Abstract
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, 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. Findings: 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. The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662–1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786–32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051–3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618–1·237, p = 0·45). Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.
Original language | English |
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Pages (from-to) | 10-24 |
Number of pages | 15 |
Journal | EClinicalMedicine |
Volume | 4-5 |
DOIs | |
Publication status | Published - 2018 Oct 1 |
Keywords
- Blood glucose-lowering
- Cardiovascular events
- Diabetes mellitus
- Myocardial infarction
- PROBE study
- Pioglitazone
ASJC Scopus subject areas
- Medicine(all)
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TY - JOUR
T1 - Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone
T2 - Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study)
AU - PPAR investigators
AU - Asakura, Masanori
AU - Kim, Jiyoong
AU - Asanuma, Hiroshi
AU - Nakama, Yasuharu
AU - Tsukahara, Kengo
AU - Higashino, Yorihiko
AU - Ishikawa, Tetsuya
AU - Koba, Shinji
AU - Tsujimoto, Mitsuru
AU - Himeno, Hideo
AU - Maruyama, Yasuyuki
AU - Ookusa, Takanori
AU - Yoda, Shunichi
AU - Suzuki, Hiroshi
AU - Okubo, Shinji
AU - Shimizu, Makoto
AU - Hashimoto, Yuji
AU - Satake, Kazuo
AU - Fujino, Susumu
AU - Uzui, Hiroyasu
AU - Nagai, Yoshiyuki
AU - Kohno, Tohru
AU - Mizuno, Sumio
AU - Nakahama, Makoto
AU - Kanaya, Hounin
AU - Murohara, Toyoaki
AU - Fukui, Kazuki
AU - Takase, Hiroyuki
AU - Ohte, Nobuyuki
AU - Shiono, Takaaki
AU - Fukunami, Masatake
AU - Endo, Tsutomu
AU - Sawada, Reimin
AU - Fujii, Kenshi
AU - Takeuchi, Motoshi
AU - Ikeda, Shuntaro
AU - Mizuno, Koichi
AU - Uematsu, Masaaki
AU - Matsubara, Taku
AU - Yano, Shoji
AU - Takahashi, Jun
AU - Ueda, Kousei
AU - Kinoshita, Yoshihiko
AU - Tamita, Koichi
AU - Hayashi, Hideki
AU - Hamasaki, Toshimitsu
AU - Kitakaze, Masafumi
N1 - Funding Information: This study was supported by Grants for PPAR study from Japan Heart Foundation , Japan. Funding Information: 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. Funding Information: 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. Funding Information: Dr. Tsukahara reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Higashino reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Ishikawa reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: 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. Funding Information: Dr. Tsujimoto reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Himeno reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Maruyama reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Saitama Medical Association, personal fees from Iwatsuki Medical Association, personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Astellas Pharma Inc., personal fees from Otsuka Pharmaceutical Co, Ltd., personal fees from Sanwa Kagaku Kenkyusho Co, Ltd., personal fees from MSD K.K., personal fees from Novartis Pharma K.K., personal fees from Sanofi K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from Kyowa Hakko Kirin Co, Ltd., personal fees from Torii Pharmaceutical Co, Ltd., personal fees from Kowa Pharmaceutical Co, Ltd., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Ono Pharmaceutical Co, Ltd., personal fees from Daiichi Sankyo Company, Ltd., personal fees from Pfizer Japan Inc., personal fees from Sumitomo Dainippon Pharma Co, Ltd., personal fees from Chugai Pharmaceutical Co, Ltd., personal fees from Eisai Co, Ltd., outside the submitted work. Funding Information: Dr. Ohkusa reports grants from Japan Heart Foundation during the conduct of the study; personal fees from Otsuka Pharmaceutical, outside the submitted work. Funding Information: Dr. Yoda reports grants from Japan heart Foundation during the conduct of the study; personal fees from Nihon Medi-Physics Co, Ltd., outside the submitted work. Funding Information: Dr. Suzuki reports grants from Japan Heart Foundation, during the conduct of the study; grants from Kanagawa Public Health Association, grants from Astellas Pharma Inc., grants from Astra Zeneca K.K., grants from Abbott Vascular Japan Co, Ltd., grants from Otsuka Pharmaceutical Co, Ltd., grants from Ono Pharmaceutical Company Ltd., grants