Clinical outcomes of finerenone in heart failure: A systematic review and meta-analysis

Abstract

BACKGROUND

Chronic kidney disease (CKD) and heart failure (HF) frequently coexist, creating a complex clinical challenge. Mineralocorticoid receptor antagonists (MRAs) have shown promise in managing both conditions, primarily by mitigating the adverse effects of aldosterone. Finerenone, a novel nonsteroidal MRA, has demonstrated significant benefits in reducing cardiovascular and renal events in patients with CKD and type 2 diabetes. However, while the efficacy and safety of finerenone have been extensively evaluated in CKD populations, its effects in patients with HF, particularly those without concurrent significant CKD, require further investigation.

AIM

To investigate the efficacy and safety of finerenone in patients with HF.

METHODS

Per the PRISMA guidelines, a thorough search was conducted in PubMed/MEDLINE, Science Direct, and Google Scholar, and relevant randomized control trials (RCTs) comparing finerenone to placebo or other agents on clinical outcomes in patients with HF were included.

RESULTS

Four RCTs involving 7457 patients with HF (mean age, 71.85 years; females, 41.0%) were included in the study. Of them, 4160 received finerenone (mean age, 71.7 years) and 3297 received a placebo (mean age, 72.04 years). The finerenone group had significantly lower odds of worsening HF [odds ratio (OR) = 0.76; 95%CI: 0.66-0.88; P = 0.0001] and improvement in the Kansas City Cardiomyopathy Questionnaire (mean differences: 1.60; 95%CI: 1.58-1.62; P < 0.0001). Furthermore, higher odds of hyperkalemia (OR = 1.32; 95%CI: 0.58-2.99; P = 0.51) and lower odds of adverse event (AE) (OR = 0.91; 95%CI: 0.72-1.15; P = 0.44) and severe AE (OR = 0.99; 95%CI: 0.88-1.10; P = 0.82).

CONCLUSION

Our meta-analysis demonstrates that finerenone significantly reduces the risk of worsening of HF and improves quality of life in HF. However, finerenone was associated with increased risks of hyperkalemia, requiring clinical vigilance. Future research should focus on long-term outcomes and the optimal dosing of finerenone in specific HF subpopulations, including those receiving other guideline-directed medical therapies.

Key Words: Finerenone; Heart failure; Nonsteroidal mineralocorticoid receptor antagonists; Kansas City Cardiomyopathy Questionnaire; Hyperkalemia; Meta-analysis

Core Tip: Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, has shown clear benefits in chronic kidney disease, but its specific impact on heart failure (HF) has required further synthesis. Our meta-analysis of 7457 patients reveals that finerenone significantly decreases the odds of worsening HF and enhances quality of life scores. However, potential safety signals, including hyperkalemia, suggest that while finerenone is a potent tool for managing HF, its use requires vigilant monitoring to balance clinical benefits against adverse events.

INTRODUCTION

Heart failure (HF) remains one of the most common and challenging cardiovascular conditions worldwide. It affects over 64 million people and continues to drive hospitalizations, morbidity, and mortality despite major strides in both medications and devices[1,2]. While significant progress has been made in managing HF, outcomes remain suboptimal across all ejection fraction phenotypes[3].

Guideline-directed medical therapy (GDMT) has improved prognosis by targeting neurohormonal pathways, particularly the renin-angiotensin-aldosterone system[4]. Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, are important components of GDMT and have demonstrated significant benefit in reducing morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF)[5,6]. However, in real-world practice, their use is often limited due to hyperkalemia, worsening renal function, and endocrine-related side effects including gynecomastia and menstrual irregularities[7,8].

Finerenone, a newer nonsteroidal selective MRA, has gained attention as a potential alternative. It has greater mineralocorticoid receptor selectivity and exhibits both anti-fibrotic and anti-inflammatory properties, with a more favorable safety profile compared to traditional steroidal MRAs[9,10]. Importantly, finerenone has reduced affinity for androgen and progesterone receptors, which may help mitigate hormonal side effects[10]. The FIDELIO-DKD and FIGARO-DKD trials demonstrated that finerenone significantly reduced cardiovascular and renal events in patients with chronic kidney disease (CKD) and type 2 diabetes, including HF hospitalizations[11,12].

However, its role in broader HF populations, including those with different ejection fraction phenotypes and comorbidities, remains under investigation. Several randomized controlled trials (RCTs) have examined the use of finerenone in HF, but heterogeneity in study designs, patient populations, and reported outcomes has led to uncertainty about its clinical applicability[13,14]. Given the growing interest in finerenone as part of contemporary HF therapy, we conducted a systematic review and meta-analysis of randomized trials. Our goal is to evaluate the effects of finerenone on clinical outcomes including mortality, HF hospitalization, renal events, and adverse effects, and to clarify its potential role within evidence-based HF management.

