Early reduction of albuminuria facilitated by finerenone contributes to optimal kidney and CV outcomes in patients with T2D: Mediation analysis of the FIDELIO-DKD and FIGARO-DKD trials

02 Feb 2024

In patients with type 2 diabetes (T2D), albuminuria is an early clinical marker of chronic kidney disease (CKD) and is associated with an increased risk of CKD progression and cardiovascular (CV) events.1 Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has exhibited efficacy in significantly improving kidney and CV outcomes and reducing the urine albumin-to-creatinine ratio (UACR) by >30% compared to placebo in 2 prior phase 3 randomized controlled trials, FIDELIO-DKD and FIGARO-DKD.1 However, the relationship between an early finerenone-induced reduction in UACR and optimal kidney and CV outcomes remains unclear.1 As such, investigators from the FIDELIO-DKD and FIGARO-DKD trials performed a causal mediation analysis based on pooled data from both trials.1 During the ASN Kidney Week 2023, Professor Rajiv Agarwal from Indiana University, Indianapolis, the United States (US), presented results from the analysis.1

A total of 12,512 patients from FIDELITY (a prespecified pooled analysis of the FIGARO-DKD and FIDELIO-DKD trials) with CKD and T2D who had available UACR data were included in this causal mediation analysis.1 Patients had been randomly assigned 1:1 to receive either finerenone (n=6,273) or placebo (n=6,239).1 Baseline characteristics such as age, sex, systolic blood pressure (SBP), history of cardiovascular disease (CVD), estimated glomerular filtration rate (eGFR) levels, SGLT-2 inhibitor, and RAS inhibitor use were similar in both the finerenone and placebo groups.1 In particular, both groups possessed comparable median UACR at baseline (finerenone: 513.6mg/g; placebo: 514.5mg/g).1 The outcomes of this causal mediation analysis consisted of a composite of kidney outcomes (time to kidney failure, sustained 57% decrease in eGFR from baseline, or kidney-related death) and CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure), which were used to evaluate the benefits of finerenone-induced UACR reduction.1

At 4 months, the finerenone group experienced a 31% greater UACR reduction compared to the placebo group (33.6% vs. 2.6%), with 53% of patients (n=3,338) in the finerenone group experiencing 30% UACR reduction from baseline compared to only 27% of patients (n=1,684) in the placebo group.1 An early reduction in UACR of 30% also contributed to a reduced risk of composite kidney outcome events compared to those with <30% UACR reduction in both treatment groups over a 4-year period.1 In addition, patients who achieved an early reduction in UACR of 30% experienced fewer composite CV outcome events than those with <30% UACR reduction in the finerenone group.1

Subsequently, the reduction in UACR, when analyzed as a continuous variable, mediated 84% (95% CI: 49-100%) and 37% (95% CI: 8-65%) of the treatment effect of finerenone on the kidney and CV outcomes respectively.1 When UACR change was analyzed as a dichotomous variable using the guideline-recommended 30% reduction threshold, the treatment of finerenone mediated 64% and 26% of kidney and CV outcomes respectively.1

In summary, early albuminuria reduction facilitated by finerenone mediated a sizable proportion of the treatment effect against CKD progression and a modest proportion of the effect against CV outcomes in patients with CKD and T2D.1 The findings of this analysis highlight that achieving early albuminuria reduction with finerenone can induce durable benefits to both kidney and CV health, further emphasizing the importance of monitoring of UACR after treatment initiation in patients with T2D.1

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