卡格列净对比非奈利酮对心肾结局的影响：FIDELIO-DKD 探索性事后分析与 CREDENCE 研究结果的比较。

Effects of canagliflozin versus finerenone on cardiorenal outcomes: exploratory post hoc analyses from FIDELIO-DKD compared to reported CREDENCE results.

机构信息

Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA.

Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany.

出版信息

Nephrol Dial Transplant. 2022 Jun 23;37(7):1261-1269. doi: 10.1093/ndt/gfab336.

DOI:10.1093/ndt/gfab336

PMID:34850173

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9217637/

Abstract

BACKGROUND

The nonsteroidal mineralocorticoid receptor antagonist finerenone and the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) canagliflozin reduce cardiorenal risk in albuminuric patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). At first glance, the results of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) (ClinicalTrials.gov, NCT02540993) and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) appear disparate. In FIDELIO-DKD, the primary endpoint had an 18% [95% confidence interval (CI) 7-27] relative risk reduction; in CREDENCE, the primary endpoint had a 30% (95% CI 18-41) relative risk reduction. Unlike CREDENCE, the FIDELIO-DKD trial included patients with high albuminuria but excluded patients with symptomatic heart failure with reduced ejection fraction. The primary endpoint in the FIDELIO-DKD trial was kidney specific and included a sustained decline in the estimated glomerular filtration rate (eGFR) of ≥40% from baseline. In contrast, the primary endpoint in the CREDENCE trial included a sustained decline in eGFR of ≥57% from baseline and cardiovascular (CV) death. This post hoc exploratory analysis investigated how differences in trial design-inclusion/exclusion criteria and definition of primary outcomes-influenced observed treatment effects.

METHODS

Patients from FIDELIO-DKD who met the CKD inclusion criteria of the CREDENCE study (urine albumin: creatinine ratio >300-5000 mg/g and an eGFR of 30-<90 mL/min/1.73 m2 at screening) were included in this analysis. The primary endpoint was a cardiorenal composite (CV death, kidney failure, eGFR decrease of ≥57% sustained for ≥4 weeks or renal death). Patients with symptomatic heart failure with reduced ejection fraction were excluded from FIDELIO-DKD. Therefore, in a sensitivity analysis, we further adjusted for the baseline prevalence of heart failure.

RESULTS

Of 4619/5674 (81.4%) patients who met the subgroup inclusion criteria, 49.6% were treated with finerenone and 50.4% received placebo. The rate of the cardiorenal composite endpoint was 43.9/1000 patient-years with finerenone compared with 59.5/1000 patient-years with placebo. The relative risk was significantly reduced by 26% with finerenone versus placebo [hazard ratio (HR) 0.74 (95% CI 0.63-0.87)]. In CREDENCE, the rate of the cardiorenal composite endpoint was 43.2/1000 patient-years with canagliflozin compared with 61.2/1000 patient-years with placebo; a 30% risk reduction was observed with canagliflozin [HR 0.70 (95% CI 0.59-0.82)].

CONCLUSIONS

This analysis highlights the pitfalls of direct comparisons between trials. When key differences in trial design are considered, FIDELIO-DKD and CREDENCE demonstrate cardiorenal benefits of a similar magnitude.

摘要

背景

非甾体类盐皮质激素受体拮抗剂非奈利酮和钠-葡萄糖共转运蛋白-2 抑制剂（SGLT-2i）卡格列净可降低伴有慢性肾脏病（CKD）和 2 型糖尿病（T2D）的白蛋白尿患者的心肾风险。乍一看，在糖尿病肾病中的肾脏失败和疾病进展降低（FIDELIO-DKD）（ClinicalTrials.gov，NCT02540993）和卡格列净和糖尿病肾病中的肾脏事件临床评估（CREDENCE）的结果似乎不同。在 FIDELIO-DKD 中，主要终点有 18%[95%置信区间（CI）7-27]的相对风险降低；在 CREDENCE 中，主要终点有 30%（95%CI 18-41）的相对风险降低。与 CREDENCE 不同，FIDELIO-DKD 试验纳入了白蛋白尿较高的患者，但排除了射血分数降低的有症状心力衰竭患者。FIDELIO-DKD 试验的主要终点是肾脏特异性的，包括肾小球滤过率（eGFR）从基线持续下降≥40%。相比之下，CREDENCE 试验的主要终点包括 eGFR 从基线持续下降≥57%和心血管（CV）死亡。本事后分析研究了试验设计的差异——纳入/排除标准和主要结局的定义——如何影响观察到的治疗效果。

方法

符合 CREDENCE 研究 CKD 纳入标准的 FIDELIO-DKD 患者（尿白蛋白：肌酐比值>300-5000mg/g，筛选时 eGFR 为 30-<90ml/min/1.73m2）被纳入本分析。主要终点是心血管-肾脏复合终点（CV 死亡、肾脏衰竭、eGFR 持续下降≥57%且持续≥4 周或肾脏死亡）。FIDELIO-DKD 排除了射血分数降低的有症状心力衰竭患者。因此，在敏感性分析中，我们进一步调整了心力衰竭的基线患病率。

结果

在符合亚组纳入标准的 4619/5674（81.4%）名患者中，49.6%接受非奈利酮治疗，50.4%接受安慰剂治疗。与安慰剂相比，非奈利酮组的心血管-肾脏复合终点发生率为 43.9/1000 患者年，而安慰剂组为 59.5/1000 患者年。非奈利酮与安慰剂相比，相对风险显著降低 26%[风险比（HR）0.74（95%CI 0.63-0.87)]。在 CREDENCE 中，卡格列净组的心血管-肾脏复合终点发生率为 43.2/1000 患者年，安慰剂组为 61.2/1000 患者年；卡格列净可降低 30%的风险[HR 0.70（95%CI 0.59-0.82)]。