Background: Management of type 2 diabetes mellitus (DM) that involves uptitration of monotherapy to the maximum dose has been associated with delays in achieving glycemic control and an increased number of adverse events (AEs). Studies have reported the benefits of adding a thiazolidinedione to metformin (MET), but none has compared the effect of adding a thiazolidinedione to MET versus increasing the daily dose of MET to 3 g. Objective: The goal of this study was to investigate the benefits of fixed-dose combination rosightazone and MET (RSG/MET) compared with high-dose MET monotherapy in patients with type 2 DM. Methods: This was a 24-week, multicenter, randomized, double-blind, parallel-group study. Patients previously treated with MET entered a 4-week, single-blind, run-in period with MET 2 g/d and were then randomized to RSG/MET 4 mg/2 g per day or MET 2.5 g/d. At week 8, medication was escalated to RSG/ MET 8 mg/2 g per day or MET 3 g/d. The primary efficacy end point was change in glycosylated hemoglobin (HbA(1c)) at week 24. Tolerability was assessed, including the frequency and severity of AEs. Results: A total of 568 patients comprised the safety population (MET, 280; RSG/MET, 288) and 551 formed the intent-to-treat group (MET, 272; RSG/ MET, 279). Baseline characteristics of the safety population were comparable in the 2 groups; body mass index (mean [SD]) was 32.2 (4.8) kg/m(2) and 32.1 (4.9) kg/m(2) in the RSG/MET and MET groups, respectively. RSG/MET reduced HbA(1c) (mean [SD]) from 7.4% (1.0%) to 7.1% (1.1%) at week 24, compared with a reduction from 7.5% (1.0%) to 7.4% (1.1%) with MET (treatment difference, -0.22%; P = 0.001). Fasting plasma glucose (mean [SD]) was reduced from 166.2 (29) to 144.1 (33) mg/dL with RSG/MET and from 169.3 (33) to 164.0 (37) mg/dL with MET (treatment difference, -18.3 mg/dL; P < 0.001). In addition, 54% of patients treated with RSG/MET achieved HbAlc levels <7.0%, compared with 36% with MET (odds ratio, 2.42; P < 0.001). RSG/MET increased homeostasis model assessment (HOMA) estimates of insulin sensitivity by 34.4% versus 6.5% with MET (treatment difference, 24.8%; P < 0.001). HOMA beta-cell function increased by 15.9% with RSG/MET versus 2.5% with MET (treatment difference, 14.0%; P < 0.001). RSG/MET decreased Greactive protein by a mean of 39.4% versus 16.0% with MET (treatment difference, -33.8%; P < 0.001). RSG/MET was generally well tolerated, with the majority of AEs mild,to moderate in nature. Serious AEs were reported in 3% of patients receiving RSG/MET and 2% with MET Overall rates of gastrointestinal AEs were 23% with RSG/MET and 26% with MET; however, there was an increased incidence of diarrhea (14% vs 6%) and abdominal pain (9% vs 6%) with MET. There was a mean (SE) increase in weight with RSG/MET (1.3 [0.22] kg) and a mean decrease (-0.9 [0.26] kg) with MET. Patients receiving RSG/MET reported improvements in treatment satisfaction compared with MET. Conclusions: In this study, the RSG/MET fixed-dose combination (8 mg/2 g per day) was an effective and well-tolerated treatment for type 2 DM and enabled more patients to reach glycemic targets than highdose MET (3 g/d).
