Finerenone Advanced Drug Monograph

Finerenone: A Novel Nonsteroidal Mineralocorticoid Receptor Antagonist for Cardiorenal Protection

Abstract

Finerenone (BAY 94-8862) is a novel, potent, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) developed to address the residual cardiorenal risk in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D), and more recently, heart failure (HF) with preserved or mildly reduced ejection fraction. Unlike traditional steroidal MRAs such as spironolactone and eplerenone, finerenone possesses a unique chemical structure and pharmacological profile that allows for targeted MR blockade with minimal off-target hormonal effects, thereby reducing the incidence of side effects like gynecomastia. Its mechanism involves specific binding to the mineralocorticoid receptor (MR), preventing the recruitment of transcriptional coactivators and subsequently attenuating MR-mediated inflammation and fibrosis, key drivers of cardiorenal disease progression. Pivotal clinical trials, FIDELIO-DKD and FIGARO-DKD, and their pooled analysis, FIDELITY, have demonstrated finerenone's efficacy in significantly reducing the risk of both CKD progression and cardiovascular events in a broad spectrum of patients with T2D and CKD, largely independent of baseline SGLT2 inhibitor use. The FINEARTS-HF trial has further shown its potential in reducing cardiovascular death and heart failure events in patients with HF and a left ventricular ejection fraction $\ge$40%. While finerenone increases the risk of hyperkalemia, a manageable adverse event through established monitoring and dose-adjustment protocols, its overall safety profile is favorable. Finerenone has been incorporated into major international clinical practice guidelines (KDIGO, ADA, ESC) as a crucial component of comprehensive cardiorenal protective strategies. This report details the pharmacology, clinical evidence, safety profile, and therapeutic positioning of finerenone in contemporary cardiorenal medicine.

1. Introduction to Finerenone: A Novel Nonsteroidal Mineralocorticoid Receptor Antagonist

1.1. Chemical Identity, Classification, and Development Rationale

Finerenone, also known by its development code BAY 94-8862, is a small molecule drug classified as a nonsteroidal, selective mineralocorticoid receptor antagonist (MRA).1 Chemically, it belongs to the classes of amides, naphthyridines, and nitriles.1 The impetus for finerenone's development stemmed from the recognized limitations of existing steroidal MRAs, primarily spironolactone and eplerenone. While these agents also block the MR, their utility has been hampered by factors such as lower selectivity for the MR and significant off-target effects. Spironolactone, for instance, exhibits affinity for androgen and progesterone receptors, leading to undesirable side effects like gynecomastia, and can also interact with glucocorticoid receptors.3 Eplerenone, while more selective than spironolactone, is also steroidal in nature [User Query]. Furthermore, concerns regarding hyperkalemia, particularly in patients with kidney impairment, have historically limited the broader application of steroidal MRAs.3

The core rationale behind finerenone's development was to create an MRA with a distinct pharmacological profile. The aim was to effectively target the overactivation of the MR—a critical pathway implicated in promoting inflammation and fibrosis in various organs, particularly the kidneys and heart—while simultaneously improving the safety and tolerability profile compared to its steroidal predecessors.[3] The successful design of finerenone as a nonsteroidal agent with high selectivity for the MR has allowed for a separation of the desired anti-inflammatory and anti-fibrotic effects from the unwanted hormonal side effects. This targeted approach is evident in the significantly lower rates of gynecomastia observed in clinical trials with finerenone, indicating a successful structural modification to avoid off-target steroid receptor interactions and thereby optimize its therapeutic index.[4]

1.2. Regulatory Approvals and Milestones

Finerenone is marketed under the brand names Kerendia and, in some countries, Firialta. It was developed by Bayer HealthCare Pharmaceuticals.1

The drug achieved a significant milestone with its initial approval by the U.S. Food and Drug Administration (FDA) on July 9, 2021. This approval was for the indication of reducing the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease (ESKD), cardiovascular (CV) death, non-fatal myocardial infarction (MI), and hospitalization for heart failure (HF) in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).[9] This landmark approval was primarily based on the robust findings from the FIDELIO-DKD clinical trial.[13]

Following the FDA's decision, the European Medicines Agency (EMA) adopted a positive opinion in December 2021, leading to formal marketing authorization in the European Union on February 16, 2022.[9] For its initial CKD/T2D indication, finerenone was granted Fast Track designation and Priority Review by the FDA, underscoring its potential to address an unmet medical need.[9] The FDA label was subsequently updated in September 2022 to incorporate findings from the FIGARO-DKD cardiovascular outcomes study, further broadening its recognized benefits.[13]

More recently, on March 17, 2025, Bayer announced that the FDA accepted its supplemental New Drug Application (sNDA) and granted Priority Review designation for finerenone for a new indication: the treatment of adult patients with heart failure (HF) with a left ventricular ejection fraction (LVEF) $\ge$40%. This application is supported by positive results from the Phase III FINEARTS-HF trial.[10] The Prescription Drug User Fee Act (PDUFA) date for a decision on this new indication is anticipated in the third quarter of 2025.[16] As of early 2025, finerenone is approved for the treatment of CKD associated with T2D in over 90 countries worldwide.[16]

The rapid sequence of regulatory approvals, label expansions, and the granting of Priority Review designations for multiple indications reflect the significant clinical need that finerenone addresses in both diabetic kidney disease and, potentially, in specific types of heart failure. Such accelerated pathways are typically reserved for therapies demonstrating substantial improvements over available options for serious conditions, highlighting the robustness of finerenone's clinical data and its perceived value in the medical community.

