Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycemic control compared with pioglitazone monotherapy in patients with type 2 diabetes.
Author(s): Wainstein J, Katz L, Engel SS, Xu L, Golm GT, Hussain S, O'Neill EA, Kaufman KD, Goldstein BJ
Affiliation(s): The E. Wolfson Medical Center, Holon, Israel Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey, U.S.A.
Publication date & source: 2011-11-07, Diabetes Obes Metab., [Epub ahead of print]
Aims: To evaluate the efficacy and safety of initial therapy with a fixed-dose combination of sitagliptin and metformin compared with pioglitazone in drug-naive patients with type 2 diabetes. Methods: After a 2-week single-blind placebo run-in period, patients with type 2 diabetes, HbA(1c) of 7.5%-12%, and not on antihyperglycemic agent therapy were randomized in a double-blind manner to initial treatment with a fixed-dose combination of sitagliptin/metformin 50/500 mg twice-daily (N=261) or pioglitazone 30 mg per day (N=256). Sitagliptin/metformin and pioglitazone were up-titrated over 4 weeks to doses of 50/1000 mg twice-daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA(1c) of 8.9% in both groups, LS mean changes in HbA(1c) at Week 32 were -1.9% and -1.4% for sitagliptin/metformin and pioglitazone, respectively (between-group difference = -0.5%; p<0.001). A greater proportion of patients had an HbA(1c) of <7% at Week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p<0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater least squares mean reductions in fasting plasma glucose (FPG) [-56.0 mg/dL (-3.11 mmol/L) vs. -44.0 mg/dL (-2.45 mmol/L), p<0.001] and in 2-hr post-meal glucose [-102.2 mg/dL (-5.68 mmol/L) vs. -82.0 mg/dL (-4.56 mmol/L), p<0.001] at Week 32. A substantially greater reduction in FPG [-40.5 mg/dL (-2.25 mmol/L) vs. -13.0 mg/dL (-0.72 mmol/L), p<0.001] was observed at Week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in HOMA-beta were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA-IR, and a greater increase in QUICKI were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well-tolerated. Sitagliptin/metformin led to weight loss (-1.4 kg) while pioglitazone led to weight gain (3.0 kg), (p<0.001 for the between-group difference). Higher incidences of diarrhea (15.3% vs. 4.3%, p<0.001), nausea (4.6% vs. 1.2%, p=0.02) and vomiting (1.9% vs. 0.0%, p=0.026), and a lower incidence of edema (1.1% vs. 7.0%, p<0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between-group difference in the incidence of hypoglycemia did not reach statistical significance (8.4% and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p=0.055). Conclusion: Compared with pioglitazone, initial therapy with a fixed-dose combination of sitagliptin and metformin led to significantly greater improvement in glycemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of edema, and weight loss vs. weight gain. (ClinicalTrials.gov: NCT00532935). (c) 2011 Blackwell Publishing Ltd.