MATERIALS AND METHODS

Per the PRISMA guidelines[15,16], a comprehensive literature search was conducted in prominent databases, including PubMed/MEDLINE, Google Scholar, and Science Direct. Subject headings and keywords for “Heart Failure”, “HFrEF”, “HFpEF”, “Finerenone”, and “Nonsteroidal MRA” were used along with appropriate Boolean operators. The references of the selected studies were also examined to verify the comprehensiveness of the search, using the snowballing method. The search strategy utilized for the study is outlined in Supplementary Table 1.

Screening of the title and abstract was done independently by two reviewers, Ndakotsu A and Palaparthi EC, and conflicts were resolved by a third reviewer, Kiyani M. Full-text screening was done independently by two reviewers, Anjum M and Kodali LSM, and conflicts were resolved by a third reviewer, Mylavarapu M. RCTs that reported clinical outcomes in patients with HF treated with finerenone were included in our analysis. A detailed list of inclusion and exclusion criteria was outlined in Supplementary Table 2.

The risk of bias assessment was conducted using the adaptations of the risk of bias in randomized trials by Cochrane Library[17]. Data extraction was carried out by Kiyani M and the extraction was validated by Mylavarapu M. Outcomes were divided into efficacy, consisting worsening HF (WHF; hospitalization for HF or urgent HF-related clinical deterioration) and change in Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) and safety outcomes, including hyperkalemia, adverse event (any registered adverse event in the trial), and serious adverse event (SAE; grade 3-5 adverse event). Binary random effects were used to estimate the odds ratio (OR), and continuous random effects were used to estimate the mean differences (MD). Heterogeneity was assessed using the (χ²) test and I² statistics. The I² statistic was interpreted as follows: < 25% (low heterogeneity), 25%-50% (moderate heterogeneity), and > 50% (high heterogeneity). A leave-one-out (LOO) sensitivity analysis was performed to address the heterogeneity and test for the robustness of the results. Visual inspection of funnel plots was utilized to estimate for publication bias. All the statistical analyses were performed using the Review Manager version 5.4.1. A P value < 0.05 was considered to be statistically significant.

RESULTS

In total, four RCTs[18-21] with 7457 patients (41% females; 71.85 mean age) were included in our analysis. The two groups were similar to the control group in terms of age (mean age 71.7 vs 72.04). However, the finerenone group had lesser number of females compared to the control group (1613, 38.77% vs 1444, 43.8%). Figure 1 depicts the study selection process[22]. Table 1 summarizes the baseline characteristics of the included studies.

Figure 1 PRISMA flowchart of study selection process. RCT: Randomised controlled trial; HF: Heart failure.

Table 1 Baseline characteristics of included studies, mean ± SD.

Ref.	Year	Study type	Patient population		Age		Sex (female)
			Finerenone	Control	Finerenone	Control	Finerenone	Control
Solomon et al[18]	2024	RCT	3003	2998	71.9 ± 9.6	72.0 ± 9.7	1355	1377
Filippatos et al[19]	2016	RCT	834	221	70.83 ± 10.17	72.4 ± 9.9	188	51
Sato et al[20]	2016	RCT	59	13	76.11 ± 9.06	76.5 ± 10.89	18	1
Pitt et al[21]	2013	RCT	264	65	71.27 ± 8.24	71.74 ± 7.54	52	15

RCT: Randomised controlled trial.

Efficacy outcomes

Finerenone group had significantly lower odds of WHF (OR = 0.76; 95%CI: 0.66-0.88; P = 0.0001; I² = 4%) and improvement in the KCCQ (MD = 1.60; 95%CI: 1.58-1.62; P < 0.0001; I² = 0%) compared to the control group (Figure 2).

Figure 2 Efficacy outcomes of finerenone in heart failure. KCCQ: Kansas City Cardiomyopathy Questionnaire.

Safety outcomes

Regarding safety outcomes, although the finerenone group had higher odds of hyperkalemia (OR = 1.32; 95%CI: 0.58-2.99; P = 0.51), the odds of AEs (OR = 0.91; 95%CI: 0.72-1.15; P = 0.44) and SAEs (OR = 0.99; 95%CI: 0.88-1.10; P = 0.82) compared to the control group were lower. However, these outcomes did not reach statistical significance (Figure 2).

