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

Background

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.

Methods

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.

Outcomes

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

• From baseline to 4 months, a ≥30% reduction in UACR was observed in 3338 patients (53.2%) in the finerenone group and 1684 patients (27.0%) in the placebo group.
• Finerenone increased the mean survival time by 15% for the composite kidney endpoint. An early reduction in log UACR mediated 84% (95%CI: 49%–100%) of finerenone’s total treatment effect.
• For the composite CV endpoint, finerenone prolonged the mean survival time by 12%, and the log UACR reduction accounted for 37% (95%CI: 8%–65%) of the treatment effect.
• A sensitivity analysis using the change in UACR as a binary variable (i.e., whether the guideline-recommended threshold of 30% UACR reduction was achieved or not) showed that a ≥30% UACR reduction explained 64% (95%CI: 31%–96%) of the total treatment effect for the composite kidney endpoint and 26% (95%CI: 0.4%–52%) of the entire treatment effect for the composite CV endpoint.
• Patients who achieved a ≥30% UACR reduction had fewer composite kidney endpoint events compared with patients with a <30% UACR reduction. Separation of the cumulative incidence curves became visible at approximately 12 months. However, in each UACR reduction group, there was little difference between patients treated with finerenone and those receiving placebo.
• For the composite CV endpoint, there was little difference between the ≥30% and <30% UACR reduction groups. Still, in the finerenone group, patients with a ≥30% UACR reduction had fewer composite CV endpoints events compared with those with a <30% UACR reduction.

Conclusion

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.”

References

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.