Heart failure (HF) is a major reason for hospital admission and is responsible for approximately 7% of cardiovascular (CV) deaths.1,2 This issue is especially severe in individuals who have both chronic kidney disease (CKD) and type 2 diabetes (T2D) because they face increased health risks. Newly diagnosed HF patients with CKD and T2D are at a higher risk for hospitalisations (for both CV and non-CV issues) and mortality.3,4 Managing these patients is challenging because existing treatment guidelines do not fully address the complexities of having these coexisting conditions.
Current global guidelines recommend the use of steroidal mineralocorticoid receptor (MR) antagonists (MRAs) for patients with HF with reduced ejection fraction (HFrEF).2,5,6 However, the broader use of steroidal MRAs in HF has been limited and there are mixed data on the efficacy and safety of steroidal MRAs in patients with HF with preserved ejection fraction (HFpEF).7–9
The European Society of Cardiology guidelines suggest considering steroidal MRAs in HF with mildly reduced ejection fraction (HFmrEF) but not in HFpEF.10 However, their use has been linked to increased risks of hyperkalaemia, acute kidney injury and gynaecomastia.11,12 The lack of long-term follow-up and insufficient power to detect benefits regarding critical clinical outcomes, such as kidney failure and major adverse CV events, leaves the risk–benefit ratio of steroidal MRAs uncertain.
Finerenone is a selective, non-steroidal MRA that was approved in 2021 by the Food and Drug Administration to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, CV death, MI and hospitalisation for HF (HHF) in patients with CKD associated with T2D.13 The initial approval of finerenone was based on the promising results of the pivotal Phase III FIDELIO-DKD trial, which indicated an 18% reduction in CKD progression events and a 14% reduction in CV events compared with placebo in patients with CKD and T2D.14
Following this, the FIGARO-DKD trial, which included a broader range of patients with CKD, found a 13% reduction in the risk of the primary CV composite endpoint with finerenone versus placebo.15 The FIGARO-DKD trial also highlighted that the CV benefits of finerenone were primarily driven by a 29% reduction in the risk of first HHF and a 32% reduction in the risk of new-onset HF in patients without a prior history of HF. A prespecified pooled analysis of both Phase III trials, FIDELITY, demonstrated that finerenone improved both CV and kidney outcomes across different stages of CKD severity.16 Thus, finerenone presents a new opportunity to mitigate the risk of adverse events in patients with HF, including those with cardio-kidney-metabolic multimorbidity. In addition, the potential advantages of finerenone over spironolactone and ongoing uncertainty about the role of MR antagonism in HF with higher ejection fractions provide rationale for a large outcome trial of finerenone in HFmrEF or HFpEF. In this review, we explore the potential role of finerenone demonstrated by ongoing preclinical and clinical landmark trials in a cohort of patients with HF and/or CKD with T2D.
Mineralocorticoid Receptor Overactivation
The MR binds mainly with aldosterone and cortisol. It is expressed in cells such as cardiomyocytes, endothelial cells, smooth muscle cells, renal tubular cells and macrophages. The MR forms a complex with aldosterone in renal cells to regulate sodium reabsorption and potassium and hydrogen ion excretion. Mechanistically, ligand binding to the nuclear MR triggers a diverse signalling cascade contributing to excess salt and water retention, systemic hypertension, and endothelial dysfunction, along with pathological fibrosis, hypertrophy and inflammation of the end organs, including the heart and kidneys.17 These core mechanisms of disease progression are thought to play a role in HF irrespective of ejection fraction.18
The MR plays a significant role in the inflammatory process by controlling the expression of cytokines and inflammatory mediators, activating inflammatory pathways and encouraging the infiltration of inflammatory cells. Excessive activation of MRs leads to the production of reactive oxygen species and drives both inflammatory and fibrotic processes, which can result in myocardial hypertrophy, ventricular remodelling, kidney damage, glomerular hypertrophy, glomerulosclerosis and vascular issues such as endothelial dysfunction and smooth muscle cell proliferation.19 This overactivation also directly affects vascular smooth muscle cells via the MR–vascular endothelial growth factor receptor 1 pathway, leading to increased cell proliferation, vascular fibrosis and stiffness. Furthermore, MR overactivation promotes the differentiation of inflammatory cells, such as macrophages and T lymphocytes, into a pro-inflammatory state, creating a chronic inflammatory environment that harms target organs and accelerates disease progression. In the kidneys, MR overactivation contributes to injury and mineralocorticoid-sensitive hypertension through the MR–Rac1 pathway, causing glomerular hyperfiltration.
