Finerenone in HFpEF and HFmrEF: Emerging Evidence and Guideline Updates

Finerenone (Kerendia) is a selective nonsteroidal mineralocorticoid receptor antagonist that blocks aldosterone and cortisol, limiting inflammation and fibrosis in the kidney, heart, and vasculature.¹ Approved by the FDA in 2021 for adults with chronic kidney disease related to type 2 diabetes, it gained an expanded approval in July 2025 for adults with heart failure and a left ventricular ejection fraction (LVEF) of 40% or greater after the phase 3 FINEARTS-HF (NCT04435626) trial showed fewer cardiovascular deaths and hospitalizations compared with placebo.

Current heart failure guidelines highlight differences in evidence across ejection fraction groups. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Heart Failure Guideline gives spironolactone or eplerenone a class I recommendation with level of evidence A for patients with reduced ejection fraction (LVEF ≤40%).² However, for mildly reduced (HFmrEF, LVEF 41%-49%) and preserved ejection fraction (HFpEF, LVEF ≥50%), mineralocorticoid receptor antagonists (MRAs) carry only a class IIb recommendation with level of evidence B-R, meaning the drug may be considered to lower heart failure hospitalizations, but the supporting evidence is limited. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT; NCT00094302) trial illustrated this gap in HFpEF: spironolactone did not significantly reduce the primary composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization, although it lowered heart failure hospitalization alone.³

The 2023 European Society of Cardiology guideline offers a similar class IIb recommendation for HFmrEF and does not recommend MRAs for HFpEF.⁴ These limitations highlight the need for more effective options and place the FINEARTS-HF findings in context. With the recent FDA approval, it will take time to see how health plans adjust formularies, how cost-effectiveness assessments such as those from the Institute for Clinical and Economic Review (ICER) evolve, and when major guidelines are updated. The most recent development came in June 2025 with the new Japanese heart failure guidelines.⁵ In this update, finerenone was elevated to a class IIa recommendation, whereas spironolactone and eplerenone remained class IIb, reflecting the FINEARTS-HF results.

Moreover, differences in mechanism of action help explain finerenone’s clinical advantages. Unlike the steroidal MRAs spironolactone and eplerenone, which recruit cofactors and act as partial agonists, finerenone blocks cofactor recruitment altogether and produces stronger anti-inflammatory and antifibrotic effects.⁶ Spironolactone has high receptor affinity but low selectivity, accumulates mainly in the kidney, and forms long-acting metabolites. Eplerenone has lower affinity and moderate selectivity and no active metabolites. Finerenone combines high affinity with high selectivity, distributes evenly between kidney and heart tissue, and lacks active metabolites. Clinical results mirror these mechanistic differences: in the BARACK-D (ISRCTN44522369) trial, spironolactone did not reduce the primary end point and had a high rate of discontinuation because of adverse effects such as declining estimated glomerular filtration rate and hyperkalemia.⁷ In contrast, pooled FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) data showed finerenone improved cardiovascular outcomes with fewer treatment-limiting adverse effects. These observations highlight the need for additional studies to determine whether steroidal and nonsteroidal agents can truly be considered interchangeable and to clarify the reasons for their differing clinical effects.

The future landscape of HFpEF and HFmrEF therapy will depend not only on emerging efficacy data but also on how these findings intersect with health system decision making, formularies, and long-term cost effectiveness. Incorporating a new comorbidity into economic models inevitably introduces uncertainty. While trial data exist for this population, the lack of robust head-to-head comparisons with legacy MRAs such as spironolactone or eplerenone complicates comparative-effectiveness estimates. Historically, these older agents were prescribed on the basis of weak or indirect evidence, making them less reliable benchmarks for modern cost-effectiveness analyses. By contrast, finerenone is supported by direct trial data and a more favorable safety profile, with the potential to reduce adverse event costs, improve quality of life, and strengthen adherence. Previous United States-based lifetime Markov models evaluating finerenone in chronic kidney disease related to type 2 diabetes have shown how ICERs, quality-adjusted life-year (QALY) gains, and probabilistic sensitivity analyses capture both value and uncertainty over extended horizons, with finerenone demonstrating an incremental cost-effectiveness ratio of $135,257 per QALY for its original indication.⁸ This figure falls below the commonly cited US willingness-to-pay threshold of $150,000 per QALY, though any potential label expansion into HFpEF or HFmrEF could alter these projections. Taken together, these factors position finerenone as a drug with the potential to deliver stronger long-term cost effectiveness than legacy alternatives, even as residual uncertainty remains regarding relative performance in HFpEF.

The SPIRRIT-HFpEF (NCT02901184) trial represents another milestone in pragmatic heart failure research, evaluating spironolactone in HFpEF and HFmrEF while demonstrating the feasibility of registry-based randomized controlled trials in real-world practice.⁹ Despite challenges such as COVID-19-related recruitment delays, limited staffing, and less intensive monitoring, the design allows broader patient capture and greater generalizability than traditional randomized trials. A parallel effort, SPIRIT-HF, will provide complementary data on spironolactone in preserved or mildly reduced ejection fraction. Together, these trials may clarify the clinical benefit of spironolactone and potentially reshape guideline recommendations and influence payer and formulary decisions. If they demonstrate clear efficacy with favorable safety, finerenone’s uptake may hinge on its incremental value in efficacy, safety, adherence, and cost effectiveness. Conversely, if spironolactone continues to show inconclusive or neutral results, finerenone could retain a relative advantage, reinforced by consistent trial evidence and growing international guideline recognition, including its class IIa recommendation in the 2025 Japanese guidelines.

READ MORE: Cardiology Resource Center

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REFERENCES

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