Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes melitus: A randomized, placebo-controlled study

Background: Their complimentary mechanisms of action suggest that a combina tion of pioglitazone hydrochloride and metformin may have clinically benefi cial effects in the treatment of patients with type 2 diabetes. Objective: This study was undertaken to assess the efficacy and tolerabilit y of pioglitazone in combination with metformin in patients with type 2 dia betes mellitus. Methods: This was a 16-week, double-blind study with the option of enrollme nt in a separate open-ended, open-label study. It included patients with po orly controlled diabetes mellitus (glycated hemoglobin [HbA(1c)] greater th an or equal to8.0%, fasting C-peptide >1.0 ng/mL) who had been receiving a stable regimen of metformin for greater than or equal to 30 days. Patients with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or ki dney function; or unstable cardiovascular or cerebrovascular conditions wer e 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 pioglitazone + metformin, 160 placebo + metformin), and 249 completed t he study. Of these, 154 elected to enter the open-label extension study. Pa tients' mean age was 56 years. most (84%) were white and slightly more than half (57%) were male. Patients receiving pioglitazone 30 mg + metformin ha d statistically significant mean decreases in HbA(1c) (-0.83%) and fasting plasma glucose (FPG) levels (-37.7 mg/dL) compared with placebo + metformin (P less than or equal to 0.05). Decreases in FPG levels occurred as early as the fourth week of therapy, the first time point at which FPG was measur ed. The pioglitazone + metformin group had significant mean percentage chan ges in levels of triglycerides (-18.2%) and high-density lipoprotein choles terol (+8.7%) compared with placebo + metformin (P less than or equal to 0. 05). Mean percentage increases were noted in low-density lipoprotein choles terol levels (7.7%, pioglitazone + metformin; 11.9%, placebo + metformin) a nd total cholesterol (4.1%, pioglitazone + metformin; 1.1%, placebo + metfo rmin), with no significant differences between groups. In the extension stu dy, 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 aminotransferas e (ALT) value greater than or equal to3 times the upper limit of normal, a commonly used marker of potential liver damage. Thus, no evidence of drug-i nduced hepatotoxicity or drug-induced elevations in serum ALT was observed. Conclusions: In this study in patients with type 2 diabetes mellitus, piogl itazone + metformin significantly improved HbA(1c) and FPG levels, with pos itive effects on serum lipid levels and no evidence of drug-induced hepatot oxicity. These effects were maintained for >1.5 years, including the open-l abel extension.