from Kowa Pharmaceutical Company Ltd., grants from Sanofi K.K., grants from Shionogi & Co, Ltd., grants from Daiichi Sankyo Company, Limited, grants from Takeda Pharmaceutical Company Limited, grants from Mitsubishi Tanabe Pharma Corporation, grants from Chugai Pharmaceutical Co, Ltd., grants from Novartis Pharma K.K., grants from Nihon-Medi-Physics Co, Ltd., grants from Bayer Yakuhin, Ltd., grants from Biotronik Japan Co, Ltd., grants from Pfizer Japan Inc., grants from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Astellas Pharma Inc., personal fees from Astra Zeneca K.K., personal fees from Abbott Vascular Japan Co, Ltd., personal fees from Otsuka Pharmaceutical Co, Ltd., personal fees from Ono Pharmaceutical Company Ltd., personal fees from Kowa Pharmaceutical Company Ltd., personal fees from Sanofi K.K., personal fees from Shionogi & Co, Ltd., personal fees from Daiichi Sankyo Company, Limited, personal fees from Takeda Pharmaceutical Company, Limited, personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Novartis Pharma K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from Toa Eiyo Ltd., personal fees from Pfizer Japan Inc., personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Jimro Co, Ltd., personal fees from Actelion Pharmaceutical Japan Ltd., personal fees from Cook Medical in Japan, personal fees from Medtronic Japan Co, Ltd., personal fees from MSD K.K., outside the submitted work. Funding Information: Dr. Okubo reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Shimizu reports grants from Japan Heart Foundation, during the conduct of the study; grants from Public Health Research Foundation, grants from Japan Cardiovascular Foundation, personal fees from The Japanese Society Of Internal Medicine, personal fees from General Association Of Izumi-Ku, Yokahama-Shi Medical Association, personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Astellas Pharma Inc., personal fees from St Marianna University School Of Medicine, personal fees from Otsuka Pharmaceutical Co, Ltd., personal fees from Yokohama City Fire Bureau, personal fees from Bristol-Myers Squibb, personal fees from Daiichi Sankyo Company, Ltd., outside the submitted work. Funding Information: Dr. Satake reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Fujii reports grants from Japan Heart Foundation during the conduct of the study; personal fees from Sanofi K.K., personal fees from Daiichi Sankyo Company, Limited, personal fees from Otsuka Pharmaceutical Co, Ltd., outside the submitted work. Funding Information: Dr. Nagai reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Novarutis Pharmaceuticals Corporation, personal fees from Sanwa Kagaku Kenkyusyo Co, Ltd., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Bayer Yakuhin Ltd., personal fees from Japan Boehringer Ingelheim Co, Ltd., personal fees from Daiichi Sankyo Company, Limited, personal fees from Actelion Pharmaceuticals Japan Ltd., personal fees from Pfizer Japan Inc., personal fees from Toa Eiyo Ltd., personal fees from MSD K.K., personal fees from Bristol Myers Squibb Company, personal fees from Eisai Co, Ltd., personal fees from Astellas Pharma Inc., personal fees from Mochida pharmaceutical Co, Ltd., personal fees from Kowa Pharmaceutical Co, Ltd., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Nippon Shinyaku Co, Ltd., outside the submitted work. Funding Information: Dr. Kohno reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Mizuno reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Sanwa Chemistry Co, Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Mitsubishi Tanabe Pharma Corporation., outside the submitted work. Funding Information: Dr. Nakahama reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Kanaya reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Murohara reports grants from Japan heart Foundation, during the conduct of the study; grants from Takeda Pharmaceutical Company Limited, grants from MSD K.K., grants from Astellas pharma Inc., grants from Daiichi Sankyo Company, Ltd., grants from Mitsubishi Tanabe Pharma Corporation, grants from Teijin Pharma Limited, grants from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Actelion Pharmaceuticals Japan Ltd., personal fees from Astellas Pharma Inc., personal fees from Amgen Astellas Bio Pharma K.K., personal fees from Astra Zeneca K.K., personal fees from MSD K.K., personal fees from Otsuka Pharmaceutical Co, Ltd., personal