Heart failure (HF) is one of the most pervasive complications occurring in patients with type 2 diabetes (T2D). The risk of HF with preserved (HFPEF) and reduced (HFREF) ejection fraction is fourto five-fold higher among patients with T2D as compared with those without the condition, and is associated with a poor prognosis, with a median survival of 4 years from the time of diagnosis. 2 Although fasting plasma glucose levels and glycated haemoglobin (HbA1c) are significantly associated with an increased risk of HF, intensive glycaemic control with oral glucose-lowering agents or insulin has failed to reduce the risk of HF-related events as compared with standard treatment. In the recent EMPA-REG OUTCOMER trial, the sodium–glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin was the first glucose-lowering drug able to reduce cardiovascular mortality and hospitalizations for HF (HHF) in T2D patients at high cardiovascular (CV) risk. In this trial, 7020 patients were randomized to receive 10 or 25 mg of empagliflozin or placebo once daily. After a median observation time of 3.1 years, empagliflozin (pooled 10 and 25 mg doses) significantly reduced the primary composite outcome of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.74–0.99; P = 0.04 for superiority]. Although empagliflozin did not reduce the rates of MI or stroke, it significantly reduced death from CV causes, HHF, and death from any cause by 38, 35, and 32%, respectively. A second analysis of the EMPA-REG OUTCOMER —aimed at elucidating the impact of empagliflozin on HF-related outcomes—showed that empaglifozin reduces the rate of HHF and CV death, with a consistent benefit in patients with and without baseline HF. Whether empagliflozin is equally effective among different categories of HF risk remain to be elucidated. In the current issue of the journal, Fitchett and associates present a further analysis of the EMPA-REG OUTCOMER , exploring the effects of empagliflozin across the spectrum of HF in patients with T2D. In patients without HF at baseline (89.9%), the 5-year risk for incident HF using the nine-variable Health ABC HF Risk score was employed to classify the study population into different HF risk categories: low to average (<10%), high (10–20%), and very high (>20%). Based on this score, 67.2% of the population was classified as having low to average, 24.2% high, and 5.1% very high 5-year risk of developing HF. The investigators found that empagliflozin exerted a similar reduction of CV death and HFF across the different risk categories (Figure 1). In line with their previous analysis, in the present study CV mortality was also significantly reduced among patients either with HF at baseline or who had an incident HF episode during follow-up (HR 0.67, 95% CI 0.47–0.97). Separation of the cumulative incidence curves appeared early, and the reduction of risk persisted for the duration of the trial in patients at low to average, high, and very high risk of HF. Taken together, these findings show for the first time that an SGLT-2 inhibitor, namely empagliflozin, reduces CV mortality and HHF in patients at both high and lower risk, as well as in patients with or without either baseline or incident HF. An increasing body of evidence confers validity to the results of Fitchett et al. The recent CANVAS trial showed that treatment with the SGLT-2 inhibitor canagliflozin (100 mg daily with an optional increase to 300 mg starting from week 13) significantly reduced the composite primary endpoint of death from CV causes, non-fatal MI, or non-fatal stroke by 14% (HR 0.86, 95% CI 0.75–0.97; P < 0.001 for non-inferiority, P = 0.02 for superiority) and HHF by 33% (HR 0.67, 95% CI 0.52–0.87) in 10 142 participants with T2D and high CV risk. Along the same line, a study on 309 056 patients comparing HHF and death in patients newly initiated on any SGLT-2 inhibitor vs. other glucose-lowering drugs in six countries showed that SGLT-2 inhibitor use was associated with lower rates of HHF (HR 0.61, 95% CI 0.51– 0.73; P < 0.001); death (HR 0.49, 95% CI 0.41–0.57; P < 0.001); and HHF or death (HR 0.54, 95% CI 0.48–0.60; P < 0.001), with no significant heterogeneity by country. Finally, a recent meta-analysis including 81 trials with a total of 37 195 patients and mean follow-up of 89 weeks showed that SGLT-2 inhibitors were associated with a

中文翻译：

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Empagliflozin 跨越糖尿病性心脏病的各个阶段