Table 1: Finerenone - Key Drug Information

Feature	Detail	Source(s)
DrugBank ID	DB16165	User Query, 2
CAS Number	1050477-31-0	User Query
Molecular Type	Small Molecule	User Query, 1
Developer	Bayer HealthCare Pharmaceuticals	1
Approved Brand Names	Kerendia, Firialta	1
Initial FDA Approval (CKD/T2D)	July 9, 2021	User Query, 9
Initial EMA Approval (CKD/T2D)	February 16, 2022	User Query, 9
FDA sNDA Acceptance (HF with LVEF $\ge$40%)	March 17, 2025 (Priority Review)	10

2. Pharmacological Profile of Finerenone

2.1. Mechanism of Action: Selective MR Blockade and Downstream Effects

Finerenone exerts its therapeutic effects as a potent, nonsteroidal, and selective antagonist of the mineralocorticoid receptor (MR).1 The MR is a nuclear receptor that, upon activation by ligands such as aldosterone or cortisol, undergoes a conformational change, dissociates from chaperone proteins, and translocates to the nucleus. Once in the nucleus, the activated MR, along with a complex of other coactivators, binds to specific DNA sequences (mineralocorticoid response elements) to induce the transcription of a variety of genes.2 Pathological overactivation of the MR is a key driver in the progression of cardiorenal diseases, promoting inflammation, collagen formation, fibrosis, and ultimately leading to target organ damage in the kidneys and heart.3

Finerenone's unique mode of action involves binding to the MR with high affinity and selectivity. This binding induces a distinct conformational change in the receptor, characterized by the prominence of helix 12 of the C-terminal ligand-binding domain, which is crucial for the receptor's activation function.[2] This specific interaction effectively prevents the binding of transcriptional coactivators necessary for gene expression. By blocking the recruitment of these coactivators, finerenone disrupts the downstream signaling cascades that lead to pro-inflammatory and pro-fibrotic gene transcription.[2] Consequently, finerenone has been demonstrated in animal models to reduce inflammation and fibrosis [2] and has shown consistent reductions in albuminuria—a key marker of kidney damage and a predictor of cardiorenal risk—in numerous clinical trials.[2]

The mechanism of finerenone offers a more direct and targeted intervention against the detrimental consequences of MR overactivation compared to traditional therapies like renin-angiotensin system (RAS) inhibitors (e.g., ACE inhibitors or ARBs). While RAS inhibitors modulate the production or action of angiotensin II, thereby reducing aldosterone levels to some extent, they do not completely abolish MR activation, as aldosterone breakthrough can occur, and cortisol can also activate the MR. Finerenone directly targets the MR itself, providing a distinct pathway for organ protection that is complementary to RAS blockade. This explains the additive benefits observed in clinical trials where finerenone was administered to patients already receiving standard-of-care RAS inhibition.[3]

2.1.1. Comparison with Steroidal MRAs (Spironolactone, Eplerenone)

Finerenone's development as a nonsteroidal MRA was specifically aimed at overcoming the limitations associated with older, steroidal MRAs like spironolactone and eplerenone. The key differences are summarized in Table 2 and detailed below:

• Selectivity and Affinity: Finerenone exhibits high selectivity for the MR and binds to it with high potency. Crucially, it demonstrates no significant affinity or activity at other steroid hormone receptors, including androgen, progesterone, estrogen, and glucocorticoid receptors.[2] This high degree of selectivity is a major distinguishing feature. In contrast, spironolactone is a nonselective MRA that binds to androgen and progesterone receptors, leading to well-documented anti-androgenic side effects such as gynecomastia, breast tenderness, and menstrual irregularities.[4] Eplerenone was developed as a more selective steroidal MRA than spironolactone, with reduced affinity for androgen and progesterone receptors, but it is considerably less potent than spironolactone in its MRA antagonism.[4]
• Receptor Binding and Co-factor Modulation: Finerenone's interaction with the MR is characterized by the formation of a bulky, inactive receptor-ligand complex. This specific binding mode results in an unstable complex that leads to less recruitment of transcriptional co-regulators compared to spironolactone. Finerenone effectively blocks the recruitment of critical transcription cofactors involved in the expression of pro-inflammatory and pro-fibrotic genes.[18] Some evidence suggests finerenone may act as an inverse agonist, capable of inhibiting transcriptional processes even in the absence of aldosterone by reducing the activation of cofactors like SRC-1.[18] Spironolactone, on the other hand, tends to promote the recruitment of co-factor SRC-1 to an MR-dependent promoter and can act as a partial agonist at the MR.[18]
• Tissue Distribution: Finerenone is reported to have a more balanced distribution and affinity for MRs in both the heart and the kidney. This contrasts with steroidal MRAs, which may exhibit a greater affinity for MRs in the kidney compared to those in the heart, potentially influencing their relative effects on different target organs.[4]
• Metabolites: A significant pharmacokinetic difference is that finerenone has no active metabolites. Its metabolism leads to inactive products.[2] Spironolactone, conversely, is metabolized to several active metabolites, including canrenone and 7-α-thiomethylspironolactone, which contribute to its overall MRA effect and its longer duration of action, but may also contribute to its side effect profile.[4]
• Impact on Inflammation and Fibrosis: Due to its high selectivity and specific mechanism of MR antagonism, finerenone demonstrates potent anti-inflammatory and anti-fibrotic effects. These effects are considered more direct and potentially stronger than those of first- and second-generation steroidal MRAs, contributing to its cardiorenal protective benefits.[3]
• Side Effect Profile: These fundamental mechanistic and pharmacokinetic distinctions translate into a more favorable side effect profile for finerenone. The most notable advantage is the significantly lower incidence of gynecomastia and other sex hormone-related side effects compared to spironolactone.[4] While hyperkalemia remains a class effect for all MRAs and requires careful monitoring with finerenone, its profile may differ from steroidal MRAs due to its unique properties, though direct large-scale comparative trials focusing on hyperkalemia rates are limited in the provided information beyond general statements of lower risk with finerenone in some contexts.[5]

The structural and mechanistic innovations embodied in finerenone—its non-steroidal nature, distinct MR binding mode, lack of active metabolites, and balanced tissue distribution—collectively contribute to an improved therapeutic window. This allows for effective MR antagonism with a reduced burden of the side effects that have historically limited the use of older steroidal MRAs, particularly spironolactone.

Table 2: Pharmacological and Safety Profile Comparison: Finerenone vs. Steroidal MRAs

Feature	Finerenone	Spironolactone	Eplerenone	Source(s)
Chemical Structure	Nonsteroidal	Steroidal	Steroidal	User Query, 1
Receptor Selectivity for MR	High	Moderate (non-specific)	High (more selective than spironolactone)	User Query, 2
Binding to Androgen/Progesterone Receptors	Negligible/No significant affinity	Significant affinity	Low affinity	User Query, 2
Active Metabolites	No	Yes (e.g., canrenone, 7-α-thiomethylspironolactone)	No major active metabolites	2
Half-life	Shorter (relative to spironolactone due to no active metabolites)	Longer (due to active metabolites)	Shorter	4 (inferred)
Tissue Affinity (Kidney vs. Heart MRs)	Balanced	Potentially greater for kidney MRs	Potentially greater for kidney MRs	4
Typical Incidence of Gynecomastia	Very low (similar to placebo, e.g., 0.1% vs 0.2% placebo in FIDELITY)	Higher (clinically significant incidence)	Low	4
Relative Risk of Hyperkalemia	Requires careful monitoring; potentially lower risk profile in some contexts	Requires careful monitoring; established risk	Requires careful monitoring; risk present, may be less than spironolactone	5 (Finerenone risk well-characterized; direct comparative risk not fully detailed in snippets for all scenarios)