fees from Ono Pharmaceutical Company Ltd., personal fees from Sanwa Kagaku Kenkyusho Co, Ltd., personal fees from Kowa Company, Ltd., personal fees from Sysmex Corporation, personal fees from Taisho Toyama Pharmaceutical Co, Ltd., personal fees from Daiichi Sankyo Company, Ltd., personal fees from Sumitomo Dainippon Pharma Co, Ltd., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Teijin Pharma Limited, personal fees from Toa Eiyo Ltd., personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Medtronic japan Co, Ltd., personal fees from Eli Lilly Japan K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from Pfizer Japan Inc., personal fees from Koninklijke Philips N.V., personal fees from Bristol-Myers Squibb, personal fees from Boston Scientific Corporation, personal fees from Mochida Pharmaceutical Co, Ltd., personal fees from Roche Diagnostics K.K., outside the submitted work. Funding Information: Dr. Fukui reports grants from Japan Heart Foundation during the conduct of the study; personal fees from Daiichi Sankyo Company, Limited, personal fees from Japan Boehriger Ingelheim, personal fees from Takeda Pharmaceutical Co, Ltd., personal fees from Mochida Pharmaceutical Co, Ltd., personal fees from Bayer Yakuhin, Ltd., outside the submitted work. Funding Information: Dr. Takase reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Astellas Pharma Inc., personal fees from Sanwa Kagaku Kenkyusho Co, Ltd., personal fees from Medical View Co, Ltd., personal fees from Medical Tribune, Inc., personal fees from Kowa Pharmaceutical Co, Ltd., personal fees from Sanofi K.K., personal fees from Sanwa Kagaku Kenkyusho Co, Ltd., personal fees from Shionogi & Co, Ltd., personal fees from Daiichi Sankyo Company, Ltd., personal fees from Smitomo Dainippon Pharma Co, Ltd., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Japan Boehringer Ingelheim Co, Ltd., personal fees from Novartis K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from Pfizer Japan Inc., personal fees from Bristol-Myers Squibb Company, outside the submitted work. Funding Information: Dr. Ohte reports grants from Japan Heart Foundation during the conduct of the study; grants from Takeda Pharmaceutical Company Co, Ltd., grants from Daiichi Sankyo Company, Limited, grants from Otsuka Pharmaceutical Co, Ltd., grants from Astellas Pharma Inc., grants from Bayer Yakuhin, Ltd., grants from MSD K.K., grants from Nippon Boehringer Ingelheim Co, Ltd., grants from Novartis Pharmaceuticals Corporation, personal fees from Daiichi Sankyo Company, Ltd., personal fees from Astra Zeneca K.K., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Ostuka Pharmaceutical Co, Ltd., outside the submitted work. Funding Information: Dr. Shiono reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Fukunami reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Endo reports grants from Japan Heart Foundation, during the conduct of the study; grants from Novartis Pharmaceuticals Corporation, grants from Public Health Research Foundation, grants from Otsuka Pharmaceutical Co, Ltd., grants from Daiichi Sankyo Company, Ltd., grants from Satt Co, Ltd., grants from Cancellation Protection Filter Research Association, grants from Japan Cardiovascular Research Foundation, personal fees from Daiichi Sankyo Company, Ltd., personal fees from Novartis Pharmaceuticals Corporation, personal fees from Pfizer Japan Inc., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Kowa Pharmaceutical Co, Ltd., from null, outside the submitted work. Funding Information: Dr. Sawada reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Nippon Boehringer Ingelheim Co, Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Kowa Pharmaceutical Co, Ltd., outside the submitted work. Funding Information: Dr. Fujino reports grants from Japan heart Foundation, during the conduct of the study; personal fees from Ostuka Pharmaceutical Co, Ltd., personal fees from Medtronic Japan Co, Ltd., personal fees from Abbott Japan Co, Ltd., personal fees from Daiichi Sankyo Company, Ltd., outside the submitted work. Funding Information: Dr. Takeuchi reports grants from Japan Heart Foundation, during the conduct of the study; grants from Thrombosis Research Institute, grants from Japan Cardiovascular Research Foundation, grants from Daiichi Sankyo Company, Limited, other from Takeda Pharmaceutical Company Co, Ltd., other from Pfizer Japan Inc., other from Mitsubishi Tanabe Pharma