Background

The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium–glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.

Methods

We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.

Results

We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).

Conclusions

In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE–TIMI 58 ClinicalTrials.gov number, NCT01730534.)

中文翻译：

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达格列净和 2 型糖尿病的心血管结局

背景

达格列净是一种钠-葡萄糖协同转运蛋白 2 的选择性抑制剂，可促进 2 型糖尿病患者的糖尿，其心血管安全性尚未确定。

方法

我们将患有动脉粥样硬化性心血管疾病或有患动脉粥样硬化性心血管疾病风险的 2 型糖尿病患者随机分配接受达格列净或安慰剂治疗。主要安全性结局是主要不良心血管事件 (MACE) 的复合结局，定义为心血管死亡、心肌梗死或缺血性中风。主要疗效结局是 MACE 和心血管死亡或因心力衰竭住院的复合结局。次要疗效结局是肾脏复合结局（估计肾小球滤过率降低≥40% 至<60 ml/min/1.73 m2 体表面积、新的终末期肾病或因肾脏或心血管原因死亡）和死亡任何原因。

结果

我们评估了 17,160 名患者，包括 10,186 名没有动脉粥样硬化性心血管疾病的患者，他们的中位随访时间为 4.2 年。在主要安全性结果分析中，达格列净在 MACE 方面符合预先指定的非劣效于安慰剂的标准（95% 置信区间 [CI] 的上限，<1.3；非劣性 P<0.001）。在两项主要疗效分析中，达格列净并没有降低 MACE 发生率（达格列净组为 8.8%，安慰剂组为 9.4%；风险比，0.93；95% CI，0.84 至 1.03；P=0.17）但确实导致心血管死亡率或心力衰竭住院率较低（4.9% 对 5.8%；风险比，0.83；95% CI，0.73 至 0.95；P=0.005），这反映了心力衰竭住院率较低（风险比，0.73；95% CI，0.61 至 0.88）；心血管死亡没有组间差异（风险比，0.98；95% CI，0.82 至 1.17）。达格列净组发生肾脏事件的发生率为 4.3%，安慰剂组为 5.6%（风险比，0.76；95% CI，0.67 至 0.87），全因死亡发生率分别为 6.2% 和 6.6%（风险比，0.76；95% CI，0.67 至 0.87）比率，0.93；95% CI，0.82 至 1.04）。与安慰剂相比，达格列净组糖尿病酮症酸中毒更常见（0.3% vs. 0.1%，P=0.02），导致该方案终止或被认为是严重不良事件的生殖器感染发生率也是如此（0.9% vs. 0.1%，P=0.02） .0.1%，P<0.001)。和全因死亡的发生率分别为 6.2% 和 6.6%（风险比，0.93；95% CI，0.82 至 1.04）。与安慰剂相比，达格列净组糖尿病酮症酸中毒更常见（0.3% vs. 0.1%，P=0.02），导致该方案终止或被认为是严重不良事件的生殖器感染发生率也是如此（0.9% vs. 0.1%，P=0.02） .0.1%，P<0.001)。和全因死亡的发生率分别为 6.2% 和 6.6%（风险比，0.93；95% CI，0.82 至 1.04）。与安慰剂相比，达格列净组糖尿病酮症酸中毒更常见（0.3% vs. 0.1%，P=0.02），导致该方案终止或被认为是严重不良事件的生殖器感染发生率也是如此（0.9% vs. 0.1%，P=0.02） .0.1%，P<0.001)。

结论

在患有动脉粥样硬化性心血管疾病或有患动脉粥样硬化性心血管疾病风险的 2 型糖尿病患者中，与安慰剂相比，使用达格列净治疗不会导致更高或更低的 MACE 发生率，但确实导致心血管死亡或因心力衰竭住院的发生率降低。这反映了较低的心力衰竭住院率。（由阿斯利康资助；DECLARE-TIMI 58 ClinicalTrials.gov 编号，NCT01730534。）