Blocking MRs results in coronary vasodilation and elevated nitric oxide levels, enhancing left-ventricular perfusion in the heart. This action also activates mitochondrial pathways excessively, leading to improved cardiac perfusion. Moreover, MR blockade benefits endothelial function, diminishes arterial stiffness and mitigates neointimal formation following vascular injury. At the renal level, it reduces albuminuria and promotes renal function preservation (Figure 1).20–23
Finerenone: Why is it Different?
Finerenone, the first non-steroidal MRA, boasts remarkable potency and selectivity for the MR. It inhibits the binding of aldosterone and cortisol, thereby curtailing the recruitment of transcriptional cofactors essential for the expression of genes linked to hypertrophy, inflammation and fibrosis – traits typically associated with MR activation.17 Unlike traditional steroidal MRAs, finerenone exhibits a balanced distribution within both cardiac and renal tissues, has a shorter half-life, lacks active metabolites, and demonstrates superior MR selectivity compared with spironolactone, along with heightened receptor binding affinity relative to eplerenone.24 Table 1 illustrates the distinctions between finerenone and steroidal MRAs, namely eplerenone and spironolactone.
Role of Finerenone across the Spectrum of Heart Failure, Diabetes and Kidney Disease
Numerous preclinical and clinical studies have suggested that finerenone provides significant benefits for CV and renal health, underscoring its potential as an effective treatment option for both HFrEF and HFpEF. Ongoing research endeavours, such as the FINEOVATE programme, are investigating the definitive role of finerenone in patients across the spectrum of HF, T2D and kidney disease. FINEARTS-HF (patients with symptomatic HF, left ventricular ejection fraction [LVEF] ≥40%;25 REDEFINE-HF (patients hospitalised for HF, LVEF ≥40%; NCT06008197), CONFIRMATION-HF (patients hospitalised for HF independent of LVEF in combination with sodium-glucose cotransporter 2 inhibitors [SGLT2I]; NCT06024746) and FINALITY-HF (patients with HFrEF not on steroidal MRAs; NCT06033950) together involve more than 15,000 patients with HF across clinical settings.
FIDELITY-CKD16 (a pooled analysis of FIDELIO-DKD14 and FIGARO-DKD15), ReFineDR (patients with diabetic retinopathy26), CONFIDENCE (combination therapy with finerenone and SGLT2I; NCT05254002), FINE-ONE (type 1 diabetes [T1D]; NCT05901831) and FIND-CKD (albuminuric CKD in patients without diabetes; NCT05047263) are trials that aim to examine cardio-renal outcomes in cohort of CKD and/or T2D/T1D.
Preclinical Studies
Finerenone has undergone testing in various rodent models relevant to HF, showing significant anti-inflammatory and anti-fibrotic effects.27–29 Additionally, it diminishes cardiac hypertrophy, reduces plasma prohormone of brain natriuretic peptide and improves parameters related to diastolic dysfunction and early signs of systolic dysfunction. In a rat disease model, finerenone has the potential to provide end-organ protection with a reduced risk of electrolyte imbalances.28 Although its antihypertensive effects in clinical studies are modest compared with placebo and spironolactone, preclinical findings suggest promising potential for finerenone as a therapeutic option in HF, although this is pending confirmation in future clinical trials.30 Grune et al. found that inhibition of profibrotic MR activation was linked to decreased cardiac fibrosis and improved left ventricular function in a mouse model.27
Phase II Clinical Trials
The Phase II clinical trial programme evaluating finerenone across various patient populations shows promising results regarding both safety and efficacy (Table 2).