2.2. Pharmacokinetics and Metabolism

• Absorption: Finerenone is administered orally and can be taken with or without food.[11] Following a 10 mg oral dose, finerenone typically reaches a maximum plasma concentration (Cmax) of 351 µg/L, with the time to reach Cmax (Tmax) being approximately 1.5 hours. The area under the plasma concentration-time curve (AUC) for this dose is around 2820 µg*h/L.[2]
• Distribution: Finerenone exhibits balanced distribution to mineralocorticoid receptors in both the heart and kidneys.[4] While specific plasma protein binding data is not explicitly detailed in the provided snippets, drugs of this nature are typically highly protein-bound.
• Metabolism: Finerenone undergoes extensive metabolism, primarily via the cytochrome P450 (CYP) enzyme system. Approximately 90% of its metabolism is mediated by CYP3A4, with the remaining 10% handled by CYP2C8. There is also a minor contribution from CYP1A1. Importantly, finerenone does not have any active metabolites; all metabolic products are inactive.[2] The metabolic pathways involve several biotransformations, including aromatization (to metabolite M1 by CYP3A4 and CYP2C8), subsequent hydroxylation (M1 to M2 by CYP3A4), and oxidation (M2 to M3 by CYP3A4). Alternative pathways include epoxidation and potential hydrolysis (to M4 by CYP3A4 and CYP2C8), followed by further hydroxylation (M4 to M5 by CYP3A4) and oxidation (to M8). Finerenone can also undergo direct hydroxylation by CYP2C8 (to M7) and further oxidation (to M9). Another metabolite, M10, is formed through demethylation, oxidation, and ring opening of the parent drug.[2]
• Excretion: The primary route and extent of excretion of finerenone and its metabolites are not specifically detailed in the provided information.
• Drug Interactions (Pharmacokinetic): The significant reliance of finerenone on CYP3A4 for its metabolism makes it susceptible to a number of clinically important drug-drug interactions. This necessitates careful review of concomitant medications when prescribing finerenone.
• Strong CYP3A4 Inhibitors: Concomitant use of finerenone with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit or grapefruit juice) is contraindicated. These inhibitors can significantly increase finerenone plasma concentrations, thereby increasing the risk of adverse effects, particularly hyperkalemia.[2]
• Moderate or Weak CYP3A4 Inhibitors: When finerenone is co-administered with moderate or weak CYP3A4 inhibitors (e.g., erythromycin, verapamil, amiodarone, fluconazole, diltiazem, acetaminophen, alprazolam, amlodipine, aprepitant), serum potassium levels should be monitored closely, especially during initiation or dosage adjustment of either finerenone or the interacting inhibitor. Dose adjustments of finerenone may be necessary due to the potential for increased exposure.[10]
• Strong or Moderate CYP3A4 Inducers: Co-administration with strong or moderate CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, St. John’s Wort) should be avoided. These agents can significantly decrease finerenone plasma concentrations, potentially reducing its therapeutic efficacy.[2]
• Warfarin: A dedicated drug interaction study investigating the co-administration of finerenone (20 mg once daily for 6 days) and warfarin in healthy male subjects found no clinically relevant pharmacokinetic or pharmacodynamic interactions between the two drugs.[26] This suggests that finerenone does not significantly affect the anticoagulation effect of warfarin, nor does warfarin significantly alter finerenone exposure.

The extensive metabolism via CYP3A4 is a critical pharmacokinetic characteristic of finerenone. This pathway dictates many of the observed drug-drug interactions and forms the basis for several contraindications and warnings associated with its use. Prescribers must be vigilant in assessing a patient's complete medication list to avoid potentially harmful interactions that could alter finerenone exposure and increase the risk of adverse events or reduce efficacy.

3. Clinical Efficacy in Chronic Kidney Disease Associated with Type 2 Diabetes

The clinical development program for finerenone in CKD associated with T2D has centered on two pivotal Phase III trials, FIDELIO-DKD and FIGARO-DKD, and their combined prespecified pooled analysis, FIDELITY. These trials have established finerenone's role in providing both renal and cardiovascular protection.

3.1. The FIDELIO-DKD Trial: Renal and Cardiovascular Outcomes

The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial was a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of finerenone in patients with CKD and T2D.20 The trial enrolled 5734 patients who had either a urinary albumin-to-creatinine ratio (UACR) of 30 to <300 mg/g with an eGFR of 25 to <60 mL/min/1.73m², and diabetic retinopathy, or a UACR of $\ge$300 to $\le$5000 mg/g with an eGFR of 25 to <75 mL/min/1.73m². All participants were receiving standard of care, including an optimized dose of a RAS inhibitor.20 The majority of patients in FIDELIO-DKD had later-stage CKD (stages 3-4).21 The median duration of follow-up was 2.6 years.20

The primary composite endpoint focused on renal outcomes and was defined as the time to first occurrence of kidney failure (defined as ESKD requiring chronic dialysis, kidney transplantation, or a sustained decrease in eGFR to <15 mL/min/1.73m²), a sustained decrease of at least 40% in eGFR from baseline over a period of at least 4 weeks, or death from renal causes.[13]

• Primary Endpoint Result: A primary outcome event occurred in 17.8% of patients (504 out of 2833) in the finerenone group compared to 21.1% (600 out of 2841) in the placebo group. This represented a statistically significant 18% relative risk reduction with finerenone (Hazard Ratio 0.82; 95% Confidence Interval [CI] 0.73–0.93; P=0.001).[20] The beneficial effect of finerenone on the primary endpoint was primarily driven by a reduction in the sustained decline in eGFR of $\ge$40% and a reduction in progression to kidney failure. Renal deaths were infrequent during the trial.[21]

The key secondary endpoint was a cardiovascular composite, defined as the time to first occurrence of CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF.[13]

• Key Secondary Endpoint Result: A key secondary outcome event occurred in 13.0% of patients (367 out of 2833) in the finerenone group and 14.8% (420 out of 2841) in the placebo group. Finerenone demonstrated a 14% relative risk reduction for this endpoint (HR 0.86; 95% CI 0.75–0.99; P=0.03 or P=0.034).[20] This treatment effect reflected reductions in CV death, non-fatal MI, and hospitalization for HF.[21]

The overall frequency of adverse events was similar between the finerenone and placebo groups, although hyperkalemia was reported more frequently with finerenone (detailed in Section 5).[20] The findings of FIDELIO-DKD were published by Bakris GL, et al. in The New England Journal of Medicine in 2020.[20]

The FIDELIO-DKD trial was instrumental in establishing finerenone as a novel therapeutic agent capable of providing significant renal and cardiovascular protection for patients with advanced CKD associated with T2D who are already receiving standard RAS inhibitor therapy. The dual benefit on both kidney and heart outcomes addressed a critical unmet need in this high-risk population, where residual risk remains substantial despite existing treatments.

