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

研究成果: Article

43 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)951-964
ページ数14
ジャーナルThe Lancet Diabetes and Endocrinology
5
発行部数12
DOI
出版物ステータスPublished - 2017 12 1

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Type 2 Diabetes Mellitus
Randomized Controlled Trials
Group Psychotherapy
Mortality
Blood Pressure
LDL Cholesterol
Cerebral Arteries
Pharmaceutical Preparations
Coronary Balloon Angioplasty
Carotid Endarterectomy
Random Allocation
Angioplasty
Carotid Arteries
Coronary Artery Bypass
Coronary Artery Disease
Japan
Stroke
Myocardial Infarction
Lipids
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

これを引用

Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3) : an open-label, randomised controlled trial. / Ueki, Kohjiro; Sasako, Takayoshi; Okazaki, Yukiko; Kato, Masayuki; Okahata, Sumie; Katsuyama, Hisayuki; Haraguchi, Mikiko; Morita, Ai; Ohashi, Ken; Hara, Kazuo; Morise, Atsushi; Izumi, Kazuo; Ishizuka, Naoki; Ohashi, Yasuo; Noda, Mitsuhiko; Kadowaki, Takashi; Haneda, Masakazu; Iwashima, Yasunori; Suda, Toshihiro; Tamasawa, Naoki; Daimon, Makoto; Satoh, Jo; Takebe, Noriko; Ishigaki, Yasushi; Watanabe, Tsuyoshi; Satoh, Hiroaki; Kasai, Kikuo; Aso, Yoshimasa; Ishibashi, Shun; Katayama, Shigehiro; Ishikawa, San e.; Kakei, Masafumi; Namai, Kazuyuki; Hashimoto, Naotake; Suzuki, Yoshifumi; Onishi, Shunichiro; Yokote, Koutaro; Matsuda, Masafumi; Masuzawa, Masahiro; Hayashi, Yoichi; Saito, Satoshi; Ogihara, Norikazu; Ishihara, Hisamitsu; Tajima, Naoko; Utsunomiya, Kazunori; Shimada, Akira; Itoh, Hiroshi; Kawamori, Ryuzo; Watada, Hirotaka; Hayashi, Michio; Mori, Yasumichi; Shiba, Teruo; Isogawa, Akihiro; Sakura, Hiroshi; Odawara, Masato; Tobe, Kazuyuki; Tsukamoto, Kazuhisa; Yamauchi, Toshimasa; Teramoto, Tamio; Hirata, Yukio; Uchimura, Isao; Ogawa, Yoshihiro; Yoshino, Gen; Hirose, Takahisa; Kajio, Hiroshi; Atsumi, Yoshihito; Shimada, Akira; Oikawa, Yoichi; Araki, Atsushi; Ueki, Akio; Ohno, Atsushi; Kitaoka, Masafumi; Fujita, Yoshikuni; Moriya, Tatsumi; Tojo, Taiki; Shichiri, Masayoshi; Suzuki, Daisuke; Toyoda, Masao; Hamano, Kumiko; Komi, Rieko; Terauchi, Yasuo; Kuzuya, Nobuaki; Yamada, Masayo; Takamura, Toshinari; Imura, Mitsuo; Tanaka, Hiroshi; Hayashi, Masayuki; Kato, Yasuhisa; Itoh, Mitsuyasu; Suzuki, Atsushi; Nakayama, Mikihiro; Sano, Takahisa; Nakashima, Eitaro; Sumida, Yasuhiro; Yano, Yutaka; Tanaka, Tsuyoshi; Murata, Kazuya; Kashiwagi, Atsunori; Maegawa, Hiroshi; Kono, Shigeo; Inagaki, Nobuya; Kosugi, Keisuke; Yasuda, Tetsuyuki; Yoshimasa, Yasunao; Kishimoto, Ichiro; Sato, Toshihiko; Hosoi, Masayuki; Yamasaki, Tomoyuki; Matsuhisa, Munehide; Shimomura, Iichiro; Taniguchi, Ataru; Kuroe, Akira; Kurose, Takeshi; Ohara, Takeshi; Sakaguchi, Kazuhiko; Namba, Mitsuyoshi; Kaku, Kohei; Fujiwara, Masazumi; Shimizu, Ikki; Ono, Keizo; Ebisui, Osamu; Tanizawa, Yukio; Okada, Yosuke; Natori, Shoichi; Kodera, Takehiko; Sato, Naoichi; Ide, Makoto; Yamada, Kentaro; Umeda, Fumio; Natori, Shoichi; Eto, Tomoaki; Mimura, Kazuo; Hiramatsu, Shinsuke; Inoue, Tomoaki; Takei, Ryoko; Ogo, Atsushi; Eguchi, Katsumi; Kawasaki, Eiji; Koide, Yuji; Araki, Eiichi; Jinnouchi, Hideaki; Yamamoto, Hiroaki; Motoyoshi, Mitsutaka; Hiyoshi, Toru; Tanaka, Yasushi; Momoki, Tadahisa; Sato, Koichiro; Yoneyama, Akihiko; Ito, Kenichi; Sobajima, Hiroshi; Ikegami, Hiroshi; Ikeda, Masaki; Ikeda, Hiroki; Takahashi, Kenji; Makino, Hirofumi; Ueda, Yasuo; Nakazato, Masamitsu.