心力衰竭 (HF) 是 2 型糖尿病 (T2D) 患者发生的最普遍的并发症之一。T2D 患者射血分数保留 (HFPEF) 和射血分数降低 (HFREF) 的 HF 风险是非 T2D 患者的 4 到 5 倍，并且与不良预后相关，中位生存期为 4 年诊断时间。2 尽管空腹血糖水平和糖化血红蛋白 (HbA1c) 与 HF 风险增加显着相关，但与标准治疗相比，口服降糖药或胰岛素强化血糖控制未能降低 HF 相关事件的风险。在最近的 EMPA-REG OUTCOMER 试验中，钠-葡萄糖协同转运蛋白-2 (SGLT-2) 抑制剂恩格列净是第一种能够降低心血管疾病 (CV) 高风险的 T2D 患者的心血管死亡率和心衰 (HHF) 住院率的降糖药物。在这项试验中，7020 名患者随机接受每天一次 10 或 25 毫克的恩格列净或安慰剂。在 3.1 年的中位观察时间后，恩格列净（10 和 25 毫克合并剂量）显着降低了心血管死亡、非致命性心肌梗死 (MI) 或非致命性卒中的主要复合结局 [风险比 (HR) 0.86， 95% 置信区间 (CI) 0.74–0.99；P = 0.04 的优越性]。尽管 empagliflozin 没有降低 MI 或中风的发生率，但它使心血管原因死亡、HHF 和全因死亡分别显着降低了 38%、35% 和 32%。EMPA-REG OUTCOMER 的第二项分析——旨在阐明恩格列净对 HF 相关结果的影响——表明恩格列净降低了 HHF 和 CV 死亡率，对有和没有基线 HF 的患者具有一致的益处。empagliflozin 在不同类别的 HF 风险中是否同样有效仍有待阐明。在本期杂志中，Fitchett 及其同事对 EMPA-REG OUTCOMER 进行了进一步分析，探讨了恩格列净对 T2D 患者心力衰竭谱的影响。在基线时没有 HF 的患者 (89.9%) 中，使用九个变量 Health ABC HF Risk 评分的 5 年 HF 事件风险用于将研究人群分为不同的 HF 风险类别：低到平均 (<10%) 、高 (10–20%) 和非常高 (>20%)。根据这个分数，67。2% 的人群被归类为具有低至平均、24.2% 的高和 5.1% 的非常高 5 年发生 HF 的风险。研究人员发现，恩格列净在不同风险类别中对心血管死亡和 HFF 的降低作用相似（图 1）。与他们之前的分析一致，在本研究中，基线时患有 HF 或在随访期间发生 HF 事件的患者的 CV 死亡率也显着降低（HR 0.67，95% CI 0.47–0.97）。累积发生率曲线的分离出现得较早，并且在试验期间，处于低至平均、高和极高 HF 风险的患者的风险降低持续存在。综上所述，这些发现首次表明 SGLT-2 抑制剂（即恩格列净）可降低高危和低危患者的心血管死亡率和 HHF，以及有或没有基线或突发 HF 的患者。越来越多的证据证明了 Fitchett 等人的结果的有效性。最近的 CANVAS 试验表明，使用 SGLT-2 抑制剂卡格列净（每天 100 毫克，从第 13 周开始可选择增加至 300 毫克）显着降低了复合主要终点，包括心血管原因死亡、非致命性心肌梗死或非致命性心肌梗死。在 10 名参与者中，致命性卒中增加 14%（HR 0.86，95% CI 0.75–0.97；非劣效性 P < 0.001，优越性 P = 0.02）和 HHF 增加 33%（HR 0.67，95% CI 0.52-0.87） 10 T2D 和高 CV 风险。同样，一项针对 309 056 名患者的研究比较了新开始使用任何 SGLT-2 抑制剂的患者的 HHF 和死亡情况。六个国家的其他降糖药物显示，使用 SGLT-2 抑制剂与较低的 HHF 发生率相关（HR 0.61，95% CI 0.51–0.73；P < 0.001）；死亡（HR 0.49，95% CI 0.41–0.57；P < 0.001）；和 HHF 或死亡（HR 0.54，95% CI 0.48–0.60；P < 0.001），各国没有显着异质性。最后，最近的一项荟萃​​分析包括 81 项试验，共 37 195 名患者，平均随访时间为 89 周，表明 SGLT-2 抑制剂与