Cardiovascular Outcomes in Patients with Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment with Pioglitazone -Reports from the Japan Working Group for the Assessment Whether Pioglitazone Protects Dm Patients Against Re-Infarction (Ppar Study)-

Background: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. Methods: In this multicentre, prospective, randomised, open, blinded-endpoint trial of PPAR study, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. HbA1C levels were 5·9 and 5·8% (p = 0.71) at baseline and 6·0 and 5·8% (p < 0.01) at 2 years for the control and pioglitazone groups, respectively. Findings: The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years, respectively; the incidence of MI and stroke was 0·3% and 2·2% and 1·0% and 0·3%, respectively. Post-hoc analyses of the 7-year observation period showed that these trends became clearer. Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI. This result contradicts the results of the IRIS trial that pioglitazone decreased cardiovascular events in stroke patients  or the results of the PROactive trial that pioglitazone decreased cardiovascular events in patients with moderate DM and macrovascular disease. Funding: The Grants of Japan Heart Foundation for PPAR study. Conflict of Interest: Dr. Asakura reports grants from Acterion Pharmaceutical Japan, grants from Boehringer Ingelheim Japan, Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Sanofi K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from MSD K.K., personal fees from Takeda Pharmaceutical Company Limited., personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from DAIICHI SANKYO COMPANY, LIMITED , personal fees from Pfizer Japan Inc., personal fees from Astellas Amgen Biopharma, outside the submitted work. Dr. Kim has nothing to disclose. Dr. Asanuma reports grants from Japan Heart Foundation, during the conduct of the study; grants from Japan Society For The Promotion Of Science (Grants-in-Aid For Scientific Research), grants from Novartis Pharmaceuticals Corporation, grants from Mitsubishi Tanabe Pharma Corporation, personal fees from Otsuka Pharmaceutical Co,Ltd, personal fees from Kyowa Hakko Kirin Co, Ltd, personal fees from Daiichi Sankyo Company, Limited, outside the submitted work. Dr. Hamasaki has nothing to disclose. Dr. Nakama has nothing to disclose. Dr. Tsukahara reports grants from Japan Heart Foundation, during the conduct of the study. Dr. Higashino reports grants from Japan Heart Foundation, during the conduct of the study. Dr. Ishikawa reports grants from Japan Heart Foundation during the conduct of the study. Dr. Koba reports grants from Japan Heart Foundation during the conduct of the study; grants from Daiichi Sankyo Company, Ltd, personal fees from MSD K.K. outside the submitted work. Ethical Approval Statement: The study was performed following the principles of the Declaration of Helsinki and the Japanese ethical guidelines for clinical research.