In the Phase II ARTS trial of patients with HFrEF (New York Heart Association [NYHA] class II–III; LVEF ≤40%) and moderate CKD, finerenone 10 mg once daily and 5 mg twice daily were similarly effective to spironolactone 25 mg or 50 mg once daily in reducing natriuretic peptides and albuminuria, but with less severe hyperkalaemia (3.7% vs. 12.7%, p0.0284) and fewer episodes of worsening kidney function (6.0 vs. 28.6%, p 0.0001).31 In another, larger Phase II trial, ARTS-HF, conducted in high-risk patients with worsening chronic HFrEF and CKD and/or diabetes, the short-term use of finerenone (2.5 mg to 20 mg once daily) versus eplerenone (25 mg every other day to 50 mg once daily) was well-tolerated, with similar proportions of patients achieving clinically meaningful reductions in natriuretic peptide levels, and showed potential benefits in reducing CV events.32 There were similar effects on serum potassium. In exploratory analysis, there was a lower risk of clinical events with the highest dose tested of finerenone compared with eplerenone, which reached nominal statistical significance.32
Phase III Clinical Trials
Finerenone has shown beneficial effects on CV and renal outcomes in CKD patients with T2D. The Phase III FIDELIO-DKD and FIGARO-DKD trials demonstrated that, compared with placebo, finerenone improved the composite CV outcomes (time to CV death, non-fatal MI and stroke or HHF) and was well tolerated in patients with CKD with albuminuria and T2D.14,15 The FIDELITY analysis combined data from both trials, involving 13,026 patients.16 Finerenone reduced the composite CV outcome by 14% and the composite kidney outcome by 23% (Table 3). The landmark clinical trials on finerenone in relation to LVEF spectrum are shown in Figure 2.
FIDELIO-DKD and FIGARO-DKD examined the effectiveness of finerenone in patients with diabetic kidney disease (DKD), with or without HF.14,15 These studies excluded patients with symptomatic HFrEF (NYHA class II–IV), meaning that HF patients included had asymptomatic HFrEF, HFrEF (NYHA class I), HFmrEF or HFpEF at baseline. In the FIDELIO-DKD analysis, 7.7% of patients had a history of HF. During a median follow-up period of 2.6 years, finerenone demonstrated a significant reduction in the composite CV outcome, irrespective of HF. Similar results were observed in the FIGARO-DKD analysis, in which 7.8% of patients had a history of HF. Finerenone significantly reduced the incidence of new-onset HF.
The FIDELITY analysis indicates that finerenone helps prevent HHF in patients with DKD. Finerenone lowered the risk of first HHF, CV death or first hospitalisation, recurrent HHF and CV death or recurrent HF. These benefits were consistent across various levels of eGFR and urine albumin–creatinine ratio.33
Both preclinical and clinical evidence regarding finerenone underscore its yet-to-be-fully-defined therapeutic potential in patients with HFpEF.34 The recently published FINEARTS-HF, a parallel group, event-driven, double-blind, randomised trial enrolled 6,001 high-risk HF patients to examine the efficacy and safety of finerenone (at a maximum dose of 20–40 mg daily, alongside usual therapy) compared with placebo.25 The study included patients with HFmrEF or HFpEF, structural heart disease and elevated natriuretic peptide levels (mean age 72 years; 36% with ejection fraction<50%). The primary endpoint included a comprehensive measure of worsening HF, incorporating CV death and total HF events. The secondary outcomes included improvements in NYHA functional class, kidney composite outcome and all-cause mortality.
The FINEARTS-HF25 results show that, after a median follow-up of 32 months, finerenone significantly reduced the risk of the primary composite endpoint, which included worsening HF events (unplanned hospitalisations or urgent visits for HF) or CV death (rate ratio 0.84; p=0.007). The reduction in worsening HF events (rate ratio 0.82, p=0.006) largely drove these results, while the difference in CV death rates was not significant (8.1% versus 8.7%; HR 0.93; 95% CI, 0.78 to 1.11). When analysing the composite of the first worsening HF event or CV death, the finerenone group had a lower risk than the placebo group (rate ratio 0.84; 95% CI, 0.74 to 0.95; p=0.007). Finerenone did not reduce the risk of the kidney composite outcome (2.5% versus 1.8% for placebo; HR 1.33;95% CI, 0.94–1.89) in these patients, who were at low risk for kidney disease progression, with minimal albuminuria and few kidney events. Finerenone was linked to higher rates of hyperkalaemia (9.7% versus 4.2% for placebo) but that did not lead to significant hospitalisations or deaths. It was also linked to a lower risk of hypokalaemia.25
REDEFINE-HF (NCT06008197) will investigate the efficacy and safety of finerenone compared with placebo in addition to standard of care (SoC) in reducing total (first and subsequent) HF events and CV death in over 5,200 patients currently hospitalised or recently discharged with a diagnosis of decompensated HFmrEF/HFpEF (ejection fraction >40%).
