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

Lancet Diabetes Endocrinol. 2017 Dec;5(12):951-964.





限られたエビデンスから、グルコース、血圧、および脂質の制御のための多因子的介入が2型糖尿病患者の大血管合併症および死亡率を低下させることを示唆している。 しかしながら、これらの危険因子に対する安全で効果的な治療、介入方法は決定されていない。


日本の81の臨床現場で行われたこの多施設共同非盲検無作為化並行群間試験では、高血圧症、脂質異常症、またはその両方を有する45〜69歳の2型糖尿病患者をランダムに(1:1)割り当てた。 グルコース、血圧、および脂質管理のための従来の治療を受けるための6.9%(52.0mmol / mol)以上のHbA1c(目標:HbA 1c <6.9%[52.0mmol / mol]、) 血圧<130/80 mm Hg、LDLコレステロール<120 mg / dL [または冠動脈疾患の既往歴のある患者では100 mg / dL]または集中治療(HbA1c <6.2%[44.3 mmol / mol]) 、血圧<120/75 mm Hg、LDLコレステロール<80 mg / dL(または冠動脈疾患の既往歴のある患者では70 mg / dL))。性別、年齢、HbA1c、および心血管疾患の病歴によって層別化された、コンピューターで生成された動的バランス調整法を使用して無作為化を行った。患者も研究者もグループ割り当てには盲見化されなかった。 主要項目は、心筋梗塞、脳卒中、血管再建(冠状動脈バイパス手術、経皮経管的冠動脈形成術、頸動脈内膜剥離術、経皮経管的脳血管形成術、および頸動脈ステント留置術)の複合、および全死因死亡のいずれかの発生であった。主要項目の分析は、 intention-to-treat で行われた。この試験はClinicalTrials.gov、番号NCT00300976に登録されています。


2006年6月16日から2009年3月31日の間に、2542人の適格患者が無作為に介入治療または通常治療に割り当てらた。各グループ1271人。中央値8.5年の追跡調査(IQR 7.3-9.0) 介入治療群の2人の患者は無作為化後に不適格であることが判明し、分析から除外した。介入期間中、平均HbA1c、収縮期血圧、拡張期血圧、およびLDLコレステロール濃度は、介入治療群の方が従来の治療群よりも有意に低かった(6±8%[51±0 mmol / mol]対7±5%)。 2%[55.2mmol/mol]; 123mmhg対129mmhg;71mmhg対71mmhg;および85mmg/dl対104mmg/dl;それぞれp <0.0001)。プライマリアウトカムは、介入治療群の109人の患者および従来の治療群の133人の患者に発生した(ハザード比[HR] 0.81、95%CI 0.63-1.04; p = 0.094)。複合アウトカムの事後分析では、全死因死亡率(HR 1.01、95%CI 0.68〜1.51; p = 0.95)および冠動脈イベント(心筋梗塞、冠状動脈バイパス)手術、経皮経管冠動脈形成術、HR 0.86、0.58〜1.27、p = 0.44は脳血管イベント(脳卒中、頸動脈内膜剥離術、経皮経管的脳血管形成術、頸動脈) (ステント留置術)は介入治療群で有意に頻度が低かった(HR 0.42、0.24〜0.74; p = 0.002)。非重症低血糖症(介入治療群の521人[41%]対標準治療群の283人[22%]、p <0.0001)および浮腫(193人[15%]対129人[10%]) 、p = 0.001)、主要な有害事象の頻度は群間で有意差無し。








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.


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.


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 hypoglypcaemia (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.


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.


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.