3.2. The FIGARO-DKD Trial: Focus on Cardiovascular Protection

The Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial was designed as a complementary study to FIDELIO-DKD, focusing on patients with earlier stages of CKD but still at high cardiovascular risk.21 This randomized, double-blind, placebo-controlled, multicenter trial enrolled 7352 patients (though some sources cite N=7437, N=7352 is more consistent across key summaries 22) with T2D and CKD. Eligible patients had a UACR of 30 to <300 mg/g with an eGFR of 25 to $\le$90 mL/min/1.73m², or a UACR of $\ge$300 to $\le$5000 mg/g with an eGFR $\ge$60 mL/min/1.73m². All patients were on optimized RAS blockade.21 The median follow-up duration was 3.4 years.21

The primary endpoint of FIGARO-DKD was a cardiovascular composite, defined as the time to CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF.[13]

• Primary Endpoint Result: The primary outcome occurred in 12.4% of patients in the finerenone group versus 14.2% in the placebo group. Finerenone significantly reduced the risk of this composite CV endpoint by 13% (HR 0.87; 95% CI 0.76–0.98; P=0.03).[30] This benefit was primarily driven by a reduction in hospitalizations for HF.[21]

The key secondary endpoint was a renal composite, defined as the time to kidney failure, a sustained eGFR decline of $\ge$40% from baseline, or renal death.[13]

• Key Secondary Endpoint Result: This renal composite outcome occurred in 9.5% of patients taking finerenone and 10.8% of patients taking placebo (HR 0.87; 95% CI 0.76–1.01; P=0.069). While there was a trend favoring finerenone, this difference was not statistically significant.[21] However, when a more stringent definition of renal progression was used (a composite of kidney failure, sustained eGFR decline of $\ge$57% from baseline, or renal death), finerenone showed a significant benefit (HR 0.77; 95% CI 0.60–0.99; P=0.041).[29] Notably, finerenone led to a 36% relative risk reduction for end-stage kidney disease (ESKD) (HR 0.64; 95% CI 0.41-0.995).[29]

As in FIDELIO-DKD, the incidence of hyperkalemia was higher with finerenone (see Section 5). The results of FIGARO-DKD were published by Pitt B, et al. in The New England Journal of Medicine in 2021 [27], and are also referenced in other summaries.[21]

FIGARO-DKD successfully extended the evidence for finerenone's cardiovascular protective effects to a broader population of patients with T2D and earlier stages of CKD, including those with moderate albuminuria. The significant reduction in the primary cardiovascular endpoint, particularly the impact on reducing hospitalizations for heart failure, was a key finding. While the primary renal composite endpoint did not reach statistical significance in this trial population (which had a lower baseline renal risk compared to FIDELIO-DKD), analyses of more severe renal outcomes (e.g., $\ge$57% eGFR decline or ESKD) still suggested renal benefits. This highlighted that finerenone's cardiorenal protective effects are relevant across a wider spectrum of diabetic kidney disease.

3.3. The FIDELITY Pooled Analysis: Comprehensive Cardiorenal Benefits

The Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis (FIDELITY) was a prespecified, individual patient-level pooled analysis of the two pivotal Phase III trials. This analysis included data from over 13,000 patients (N=13,171 30 or N=13,026 28) with CKD and T2D, covering a wide spectrum of disease severity, from earlier to later stages.6

The FIDELITY analysis assessed key composite cardiovascular and renal outcomes:

• Cardiovascular Composite Endpoint (CV death, non-fatal MI, non-fatal stroke, or hospitalization for HF):
• Incidence: 12.7% in the finerenone group versus 14.4% in the placebo group.
• Result: Finerenone significantly reduced the risk of the CV composite endpoint by 14% (HR 0.86; 95% CI 0.78–0.95; P=0.0018).[23]
• Renal Composite Endpoint (Kidney failure, sustained $\ge$57% eGFR decline from baseline, or renal death):
• Incidence: 5.5% in the finerenone group versus 7.1% in the placebo group.
• Result: Finerenone significantly reduced the risk of the renal composite endpoint by 23% (HR 0.77; 95% CI 0.67–0.88; P=0.0002).[23] [23]
• All-cause Mortality: The analysis showed a trend towards a reduction in all-cause mortality with finerenone, but this did not reach conventional statistical significance (HR 0.89; 95% CI 0.79–1.00; P=0.05 or P=0.051).[30]
• Effect of SGLT2 Inhibitor Use: An important sub-analysis within FIDELITY evaluated the effects of finerenone in patients based on their use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) at baseline or initiated during the trial. The benefits of finerenone on both cardiorenal composite outcomes were observed irrespective of SGLT2i use. The p-values for interaction were 0.46 for the cardiovascular composite and 0.29 for the kidney composite with respect to baseline SGLT2i use, indicating that the efficacy of finerenone was consistent whether or not patients were also receiving an SGLT2i.[28]

The incidence of hyperkalemia in the pooled analysis was consistent with the individual trials, being higher in the finerenone group, but discontinuations due to hyperkalemia remained low.[31]

The FIDELITY pooled analysis provides the most robust and comprehensive evidence to date on the cardiorenal benefits of finerenone. By combining data from two large, well-conducted trials, it confirms with greater statistical power that finerenone consistently reduces the risk of both major kidney disease progression events and significant cardiovascular events across a wide spectrum of patients with T2D and CKD. The finding that these benefits are maintained in patients also treated with SGLT2 inhibitors is particularly crucial, as it supports the integration of finerenone into modern, multi-faceted treatment regimens aimed at comprehensive cardiorenal risk reduction. This positions finerenone as a third pillar of therapy, alongside RAS inhibitors and SGLT2 inhibitors, for this vulnerable patient population.

