Background: Their complimentary mechanisms of action suggest that a combination of pioglitazone hydrochloride and metformin may have clinically beneficial effects in the treatment of patients with type 2 diabetes. Objective: This study was undertaken to assess the efficacy and tolerability of pioglitazone in combination with metformin in patients with type 2 diabetes mellitus. Methods: This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled diabetes mellitus (glycated hemoglobin [HbA 1c] ≥8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded. Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the open-label extension received pioglitazone 30 mg (with optional titration to 45 mg) + metformin. Results: Three hundred twenty-eight patients were randomized to treatment (168 pio-glitazone + metformin, 160 placebo + metformin), and 249 completed the study. Of these, 154 elected to enter the open-label extension study. Patients' mean age was 56 years; most (84%) were white and slightly more than half (57%) were male. Patients receiving pioglitazone 30 mg + metformin had statistically significant mean decreases in HbA 1c (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P ≤ 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measured. The pioglitazone + metformin group had significant mean percentage changes in levels of triglycerides (-18.2%) and high-density lipoprotein cholesterol (+8.7%) compared with placebo + metformin (P ≤ 0.05). Mean percentage increases were noted in low-density lipoprotein cholesterol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) and total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metformin), with no significant differences between groups. In the extension study, patients treated with open-label pioglitazone + metformin for 72 weeks had mean changes from baseline of -1.36% in HbA 1c and -63.0 mg/dL in FPG. The incidence of adverse events was similar in both groups. Throughout the study, no patient in either treatment group had an alanine aminotransferase (ALT) value ≥3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-induced hepatotoxicity or drug-induced elevations in serum ALT was observed. Conclusions: In this study in patients with type 2 diabetes mellitus, pioglitazone + metformin significantly improved HbA 1c and FPG levels, with positive effects on serum lipid levels and no evidence of drug-induced hepatotoxicity. These effects were maintained for >1.5 years, including the open-label extension.
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