FINALITY-HF (NCT06033950) is a study to investigate efficacy and safety of finerenone in addition to SoC compared with placebo in reducing CV death or HF events in over 2,600 patients with HFrEF (ejection fraction <40%) who are intolerant to or not eligible for treatment with a steroidal MRA such as spironolactone or eplerenone.
Safety Profile and Adverse Events Related to Finerenone
In the FIDELITY study, hyperkalemia was more common with finerenone than placebo, but incidence of clinically significant hyperkalemia-related events were low, leading to hyperkalaemia-related permanent discontinuation in only 1.7% of finerenone users versus 0.6% with placebo over a median 3-year follow-up. Hypokalemia was less frequent in finerenone-treated patients. Overall, finerenone improves cardiorenal outcomes in CKD and type 2 diabetes with a manageable hyperkalemia risk.16 Treatment-emergent adverse events were similar between the finerenone and placebo groups, with no increase in sex hormone-related adverse effects or impact on glycated haemoglobin levels. The safety profile of finerenone in patients with stage 4 CKD was consistent with those in earlier stages.16 The FIDELIO-DKD study reported similar rates of adverse events such as diarrhoea, nausea, vomiting and hypovolaemia in both the finerenone and placebo groups.14 While traditional steroidal MRAs are limited by the risk of hyperkalaemia, finerenone presents a promising option for treating T2D with CKD and CVD, although hyperkalaemia remains a key safety concern.35,36
Combination of Finerenone with Other Guideline-directed Therapies
Early evidence from a preclinical model of hypertension-induced end-organ damage suggests a synergistic effect from the combination of finerenone and an SGLT2I. In rats, low doses of finerenone with empagliflozin were more effective in reducing cardiac and renal fibrotic lesions, albuminuria and blood pressure compared with either treatment alone.37
Neuen et al. analysed data from two trials involving SGLT2Is (CANVAS and CREDENCE), two trials involving non-steroidal MRAs (FIDELIO-DKD and FIGARO-DKD), and eight trials involving glucagon-like peptide-1 (GLP-1) receptor agonists to compare the effects of combination therapy with SoC on CV, kidney and mortality outcomes in patients with T2D and moderately elevated albuminuria.38 Findings suggested that combining SGLT2Is, GLP-1 receptor agonists and non-steroidal MRAs may offer significant benefits in CV and kidney health and overall survival.
CONFIRMATION-HF (NCT06024746) is a randomised, controlled, open-label Phase III study to evaluate finerenone in addition to an SGLT2I compared with SoC in approximately 1,500 patients hospitalised with HF (or recently discharged following HHF), independent of LVEF. The primary outcomes of the CONFIRMATION-HF trial, assessed over 6 months, include a hierarchical composite of clinical benefits evaluated by the win-ratio: time to death from any cause, number of HF events and time to the first HF event.
Conclusion
Finerenone has shown promising potential in improving CV and renal outcomes in pivotal clinical trials involving patients with CKD and T2D (FIDELIO-DKD and FIGARO-DKD). FIDELIO-DKD and FIGARO-DKD also hint at a possible beneficial impact of finerenone on HFpEF. Finerenone demonstrated a significant reduction in the composite CV outcome, irrespective of HF. Its higher selectivity and balanced tissue distribution between the heart and kidneys offer advantages over traditional steroidal MRAs, such as spironolactone and eplerenone, with fewer risks of hyperkalaemia and kidney function deterioration. The FINEARTS-HF trial found that finerenone significantly reduced the risk of worsening HF events or CV death in patients with HFmrEF or HFpEF. Ongoing and upcoming large-scale clinical trials, including REDEFINE-HF, FINALITY-HF and CONFIRMATION-HF, aim to further elucidate the efficacy and safety of finerenone in a broad spectrum of HF populations, including those with HFmrEF and HFpEF. These studies will also explore the potential benefits of combining finerenone with other guideline-directed therapies, potentially paving the way for new, evidence-based treatment strategies for HF and related cardio-kidney-metabolic conditions.