Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM

Background: Studies have shown that many patients with type 2 diabetes do not achieve optimal glycemic control, and progression of diabetes over time requires more than one pharmacotherapy to achieve glycemic goal. Objective: To examine the efficacy and safety of the fixed-dose combination (FDC) of pioglitazone 15 mg and metformin 850 mg versus its individual components in a twice-daily regimen over 24 weeks of treatment in type 2 diabetes patients who were currently not receiving antidiabetes therapy. Methods: This was a double-blind, randomized, parallel-group, controlled study. The primary endpoint was change from baseline in hemoglobin A1c (HbA1c) of pioglitazone/metformin FDC therapy compared with pioglitazone and metformin monotherapy. Secondary endpoints included change from baseline in fasting plasma glucose (FPG), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerability of pioglitazone/metformin FDC therapy and its individual components were also evaluated. Study limitations to be noted include the early stage of diabetes in these patients, which may be more responsive to treatment, and the 6 month treatment period, which does not provide durability data. Clinical trial registration: ClinicalTrials. gov, NCT00727857. Results: From a baseline HbA1c >8.6%, mean HbA1c decreased the most with pioglitazone/metformin FDC (-1.83%) (P<0.0001), compared with pioglitazone (-0.96%) and metformin (-0.99%) monotherapy, with 63.8% of FDC patients achieving HbA1c <= 7% versus 46.9% of pioglitazone-and 38.9% of metformin-treated patients. The decrease from baseline to final visit in FPG was significantly larger in the pioglitazone/metformin FDC group (-39.9 mg/dL) (P<0.01) compared with either monotherapy; the decrease in mean HOMA-IR was greatest with pioglitazone/metformin FDC. The pioglitazone/metformin FDC was well tolerated with no unexpected findings in adverse events of special interest, including hypoglycemia, bone fractures, peripheral edema, and cardiac failure. Conclusions: Overall, treatment with pioglitazone/metformin FDC demonstrated greater efficacy than its individual components. The FDC therapy was well tolerated, with reduced or similar adverse event rates compared with each individual monotherapy.