Corporation, other from Sanwa Kagaku Kenkyusho Co, Ltd., other from Chugai Pharmaceutical Co, Ltd., other from Daiichi Sankyo Company, Limited, other from Bayer Yakuhin, Ltd., other from Bristol-Myers Ingelheim Co, Ltd., other from Nippon Boehringer Ingelheim Co, Ltd., other from Novartis Pharmaceuticals Corporation, other from MSD K.K., other from Sanofi K.K., other from Teijin Home Healthcare Limited, outside the submitted work. Funding Information: Dr. Mizuno reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Uematsu reports grants from Japan Heart Foundation, during the conduct of the study; grants from Terumo Corporation, grants from Abbott Vascular Japan Co., Ltd., grants from Boston Scientific Japan Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from Abott Vascular Japan Co., Ltd., other from Medtronic Japan Co., Ltd. other from Coridien Japan Co., Ltd., other from Nipro Corporation, other from DVx Inc., other from W.L. Gore & Associates, Co, Ltd., other from Goodman Co, Ltd., other from Toa Eiyo Ltd., other from Teijin Pharma Limited., other from Japan Lifeline Co, Ltd., other from Nippon Boehriinger Ingelheim Co, Ltd., other from Eisai Co, Ltd., other from Boston Scientific Japan Co, Ltd., other from Terumo Corporation, other from JIMRO Co, Ltd., other from Associations For Establishment Of Evidence in interventions., other from Cardinal Health Japan, other from Bayer Yakuhin, Ltd., other from Abbott Vascular Japan Co, Ltd., other from Biotronik Japan Co, Ltd., other from Medicos Hirata INC., other from Bristol-Myers Squibb Company., other from Pfizer Japan Inc., other from Actelion Pharmaceuticals Japan Ltd., outside the submitted work. Funding Information: Dr. Matsubara reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Daiichi Sankyo Co, Ltd., personal fees from Kowa Pharmaceutical Co, Ltd., personal fees from Toa Eiyo Ltd., personal fees from MSD K.K., outside the submitted work. Funding Information: Dr. Takahashi reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Tamita reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Hayashi reports grants from Japan Heart Foundation during the conduct of the study. Funding Information: Dr. Kitakaze reports grants from Japanese government, during the conduct of the study; grants from Japanese government, grants from Japan Heart Foundation, grants from Japan Cardiovascular Research Foundation, grants and personal fees from Asteras, personal fees from Daiichi-sankyo, grants and personal fees from Pfizer, grants and personal fees from Ono, personal fees from Bayer, grants from Novartis, grants and personal fees from Tanabe-mitubishi, personal fees from Kowa, personal fees from MSD, grants from Nihon Kohden, personal fees from Shionogi, personal fees from Astrazeneca, grants and personal fees from Astra Zeneca, personal fees from Taisho-Toyama, personal fees from Toyama-Kagaku, grants and personal fees from Kureha, personal fees from Toaeiyo, outside the submitted work. Funding Information: ports grants and personal fees from Pfizer, grants from Takeda Pharmaceutical, personal fees from Mitsubishi Tanabe Pharma, personal fees from Nippon Boehringer Ingelheim, personal fees from Kowa Pharmaceutical. Funding Information: Dr. Tsukahara reports grants from Japan Heart Foundation, during the conduct of the study; grants and personal fees from Daiichi-Sankyo, grants from Astra Zeneca, personal fees from Takeda Pharmaceutical, personal fees from Sanofi, personal fees from Astra Zeneka, personal fees from Bayer Yakuhin, personal fees from Nippon Boehringer Ingelheim. Funding Information: Dr. Ishikawa reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Nakama reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Koba reports grants from Japan Heart Foundation, during the conduct of the study; grants from MSD, grants from Mochida, personal fees from Astra Zeneca, personal fees from Takeda Pharmaceutical, personal fees from Novartis Phama, personal fees from Shionogi Pharm, personal fees from Daiichi-Sankyo, personal fees from Mitsubishi Tanabe Pharma, personal fees from Pfizer. Funding Information: Dr. Tsujimoto reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Astellas Pharma, personal fees from Otsuka Pharmaceutical, personal fees from Kyowa Hakko Krin, personal fees from Kowa Pharmaceutical, personal fees from Sanofi, personal fees from Shionogi Pharm, personal fees from Daiichi-Sankyo, personal fees from