Table 3: Overview of Pivotal Clinical Trials for Finerenone in CKD with T2D

Feature	FIDELIO-DKD	FIGARO-DKD	FIDELITY Pooled Analysis
Patient Population (Key Characteristics, N)	T2D, later-stage CKD (eGFR <60 or eGFR <75 with severe albuminuria), UACR $\ge$30 mg/g, on max RASi. N=5734	T2D, earlier-stage CKD (eGFR 25-90 with mod albuminuria or eGFR $\ge$60 with severe albuminuria), UACR $\ge$30 mg/g, on max RASi. N=7352	T2D, broad spectrum of CKD severity (from FIDELIO & FIGARO), UACR $\ge$30 mg/g, on max RASi. N >13,000
Median Follow-up	2.6 years	3.4 years	Weighted average from FIDELIO & FIGARO
Primary Endpoint Definition	Kidney Composite: Kidney failure (ESKD or eGFR <15), sustained $\ge$40% eGFR decline, or renal death.	CV Composite: CV death, non-fatal MI, non-fatal stroke, or HHF.	CV Composite: CV death, non-fatal MI, non-fatal stroke, or HHF.
Primary Endpoint Result	Finerenone: 17.8% vs. Placebo: 21.1%. HR 0.82 (95% CI: 0.73–0.93; P=0.001).	Finerenone: 12.4% vs. Placebo: 14.2%. HR 0.87 (95% CI: 0.76–0.98; P=0.03).	Finerenone: 12.7% vs. Placebo: 14.4%. HR 0.86 (95% CI: 0.78–0.95; P=0.0018).
Key Secondary/Other Major Endpoint Definition	CV Composite: CV death, non-fatal MI, non-fatal stroke, or HHF.	Kidney Composite: Kidney failure, sustained $\ge$40% eGFR decline, or renal death. (Also reported: $\ge$57% eGFR decline composite, ESKD).	Kidney Composite: Kidney failure, sustained $\ge$57% eGFR decline, or renal death.
Key Secondary/Other Major Endpoint Result	Finerenone: 13.0% vs. Placebo: 14.8%. HR 0.86 (95% CI: 0.75–0.99; P=0.03/0.034).	$\ge$40% eGFR decline composite: Finerenone 9.5% vs Placebo 10.8%. HR 0.87 (95% CI: 0.76–1.01; P=0.069). $\ge$57% eGFR decline composite: HR 0.77 (P=0.041). ESKD: HR 0.64.	Finerenone: 5.5% vs. Placebo: 7.1%. HR 0.77 (95% CI: 0.67–0.88; P=0.0002).
Incidence of Hyperkalemia (Finerenone vs. Placebo)	Higher with finerenone (specific % not in all summaries, but consistent finding). Pooled data: 14% vs 6.9%.10	Higher with finerenone. Pooled data: 14% vs 6.9%.10	Higher with finerenone. Pooled data: 14% vs 6.9%.10
Discontinuation due to Hyperkalemia (Finerenone vs. Placebo)	Low (e.g., FIDELIO-DKD: 2.3% vs 0.9%).20 Pooled data: 1.7% vs 0.6%.31	Low. Pooled data: 1.7% vs 0.6%.31	Low (1.7% vs 0.6%).31

Sources:.[10]

4. Emerging Therapeutic Applications: Finerenone in Heart Failure

Beyond its established role in CKD associated with T2D, finerenone is being investigated for its potential benefits in patients with heart failure (HF), particularly those with a left ventricular ejection fraction (LVEF) of $\ge$40%, encompassing HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%) and HF with preserved ejection fraction (HFpEF; LVEF $\ge$50%).

4.1. Rationale for MRA in Heart Failure with LVEF $\ge$40% (HFmrEF and HFpEF)

HFmrEF and HFpEF represent a substantial and growing segment of the HF population. These conditions are characterized by significant morbidity and mortality, yet historically, there have been limited therapeutic options with proven efficacy in reducing major cardiovascular events.10 The pathophysiology of HFmrEF and HFpEF is complex and multifactorial, but overactivation of the mineralocorticoid receptor, leading to chronic inflammation, myocardial and vascular fibrosis, and endothelial dysfunction, is recognized as a key contributing mechanism.16 Finerenone, with its targeted blockade of MR-driven inflammation and fibrosis, offers a mechanistically plausible therapeutic approach to address these underlying pathological processes in this challenging patient population.16

4.2. The FINEARTS-HF Trial: Efficacy and Safety

The Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) was a large-scale, randomized, double-blind, placebo-controlled Phase III clinical trial. It enrolled nearly 6,000 adult patients (specific numbers vary slightly between sources, e.g., "nearly 6,000" 10, 5,797 participants 32) with symptomatic HF and an LVEF $\ge$40%.10 Patients received either finerenone (titrated to a maximum dose of 20 or 40 mg once daily, though standard dosing is typically up to 20mg) or placebo, in addition to their usual HF therapy. The median follow-up duration was reported as 2.6 years 32 or 32 months.33

The primary endpoint of the FINEARTS-HF trial was a composite of cardiovascular death and total (first and recurrent) HF events, defined as either an unplanned hospitalization for HF or an urgent HF visit.[10]

• Primary Endpoint Result: Finerenone demonstrated a statistically significant 16% relative risk reduction in the primary composite endpoint compared to placebo (Rate Ratio 0.84; 95% CI 0.74–0.95; P=0.007).[10] This indicates a substantial benefit of finerenone in reducing the burden of major cardiovascular and HF-related events in this patient population.

Secondary kidney outcomes were also explored in a prespecified analysis of FINEARTS-HF [32]:

• A composite kidney outcome (sustained $\ge$50% eGFR decline or kidney failure) occurred in 75 patients in the finerenone group versus 55 in the placebo group (HR 1.33; 95% CI 0.94–1.89), a difference that was not statistically significant.
• Similar non-significant results were observed for a composite of sustained $\ge$57% eGFR decline or kidney failure (41 vs 31 events; HR 1.28; 95% CI 0.80–2.05).
• Finerenone led to an acute decline in eGFR during the first 3 months of treatment (mean -2.9 mL/min/1.73m²), but it did not significantly alter the chronic eGFR slope (from 3 months onwards) compared to placebo.
• However, finerenone did lead to early and sustained reductions in UACR by approximately 30% over 6 months versus placebo and significantly reduced the risk of new-onset microalbuminuria (HR 0.76) and macroalbuminuria (HR 0.62).[32] The differing kidney outcomes in FINEARTS-HF compared to the CKD trials (FIDELIO-DKD, FIGARO-DKD) likely reflect the different baseline renal risk profiles of the study populations. Patients in FINEARTS-HF were primarily enrolled based on their heart failure status and generally had a lower baseline risk of adverse kidney outcomes compared to the populations in the CKD-focused trials.[32] Despite the lack of significant benefit on hard renal endpoints in this lower-risk HF population, the positive effects on albuminuria suggest some level of renal modulation.

