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

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and 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 ≥ 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%).

Conclusion: 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.

Clinical trial registration number: UMIN 000001110.

Key words: :

• Combination therapy
• Metformin
• Pioglitazone
• Type 2 diabetes

Acknowledgements

Declaration of interest: This clinical trial was supported by a financial grant from Takeda Pharmaceutical Co., Ltd, Osaka, Japan. Editorial assistance was provided by Steve Clissold PhD, ContentEdNet, with funding provided by Takeda.

Participating institutions and investigators – Utsunomiya Higashi Hospital: Ozaki Shiro, Kadota Satoru; Oyama East Clinic: Ohashi Hiroshi; Misaki Naika Clinic: Kuribayashi Nobuichi; Yanagida Clinic: Yanagida Kazuhiro; Fujibashi Internal Medicine Clinic; Kitagawa Setsuji; Saiseikai Niigata Daini Hospital; Suzuki Katsunori; Yoshimi Internal Medicine Clinic; Yoshimi Teruya, Sen Seiko; Komatsu Clinic; Komatsu Katsutoshi; Hinata Clinic: Hinata Shinichi; Saishukan Hospital: Imamura Masako, Ogawa Yasuhiro, Miyake Yumiko, Suzuki Shigeo, Imamura Akiko, Mizutani Kazuhiro, Oguma Tetsuya, Yasuda Keiko; Ikebuchi Clinic: Ikebuchi Motoyoshi; Nara Prefectural Nara Hospital: Kikuchi Eiryo, Nakatani Toshinari, Uejima Masakazu; Okayama Rosai Hospital: Kato Kenichi, Kurokawa Kazuyoshi; Kagawa Prefectural Central Hospital: Nakata Kenichi; Fukuoka Teishin Hospital: Higuchi Kazumi; Fukuoka City Medical Association Hospital: Tajiri Yuji, Umeda Fumio, Takei Ryoko; Fukuseikai Kawanami Hospital: Sugimoto Masahiro, Ogata Hideaki; Kyushu Rosai Hospital: Haji Masafumi, Tanaka Seiichi, Ichino Isao; Saiseikai Fukuoka General Hospital: Sako Yasuhiro, Sekiguchi Naotaka, Ashida Kenji; Clinic Minami Masae: Minami Masae; The Japanese Red Cross Nagasaki Atomic Bomb Hospital: Ueda Yasuo, Morita Shigeki; Kumamoto Municipal Citizen's Hospital: Todaka Mikio; Kumamoto Rosai Hospital: Kaneko Kengo, Kiritoshi Shinsuke; Nippon Kokan Fukuyama Hospital: Okuno Tetsuji, Hakoda Tomomi; Fukuoka Shin Mizumaki Hospital: Fujii Shigeru, Miyazono Hirotaka.