Age and sex do not influence efficacy and safety of finerenone in patients with T2D and CKD

A post-hoc FIDELITY analysis showed the beneficial effects of finerenone versus placebo on composite CV and kidney outcomes were not modified by age or sex. The drug’s safety profile was also similar across age and sex groups.

This summary is based on the publication of Bansal S, Canziani MEF, Birne R, et al. - Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials. BMJ Open. 2024 Mar 19;14(3):e076444. doi: 10.1136/bmjopen-2023-076444

Introduction and methods

Background

The selective, nonsteroidal MRA finerenone reduced the risk of CKD progression and CV outcomes compared with placebo in patients with T2D and CKD, as shown by FIDELITY (FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis) [1]. However, the influence of age and sex on the treatment effects of finerenone is unknown.

Aim of the study

In a post-hoc analysis of the FIDELITY dataset, the authors evaluated the efficacy and safety of finerenone on CV and kidney outcomes by age and/or sex.

Methods

The FIDELITY dataset is 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 patients with T2D and CKD (serum potassium ≤4.8 mmol/L at screening) receiving maximum-tolerated RAASi therapy who were randomized to finerenone (10 or 20 mg once daily based on eGFR at screening visit) or placebo. Median follow-up duration was 3.0 years (IQR: 2.3–3.8).

Males constituted 69.8% (n=9088) of the study population. Females aged <51.4  years at baseline were categorized as premenopausal (n=323; 2.5% of the study population) and those aged ≥51.4 years at baseline as postmenopausal (n=3615; 27.8% of the study population).

Outcomes

Efficacy endpoints were: (1) a composite CV outcome, comprising time to first event of CV death, nonfatal MI, nonfatal stroke, or HF hospitalization; and (2) a composite kidney outcome, encompassing time to first event of kidney failure, sustained eGFR decrease ≥57% from baseline for ≥4 weeks, or kidney disease death.

Safety endpoints included frequency of investigator-reported adverse events, including adverse events leading to treatment discontinuation, serum potassium levels >5.5 and >6.0 mmol/L, and other safety events of interest, such as hypotension, hyperkalemia, and gynecomastia in males.

Main results

Efficacy

• The beneficial effect of finerenone over placebo on the risk of the composite CV outcome was consistent across age groups (HR for <65 years: 0.94; 95%CI: 0.81–1.10; HR for 65–74 years: 0.84; 95%CI: 0.73–0.98; HR for ≥75 years: 0.80; 95%CI: 0.65–0.99; P for interaction=0.4198) and sex categories (HR for males: 0.86; 95%CI: 0.77–0.96; HR for premenopausal females: 0.89; 95%CI: 0.35–2.27; HR for postmenopausal females: 0.87; 95%CI: 0.73–1.05; P for interaction=0.9942).
• The treatment effect of finerenone on risk reduction of HF hospitalization was not modified by age (P for interaction=0.6977). However, statistical heterogeneity was observed in the reduction of HF hospitalizations with finerenone versus placebo across sex categories (HR for males: 0.66; 95%CI: 0.54–0.81; HR for premenopausal females: 1.39; 95%CI: 0.33–5.93; HR for postmenopausal females: 1.06; 95%CI: 0.78–1.44; P for interaction=0.0245). These results persisted after adjustment for differences in baseline variables such as age, systolic blood pressure, and eGFR (P for interaction=0.02).
• Finerenone’s effect on reducing the risk of the composite kidney outcome was also consistent across age groups (HR for <65 years: 0.76; 95%CI: 0.63–0.92; HR for 65–74 years: 0.75; 95%CI: 0.59–0.95; HR for ≥75 years: 0.98; 95%CI: 0.61–1.57; P for interaction=0.5088) and sex categories (HR for males: 0.75; 95%CI: 0.64–0.89; HR for premenopausal females: 0.67; 95%CI: 0.28–1.62; HR for postmenopausal females: 0.81; 95%CI: 0.61–1.07; P for interaction=0.8524).
• Finerenone attenuated the annualized least-squares mean change in eGFR slope from 4 months to end of treatment (i.e., chronic eGFR slope) compared with placebo across the 3 age groups (all P<0.0001) and sex categories (all P<0.05).
• In addition, finerenone versus placebo reduced the urine albumin-to-creatinine ratio over time regardless of age or sex.

Safety

• The frequencies of any adverse event and any serious adverse events were similar between treatment groups regardless of age or sex.
• In patients treated with finerenone, the incidence of hyperkalemia was increased compared with placebo-treated patients in all age and sex groups, except premenopausal females. The rates of hyperkalemia leading to discontinuation of the study drug and any serious hyperkalemia event leading to hospitalization were low across all age and sex groups (<3% and <2%, respectively).
• The frequencies of treatment-emergent serum potassium levels >5.5 mmol/L and >6.0 mmol/L were higher in the finerenone group than the placebo group, but they were consistent across all age and sex groups.
• The incidence of gynecomastia in males was similar in the finerenone and placebo groups across all ages (≤0.2%).

Conclusion

This post-hoc analysis of the FIDELITY dataset showed that the beneficial effects of finerenone versus placebo on composite CV and kidney outcomes were not modified by age or sex, although the effect on risk reduction of HF hospitalization appeared to be more pronounced in men compared with premenopausal and postmenopausal women. The safety profile of finerenone was similar across age and sex groups.

Find this article online at BMJ Open.

Reference

1. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9:22–31.