In terms of safety, the overall profile of finerenone in FINEARTS-HF was consistent with previous studies. Serious adverse events were comparable between the finerenone group (38.7%) and the placebo group (40.5%).[10] Discontinuation rates of the trial drug for reasons other than death were also similar between the groups (20.4% vs. 20.6%, respectively).[12]

• Investigator-reported hyperkalemia occurred in 9.7% of finerenone-treated patients versus 4.2% in the placebo group.[10]
• Hospitalization due to hyperkalemia was infrequent, occurring in 0.5% of patients in the finerenone group compared to 0.2% in the placebo group. Importantly, no deaths were attributed to hyperkalemia in either group.[10]

The results of the FINEARTS-HF trial were presented at the European Society of Cardiology (ESC) Congress in 2024 and simultaneously published in The New England Journal of Medicine.[16] These findings are significant as they provide the first Phase III evidence demonstrating that a nonsteroidal MRA can improve cardiovascular outcomes in the challenging HFpEF and HFmrEF patient populations, for whom effective therapies have been scarce. This potentially positions finerenone as an important new therapeutic pillar for managing these types of heart failure.

4.3. Regulatory Status and Future Implications for Heart Failure Management

Following the positive results from FINEARTS-HF, Bayer submitted a supplemental New Drug Application (sNDA) to the FDA for finerenone. On March 17, 2025, the FDA accepted this sNDA and granted Priority Review designation for finerenone for the treatment of adult patients with HF and an LVEF $\ge$40%.10 A Priority Review designation is typically granted to drugs that, if approved, would offer significant improvements in the safety or effectiveness of the treatment of serious conditions. This accelerates the FDA's review timeline, with a PDUFA (Prescription Drug User Fee Act) target date anticipated in the third quarter of 2025.16

If approved for this new indication, finerenone has the potential to become an important new treatment option and a pillar of therapy for the underserved population of patients with HFmrEF and HFpEF.[10] The MOONRAKER clinical trial program, which includes FINEARTS-HF and other studies, is designed to build a comprehensive body of evidence for finerenone's use in HF across a broad spectrum of patients and clinical settings, further defining its role in cardiovascular medicine.[12] The FDA's decision to grant Priority Review highlights the potential of finerenone to address a significant unmet medical need and could herald a shift in the management paradigm for HFpEF and HFmrEF, where effective, evidence-based therapies have been lacking.

5. Safety, Tolerability, and Risk Management Strategies

5.1. Overview of Adverse Event Profile

Finerenone has been generally well-tolerated in large-scale clinical trials, including FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF.10 The most commonly reported adverse reactions (occurring in $\ge$1% of patients on finerenone and more frequently than placebo), based on pooled data from the two placebo-controlled studies in patients with CKD and T2D (FIDELIO-DKD and FIGARO-DKD), were hyperkalemia (14% vs. 6.9%), hypotension (4.6% vs. 3.9%), and hyponatremia (1.3% vs. 0.7%).10 The incidence of serious adverse events was generally comparable between the finerenone and placebo groups in these major trials.10

5.2. Hyperkalemia: Incidence, Risk Factors, and Management Protocols

Hyperkalemia is a known class effect of MRAs, and finerenone can cause elevations in serum potassium levels.10

• Incidence: In the pooled CKD/T2D studies (FIDELITY), hyperkalemia was reported in 14% of patients treated with finerenone compared to 6.9% of those receiving placebo.[10] In the FINEARTS-HF trial, investigator-reported hyperkalemia occurred in 9.7% of the finerenone group versus 4.2% of the placebo group.[10]
• Risk Factors: The risk of developing hyperkalemia with finerenone increases with decreasing kidney function (i.e., lower eGFR). Patients with higher baseline serum potassium levels or other predisposing factors for hyperkalemia (e.g., concomitant use of medications that impair potassium excretion or increase serum potassium, such as potassium supplements or certain diuretics) are also at greater risk.[10]
• Management Protocol: Structured protocols for potassium monitoring and dose adjustment are essential for the safe use of finerenone. These protocols, employed in clinical trials and recommended in prescribing information and guidelines, are detailed in Table 4.
• Baseline Assessment: Before initiating finerenone, serum potassium and eGFR must be measured in all patients. Finerenone should not be initiated if the serum potassium level is >5.0 mEq/L.[10]
• Starting Dose: The initial dose is determined by the patient's eGFR:
• eGFR $\ge$60 mL/min/1.73m²: 20 mg once daily.[11]
• eGFR 25 to <60 mL/min/1.73m²: 10 mg once daily.[11]
• eGFR <25 mL/min/1.73m²: Finerenone use is not recommended.[25]
• Monitoring: Serum potassium levels should be checked 4 weeks after starting treatment and after any dosage adjustment. Thereafter, periodic monitoring (e.g., every 4 months according to KDIGO guidelines [37], or as clinically indicated per prescribing information [25]) is necessary. Patients at higher risk for hyperkalemia may require more frequent monitoring.[10]
• Dose Adjustment/Interruption: Dose adjustments are based on current serum potassium levels and the current finerenone dose:
• If serum potassium is $\le$4.8 mEq/L: If the patient is on 10 mg daily, the dose should be increased to 20 mg daily (unless eGFR has decreased by more than 30% compared to the previous measurement, in which case the 10 mg dose should be maintained). If already on 20 mg daily, the dose should be maintained.[11]
• If serum potassium is >4.8–5.5 mEq/L: The current dose (10 mg or 20 mg) should be maintained.[11]
• If serum potassium is >5.5 mEq/L: Finerenone should be withheld. Treatment may be restarted at 10 mg once daily when the serum potassium level is $\le$5.0 mEq/L.[11]
• Clinical Trial Experience: Despite the higher incidence of hyperkalemia with finerenone, the rates of treatment discontinuation due to hyperkalemia were low in the FIDELITY pooled analysis (1.7% for finerenone vs. 0.6% for placebo) [31] and in the individual FIDELIO-DKD trial. Hospitalizations for hyperkalemia were also infrequent (e.g., 0.5% with finerenone vs. 0.2% with placebo in FINEARTS-HF).[10] Importantly, no deaths attributable to hyperkalemia were reported in the major clinical trials.[10]

The established protocols for potassium monitoring and dose adjustments are critical for mitigating the risk of severe hyperkalemia, thereby allowing patients to benefit from finerenone's cardiorenal protective effects. The manageability of this primary safety concern, as demonstrated in large clinical trials, is a key factor in its favorable risk-benefit assessment.