Assessment of bias and heterogeneity

Our analyses revealed low heterogeneity in most of outcomes assessed, including WHF (I² = 4%), improvement in KCCQ (I² = 0%), and SAE (I² = 0%), except hyperkalemia (I² = 78%). Supplementary Figure 1 and Supplementary Table 3 outlines the heterogeneity assessment and LOO sensitivity analyses, respectively. Regarding risk of bias assessment, all of the included studies demonstrated a low risk across most domains except for D3: Missing Outcomes Data (1/4 studies) and D4: Measurements of Outcomes (1/4 studies) for the majority of the literature. Supplementary Table 4 reports the risk of bias assessment of the included studies. Supplementary Figures 2-6 outlines the funnel plots for publication bias.

DISCUSSION

To our knowledge, this is the most comprehensive meta-analysis to date evaluating finerenone in HF, comprising four RCTs with a total population of 7457 patients. Our pooled analysis demonstrates that finerenone, when added to standard-of-care, yields clear improvements in WHF events and KCCQ scores. Statistical heterogeneity remained low for most outcomes despite variations in trial design, with the substantial FINE-ARTS HF trial contributing the majority of the analytical weight[18]. While early-phase studies were limited by sample size, they demonstrated consistent trends toward improved biomarkers, including natriuretic peptide reduction, even at lower dosages[19-21].

Finerenone has emerged as a pivotal therapeutic option addressing the intersection of cardiovascular, kidney, and metabolic pathologies. While steroidal MRAs are established class I recommendations for HFrEF, their utility in HF with midrange ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF) remained equivocal following the mixed results of the TOPCAT trial[23]. Finerenone possesses a distinct pharmacodynamic profile compared to steroidal MRAs; its nonsteroidal structure confers high affinity and selectivity for the mineralocorticoid receptor with negligible activity at androgen receptors. This distinct receptor interplay promotes a balanced cardiorenal distribution, effectively attenuating myocardial and renal fibrosis, inflammation, and oxidative stress[24]. By inhibiting mineralocorticoid receptor overactivation, finerenone prevents the recruitment of transcriptional cofactors responsible for the expression of proinflammatory and profibrotic genes[25]. A detailed mechanism of action is illustrated in Figure 3.

Figure 3 Mechanism of action of finerenone on heart failure. MR: Mineralocorticoid receptor; ROS: Reactive oxygen species.

The reduction in WHF events, comprising urgent visits and hospitalizations, is clinically paramount, as recurrent decompensation drives progressive myocardial injury and mortality[26]. In the FINE-ARTS HF trial, finerenone reduced the composite of WHF and cardiovascular mortality by 16%, a benefit primarily driven by the prevention of WHF[18]. Notably, these benefits were consistent across the ejection fraction spectrum, underscoring finerenone’s efficacy in phenotypes with historically limited therapeutic options. Earlier dose-finding studies, such as ARTS-HF and ARTS-HF Japan, corroborated these findings, showing that lower doses (5-10 mg) reduced natriuretic peptides and cardiovascular events comparably to eplerenone, yet with a more favorable safety profile regarding hyperkalemia[27]. Similarly, Pei et al[28] reported that 10 mg of finerenone elicited anti-remodeling effects equivalent to 25-50 mg of steroidal MRAs, while maintaining higher epidermal growth factor receptor (eGFR) levels and lower serum potassium, suggesting superior cardiorenal protection.

Our findings align with decades of evidence supporting mineralocorticoid receptor antagonism in HF. The landmark RALES trial established that spironolactone reduces all-cause mortality in HFrEF[29]. Subsequently, EPHESUS demonstrated that eplerenone reduced mortality and hospitalization in post-myocardial infarction patients with left ventricular dysfunction, while EMPHASIS-HF extended these benefits to mildly symptomatic (NYHA II) patients[6,30]. In contrast, the TOPCAT trial, focusing on HFpEF, showed only a modest reduction in hospitalizations at the cost of significant hyperkalemia and renal adverse events[5]. The results of our meta-analysis suggest that finerenone bridges this gap. While the reduction in WHF is robust, head-to-head comparisons with steroidal MRAs across HFrEF and HFpEF phenotypes are required to definitively establish its comparative efficacy.

Our analysis revealed statistically significant improvements in KCCQ scores with finerenone. Although the mean improvement remains numerically below the 5-point threshold often cited as the minimal clinically important difference for individuals, the population-level significance is substantial. Health-status improvements are incremental; indeed, many foundational HF therapies produce modest KCCQ gains of 1-3 points[31]. Observational data from HF-ACTION indicate that KCCQ shifts are prognostically potent: A 5-point decline correlates with a 7% increase in mortality/hospitalization risk and quantifiable reductions in functional capacity[31,32]. In FINE-ARTS HF, finerenone not only improved total KCCQ scores but also preserved NYHA class better than placebo, indicating a tangible attenuation of symptom progression[18].