Taisho Pharmaceutical, personal fees from Takeda Pharmaceutical, personal fees from Mitsubishi Tanabe Pharma, personal fees from Toa Eiyo, personal fees from Nippon Boehringer Ingelheim, personal fees from Bayer Yakuhin, personal fees from Pfizer, personal fees from Bristol-Myers, personal fees from Mochida Pharmaceutical, personal fees from Abbott Vascular, personal fees from Shimadzu, personal fees from Terumo, personal fees from Biosensors, personal fees from Medtronic, personal fees from Biotronik, personal fees from Fukuda Denshi, personal fees from Boston Scientific. Funding Information: Dr. Ookusa reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Fujino reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Shimizu reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Yokohama City Fire Bureau, personal fees from The Japanese Society of Internal Medicine, personal fees from Yokohama izumi-ku Medical Association, personal fees from Yokohama City University, personal fees from St. Marianna University School of Medicine, personal fees from Kowa Pharmaceutical, personal fees from Nippon Boehringer Ingelheim, personal fees from Astelles Pharma, personal fees from Otsuka Pharmaceutical, outside the submitted work. Funding Information: Dr. Endo reports grants from Japan Heart Foundation, during the conduct of the study; grants and personal fees from Novartis, personal fees from Daiichi-sankyo, personal fees from Takeda, personal fees from Kyowa-hakko-kirin, personal fees from Eaisai, grants from Public Health Research Foundation. Funding Information: Dr. Yoda reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Muroya reports grants from Japan Heart Foundation, during the conduct of the study; grants from Public Health Research Foundation, personal fees from Boehringer Ingelheim, personal fees from Terumo, personal fees from Kowa Pharmaceutical, personal fees from Abbott Vascular, personal fees from Daiichi-Sankyo. Funding Information: Dr. Murohara reports grants from Japan Heart Foundation, grants and personal fees from Takeda Pharmaceutical, during the conduct of the study; grants from Teijin Pharma, grants from Astellas Phama, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from MSD, grants from Bristol-Myers, grants and personal fees from Takeda Pharmaceutical, grants from Daiichi-Sankyo, grants from Eisai, grants from Otsuka Pharmaceutical, grants and personal fees from Mitsubishi Tanabe Pharma, grants from Sumitomo Dainippon Pharma, personal fees from Bayer Yakuhin. Funding Information: Dr. Ohte reports grants from Japan Heart Foundation, during the conduct of the study; grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Daiichi-Sankyo, grants and personal fees from MSD, grants and personal fees from Othuka Pharmaceutical, grants and personal fees from Kowa Pharmaceutical, grants and personal fees from Sumitomo Dainippon Pharma, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Bayer Yakuhin, grants and personal fees from Astellas Pharma, grants and personal fees from Mitsubishi Tanabe Pharma, grants and personal fees from Actelion pharmaceuticals, personal fees from Sanwa kagaku kenkyusho, personal fees from Astra Zeneca, personal fees from General Electric, personal fees from Siemens, personal fees from Toshiba, personal fees from Toa Eiyo. Funding Information: Dr. Suzuki reports grants from Japan Heart Foundation, during the conduct of the study; grants from Foundation for Biomedical Research and Innovation, grants from Japan Heart Foundation., grants from Astellas Phama, grants from Abbott Vascular, grants and personal fees from MSD, grants and personal fees from Otsuka Pharmaceutical, grants from Ono Pharmaceutical, grants from Kyowa Hakko Kirin, grants from Kowa Pharmaceutical, grants from Sanofi, grants and personal fees from Shionogi Pharm, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Takeda Pharmaceutical, grants from Mitsubishi Tanabe Pharma, grants from Chugai Pharma, grants from Novartis Phama, grants from Nihon Medi-Physics, grants from Bayer Yakuhin, grants and personal fees from Pfizer, grants from Nippon Boehringer Ingelheim, grants from JCT, grants from Terumo, personal fees from Astra Zeneca. Funding Information: Dr. Fukui reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Takeda, personal fees from Eisai, personal fees from Bayer Yakuhin, personal fees from Mochida, personal fees from Bristol-Myers, personal fees from