Early kidney protection by nonsteroidal MRA accounts for large proportion of long-term CKD outcomes


In a post-hoc FIDELITY analysis, early albuminuria reduction induced by finerenone appeared to mediate a large proportion of renal outcomes and a modest proportion of CV outcomes in patients with CKD and T2D.

This summary is based on the publication of Agarwal R, Tu W, Farjat AE, et al. - Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes: A Mediation Analysis. Ann Intern Med. 2023 Dec 5. doi: 10.7326/M23-1023

Introduction and methods


As shown by 2 RCTs, finerenone reduced the risk of the composite kidney failure and CV outcomes compared with placebo in patients with CKD and T2D [1-3]. This selective, nonsteroidal MRA also lowered the urine albumin-to-creatinine ratio (UACR) by ≥30% [1-3]. A 30% reduction in UACR is associated with a lower risk of end-stage kidney disease [4] and is recommended by the American Diabetes Association as a therapeutic goal [5]. However, whether the finerenone-induced changes in UACR mediate the observed CV and renal outcomes is unknown.

Aim of the study

In a post-hoc analysis of the combined RCT data, the authors aimed to identify a potential mechanism (or mediator) through which finerenone improves renal and CV outcomes in patients with CKD and T2D, by examining early (from baseline to 4 months) changes in albuminuria.


This was a post-hoc mediation analysis of FIDELITY (FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis), a prespecified pooled analysis of individual patient-level data from 2 international, double-blind, phase 3 RCTs: the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials. The combined dataset comprised 13,026 T2D patients with UACR 30–5000 mg/g despite ACEi/ARB therapy who were randomized to finerenone (10 or 20 mg once daily based on eGFR at screening visit) or placebo.

For the current analysis, UACR measurements at baseline and/or 4 months were available for 12,512 patients. Median follow-up duration was 2.8 years.


Separate mediation analysis were conducted for: (1) the composite kidney endpoint, which encompassed time to kidney failure, sustained eGFR decrease ≥57% from baseline for ≥4 weeks (i.e., approximately doubling of serum creatinine level), or kidney disease death; and (2) the composite CV endpoint, comprising time to CV death, nonfatal MI, nonfatal stroke, or HF hospitalization.

Main results


In this post-hoc mediation analysis of the FIDELITY dataset, finerenone-induced changes in kidney injury—as assessed by an early UACR reduction—appeared to mediate a large proportion of renal outcomes and a modest proportion of CV outcomes at ~3 years in patients with CKD and T2D. The authors note that although mediation analysis “can lend support to causal inference and provide estimates to the magnitudes of such mediation [...], it cannot prove that early kidney injury (as measured by UACR) is the underlying causal mechanism.”

They conclude that “the current results emphasize the importance of monitoring UACR after initiating treatment, as it can serve as a valuable surrogate indicator of the early treatment efficacy and offer insights into potential long-term kidney and CV benefits.”


  1. Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229. [PMID: 33264825] doi:10.1056/NEJMoa2025845
  2. Ruilope LM, Pitt B, Anker SD, et al. Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study. Nephrol Dial Transplant. 2023;38:372-383. [PMID: 35451488] doi:10.1093/ndt/gfac157
  3. Agarwal R, Filippatos G, Pitt B, et al; FIDELIO-DKD and FIGARO-DKD Investigators. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474-484. [PMID: 35023547] doi:10.1093/eurheartj/ehab777
  4. Heerspink HJ, Kröpelin TF, Hoekman J, et al; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol. 2015;26:2055-2064. [PMID: 25421558] doi:10.1681/ASN.2014070688
  5. ElSayed NA, Aleppo G, Aroda VR, et al. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46:S191-S202. [PMID: 36507634] doi:10.2337/dc23-S011

Find this article online at Ann Intern Med.

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