:: The Lancet Diabetes and Endocrinology, 巻 5, 番号 12, 01.12.2017, p. 951-964.

研究成果: Article

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, Tamasawa, N, Daimon, M, Satoh, J, Takebe, N, Ishigaki, Y, Watanabe, T, Satoh, H, Kasai, K, Aso, Y, Ishibashi, S, Katayama, S, Ishikawa, SE, Kakei, M, Namai, K, Hashimoto, N, Suzuki, Y, Onishi, S, Yokote, K, Matsuda, M, Masuzawa, M, Hayashi, Y, Saito, S, Ogihara, N, Ishihara, H, Tajima, N, Utsunomiya, K, Shimada, A, Itoh, H, Kawamori, R, Watada, H, Hayashi, M, Mori, Y, Shiba, T, Isogawa, A, Sakura, H, Odawara, M, Tobe, K, Tsukamoto, K, Yamauchi, T, Teramoto, T, Hirata, Y, Uchimura, I, Ogawa, Y, Yoshino, G, Hirose, T, Kajio, H, Atsumi, Y, Shimada, A, Oikawa, Y, Araki, A, Ueki, A, Ohno, A, Kitaoka, M, Fujita, Y, Moriya, T, Tojo, T, Shichiri, M, Suzuki, D, Toyoda, M, Hamano, K, Komi, R, Terauchi, Y, Kuzuya, N, Yamada, M, Takamura, T, Imura, M, Tanaka, H, Hayashi, M, Kato, Y, Itoh, M, Suzuki, A, Nakayama, M, Sano, T, Nakashima, E, Sumida, Y, Yano, Y, Tanaka, T, Murata, K, Kashiwagi, A, Maegawa, H, Kono, S, Inagaki, N, Kosugi, K, Yasuda, T, Yoshimasa, Y, Kishimoto, I, Sato, T, Hosoi, M, Yamasaki, T, Matsuhisa, M, Shimomura, I, Taniguchi, A, Kuroe, A, Kurose, T, Ohara, T, Sakaguchi, K, Namba, M, Kaku, K, Fujiwara, M, Shimizu, I, Ono, K, Ebisui, O, Tanizawa, Y, Okada, Y, Natori, S, Kodera, T, Sato, N, Ide, M, Yamada, K, Umeda, F, Natori, S, Eto, T, Mimura, K, Hiramatsu, S, Inoue, T, Takei, R, Ogo, A, Eguchi, K, Kawasaki, E, Koide, Y, Araki, E, Jinnouchi, H, Yamamoto, H, Motoyoshi, M, Hiyoshi, T, Tanaka, Y, Momoki, T, Sato, K, Yoneyama, A, Ito, K, Sobajima, H, Ikegami, H, Ikeda, M, Ikeda, H, Takahashi, K, Makino, H, Ueda, Y & 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, 巻. 5, 番号 12, pp. 951-964. https://doi.org/10.1016/S2213-8587(17)30327-3
Ueki, Kohjiro ; Sasako, Takayoshi ; Okazaki, Yukiko ; Kato, Masayuki ; Okahata, Sumie ; Katsuyama, Hisayuki ; Haraguchi, Mikiko ; Morita, Ai ; Ohashi, Ken ; Hara, Kazuo ; Morise, Atsushi ; Izumi, Kazuo ; Ishizuka, Naoki ; Ohashi, Yasuo ; Noda, Mitsuhiko ; Kadowaki, Takashi ; Haneda, Masakazu ; Iwashima, Yasunori ; Suda, Toshihiro ; Tamasawa, Naoki ; Daimon, Makoto ; Satoh, Jo ; Takebe, Noriko ; Ishigaki, Yasushi ; Watanabe, Tsuyoshi ; Satoh, Hiroaki ; Kasai, Kikuo ; Aso, Yoshimasa ; Ishibashi, Shun ; Katayama, Shigehiro ; Ishikawa, San e. ; Kakei, Masafumi ; Namai, Kazuyuki ; Hashimoto, Naotake ; Suzuki, Yoshifumi ; Onishi, Shunichiro ; Yokote, Koutaro ; Matsuda, Masafumi ; Masuzawa, Masahiro ; Hayashi, Yoichi ; Saito, Satoshi ; Ogihara, Norikazu ; Ishihara, Hisamitsu ; Tajima, Naoko ; Utsunomiya, Kazunori ; Shimada, Akira ; Itoh, Hiroshi ; Kawamori, Ryuzo ; Watada, Hirotaka ; Hayashi, Michio ; Mori, Yasumichi ; Shiba, Teruo ; Isogawa, Akihiro ; Sakura, Hiroshi ; Odawara, Masato ; Tobe, Kazuyuki ; Tsukamoto, Kazuhisa ; Yamauchi, Toshimasa ; Teramoto, Tamio ; Hirata, Yukio ; Uchimura, Isao ; Ogawa, Yoshihiro ; Yoshino, Gen ; Hirose, Takahisa ; Kajio, Hiroshi ; Atsumi, Yoshihito ; Shimada, Akira ; Oikawa, Yoichi ; Araki, Atsushi ; Ueki, Akio ; Ohno, Atsushi ; Kitaoka, Masafumi ; Fujita, Yoshikuni ; Moriya, Tatsumi ; Tojo, Taiki ; Shichiri, Masayoshi ; Suzuki, Daisuke ; Toyoda, Masao ; Hamano, Kumiko ; Komi, Rieko ; Terauchi, Yasuo ; Kuzuya, Nobuaki ; Yamada, Masayo ; Takamura, Toshinari ; Imura, Mitsuo ; Tanaka, Hiroshi ; Hayashi, Masayuki ; Kato, Yasuhisa ; Itoh, Mitsuyasu ; Suzuki, Atsushi ; Nakayama, Mikihiro ; Sano, Takahisa ; Nakashima, Eitaro ; Sumida, Yasuhiro ; Yano, Yutaka ; Tanaka, Tsuyoshi ; Murata, Kazuya ; Kashiwagi, Atsunori ; Maegawa, Hiroshi ; Kono, Shigeo ; Inagaki, Nobuya ; Kosugi, Keisuke ; Yasuda, Tetsuyuki ; Yoshimasa, Yasunao ; Kishimoto, Ichiro ; Sato, Toshihiko ; Hosoi, Masayuki ; Yamasaki, Tomoyuki ; Matsuhisa, Munehide ; Shimomura, Iichiro ; Taniguchi, Ataru ; Kuroe, Akira ; Kurose, Takeshi ; Ohara, Takeshi ; Sakaguchi, Kazuhiko ; Namba, Mitsuyoshi ; Kaku, Kohei ; Fujiwara, Masazumi ; Shimizu, Ikki ; Ono, Keizo ; Ebisui, Osamu ; Tanizawa, Yukio ; Okada, Yosuke ; Natori, Shoichi ; Kodera, Takehiko ; Sato, Naoichi ; Ide, Makoto ; Yamada, Kentaro ; Umeda, Fumio ; Natori, Shoichi ; Eto, Tomoaki ; Mimura, Kazuo ; Hiramatsu, Shinsuke ; Inoue, Tomoaki ; Takei, Ryoko ; Ogo, Atsushi ; Eguchi, Katsumi ; Kawasaki, Eiji ; Koide, Yuji ; Araki, Eiichi ; Jinnouchi, Hideaki ; Yamamoto, Hiroaki ; Motoyoshi, Mitsutaka ; Hiyoshi, Toru ; Tanaka, Yasushi ; Momoki, Tadahisa ; Sato, Koichiro ; Yoneyama, Akihiko ; Ito, Kenichi ; Sobajima, Hiroshi ; Ikegami, Hiroshi ; Ikeda, Masaki ; Ikeda, Hiroki ; Takahashi, Kenji ; Makino, Hirofumi ; Ueda, Yasuo ; Nakazato, Masamitsu. / 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. 2017 ; 巻 5, 番号 12. pp. 951-964.
@article{3d64643aafd34ac6b4c5ff2f9852c687,
title = "Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial",
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.",
author = "Kohjiro Ueki and Takayoshi Sasako and Yukiko Okazaki and Masayuki Kato and Sumie Okahata and Hisayuki Katsuyama and Mikiko Haraguchi and Ai Morita and Ken Ohashi and Kazuo Hara and Atsushi Morise and Kazuo Izumi and Naoki Ishizuka and Yasuo Ohashi and Mitsuhiko Noda and Takashi Kadowaki and Masakazu Haneda and Yasunori Iwashima and Toshihiro Suda and Naoki Tamasawa and Makoto Daimon and Jo Satoh and Noriko Takebe and Yasushi Ishigaki and Tsuyoshi Watanabe and Hiroaki Satoh and Kikuo Kasai and Yoshimasa Aso and Shun Ishibashi and Shigehiro Katayama and Ishikawa, {San e.