Clinically, while a 1-2 points KCCQ gain may be imperceptible daily to an individual, it reflects a meaningful shift in symptom burden across a population that may accumulate over time. Importantly, these quality-of-life benefits were achieved without a concomitant increase in severe adverse events. As the KCCQ captures physical limitations, symptom frequency, and social participation, even modest improvements facilitate better adherence to GDMT and maintenance of functional independence. Clinicians should view finerenone not as a standalone solution for symptom management, but as a component of comprehensive therapy that improves overall health status while reducing clinical events.

The safety profile of finerenone requires nuanced interpretation, particularly regarding hyperkalemia. In our meta-analysis, the OR for hyperkalemia was elevated but not statistically significant. Granular data from FINE-ARTS HF showed that while finerenone increased potassium levels > 5.5 mmol/L (14.3% vs 6.9%) and > 6.0 mmol/L (3.0% vs 1.4%) compared to placebo, the clinical consequences were minimal. Hyperkalemia-related hospitalization occurred in only 0.5% of the treatment arm, with no attributed deaths[18]. This dissociation between laboratory hyperkalemia and adverse clinical outcomes suggests that with routine monitoring and dose modification, the risk is manageable and does not negate the cardiovascular benefit[33]. As expected, patients with lower baseline eGFR (< 45 mL/minute/1.73 m²) exhibited higher rates of hyperkalemia compared to those with preserved renal function[25].

Comparatively, finerenone demonstrates a superior safety profile to steroidal MRAs. In the ARTS trial, finerenone resulted in significantly lower rates of hyperkalemia (5.3% vs 12.7%) and fewer treatment discontinuations than spironolactone[34]. This safety advantage is likely attributable to finerenone’s nonsteroidal structure, optimizing tissue distribution and minimizing off-target hormonal effects. In FINE-ARTS HF, discontinuation rates were virtually identical between finerenone (20.4%) and placebo (20.6%), reinforcing its tolerability. Minor signals for increased creatinine and hypotension were observed but did not translate into SAE[35].

Finerenone as a pillar of GDMT

The integration of finerenone with SGLT2 inhibitors represents a significant advancement in quadruple therapy. Prespecified analyses from FINE-ARTS HF confirm that finerenone’s efficacy is independent of background SGLT2 inhibitor use (P = 0.76), with recent data suggesting additive cardiovascular protection when combined[36]. The CONFIDENCE trial further supports this combination, demonstrating a 52% reduction in urinary albumin-to-creatinine ratio, implying a synergistic effect on renal preservation[37]. Modeling studies project that the combination of SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone could extend major cardiovascular and kidney event-free survival by several years[38].

Strengths and limitations

A primary strength of this meta-analysis is the inclusion of the recent, large-scale FINE-ARTS HF trial, which provides high-fidelity evidence for finerenone in HFmrEF/HFpEF[18]. Large trials minimize bias and improve the precision of treatment effect estimates[39]. Furthermore, the consistency of benefit across prespecified subgroups-including ejection fraction and concurrent SGLT2 inhibitor use enhances the external validity of our results[18,40-42].

However, limitations exist. The relatively small number of eligible RCTs constrains the power of subgroup analyses and the detection of rare safety signals[43,44]. While statistical heterogeneity was low, this must be interpreted with caution given the low power of Cochran’s Q in small meta-analyses[42]. Additionally, our results are heavily influenced by FINE-ARTS HF; while robust, reliance on a single dominant trial limits the assessment of consistency across diverse clinical settings[39]. Finally, the median follow-up of 32 months may not fully capture the long-term cumulative benefits or late-emerging risks inherent to lifelong HF therapy[43-45].

CONCLUSION

This meta-analysis establishes that finerenone significantly improves clinical outcomes in patients with HF, particularly those with mildly reduced or preserved ejection fraction, a phenotype with historically few evidence-based therapies. The consistency of benefit across the ejection fraction spectrum and regardless of background SGLT2 inhibitor use supports finerenone as a high-value addition to GDMT. The safety profile is favorable, with hyperkalemia proving manageable and rarely leading to treatment discontinuation. Future research should prioritize long-term outcome data and real-world effectiveness. Ongoing trials, including REDEFINE-HF, CONFIRMATION-HF, and FINALITY-HF, will further elucidate the role of finerenone across the continuum of HF.