Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial.
OBJECTIVE
To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.


METHODS
During a 12-week observation period 236 patients were treated with metformin 500 or 750 mg/day. 169 patients with a confirmed HbA(1c) level >or= 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15 mg/day for 12 weeks then increased to 30 mg/day for a further 16 weeks (n = 83), or placebo (n = 86). Outcome measures included HbA(1c), fasting blood glucose (FBG), percentage of patients achieving HbA(1c) < 6.5%, lipid profile, and other metabolic parameters.


RESULTS
Mean HbA(1c) was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p < 0.0001). After 8 weeks' treatment and until the end of the study, HbA(1c) was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA(1c) < 6.5% (38.6% vs. 8.1%; p < 0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (-20.5 vs. 1.9 mg/dl; p < 0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects 'possibly' related to therapy was 15.7% and 11.6% (p = 0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).


CONCLUSIONS
Pioglitazone plus metformin significantly improved glycemic control (HbA(1c) and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.


BACKGROUND
UMIN 000001110.
Kaku
Kohei
K
Diabetes and Endocrine Division, Department of Medicine, Kawasaki Medical School, Okayama, Japan. kka@med.kawasaki-m.ac.jp
D000328:Adult; D000465:Algorithms; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects*; D008875:Middle Aged; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects*; D016896:Treatment Outcome
D001786:Blood Glucose; D004338:Drug Combinations; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008055:Lipids; D008687:Metformin; D000077205:Pioglitazone; D010919:Placebos; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human