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. 2018 Oct 22:4-5:10-24.
doi: 10.1016/j.eclinm.2018.09.006. eCollection 2018 Oct-Nov.

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether P ioglitazone P rotects DM Patients A gainst R e-Infarction (PPAR Study)

Masanori Asakura  1   2   3 , Jiyoong Kim  1   4 , Hiroshi Asanuma  5 , Yasuharu Nakama  6 , Kengo Tsukahara  7 , Yorihiko Higashino  8 , Tetsuya Ishikawa  9 , Shinji Koba  10 , Mitsuru Tsujimoto  11 , Hideo Himeno  12 , Yasuyuki Maruyama  13 , Takanori Ookusa  14 , Shunichi Yoda  15 , Hiroshi Suzuki  16 , Shinji Okubo  17 , Makoto Shimizu  18 , Yuji Hashimoto  19 , Kazuo Satake  20 , Susumu Fujino  21 , Hiroyasu Uzui  22 , Yoshiyuki Nagai  23 , Tohru Kohno  24 , Sumio Mizuno  25 , Makoto Nakahama  26 , Hounin Kanaya  27 , Toyoaki Murohara  28 , Kazuki Fukui  29 , Hiroyuki Takase  30 , Nobuyuki Ohte  31 , Takaaki Shiono  32 , Masatake Fukunami  33 , Tsutomu Endo  34 , Reimin Sawada  35 , Kenshi Fujii  21 , Motoshi Takeuchi  36 , Shuntaro Ikeda  37 , Koichi Mizuno  38 , Masaaki Uematsu  39 , Taku Matsubara  40 , Shoji Yano  41 , Jun Takahashi  42 , Kousei Ueda  43 , Yoshihiko Kinoshita  44 , Koichi Tamita  45 , Hideki Hayashi  46 , Toshimitsu Hamasaki  47 , Masafumi Kitakaze  1   2 ; PPAR investigators
Affiliations

Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether P ioglitazone P rotects DM Patients A gainst R e-Infarction (PPAR Study)

Masanori Asakura et al. EClinicalMedicine. .

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.

Keywords: Blood glucose-lowering; Cardiovascular events; Diabetes mellitus; Myocardial infarction; PROBE study; Pioglitazone.

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Figures

Fig. 1
Fig. 1
Trial profile of the PPAR study.
Fig. 2
Fig. 2
Effects of pioglitazone on composite cardiovascular events of primary endpoints for 2 years in patients with mild DM and history of MI using ITT analysis.
Fig. 3
Fig. 3
Effects of pioglitazone on composite cardiovascular events of the primary endpoints for approximately 7 years until the end of the study in patients with mild DM and history of MI using ITT analysis.
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