Table 4: Finerenone Dosing and Serum Potassium Monitoring Guidelines

Patient's eGFR (mL/min/1.73m²)	Initial Serum K$^+$ (mEq/L)	Recommended Starting Dose	Monitoring	Dose Titration/Adjustment based on current Serum K$^+$
$\ge$60	$\le$4.8	20 mg once daily	Serum K$^+$ and eGFR at 4 weeks after initiation or dose adjustment, then periodically (e.g., every 4 months or as needed).	If current dose is 20 mg: <br> - K$^+$ $\le$4.8: Maintain 20 mg. <br> - K$^+$ >4.8-5.5: Maintain 20 mg. <br> - K$^+$ >5.5: Withhold. Restart at 10 mg when K$^+$ $\le$5.0.
25 to <60	$\le$4.8	10 mg once daily	Serum K$^+$ and eGFR at 4 weeks after initiation or dose adjustment, then periodically (e.g., every 4 months or as needed).	If current dose is 10 mg: <br> - K$^+$ $\le$4.8: Increase to 20 mg (if eGFR decrease is $\le$30% from previous; otherwise maintain 10 mg). <br> - K$^+$ >4.8-5.5: Maintain 10 mg. <br> - K$^+$ >5.5: Withhold. Consider restarting at 10 mg when K$^+$ $\le$5.0.
<25	N/A	Not Recommended	N/A	N/A
Any eGFR	>5.0	Do Not Initiate	N/A	N/A

Sources:.[10] This table synthesizes general principles; prescribers should always consult the full, current prescribing information.

5.3. Drug Interactions and Contraindications

• Contraindications:
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, cobicistat, clarithromycin, telithromycin, nefazodone) is contraindicated due to the risk of significantly increased finerenone exposure and subsequent adverse effects.[2]
• Patients with adrenal insufficiency should not use finerenone.[10]
• Significant Drug Interactions (requiring avoidance or specific management):
• CYP3A4 Inhibitors (Moderate and Weak): Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, verapamil, fluconazole) or weak CYP3A4 inhibitors (e.g., amiodarone, diltiazem) can increase finerenone exposure. Serum potassium should be monitored during initiation or dosage adjustment of either finerenone or the inhibitor, and finerenone dosage adjusted as appropriate.[10]
• CYP3A4 Inducers (Strong and Moderate): Concomitant use of finerenone with strong or moderate CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, St. John’s Wort) should be avoided, as these can substantially decrease finerenone plasma concentrations and reduce its efficacy.[10]
• Grapefruit or Grapefruit Juice: Consumption of grapefruit or grapefruit juice should be avoided during treatment with finerenone, as they are strong inhibitors of CYP3A4 and can increase finerenone levels.[11]
• Potassium-Sparing Diuretics and other MRAs: Concomitant use with other potassium-sparing diuretics (e.g., amiloride, triamterene) or other MRAs (e.g., spironolactone, eplerenone) is expected to increase the risk of hyperkalemia and is generally not recommended or requires very close monitoring.[2]
• Potassium Supplements and Salt Substitutes Containing Potassium: These can increase the risk of hyperkalemia and should be used with caution, if at all, and with frequent potassium monitoring.
• Specific Populations:
• Hepatic Impairment: Finerenone should be avoided in patients with severe hepatic impairment (Child-Pugh Class C). For patients with moderate hepatic impairment (Child-Pugh Class B), additional serum potassium monitoring should be considered, although no initial dose adjustment is typically recommended.[10] No dosage adjustment is needed for mild hepatic impairment (Child-Pugh Class A).[25]
• Lactation: Breastfeeding should be avoided during treatment with finerenone and for 1 day after the last dose, as it is not known whether finerenone is excreted in human milk and what the potential effects on the breastfed infant might be.[10]

5.4. Comparative Safety: Reduced Risk of Gynecomastia vs. Steroidal MRAs

A key differentiating safety feature of finerenone is its significantly reduced risk of causing gynecomastia and other sex hormone-related side effects when compared to the steroidal MRA spironolactone. This advantage stems directly from finerenone's nonsteroidal chemical structure and its high selectivity for the mineralocorticoid receptor, with negligible binding affinity for androgen or progesterone receptors.2 Spironolactone, due to its non-selective binding to these hormonal receptors, is commonly associated with gynecomastia (breast development in males), breast pain, and menstrual irregularities, which can lead to patient discomfort and non-adherence to therapy.5

Clinical trial data for finerenone have consistently shown a very low incidence of gynecomastia, comparable to that observed with placebo. For instance, in the FIDELITY pooled analysis, which included over 13,000 patients, gynecomastia was reported in only 8 patients (0.1%) in the finerenone group versus 11 patients (0.2%) in the placebo group.[4] This low incidence contrasts sharply with the known rates for spironolactone, which can be significantly higher depending on the dose and patient population. This improved tolerability profile, particularly for male patients, is a clinically relevant advantage of finerenone, potentially leading to better long-term adherence to MRA therapy, which is crucial for achieving sustained cardiorenal benefits.

6. Finerenone in Clinical Practice: Guideline Recommendations and Therapeutic Positioning

The robust clinical evidence supporting finerenone's efficacy and manageable safety profile has led to its incorporation into major international clinical practice guidelines for the management of patients with CKD associated with T2D.

