Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity

Abstract

Objective:

To evaluate the efficacy of pioglitazone for the prevention of macrovascular outcomes in Japanese patients with type 2 diabetes, without a recent history of macrovascular morbidity.

Research design and methods:

This 2.5–4 year, prospective, randomized, open-label, blinded-endpoint study was conducted in 20 Japanese centers. Patients received pioglitazone ± other oral glucose-lowering drugs (excluding another thiazolidinedione) [n = 293] or oral glucose-lowering drugs excluding thiazolidinediones (n = 294). Treatment was adjusted to achieve HbA_1c < 6.5%. The primary endpoint was the time to onset of a macrovascular event.

Results:

Pioglitazone delayed the time to onset of macrovascular events and was associated with a lower cumulative incidence of such events (3.56% vs. 4.49% for controls). Neither finding achieved statistical significance. This was likely because of the type of patient included in the study (i.e. no recent history of cardiovascular events) and the high use of concomitant anti-diabetic agents. Reductions in HbA_1c, fasting blood glucose and fasting blood insulin levels, and an increase in HDL-C were significantly greater with pioglitazone throughout most of the study (p < 0.05). Fewer patients in the pioglitazone group commenced permanent treatment with insulin (3.3% vs. 13.7% in the control group). Adverse events were reported by 97.6% of the pioglitazone group and 96.9% of the control group (serious adverse events, including deaths, were 20.1 vs. 22.2%, respectively). The only notable difference between the two groups was a higher incidence of edema in the pioglitazone group. The main limitation of this study was that too few patients were included to identify statistically significant differences in the primary endpoint.

Conclusions:

Pioglitazone produced good glycemic control in Japanese patients with type 2 diabetes, and significantly fewer patients treated with pioglitazone needed long-term insulin therapy. These changes were associated with a trend towards delayed onset of macrovascular events.

Clinical trial registration:

UMIN000001363.

Key words::

• Japanese patients
• Macrovascular events
• Pioglitazone
• Type 2 diabetes

Transparency

Declaration of funding

This clinical study was supported by a financial grant from Takeda Pharmaceutical Co. Ltd, Osaka, Japan.

Declaration of financial/other relationships

K. Kaku has disclosed receiving research grant funding from Takeda, Novo Nordisk, Daiichi-Sankyo, Astellas, Sanofi-aventis, Banyu T has acted as a consultant to Novo Nordisk, and has served on speakers bureau for Takeda, Sanofi-aventis, Daiichi-Sankyo, Novo Nordisk, Novartis, Banyu, Astellas, Dainippon-Sumitomo, AstraZeneca, Sanwa. H.D. has disclosed receiving research grant funding from Takeda, Novartis, Astellas, Dainippon Sumitomo Pharma, Schering-Plough, Daiichi-Sankyo, Mochida, AstraZeneca, Shionogi, Boehringer Ingelheim, Sanofi-aventis; has served on speakers bureau for Kowa, Astellas, Schering-Plough, Pfizer, Daiichi-Sankyo, Mochida, AstraZeneca, Shionogi; and acted as a consultant to Kowa, AstraZeneca, Sanofi-aventis; A.K. has disclosed receiving research grant funding, travel grants and speaking honoraria from Takeda, T.Y. Tanabe, AstraZeneca and Shionogi and has acted as a consultant to AstraZeneca; S.M. has disclosed he has acted as a consultant to GlaxoSmithKline. R.K. has disclosed receiving research grant funding from Takeda, Novo Nordisk, Lilly, Daiichi-Sankyo, Astellas, Sanofi-aventis, Sanwa; has served on speakers bureau for Takeda, Sanofi-aventis, Daiichi-Sankyo, Novo Nordisk, Novartis, Astellas, Dainippon-Sumitomo, AstraZeneca, Sanwa, Pfeiser, Lilly, Bayer; and has acted as a consultant to Dainippon-Sumitomo. A.Y., T.I., Y.Y., K.N., K. Kitagawa have disclosed no relevant financial relationships.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed being on the speakers’ bureau for Takeda (Europe) and MSD; Peer Reviewer 2 has disclosed no relevant financial relationships.

Acknowledgements

Editorial assistance was provided by Katherine Croom BM and Steve Clissold PhD, ContentEdNet, with financial support from Takeda.

The authors would like to thank all the investigators and participants in the study, for which the investigational sites and principal investigators were:

Kurihara Diabetic Care Clinic: Yoshio Kurihara; Keijinkai Sasaki Diabetic Hospital; Takashi Sasaki; Toei Hospital: Ryo Sugiura; Kenichi Yamada Clinic: Kenichi Yamada; Okuguchi Clinic: Fuminobu Okuguchi; Nakakinen Clinic: Takeshi Osonoi; Minamiakatsuka Clinic: Hideo Takahashi; Kawai Clinic: Koichi Kawai; Arisaka Clinic: Tomoyuki Arisaka; Kobayashi Clinic of Internal Medicine and Gastroenterology: Izuru Kobayashi; Aiso Clinic: Yoshitaka Aiso; Sugawara Medicine Clinic: Masahiro Sugawara; Kenkoukan Suzuki Clinic: Kazuo Suzuki; Matsuba Clinic: Ikuro Matsuba; Okada Clinic: Akira Okada; Abe Diabetes Clinic: Nobuyuki Abe; Jinnouchi Clinic Diabetes Center: Hideaki Jinnouchi; Heiwadai Hospital: Syuji Nakamura; Yano Clinic: Nobuki Yano; Tempozan Naika Clinic: Jun Hashiguchi; Independent Safety Data Monitoring Committee Members: First Department of Internal Medicine, Osaka Medical College: Toshiaki Hanafusa; Health Care Center, Kwansei Gakuin University: Minoru Kubota; Department of Cardiology, Kawasaki Medical School: Kiyoshi Yoshida.