Large-scale trials have evaluated the effects of treatments on major renal outcomes, but the definition of a renal event has varied from trial to trial. In defining a renal event, trialists included patients who needed renal replacement therapy or whose estimated glomerular filtration rate (eGFR) declined to <10–15 mL/min/1.73 m², and they also included patients who experienced large and sustained decreases in eGFR from baseline. Different trials have designated different threshold values for a critical change in eGFR — with some trials designating a sustained ≥40% decline and other specifying a sustained ≥50% decrease. Still others have required a sustained doubling of serum creatinine, which corresponds to a ≥57% decline in eGFR.

Two large-scale trials have evaluated the effect of sodium–glucose co-transporter 2 (SGLT2) inhibitors in patients with heart failure and a reduced ejection fraction.¹ They reported a favourable effect of dapagliflozin and empagliflozin on heart failure hospitalizations, but the two trials prespecified different definitions of a major renal event. Both trials included patients who required renal replacement therapy or who experienced a sustained decrease in eGFR to <10–15 mL/min/1.73 m². However, the EMPEROR-Reduced trial also included patients with a sustained ≥40% decrease in eGFR, whereas the DAPA-HF investigators specified a sustained ≥50% decrease in eGFR, and they also included the occurrence of renal death.^{1, 2} The definition used by the DAPA-HF trial was used in a meta-analysis of the two trials.¹ In DAPA-HF, the hazard ratio for the effect of dapagliflozin using the meta-analysis renal endpoint was 0.71 [95% confidence interval (CI) 0.44–1.16].¹ In EMPEROR-Reduced, the hazard ratio for the effect of empagliflozin was 0.50 (95% CI 0.32–0.77) using the EMPEROR definition, and it was 0.52 (95% CI 0.29–0.92) using the meta-analysis definition.^{1, 2} The use of different definitions for a renal event did not influence conclusions concerning a benefit of empagliflozin on renal outcomes in heart failure and a reduced ejection fraction.

The EMPEROR-Preserved trial was a large, international, double-blind and placebo-controlled trial of empagliflozin in patients with heart failure and a preserved ejection fraction. Patients with heart failure and an ejection fraction >40% were randomly assigned to placebo or empagliflozin for a median of 26 months. Empagliflozin reduced the primary endpoint of cardiovascular death or heart failure hospitalization by 21% [hazard ratio 0.79 (95% CI 0.69–0.90)] and decreased total (first and recurrent) hospitalizations for heart failure by 27% [hazard ratio 0.73 (95% CI 0.61–0.88)].³ When the influence of baseline ejection fraction on these results was evaluated according to prespecified subgroups of 41–49%, 50–59% and ≥60%, baseline ejection fraction did not influence the effect of empagliflozin on the primary endpoint. However, ejection fraction did influence the effect of empagliflozin on total hospitalizations for heart failure (P-trend = 0.008), with an attenuated effect in patients with an ejection fraction ≥60%.⁴

In contrast to these favourable effects of empagliflozin on heart failure outcomes in EMPEROR-Preserved, empagliflozin did not exert a favourable effect on major renal outcomes using the EMPEROR definition,⁵ which relied on a threshold of a sustained ≥40% decrease in eGFR and did not include the occurrence of renal death. The hazard ratio for the effect of empagliflozin on major renal events was 0.95 (95% CI 0.73–1.24). The neutral effect of empagliflozin on kidney outcomes was similarly observed across the prespecified ejection fraction subgroups of 41–49%, 50–59% and ≥60% (Figure 1).⁵

Therefore, according to the analyses that had been prespecified in EMPEROR-Preserved, we found a striking discordance between the effect of empagliflozin on heart failure outcomes and major renal events, both in the overall population and in prespecified subgroups. When considering all patients with an ejection fraction >40%, empagliflozin reduced heart failure hospitalizations with no effect on major renal outcomes; when considering prespecified subgroups, ejection fraction significantly influenced the effect of empagliflozin on heart failure admissions but not on renal events. These discordances were extraordinarily puzzling, since in prior large-scale clinical trials, the effect of SGLT2 inhibitors on heart failure and renal outcomes had consistently tracked together.^{6, 7}