} and Masafumi Kakei and Kazuyuki Namai and Naotake Hashimoto and Yoshifumi Suzuki and Shunichiro Onishi and Koutaro Yokote and Masafumi Matsuda and Masahiro Masuzawa and Yoichi Hayashi and Satoshi Saito and Norikazu Ogihara and Hisamitsu Ishihara and Naoko Tajima and Kazunori Utsunomiya and Akira Shimada and Hiroshi Itoh and Ryuzo Kawamori and Hirotaka Watada and Michio Hayashi and Yasumichi Mori and Teruo Shiba and Akihiro Isogawa and Hiroshi Sakura and Masato Odawara and Kazuyuki Tobe and Kazuhisa Tsukamoto and Toshimasa Yamauchi and Tamio Teramoto and Yukio Hirata and Isao Uchimura and Yoshihiro Ogawa and Gen Yoshino and Takahisa Hirose and Hiroshi Kajio and Yoshihito Atsumi and Akira Shimada and Yoichi Oikawa and Atsushi Araki and Akio Ueki and Atsushi Ohno and Masafumi Kitaoka and Yoshikuni Fujita and Tatsumi Moriya and Taiki Tojo and Masayoshi Shichiri and Daisuke Suzuki and Masao Toyoda and Kumiko Hamano and Rieko Komi and Yasuo Terauchi and Nobuaki Kuzuya and Masayo Yamada and Toshinari Takamura and Mitsuo Imura and Hiroshi Tanaka and Masayuki Hayashi and Yasuhisa Kato and Mitsuyasu Itoh and Atsushi Suzuki and Mikihiro Nakayama and Takahisa Sano and Eitaro Nakashima and Yasuhiro Sumida and Yutaka Yano and Tsuyoshi Tanaka and Kazuya Murata and Atsunori Kashiwagi and Hiroshi Maegawa and Shigeo Kono and Nobuya Inagaki and Keisuke Kosugi and Tetsuyuki Yasuda and Yasunao Yoshimasa and Ichiro Kishimoto and Toshihiko Sato and Masayuki Hosoi and Tomoyuki Yamasaki and Munehide Matsuhisa and Iichiro Shimomura and Ataru Taniguchi and Akira Kuroe and Takeshi Kurose and Takeshi Ohara and Kazuhiko Sakaguchi and Mitsuyoshi Namba and Kohei Kaku and Masazumi Fujiwara and Ikki Shimizu and Keizo Ono and Osamu Ebisui and Yukio Tanizawa and Yosuke Okada and Shoichi Natori and Takehiko Kodera and Naoichi Sato and Makoto Ide and Kentaro Yamada and Fumio Umeda and Shoichi Natori and Tomoaki Eto and Kazuo Mimura and Shinsuke Hiramatsu and Tomoaki Inoue and Ryoko Takei and Atsushi Ogo and Katsumi Eguchi and Eiji Kawasaki and Yuji Koide and Eiichi Araki and Hideaki Jinnouchi and Hiroaki Yamamoto and Mitsutaka Motoyoshi and Toru Hiyoshi and Yasushi Tanaka and Tadahisa Momoki and Koichiro Sato and Akihiko Yoneyama and Kenichi Ito and Hiroshi Sobajima and Hiroshi Ikegami and Masaki Ikeda and Hiroki Ikeda and Kenji Takahashi and Hirofumi Makino and Yasuo Ueda and Masamitsu Nakazato",
year = "2017",
month = "12",
day = "1",
doi = "10.1016/S2213-8587(17)30327-3",
language = "English",
volume = "5",
pages = "951--964",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
publisher = "Elsevier BV",
number = "12",

