Abstract Aims Hypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin. Methods and results About 7020 patients with T2D (HbA1c 7–10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia [HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia] was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad [hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25–2.93)] and HYPO-strict [1.72 (1.06–2.78)]. HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) [HR 1.56 (1.06–2.29)]. Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05). Conclusion In this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.

中文翻译：

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EMPA-REG OUTCOME® 试验中低血糖、心血管结局和恩格列净治疗之间的关系

摘要 目的 2 型糖尿病 (T2D) 患者的低血糖与心血管 (CV) 事件风险增加有关。在 EMPA-REG OUTCOME 中，钠-葡萄糖协同转运蛋白 2 抑制剂 empagliflozin 将心血管死亡风险降低了 38%，将心力衰竭住院 (HHF) 风险降低了 35%，同时降低了糖化血红蛋白 (HbA1c) 而不增加低血糖。我们调查了试验期间低血糖患者的心血管结局以及低血糖对恩格列净治疗效果的影响。方法和结果 大约 7020 名 T2D 患者（HbA1c 7–10%）接受了 empagliflozin 10 或 25 mg 或安慰剂治疗，随访中位时间为 3.1 年。试验中低血糖和 CV 结果之间的关系，以及恩格列净对偶发低血糖的影响 [HYPO-broad: 血糖 (PG) ≤ 70 mg/dL 的症状性低血糖症、PG <54 mg/dL 的任何低血糖症或严重低血糖症，以及 HYPO 严格：PG <54 mg/dL 的低血糖症或严重低血糖症] 使用调整后的Cox 回归模型具有低血糖和治疗相互作用的时变协变量。HYPO-broad 发生率为 28%，HYPO-strict 发生率为 19%。在安慰剂组中，低血糖与 HYPO-broad [风险比（HR，95% 置信区间，CI）1.91 (1.25–2.93)] 和 HYPO-strict [1.72 (1.06–2.78) 的 HHF 风险增加有关]。HYPO-broad（但不是 HYPO-strict）与心肌梗死 (MI) 风险增加相关 [HR 1.56 (1.06–2.29)]。Empagliflozin 改善了 CV 结果，无论是否发生低血糖（相互作用 P->0.05）。结论 在此事后探索性分析中，低血糖与 HHF 和 MI 风险增加有关。恩格列净并没有增加低血糖风险，偶发低血糖也没有减弱其心脏保护作用。