Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study.
OBJECTIVE: This study was designed to compare the efficacy, safety and tolerability of rosiglitazone (RSG) added to submaximal doses of metformin (MET) with dose escalation to the maximal effective dose of MET monotherapy in type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: In this multi-center, double-blind, randomized, parallel-group study, 766 subjects with a baseline MET dose of 1000 mg/day were randomized to receive either RSG 4 mg/day (4 mg/1000 mg) or MET 500 mg/day (1500 mg/day total dose) for 8 weeks. Only the RSG dose was increased in the combination group - to 8 mg/day (8 mg/1000 mg) - and only the MET dose was increased in the MET monotherapy group - to 2000 mg/day for the remaining 16 weeks. RESULTS: After 24 weeks, RSG added to MET (8 mg/1000 mg/day) was at least as effective as 2000 mg/day of MET in improving HbA(1c), with mean reductions of -0.93% (95% CI: -1.06%, -0.80%) and -0.71% (95% CI: -0.83%, -0.60%), respectively, from baseline in subjects that completed the study according to the investigator (mean treatment effect/difference of -0.20% [95% CI: -0.36%, -0.04%]). In addition, a higher percentage of subjects in the RSG + MET group achieved American Diabetes Association target levels of HbA(1c) < 7% (58.1% versus 48.4%) and American Association of Clinical Endocrinologists target levels of HbA(1c) <or= 6.5% (40.9% versus 28.2%). This combination provided significantly greater reductions from baseline in fasting plasma glucose (FPG; -2.29 mmol/L [+/- 2.37 mmol/L] and -1.12 mmol/L [+/- 2.41 mmol/L], respectively), with a treatment difference of -0.85 mmol/L (95% Cl: -1.23 mmol/L, -0.47 mmol/L). For the intent-to-treat (ITT) population, the percentage of subjects experiencing a gastrointestinal side-effect was 27.9% and 38.7% for the RSG + MET and MET groups, respectively (OR = 1.63, 95% CI: 1.19, 2.24). Mean body weight (+/- SD) increased in all randomized subjects treated with the combination therapy (+ 1.79 +/- 4.15 kg) compared with a mean weight loss in the up-titrated MET group (-1.78 +/- 3.50 kg). CONCLUSIONS: This study suggests that addition of RSG to submaximal doses of MET may be a suitable alternative to the maximal effective dose of MET monotherapy.