Kowa Pharmaceutical, personal fees from Astellas Pharma, personal fees from Otsuka Pharmaceutical, personal fees from AstraZeneca, personal fees from Nihon Medi-Physics, personal fees from Daiichi-Sankyo, personal fees from Nippon Boehringer Ingelheim, outside the submitted work. Funding Information: Dr. Shiono reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Takeda Pharmaceutical, personal fees from Daiichi-Sankyo, personal fees from Nippon Boehringer Ingelheim, personal fees from Bayer Yakuhin, personal fees from Mochida Pharmaceutical, personal fees from Kyowa Hakko Kirin, personal fees from Pfizer, personal fees from MSD, personal fees from Otsuka Pharmaceutical. Funding Information: Dr. Takase reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from MSD, personal fees from Astellas Pharma, personal fees from AstraZeneca, personal fees from Ono Pharmaceutical, personal fees from Sanwa kakagu kenkyusho, personal fees from Medical View, personal fees from Medical Tribune, personal fees from Kowa Pharmaceutical, personal fees from Sanofi, personal fees from Shionogi, personal fees from Daiichi-Sankyo, personal fees from Sumitomo Dainippon, personal fees from Takeda Pharmaceutical, personal fees from Toa Eiyo, personal fees from Nippon Boehringer Ingelheim, personal fees from Novartis Pharma, personal fees from Bayer Yakuhin, personal fees from Pfizer, personal fees from Fujifilm Ri Pharma, personal fees from Bristol-Myers, personal fees from Mochida. Funding Information: Dr. Uzui reports grants from Japan Heart Foundation, during the conduct of the study; grants from Fukui Medical Instruments, grants from Mochida Pharmaceutical, grants from Bolnono. Funding Information: Dr. Nagai reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Kyowa Hakko Kirin, personal fees from Bayer Yakuhin, personal fees from Mochida, personal fees from Daiichi-Sankyo, personal fees from Kowa Pharmaceutical, personal fees from Novartis Phama, personal fees from Takeda Pharmaceutical, personal fees from MSD, personal fees from Astellas Pharma, personal fees from Nippon Shinyaku, personal fees from Nippon Boehringer Ingelheim, personal fees from Eli Lilly Japan, personal fees from Sanofi, personal fees from Mitsubishi Tanabe Pharma, personal fees from Eisai, personal fees from Toa Pharmaceutical, personal fees from Bristol-Myers. Funding Information: Dr. Hashimoto reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Mizuno reports grants from Japan Heart Foundation., during the conduct of the study. Funding Information: Dr. Tamita reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Medtronic, personal fees from Otsuka Pharmaceutical, personal fees from Abbtt Vascular, personal fees from Nipro, personal fees from St. Jude Medical, personal fees from Nippon Boehringer Ingelheim, personal fees from Bristol-Myers, personal fees from Ono Pharmaceutical. Funding Information: Dr. Fujita reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Satake reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Kinoshita reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Nunohiro reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Otsuka Pharmaceutical, personal fees from Bayer Yakuhin, personal fees from Sumitomo Dainippon Pharma, personal fees from Takeda Pharmaceutical, personal fees from Kowa Pharmaceutical. Funding Information: Dr. Sakagami reports grants from Japan Heart Foundation, during the conduct of the study; grants from Bayer Yakuhin, grants from Takeda Pharmaceutical, grants from Otsuka Pharmaceutical, grants and personal fees from Daiichi-Sankyo, grants from Astra Zeneca, grants from Pfizer, grants from Novartis Pharma, grants from Amgen, grants and personal fees from Nippon Boehringer Ingelheim, personal fees from Bayer Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Johnson&Johnson, personal fees from St. Jude Medical, personal fees from Medtronic Japan, personal fees from Bristol-Myers. Funding Information: Dr. Higaki reports grants from Japan Heart Foundation, during the conduct of the study; grants and personal fees from Asteras Pharm, grants and personal fees from Nippon Beringer-Ingelheim, grants and personal fees from Takeda Industrial, grants and personal fees from Mochida, grants and personal fees from MSD, grants and personal fees from Diichi-Sankyo, grants and personal fees from Phaisar, grants and personal fees from Novartis, grants and personal fees from Shionogi