin Study 035 investigators.
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin
Article first published online: 26 JUN 2007
2007 Blackwell Publishing Ltd
Diabetes, Obesity and Metabolism
Volume 9, Issue 5, pages 733–745, September 2007
How to Cite
Hermansen, K., Kipnes, M., Luo, E., Fanurik, D., Khatami, H., Stein, P. and Sitagliptin Study 035 Group (2007), Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, Obesity and Metabolism, 9: 733–745. doi: 10.1111/j.1463-1326.2007.00744.x
- Issue published online: 26 JUN 2007
- Article first published online: 26 JUN 2007
- Received 11 April 2007; returned for revision 11 May 2007; revised version accepted 14 May 2007
- combination therapy;
- dipeptidyl peptidase-IV;
Aim: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA1c) ≥7.5% and ≤10.5%] while on glimepiride alone or in combination with metformin.
Methods: After a screening, diet/exercise run-in and drug wash-off period, a glimepiride ± metformin dose titration/stabilization period and a 2-week, single-blind placebo run-in, 441 patients (of ages 18–75 years) were randomized to receive the addition of sitagliptin 100 mg once daily or placebo in a 1 : 1 ratio for 24 weeks. Of these patients, 212 were on glimepiride (≥4 mg/day) monotherapy and 229 were on glimepiride (≥4 mg/day) plus metformin (≥1500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA1c from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements.
Results: Mean baseline HbA1c was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA1c by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA1c by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-β, a marker of β-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. −0.4 kg; p < 0.001).
Conclusions: Sitagliptin 100 mg once daily significantly improved glycaemic control and β-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.