Heart failure with preserved ejection fraction was until recently considered the greatest unmet need in cardiovascular medicine. The FINEARTS-HF trial, published in 2024, represents a significant advancement in this field, establishing finerenone as an effective treatment for patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF).¹

The Need in HFpEF Management

HFpEF accounts for approximately half of all HF cases, yet therapeutic options remain limited. Steroidal mineralocorticoid receptor antagonists (MRAs) like spironolactone and eplerenone have demonstrated efficacy in heart failure with reduced ejection fraction (HFrEF); however, their effectiveness in HFpEF has been debated. The mixed results of the TOPCAT trial with spironolactone left clinicians uncertain about the role of MRAs in this context. Furthermore, concerns regarding hyperkalemia, renal dysfunction and hormonal side effects have restricted their widespread use.

Enter finerenone – a chemically distinct, nonsteroidal MRA with unique pharmacological properties. Unlike its steroidal predecessors, finerenone shows greater selectivity for the mineralocorticoid receptor and a more balanced distribution between the heart and kidneys, potentially providing cardiovascular benefits with a lower risk of hyperkalemia and worsening kidney function.²

The FINEARTS-HF Trial

The FINEARTS-HF trial was a multinational, double-blind, randomized controlled study that enrolled 6,001 participants across 37 countries. The study population included adults aged 40 years or older with symptomatic heart failure (NYHA class II-IV) and an LVEF ≥40%.

Key inclusion criteria were elevated natriuretic peptides, evidence of structural heart disease and recent diuretic use for at least 30 days.

Participants were randomized to finerenone or a placebo, with dosing determined by kidney function (10 mg titrated to 20 mg daily for an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² and 20 mg or 40 mg for those with higher eGFR).

Primary Results

Over a median follow-up of 2.6 years, finerenone demonstrated a statistically significant 16% reduction in the primary composite outcome of total worsening HF events and cardiovascular death (rate ratio, 0.84; 95% CI, 0.74-0.95; p=0.007). This translated to 14.9 events per 100 patient-years in the finerenone group vs. 17.7 in the placebo group.

Breaking down the components, finerenone reduced worsening HF events by 18% (842 vs. 1,024 events), with no significant difference in cardiovascular death (8.1% vs. 8.7% with finerenone and placebo respectively; hazard ratio [HR], 0.93; p=NS). All-cause mortality did not differ between groups.

Patient-reported symptom scores improved with finerenone compared to placebo (p<0.001), but no significant difference was observed in the improvement in NYHA class at 12 months.

Since the main results were published, the FINEARTS-HF investigators have refined those findings into no fewer than 30 publications, analyzing subpopulations and outcomes to determine in whom the drug is safe and offers the most benefit.

Metabolic Benefits: New-Onset Diabetes Prevention

A particularly noteworthy finding from FINEARTS-HF was finerenone's effect on glucose metabolism. In a prespecified analysis of 3,222 participants without type 2 diabetes (T2D) at baseline, finerenone reduced the risk of new-onset T2D by 24% (95% CI, 0.59-0.97; p=0.026).³ During the median follow-up of 31.3 months, 7.2% of participants taking finerenone developed T2D compared to 9.1% taking placebo.

This metabolic benefit appears unique among MRAs, as spironolactone has been associated with elevations in HbA1c levels in individuals with and without T2D. The mechanism may relate to finerenone's distinct pharmacological profile, including its nonsteroidal structure and more selective mineralocorticoid receptor binding.

Safety Profile and Tolerability

Safety considerations have historically limited MRA use. In FINEARTS-HF, while hyperkalemia (potassium >5.5 mmol/L) occurred more frequently with finerenone (14.6% vs. 7.1%), severe hyperkalemia requiring hospitalization remained rare (0.8% vs. 0.2%). Importantly, finerenone reduced the risk of hypokalemia by half (<3.5 mmol/L: 5% vs. 10.3%), a clinically relevant finding given the prognostic implications of low potassium in HF.

An initial "acute" decline in eGFR was observed with finerenone (–2.9 mL/min/1.73 m² at three months), which did not translate into progressive kidney dysfunction.⁴ In fact, chronic eGFR slope from three months onward showed no significant difference from placebo and finerenone demonstrated sustained reductions in both micro- and macro-albuminuria throughout follow-up.

Special Populations and Consistent Benefits

Subgroup analyses from FINEARTS-HF demonstrated consistent benefits across key populations, including those with and without T2D, varying degrees of kidney dysfunction and different baseline medication regimens. Notably, the treatment effect was maintained in patients already receiving SGLT2 inhibitors (13.6% at baseline), suggesting complementary mechanisms of action.⁵

In the CONFIDENCE trial, published in June 2025, combination therapy with finerenone plus empagliflozin leads to a greater reduction in the urinary albumin-to-creatinine ratio than either drug alone, among persons with chronic kidney disease (CKD) and T2D.⁶

The trial randomized 800 patients (mean age, 66 years, 25% women) to receive 10 or 20 mg of finerenone once daily (with empagliflozin-matching placebo), 10 mg of empagliflozin once daily (with finerenone-matching placebo), or a combination of finerenone plus empagliflozin. All patients were also taking a renin-angiotensin system inhibitor.