}

TY - JOUR

T1 - Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3)

T2 - an open-label, randomised controlled trial

AU - Ueki, Kohjiro

AU - Sasako, Takayoshi

AU - Okazaki, Yukiko

AU - Kato, Masayuki

AU - Okahata, Sumie

AU - Katsuyama, Hisayuki

AU - Haraguchi, Mikiko

AU - Morita, Ai

AU - Ohashi, Ken

AU - Hara, Kazuo

AU - Morise, Atsushi

AU - Izumi, Kazuo

AU - Ishizuka, Naoki

AU - Ohashi, Yasuo

AU - Noda, Mitsuhiko

AU - Kadowaki, Takashi

AU - Haneda, Masakazu

AU - Iwashima, Yasunori

AU - Suda, Toshihiro

AU - Tamasawa, Naoki

AU - Daimon, Makoto

AU - Satoh, Jo

AU - Takebe, Noriko

AU - Ishigaki, Yasushi

AU - Watanabe, Tsuyoshi

AU - Satoh, Hiroaki

AU - Kasai, Kikuo

AU - Aso, Yoshimasa

AU - Ishibashi, Shun

AU - Katayama, Shigehiro

AU - Ishikawa, San e.

AU - Kakei, Masafumi

AU - Namai, Kazuyuki

AU - Hashimoto, Naotake

AU - Suzuki, Yoshifumi

AU - Onishi, Shunichiro

AU - Yokote, Koutaro

AU - Matsuda, Masafumi

AU - Masuzawa, Masahiro

AU - Hayashi, Yoichi

AU - Saito, Satoshi

AU - Ogihara, Norikazu

AU - Ishihara, Hisamitsu

AU - Tajima, Naoko

AU - Utsunomiya, Kazunori

AU - Shimada, Akira

AU - Itoh, Hiroshi

AU - Kawamori, Ryuzo

AU - Watada, Hirotaka

AU - Hayashi, Michio

AU - Mori, Yasumichi

AU - Shiba, Teruo

AU - Isogawa, Akihiro

AU - Sakura, Hiroshi

AU - Odawara, Masato

AU - Tobe, Kazuyuki

AU - Tsukamoto, Kazuhisa

AU - Yamauchi, Toshimasa

AU - Teramoto, Tamio

AU - Hirata, Yukio

AU - Uchimura, Isao

AU - Ogawa, Yoshihiro

AU - Yoshino, Gen

AU - Hirose, Takahisa

AU - Kajio, Hiroshi

AU - Atsumi, Yoshihito

AU - Shimada, Akira

AU - Oikawa, Yoichi

AU - Araki, Atsushi

AU - Ueki, Akio

AU - Ohno, Atsushi

AU - Kitaoka, Masafumi

AU - Fujita, Yoshikuni

AU - Moriya, Tatsumi

AU - Tojo, Taiki

AU - Shichiri, Masayoshi

AU - Suzuki, Daisuke

AU - Toyoda, Masao

AU - Hamano, Kumiko

AU - Komi, Rieko

AU - Terauchi, Yasuo

AU - Kuzuya, Nobuaki

AU - Yamada, Masayo

AU - Takamura, Toshinari

