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 HbA_1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA_1c <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 (HbA_1c <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, HbA_1c, 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 HbA_1c, 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.

中文翻译：

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强化多因素干预对2型糖尿病（J-DOIT3）心血管结局和死亡率的影响：一项开放标签，随机对照试验

背景

有限的证据表明，控制血糖，血压和脂质的多因素干预措施可降低2型糖尿病患者的大血管并发症和死亡率。但是，尚未针对这些干预措施确定针对这些危险因素的安全有效的治疗目标。

方法

在这项在日本的81个临床地点进行的多中心，开放标签，随机，平行分组的试验中，我们随机分配了（1：1）年龄在45-69岁的2型糖尿病，高血压，血脂异常或两者兼而有之的患者， HbA _1c为6·9％（52·0 mmol / mol）或更高，以接受常规治疗以控制血糖，血压和血脂（目标：HbA _1c <6·9％[52·0 mmol / mol] ，血压<130/80 mm Hg，LDL胆固醇<120 mg / dL [或有冠心病史的患者为10​​0 mg / dL]）或强化治疗（HbA _1c<6·2％[44·3 mmol / mol]，血压<120/75 mm Hg，LDL胆固醇<80 mg / dL [或有冠心病病史的患者为70 mg / dL]。使用计算机生成的动态平衡方法进行随机分组，并按性别，年龄，HbA _1c和心血管疾病病史进行分层。患者和研究者都没有被掩盖到小组分配中。主要结局是发生心肌梗塞，中风，血运重建（冠状动脉搭桥手术，经皮腔内冠状动脉成形术，颈动脉内膜切除术，经皮腔内脑血管成形术和颈动脉支架置入）和全因死亡率。初步分析是在意向性治疗人群中进行的。该研究已在ClinicalTrials.gov上注册。，编号NCT00300976。

发现

在2006年6月16日至2009年3月31日之间，将2542例符合条件的患者随机分配至强化治疗或常规治疗（每组1271名），并进行中位随访8·5年（IQR 7·3–9·0 ）。强化治疗组中的两名患者在随机分组后被发现不符合资格，因此被排除在分析之外。在干预期间，强化治疗组的平均HbA _1c，收缩压，舒张压和LDL胆固醇浓度显着低于常规治疗组（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；以及85 mg / dL vs分别为104 mg / dL; 全部p <0·0001）。主要结果发生在强化治疗组的109例患者和常规治疗组的133例患者中（危险比[HR] 0·81，95％CI 0·63-1·04； p = 0·094）。在复合结果的事后分析中，全因死亡率（HR 1·01，95％CI 0·68-1·51； p = 0·95）的发生频率和冠状动脉事件（心肌梗塞，冠状动脉搭桥术）手术和经皮腔内冠状动脉成形术； HR 0·86、0·58-1·27； p = 0·44）在两组之间无差异，但脑血管事件（中风，颈动脉内膜切除术，经皮腔内脑血管成形术和颈动脉）在强化治疗组中，支架置入术的频率明显降低（HR 0·42、0·24-0·74； p = 0·002）。除了非严重的低血糖症（强化治疗组中有521名患者[41％]与常规治疗组中的283 [22％]，p <0·0001）和水肿（193 [15％]对129 [10％]，p = 0·0001）相比，主要不良事件的发生率在两组之间没有差异组。

解释

与目前标准的预防冠心病，脑血管事件和全因死亡率综合症的标准治疗相比，我们的结果不能完全支持进一步加强多因素干预的疗效。尽管如此，我们的研究结果表明，加强干预对预防2型糖尿病患者脑血管事件的潜在益处。

资金

日本厚生劳动省，旭化成制药，阿斯特拉斯制药，阿斯利康，拜耳，勃林格殷格翰，百时美施贵宝，第一三共制药，礼来制药，葛兰素史克，基塞制药，兴和制药，三菱田边制药，町田制药， MSD，诺华制药（Novartis Pharma），诺和诺德（Novo Nordisk），小野制药（Ono Pharmaceutical），辉瑞（Pfizer），三和化学药典（Kawasaku Kenkyusho），盐野义制药（Shionogi），住友大日本制药（Sumitomo Dainippon Pharma），大正富山制药（Thosho Toyama Pharmaceutical）和武田（Takeda）。