Finerenone’s effects in HFmrEF/HFpEF remain consistent regardless of obesity

Finerenone reduced CV death or worsening HF events compared with placebo in HFmrEF/HFpEF patients irrespective of baseline BMI, with possibly a greater effect in those with a higher BMI, as shown by a prespecified analysis of FINEARTS-HF.

This summary is based on the publication of Butt JH, Henderson AD, Jhund PS, et al. - Finerenone, Obesity, and Heart Failure With Mildly Reduced/Preserved Ejection Fraction: Prespecified Analysis of FINEARTS-HF. J Am Coll Cardiol. 2025 Jan 21;85(2):140-155. doi: 10.1016/j.jacc.2024.10.111

Introduction and methods

Background

Obesity may lead to excessive adipocyte-derived aldosterone secretion, independent of the classical RAAS cascade [1,2]. Therefore, MRAs could have an important therapeutic role in patients with both HF and obesity, especially in those with HFmrEF or HFpEF, in whom obesity is more prevalent than in HFrEF patients [3,4]. Recently, the FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) trial showed the nonsteroidal MRA finerenone reduced the risk of the primary composite endpoint of CV death or total worsening HF events (WHFEs) and improved health-related quality of life compared with placebo in patients with HFmrEF/HFpEF [5].

Aim of the study

In a prespecified analysis of the FINEARTS-HF trial, the authors examined the association between bodyweight and clinical outcomes and the efficacy and safety of finerenone in patients with HFmrEF/HFpEF stratified by BMI and other anthropometric indices.

Methods

The FINEARTS-HF trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 6001 HFmrEF/HFpEF patients with NYHA class II–IV HF symptoms, LVEF ≥40%, evidence of structural heart disease, and elevated NT-proBNP levels were randomized to finerenone (maximum dose: 20 or 40 mg once daily based on eGFR) or placebo, in addition to usual care. Median follow-up duration was 32 months. Baseline BMI data were available for 5988 patients (99.8%).

Outcomes

The primary efficacy endpoint was a composite outcome of CV death or total (first and recurrent) WHFEs (i.e., HF hospitalization or urgent HF visit). Secondary efficacy endpoints included total WHFEs; improvement in NYHA functional class from baseline to 12 months; changes in KCCQ – Total Symptom Score, Overall Summary Score, and Clinical Summary Score from baseline to 12 months; and all-cause mortality.

Main results

Clinical outcomes according to BMI

• In models only adjusted for treatment assignment, patients with obesity class II or III (≥35.0 kg/m²; n=1146) had higher risks of the primary composite endpoint (unadjusted rate ratio (RR): 1.26; 95%CI: 1.03–1.54), total WHFEs (unadjusted RR: 1.38; 95%CI: 1.10-1.74), and first WHFE (unadjusted HR: 1.30; 95%CI: 1.07–1.58) compared with patients with underweight or normal weight (BMI <25.0 kg/m²; n=1306).

• No significant differences in the rate of the primary endpoint were seen for patients with overweight (BMI 25.0–29.9 kg/m²; n=1990) and those with obesity class I (BMI 30.0–34.9 kg/m²; n=1546) compared with the reference group.

• In contrast, patients with overweight or obesity (classes I-III) experienced a lower risk of all-cause mortality compared with those with underweight/normal weight, with unadjusted HRs ranging from 0.69 (95%CI: 0.57–0.83) to 0.77 (95%CI: 0.65–0.91).

• In fully adjusted models, all patients with BMI ≥30 kg/m² had a higher risk of the primary endpoint, total WHFEs, and first WHFE, but they no longer had a lower all-cause mortality risk.

Efficacy of finerenone

• Treatment with finerenone reduced the risk of the primary endpoint compared with placebo regardless of baseline BMI (unadjusted RR for underweight/normal weight: 0.80; 95%CI: 0.62–1.04; unadjusted RR for overweight: 0.91; 95%CI: 0.72–1.15; unadjusted RR for obesity class I: 0.92; 95%CI: 0.72–1.19; unadjusted RR for obesity classes II–III: 0.67; 95%CI: 0.50–0.89; P for interaction=0.32).

• The treatment effect of finerenone versus placebo on the secondary endpoints also did not differ between BMI categories (all P for interaction>0.05).

• When BMI was analyzed as a continuous variable, the beneficial effect of finerenone seemed to be greater in patients with a higher BMI for the primary endpoint (P for interaction=0.005) and total WHFEs (P for interaction<0.001).

Conclusion

In this prespecified analysis of the FINEARTS-HF trial among patients with HFmrEF/HFpEF, finerenone reduced the risk of the primary composite endpoint of CV death or total WHFEs compared with placebo irrespective of baseline BMI. The beneficial effect of finerenone seemed to be greater in patients with a higher BMI. In addition, as the authors point out, there was no consistent evidence that adiposity is associated with better survival in HF patients (i.e., the obesity-survival paradox).

Find this article online at J Am Coll Cardiol.

References

1. Dinh Cat AN, Friederich-Persson M, White A, Touyz RM. Adipocytes, aldosterone and obesity-related hypertension. J Mol Endocrinol. 2016;57:F7–F21.
2. Briones AM, Nguyen Dinh, Cat A, Callera GE, et al. Adipocytes produce aldosterone through calcineurin-dependent signaling pathways. Hypertension. 2012;59:1069–1078.
3. Ho JE, Lyass A, Lee DS, et al. Predictors of new-onset heart failure. Circ Heart Fail. 2013;6:279–286.
4. Savji N, Meijers WC, Bartz TM, et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. J Am Coll Cardiol HF. 2018;6:701–709.
5. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024;391(16):1475–1485. https://doi.org/10.1056/NEJMoa2407107