To determine if the observed discordances were related to the definition that we specified for the identification of a renal event, we asked if our results would differ if we had prespecified the more conventional meta-analysis criteria for a renal event. Accordingly, we re-analysed the data from EMPEROR-Preserved using the meta-analysis definition. The hazard ratio for the effect of empagliflozin on major renal outcomes for the overall population was 0.78 (95% CI 0.54–1.13), a finding similar to that previously reported with dapagliflozin in patients with a reduced ejection fraction.¹ Additionally, using the meta-analysis definition, ejection fraction had a significant influence on the magnitude of the effect of empagliflozin on kidney outcomes in EMPEROR-Preserved (P-trend = 0.02) (Figure 1). In patients with an ejection fraction of 41–49%, the hazard ratio was 0.41 (95% CI 0.20–0.85), an effect comparable to that which we previously reported for patients with an ejection fraction of ≤40% using the same endpoint [hazard ratio 0.52 (95% CI 0.29–0.92)]¹ — a finding consistent with the premise that patients with an ejection fraction of 41–49% should be classified as having heart failure and a reduced ejection fraction.⁸ In contrast, in patients with an ejection fraction ≥60%, the hazard ratio was 1.24 (95% CI 0.66–2.33). Accordingly, the influence of ejection fraction on renal outcomes (P-trend = 0.02) now closely paralleled the influence of ejection fraction on heart failure hospitalizations (P-trend = 0.008), noted above.⁴

Our results indicate that the definition of a major renal outcome can influence conclusions concerning the effect of a treatment on the progression of kidney disease in patients with heart failure. In the EMPEROR-Preserved trial, we found a discordance between the effects of empagliflozin on heart failure hospitalizations and renal outcomes using the EMPEROR definition of a kidney event, but we noted a concordance between the heart failure and renal effects of SGLT2 inhibition (overall and in prespecified subgroups) when we used a more conventional definition, a finding that is closely aligned with observations of the effects of these drugs in large-scale trials in type 2 diabetes.^{6, 7} Further exploration of these findings is warranted.

Conflict of interest: M.B., C.Z. and S.H. are employees of Boehringer Ingelheim. The other authors serve on the Executive Committee of the EMPEROR trials and receive consulting fees from Boehringer Ingelheim related to this activity.

大规模试验评估了治疗对主要肾脏结局的影响，但肾脏事件的定义因试验而异。在定义肾脏事件时，试验者包括需要肾脏替代治疗或估计肾小球滤过率 (eGFR) 降至 <10–15 mL/min/1.73 m ²的患者，他们还包括 eGFR 大幅持续下降的患者从基线。不同的试验为 eGFR 的关键变化指定了不同的阈值——一些试验指定持续下降 ≥40%，而其他试验指定持续下降 ≥50%。还有一些人需要血清肌酐持续加倍，这对应于 eGFR 下降 ≥57%。

两项大规模试验评估了钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂对射血分数降低的心力衰竭患者的作用。¹他们报告了 dapagliflozin 和 empagliflozin 对心力衰竭住院的有利影响，但这两项试验预先规定了重大肾脏事件的不同定义。两项试验均包括需要肾脏替代治疗或 eGFR 持续下降至 <10–15 mL/min/1.73 m ²的患者。然而，EMPEROR-Reduced 试验还纳入了 eGFR 持续下降 ≥40% 的患者，而 DAPA-HF 研究人员指定 eGFR 持续下降 ≥50%，并且还包括了肾性死亡的发生。^{1, 2}DAPA-HF 试验使用的定义用于两项试验的荟萃分析。¹在 DAPA-HF 中，达格列净作用的风险比使用荟萃分析肾脏终点为 0.71 [95% 置信区间 (CI) 0.44–1.16]。¹在 EMPEROR-Reduced 中，依格列净作用的风险比使用 EMPEROR 定义为 0.50 (95% CI 0.32–0.77)，使用荟萃分析定义为 0.52 (95% CI 0.29–0.92)。^{1, 2}对肾脏事件使用不同的定义并不影响关于恩格列净对心力衰竭和射血分数降低的肾脏结局有益的结论。

