Background The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. Methods The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. Results Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28–2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35–2.91); all-cause mortality, HR 1.8 (95% CI 1.29–2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: −1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52–0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65–0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69–0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively). Conclusion Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.

中文翻译：

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恩格列净在射血分数降低的心力衰竭中的尿酸和钠-葡萄糖协同转运蛋白 2 抑制作用：EMPEROR-reduced 试验

背景钠-葡萄糖协同转运蛋白 2 抑制剂恩格列净可降低射血分数降低的 HF 患者心血管死亡或心力衰竭 (HF) 住院的风险。Empagliflozin 可降低血清尿酸 (SUA)，但这种作用在 HF 患者中的相关性尚不清楚。本研究旨在探讨恩格列净对 SUA 水平的影响以及恩格列净对 SUA 的治疗效果。方法 在 EMPEROR-Reduced 试验的 3676 名患者（研究队列的 98.6%）中调查了 SUA 与心血管死亡或因 HF 恶化而住院、其组成部分和全因死亡率的复合主要结局之间的关联。依格列净的治疗效果与作为连续变量的 SUA 与临床高尿酸血症 (SUA > 5. 女性为 7 mg/dL，男性＞7.0 mg/dL）和 SUA 三分位数患者亚组。结果 53%的患者普遍存在高尿酸血症，无性别差异。升高的 SUA（最高三分位数，平均 SUA 9.38 ± 1.49 mg/dL）与 HF 的严重程度和最差结果相关[综合结果，风险比 (HR) 1.64（95% 置信区间，CI 1.28-2.10）；心血管死亡率，HR 1.98 (95% CI 1.35–2.91)；全因死亡率，HR 1.8 (95% CI 1.29–2.49)，所有 P < 0.001] 在多变量调整分析中，与最低三分位数相比。恩格列净治疗 4 周后 SUA 降低（与安慰剂相比：-1.12 ± 0.04 mg/dL，P < 0.0001），并且在整个随访期间保持较低水平，所有预先指定的亚组也有类似的降低。Empagliflozin 将临床相关的高尿酸血症事件（急性痛风、痛风性关节炎或开始抗痛风治疗）减少了 32% [HR 0.68 (95% CI 0.52–0.89)，P = 0.004]。恩格列净对主要终点的有益作用与基线 SUA 无关 [HR 0.76 (95% CI 0.65–0.88)，P < 0.88。0.001) 和 4 周时 SUA 的变化 [HR 0.81 (95% CI 0.69–0.95), P = 0.012]。作为一个产生假设的发现，SUA 和治疗效果之间的相互作用表明，恩格列净对 SUA 升高患者的死亡率（心血管和全因死亡率）有益（相互作用的 P 分别 = 0.005 和 = 0.011）。结论 高尿酸血症在 HF 中很常见，是晚期疾病严重程度和死亡率增加的独立预测因素。Empagliflozin 诱导了 SUA 水平和与高尿酸血症相关的临床事件的快速和持续降低。独立于 SUA 观察到 empagliflozin 对主要结局的益处。