Pharm, grants and personal fees from Kowa Pharm, grants from Dainihon-Sumitomo, personal fees from Actellion Pharm. Funding Information: Dr. Morii reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Sawada reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Pfizer, personal fees from Takeda Pharmaceutical, personal fees from Bayer Yakuhin. Funding Information: Dr. Shigemasa reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Eisai, personal fees from Astellas Pharma, personal fees from Novartis Pharma. Funding Information: Dr. Nakahama reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Sata reports grants from Japan Heart Foundation, during the conduct of the study; grants and personal fees from Bayer Yakuhin, grants from Ono Pharmaceutical, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Novartis Phama, grants and personal fees from Takeda Pharmaceutical, grants and personal fees from Mitsubishi Tanabe, grants and personal fees from Astellas Phama, grants and personal fees from MSD, personal fees from Mochida Pharmaceutical, personal fees from Shionogi Pharm, personal fees from Astra Zeneca. Funding Information: Dr. Doi reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Ueda reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Sumitomo Dainippon Pharma, personal fees from Nippon Boehringer Ingelheim. Funding Information: Dr. Yamanouchi reports grants from Japan Heart Foundation, during the conduct of the study; personal fees from Daiichi-Sankyo, personal fees from Nippon Boehringer Ingelheim, personal fees from Bayer Yakuhin, personal fees from Takeda Pharmaceutical, personal fees from Mochida Pharmaceutical. Funding Information: Dr. Yamaguchi reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Morita reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Hayashi reports grants from Japan Heart Foundation, during the conduct of the study. Funding Information: Dr. Kitakaze reports grants and personal fees from Takeda, during the conduct of the study; grants from Japanese government, grants from Japan Heart Foundation, grants from Japan Cardiovascular Research Foundation, grants and personal fees from Asteras, grants and personal fees from Sanofi, personal fees from Daiichi-sankyo, grants and personal fees from Pfizer, grants and personal fees from Ono, personal fees from Bayer, grants and personal fees from Novartis, personal fees from Bheringer, grants and personal fees from Tanabe-mitubishi, personal fees from Kowa, grants and personal fees from Kyowa-hakko-kirin, personal fees from Dainihon-sumitomo, personal fees from Sawai, personal fees from MSD, grants and personal fees from Abott, grants and personal fees from Otsuka, grants from Calpis, grants from Nihon Kohden, personal fees from Shionogi, personal fees from Astrazeneca, personal fees from Asahikasei Med., personal fees from Novo nordisk, personal fees from Fuji-film RI, personal fees from Japan Medical Data.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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, 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. Findings: 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. The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662–1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786–32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051–3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618–1·237, p = 0·45). Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.
AB - 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, 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. Findings: 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. The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662–1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786–32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051–3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618–1·237, p = 0·45). Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.
KW - Blood glucose-lowering
KW - Cardiovascular events
KW - Diabetes mellitus
KW - Myocardial infarction
KW - PROBE study
KW - Pioglitazone
UR - http://www.scopus.com/inward/record.url?scp=85064151391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064151391&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2018.09.006
DO - 10.1016/j.eclinm.2018.09.006
M3 - Article
AN - SCOPUS:85064151391
VL - 4-5
SP - 10
EP - 24
JO - EClinicalMedicine
JF - EClinicalMedicine
SN - 2589-5370
ER -