Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial

Kohjiro Ueki, Takayoshi Sasako, Yukiko Okazaki, Masayuki Kato, Sumie Okahata, Hisayuki Katsuyama, Mikiko Haraguchi, Ai Morita, Ken Ohashi, Kazuo Hara, Atsushi Morise, Kazuo Izumi, Naoki Ishizuka, Yasuo Ohashi, Mitsuhiko Noda, Takashi Kadowaki, Masakazu Haneda, Yasunori Iwashima, Toshihiro Suda, Naoki TamasawaMakoto Daimon, Jo Satoh, Noriko Takebe, Yasushi Ishigaki, Tsuyoshi Watanabe, Hiroaki Satoh, Kikuo Kasai, Yoshimasa Aso, Shun Ishibashi, Shigehiro Katayama, San e. Ishikawa, Masafumi Kakei, Kazuyuki Namai, Naotake Hashimoto, Yoshifumi Suzuki, Shunichiro Onishi, Koutaro Yokote, Masafumi Matsuda, Masahiro Masuzawa, Yoichi Hayashi, Satoshi Saito, Norikazu Ogihara, Hisamitsu Ishihara, Naoko Tajima, Kazunori Utsunomiya, Akira Shimada, Hiroshi Itoh, Ryuzo Kawamori, Hirotaka Watada, Michio Hayashi, Yasumichi Mori, Teruo Shiba, Akihiro Isogawa, Hiroshi Sakura, Masato Odawara, Kazuyuki Tobe, Kazuhisa Tsukamoto, Toshimasa Yamauchi, Tamio Teramoto, Yukio Hirata, Isao Uchimura, Yoshihiro Ogawa, Gen Yoshino, Takahisa Hirose, Hiroshi Kajio, Yoshihito Atsumi, Akira Shimada, Yoichi Oikawa, Atsushi Araki, Akio Ueki, Atsushi Ohno, Masafumi Kitaoka, Yoshikuni Fujita, Tatsumi Moriya, Taiki Tojo, Masayoshi Shichiri, Daisuke Suzuki, Masao Toyoda, Kumiko Hamano, Rieko Komi, Yasuo Terauchi, Nobuaki Kuzuya, Masayo Yamada, Toshinari Takamura, Mitsuo Imura, Hiroshi Tanaka, Masayuki Hayashi, Yasuhisa Kato, Mitsuyasu Itoh, Atsushi Suzuki, Mikihiro Nakayama, Takahisa Sano, Eitaro Nakashima, Yasuhiro Sumida, Yutaka Yano, Tsuyoshi Tanaka, Kazuya Murata, Atsunori Kashiwagi, Hiroshi Maegawa, Shigeo Kono, Nobuya Inagaki, Keisuke Kosugi, Tetsuyuki Yasuda, Yasunao Yoshimasa, Ichiro Kishimoto, Toshihiko Sato, Masayuki Hosoi, Tomoyuki Yamasaki, Munehide Matsuhisa, Iichiro Shimomura, Ataru Taniguchi, Akira Kuroe, Takeshi Kurose, Takeshi Ohara, Kazuhiko Sakaguchi, Mitsuyoshi Namba, Kohei Kaku, Masazumi Fujiwara, Ikki Shimizu, Keizo Ono, Osamu Ebisui, Yukio Tanizawa, Yosuke Okada, Shoichi Natori, Takehiko Kodera, Naoichi Sato, Makoto Ide, Kentaro Yamada, Fumio Umeda, Shoichi Natori, Tomoaki Eto, Kazuo Mimura, Shinsuke Hiramatsu, Tomoaki Inoue, Ryoko Takei, Atsushi Ogo, Katsumi Eguchi, Eiji Kawasaki, Yuji Koide, Eiichi Araki, Hideaki Jinnouchi, Hiroaki Yamamoto, Mitsutaka Motoyoshi, Toru Hiyoshi, Yasushi Tanaka, Tadahisa Momoki, Koichiro Sato, Akihiko Yoneyama, Kenichi Ito, Hiroshi Sobajima, Hiroshi Ikegami, Masaki Ikeda, Hiroki Ikeda, Kenji Takahashi, Hirofumi Makino, Yasuo Ueda, Masamitsu Nakazato

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Abstract

Background Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. Methods In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45–69 years with hypertension, dyslipidaemia, or both, and an HbA1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA1c <6·9% [52·0 mmol/mol], blood pressure <130/80 mm Hg, LDL cholesterol <120 mg/dL [or 100 mg/dL in patients with a history of coronary artery disease]) or intensive therapy (HbA1c <6·2% [44·3 mmol/mol], blood pressure <120/75 mm Hg, LDL cholesterol <80 mg/dL [or 70 mg/dL in patients with a history of coronary artery disease]). Randomisation was done using a computer-generated, dynamic balancing method, stratified by sex, age, HbA1c, and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Findings Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3–9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA1c, systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p<0·0001). The primary outcome occurred in 109 patients in the intensive therapy group and in 133 patients in the conventional therapy group (hazard ratio [HR] 0·81, 95% CI 0·63–1·04; p=0·094). In a post-hoc breakdown of the composite outcome, frequencies of all-cause mortality (HR 1·01, 95% CI 0·68–1·51; p=0·95) and coronary events (myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angioplasty; HR 0·86, 0·58–1·27; p=0·44) did not differ between groups, but cerebrovascular events (stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting) were significantly less frequent in the intensive therapy group (HR 0·42, 0·24–0·74; p=0·002). Apart from non-severe hypoglycaemia (521 [41%] patients in the intensive therapy group vs 283 [22%] in the conventional therapy group, p<0·0001) and oedema (193 [15%] vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Interpretation Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Funding Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.

Original languageEnglish
Pages (from-to)951-964
Number of pages14
JournalThe Lancet Diabetes and Endocrinology
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 2017
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Ueki, K., Sasako, T., Okazaki, Y., Kato, M., Okahata, S., Katsuyama, H., Haraguchi, M., Morita, A., Ohashi, K., Hara, K., Morise, A., Izumi, K., Ishizuka, N., Ohashi, Y., Noda, M., Kadowaki, T., Haneda, M., Iwashima, Y., Suda, T., ... Nakazato, M. (2017). Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial. The Lancet Diabetes and Endocrinology, 5(12), 951-964. https://doi.org/10.1016/S2213-8587(17)30327-3