EMPEROR-Preserved 试验是一项大型、国际、双盲和安慰剂对照试验，将恩格列净用于心力衰竭和保留射血分数的患者。心力衰竭和射血分数 > 40% 的患者被随机分配到安慰剂组或依格列净组，中位时间为 26 个月。Empagliflozin 将心血管死亡或心力衰竭住院的主要终点降低了 21% [风险比 0.79 (95% CI 0.69–0.90)] 并将心力衰竭的总（首次和复发）住院率降低了 27% [风险比 0.73 (95% CI 0.61–0.88)]。³当根据预先指定的 41-49%、50-59% 和≥60% 的亚组评估基线射血分数对这些结果的影响时，基线射血分数不影响恩格列净对主要终点的影响。然而，射血分数确实影响了恩格列净对心力衰竭住院总人数的影响（P趋势 = 0.008），在射血分数 ≥ 60% 的患者中影响减弱。⁴

与 empagliflozin 对 EMPEROR-Preserved 心衰结局的这些有利影响相比，empagliflozin 对使用 EMPEROR 定义的主要肾脏结局没有产生有利影响，⁵该定义依赖于 eGFR 持续下降 ≥40% 的阈值，并且确实不包括肾性死亡的发生。恩格列净对主要肾脏事件影响的风险比为 0.95（95% CI 0.73–1.24）。在预先指定的 41-49%、50-59% 和 ≥60% 的射血分数亚组中，类似地观察到 empagliflozin 对肾脏结局的中性影响（图 1）。⁵

因此，根据 EMPEROR-Preserved 中预先指定的分析，我们发现在总体人群和预先指定的亚组中，恩格列净对心力衰竭结局和主要肾脏事件的影响之间存在显着差异。当考虑所有射血分数 > 40% 的患者时，恩格列净可减少心衰住院率，但对主要肾脏结局没有影响；在考虑预先指定的亚组时，射血分数显着影响恩格列净对心力衰竭入院的影响，但对肾脏事件没有影响。这些不一致非常令人费解，因为在之前的大规模临床试验中，SGLT2 抑制剂对心力衰竭和肾脏结局的影响一直被同时跟踪。^6、7

为了确定观察到的不一致是否与我们为识别肾脏事件而指定的定义相关，我们询问如果我们预先为肾脏事件指定了更传统的荟萃分析标准，我们的结果是否会有所不同。因此，我们使用荟萃分析定义重新分析了来自 EMPEROR-Preserved 的数据。恩格列净对总体人群主要肾脏结局影响的风险比为 0.78（95% CI 0.54-1.13），这一发现与之前报道的射血分数降低患者使用达格列净相似。¹此外，使用荟萃分析定义，在 EMPEROR-Preserved 中，射血分数对恩格列净对肾脏结局的影响程度有显着影响（P趋势 = 0.02）（图 1)。在射血分数为 41-49% 的患者中，风险比为 0.41（95% CI 0.20-0.85），这一效果与我们之前使用相同终点对射血分数≤40% 的患者报告的效果相当[风险比 0.52 (95% CI 0.29–0.92)] ¹  — 这一发现与射血分数为 41–49% 的患者应归类为心力衰竭和射血分数降低的前提一致。⁸相反，在射血分数 ≥ 60% 的患者中，风险比为 1.24 (95% CI 0.66–2.33)。因此，射血分数对肾脏结局的影响（P-趋势 = 0.02）现在与射血分数对心力衰竭住院的影响密切相关（P-trend = 0.008)，如上所述。⁴

我们的研究结果表明，主要肾脏结果的定义会影响有关治疗对心力衰竭患者肾脏疾病进展的影响的结论。在 EMPEROR-Preserved 试验中，使用 EMPEROR 肾脏事件定义，我们发现恩格列净对心力衰竭住院治疗的影响与肾脏结局之间存在不一致，但我们注意到 SGLT2 抑制的心力衰竭和肾脏影响之间存在一致性（总体和在预先指定的亚组中），当我们使用更传统的定义时，这一发现与这些药物在 2 型糖尿病的大规模试验中的作用观察结果非常一致。^{6, 7}有必要进一步探索这些发现。

利益冲突：MB、CZ 和 SH 是 Boehringer Ingelheim 的员工。其他作者在 EMPEROR 试验的执行委员会任职，并从勃林格殷格翰获得与该活动相关的咨询费。