AU - Imura, Mitsuo

AU - Tanaka, Hiroshi

AU - Hayashi, Masayuki

AU - Kato, Yasuhisa

AU - Itoh, Mitsuyasu

AU - Suzuki, Atsushi

AU - Nakayama, Mikihiro

AU - Sano, Takahisa

AU - Nakashima, Eitaro

AU - Sumida, Yasuhiro

AU - Yano, Yutaka

AU - Tanaka, Tsuyoshi

AU - Murata, Kazuya

AU - Kashiwagi, Atsunori

AU - Maegawa, Hiroshi

AU - Kono, Shigeo

AU - Inagaki, Nobuya

AU - Kosugi, Keisuke

AU - Yasuda, Tetsuyuki

AU - Yoshimasa, Yasunao

AU - Kishimoto, Ichiro

AU - Sato, Toshihiko

AU - Hosoi, Masayuki

AU - Yamasaki, Tomoyuki

AU - Matsuhisa, Munehide

AU - Shimomura, Iichiro

AU - Taniguchi, Ataru

AU - Kuroe, Akira

AU - Kurose, Takeshi

AU - Ohara, Takeshi

AU - Sakaguchi, Kazuhiko

AU - Namba, Mitsuyoshi

AU - Kaku, Kohei

AU - Fujiwara, Masazumi

AU - Shimizu, Ikki

AU - Ono, Keizo

AU - Ebisui, Osamu

AU - Tanizawa, Yukio

AU - Okada, Yosuke

AU - Natori, Shoichi

AU - Kodera, Takehiko

AU - Sato, Naoichi

AU - Ide, Makoto

AU - Yamada, Kentaro

AU - Umeda, Fumio

AU - Natori, Shoichi

AU - Eto, Tomoaki

AU - Mimura, Kazuo

AU - Hiramatsu, Shinsuke

AU - Inoue, Tomoaki

AU - Takei, Ryoko

AU - Ogo, Atsushi

AU - Eguchi, Katsumi

AU - Kawasaki, Eiji

AU - Koide, Yuji

AU - Araki, Eiichi

AU - Jinnouchi, Hideaki

AU - Yamamoto, Hiroaki

AU - Motoyoshi, Mitsutaka

AU - Hiyoshi, Toru

AU - Tanaka, Yasushi

AU - Momoki, Tadahisa

AU - Sato, Koichiro

AU - Yoneyama, Akihiko

AU - Ito, Kenichi

AU - Sobajima, Hiroshi

AU - Ikegami, Hiroshi

AU - Ikeda, Masaki

AU - Ikeda, Hiroki

AU - Takahashi, Kenji

AU - Makino, Hirofumi

AU - Ueda, Yasuo

AU - Nakazato, Masamitsu

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85033454556&partnerID=8YFLogxK

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U2 - 10.1016/S2213-8587(17)30327-3

DO - 10.1016/S2213-8587(17)30327-3

M3 - Article

C2 - 29079252

AN - SCOPUS:85033454556

VL - 5

SP - 951

EP - 964

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 12

ER -