FINEARTS-HF also included a substantial proportion of patients enrolled during or shortly after worsening HF events, with 20.3% enrolled within seven days of an event.⁷ Finerenone's benefits appeared particularly pronounced in this high-risk population, addressing an important evidence gap for intensified treatment in the vulnerable post-hospitalization period.

Broader Evidence Base: Meta-Analyses and Pooled Data

The evidence for finerenone extends beyond FINEARTS-HF. An individual patient-level meta-analysis combined data from the RALES, EMPHASIS-HF, TOPCAT and FINEARTS-HF trials, encompassing 13,846 participants.⁸ This analysis revealed important distinctions between steroidal and nonsteroidal MRAs across the HF spectrum.

The investigators pooled analysis demonstrated that overall MRAs reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (HR, 0.77; 95% CI, 0.72-0.83). But there were significant interactions by trials and treatment: treatment with an MRA significantly reduced the primary endpoint and the individual endpoint of HF hospitalization across all HF groups, but the effect was stronger in the HFrEF population than in the HFmrEF/HFpEF population. Cardiovascular death was significantly reduced in the HFrEF trials (HR, 0.73) but not in the HFmrEF/HFpEF trials (HR, 0.94).

The FINE-HEART pooled analysis, incorporating FIDELIO-DKD, FIGARO-DKD and FINEARTS-HF trials (18,991 participants), further strengthened the evidence base by looking at patients with cardiovascular-kidney-metabolic syndrome.² This analysis showed finerenone nonsignificantly reduced the relative risk of cardiovascular death by 11% in this emerging patient population (95% CI, 0.78-1.01; p=0.076), but reduced all-cause mortality by 9% (95% CI, 0.84-0.99), HF hospitalizations by 17% (95% CI, 0.75-0.92) and kidney composite outcomes by 20% (95% CI, 0.72-0.90).

Subsequent analyses from FINE-HEART and the FIDELIO pooled analysis have shown that treatment with finerenone is associated with a reduction in adverse cardiovascular outcomes in diabetes across a range of glycemia and glycemia-lowering regimens, and in patients across a wide range of abdominal adiposity.^9,10 The investigators also found treatment reduced the risk of new onset atrial fibrillation/atrial flutter across the spectrum of patients with T2D and CKD.¹¹

Clinical Implications and Future Directions

The FINEARTS-HF trial and supporting meta-analyses establish finerenone as an important therapeutic option for patients with HFmrEF and HFpEF. Its unique profile – combining cardiovascular benefits, kidney protection, metabolic advantages and acceptable safety – positions it as a valuable addition to contemporary HF management.

Questions remain regarding optimal sequencing with other foundational therapies, particularly SGLT2 inhibitors and longer-term outcomes. However, the consistency of benefits across diverse populations and the novel metabolic effects suggest finerenone addresses multiple pathophysiological pathways in HF, offering hope for improved outcomes in this challenging patient population.

References

1. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024;391:1475-85.
2. Vaduganathan M, Filippatos G, Claggett BL, et al. Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes. Nat Med. 2024;30:3758-64.
3. Butt JH, Jhund PS, Henderson AD, et al. Finerenone and new-onset diabetes in heart failure: a prespecified analysis of the FINEARTS-HF trial. Lancet Diabetes Endocrinol. 2025;13:107-18.
4. Mc Causland FR, Vaduganathan M, Claggett BL, et al. Finerenone and kidney outcomes in patients with heart failure: The FINEARTS-HF Trial. JACC. 2025;85:159-68.
5. Vaduganathan M, Claggett BL, Kulac IJ, et al. Effects of the nonsteroidal mra finerenone with and without concomitant SGLT2 inhibitor use in heart failure. Circulation. 2025;151:149-58.
6. Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N Engl J Med. 2025;393:533-43.
7. Desai AS, Vaduganathan M, Claggett BL, et al. Finerenone in patients with a recent worsening heart failure event: the FINEARTS-HF trial. JACC. 2025;85:106-16.
8. Jhund PS, Talebi A, Henderson AD, et al. Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis. Lancet. 2024;404:1119-31.
9. Ostrominski JW, Harrington J, Claggett BL, et al. Anthropometric measures, cardiovascular outcomes, and treatment effects of finerenone in cardiovascular-kidney-metabolic disease: pooled participant-level analysis of three global trials. JACC. 2025;86:1781-1801.
10. Ostrominski JW, Claggett BL, Miao ZM, et al. Efficacy and safety of finerenone in type 2 diabetes: a pooled analysis of trials of heart failure and chronic kidney disease. Diabetes Care. 2025;48:745-55.
11. Pabon MA, Filippatos G, Claggett BL, et al. Finerenone reduces new-onset atrial fibrillation across the spectrum of cardio-kidney-metabolic syndrome: the FINE-HEART pooled analysis. JACC. 2025;85:1649-60.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Cardiology Magazine, ACC Publications, CM-Jan-Feb-2026, Mineralocorticoid Receptor Antagonists, Natriuretic Peptides, Kidney Diseases, Stroke Volume, Hyperkalemia, Heart Failure