6.1. Kidney Disease: Improving Global Outcomes (KDIGO) Guideline Recommendations

The Kidney Disease: Improving Global Outcomes (KDIGO) organization has recognized the role of finerenone in its clinical practice guidelines. The KDIGO 2022 guidelines recommend finerenone as a component of a comprehensive treatment strategy for patients with CKD associated with T2D.13 Specifically, finerenone is suggested for patients who have an eGFR $\ge$25 mL/min/1.73m², normal serum potassium concentrations, and persistent albuminuria (defined as UACR $\ge$30 mg/g or $\ge$3 mg/mmol) despite receiving a maximum tolerated dose of a RAS inhibitor (ACE inhibitor or ARB).13

The KDIGO guidelines also provide specific recommendations for initiating finerenone: a starting dose of 10 mg once daily for patients with an eGFR of 25 to <60 mL/min/1.73m², and 20 mg once daily for those with an eGFR $\ge$60 mL/min/1.73m², provided the serum potassium is $\le$4.8 mmol/L. Potassium monitoring is advised at 1 month post-initiation and every 4 months thereafter, with dose adjustments based on potassium levels.[37] The KDIGO 2024 clinical practice guideline update continues to support the use of finerenone in patients with CKD and T2D to reduce the risk of kidney function decline and cardiovascular events.[36]

6.2. American Diabetes Association (ADA) Recommendations

The American Diabetes Association (ADA), in its 2022 Consensus Report (developed jointly with KDIGO) and its 2024 Standards of Care in Diabetes, also recommends finerenone for individuals with T2D, an eGFR $\ge$25 mL/min/1.73m², normal serum potassium levels, and albuminuria (UACR $\ge$30 mg/g) despite treatment with a maximum tolerated dose of a RAS inhibitor. The stated goals are to improve cardiovascular outcomes and reduce the risk of CKD progression.10 The ADA guidelines specifically highlight finerenone's role in reducing the risk of hospitalization for heart failure in this patient population.35

6.3. European Society of Cardiology (ESC) Perspectives

The European Society of Cardiology (ESC) 2023 guidelines for the management of cardiovascular disease in patients with diabetes also include recommendations for finerenone. The ESC suggests finerenone, in addition to an ACE inhibitor or ARB, for patients with T2DM and either an eGFR >60 mL/min/1.73m² with a UACR $\ge$30 mg/mmol ($\ge$300 mg/g), or an eGFR of 25-60 mL/min/1.73m² with a UACR $\ge$3 mg/mmol ($\ge$30 mg/g). The aim is to reduce the risk of cardiovascular events and kidney failure in these patients.10

6.4. Integration into Comprehensive Cardiorenal Protective Strategies

Finerenone is increasingly positioned as a crucial component of a multi-pillar therapeutic strategy for patients with CKD and T2D. This strategy emphasizes a holistic approach to cardiorenal protection, typically involving the concurrent use of RAS inhibitors, SGLT2 inhibitors, and now, nonsteroidal MRAs like finerenone.3

The mechanism of action of finerenone, which directly targets MR-mediated inflammation and fibrosis, is distinct from and complementary to the primary hemodynamic and metabolic effects of RAS inhibitors and SGLT2 inhibitors.[3] This mechanistic complementarity provides a strong rationale for combination therapy. The FIDELITY pooled analysis confirmed that the cardiorenal benefits of finerenone were observed irrespective of baseline or concomitant SGLT2 inhibitor use, supporting its role in additive risk reduction.[28]

The rapid incorporation of finerenone into major international guidelines shortly after the publication of its pivotal trial results signifies a swift recognition by the medical community of its substantial value in addressing the significant residual cardiorenal risk that persists in many patients with T2D and CKD, even when treated with other established therapies. Finerenone is thus emerging as a third pillar of therapy for comprehensive cardiorenal protection in diabetic kidney disease, targeting a distinct pathophysiological pathway—inflammation and fibrosis mediated by MR overactivation—that is not fully addressed by RAS inhibitors or SGLT2 inhibitors alone. This multi-faceted approach, addressing hemodynamic, metabolic, inflammatory, and fibrotic pathways, is becoming the standard of care for maximizing cardiorenal outcomes in this high-risk patient population.

7. Conclusion and Future Perspectives

7.1. Summary of Finerenone's Role in Cardiorenal Medicine

Finerenone represents a significant therapeutic advancement in the field of mineralocorticoid receptor antagonism. Its development as a selective, nonsteroidal MRA provides a targeted approach to counteract the deleterious effects of MR overactivation—namely inflammation and fibrosis—which are key contributors to the progression of cardiorenal diseases.

The robust clinical evidence derived from the FIDELIO-DKD and FIGARO-DKD trials, and powerfully consolidated in the FIDELITY pooled analysis, has unequivocally established finerenone's efficacy in reducing both the progression of kidney disease and the incidence of major cardiovascular events in a broad spectrum of adult patients with CKD associated with T2D. These benefits are observed on top of standard-of-care treatments, including RAS inhibitors and, importantly, are consistent irrespective of concomitant SGLT2 inhibitor use.

A critical advantage of finerenone is its distinct pharmacological profile compared to older, steroidal MRAs. Its high selectivity for the MR and lack of significant interaction with androgen or progesterone receptors translate into a markedly improved side-effect profile, most notably a significantly reduced risk of gynecomastia. While hyperkalemia remains an important consideration requiring diligent monitoring and management according to established protocols, the overall safety and tolerability of finerenone have been favorable in large clinical trials.

Furthermore, emerging data from the FINEARTS-HF trial suggest a promising new role for finerenone in the treatment of heart failure with a left ventricular ejection fraction $\ge$40% (HFmrEF and HFpEF), a patient population with substantial unmet medical needs and limited therapeutic options. The FDA's granting of Priority Review for this indication underscores its potential impact.

7.2. Unanswered Questions and Ongoing Research

Despite the significant progress made with finerenone, several areas warrant further investigation to fully delineate its therapeutic potential and optimize its use:

• Long-term Outcomes: While current trials provide follow-up for several years, the very long-term efficacy and safety of finerenone beyond these durations remain to be fully characterized.
• Non-Diabetic CKD: The primary evidence for finerenone is in patients with CKD associated with T2D. Its efficacy and safety in patients with non-diabetic CKD represent an important area for future research, as MR overactivation is also implicated in these conditions.
• Optimal Combination Strategies: Further studies are needed to determine the optimal sequencing and combination strategies for finerenone with other cardiorenal protective agents (RAS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists) in diverse patient subgroups to maximize benefits and manage potential interactions or cumulative risks.
• Real-World Evidence: Large-scale observational studies and real-world evidence will be crucial to confirm the findings from randomized controlled trials in broader, more heterogeneous patient populations and to further characterize long-term safety, effectiveness, and patterns of use, including in patients who may have been excluded from pivotal trials.
• Expanded Heart Failure Applications: The MOONRAKER clinical trial program [12] and other ongoing research will continue to explore finerenone's benefits across different stages, phenotypes, and etiologies of heart failure. Understanding its role in patients with HFrEF (though largely excluded from FINEARTS-HF) or in specific HF subpopulations could further expand its utility.
• Pediatric Populations: The FIONA OLE study is assessing long-term safety in children and young adults with CKD and proteinuria, which will provide valuable data for this age group.[17]
• Cost-Effectiveness: As with any new therapy, comprehensive cost-effectiveness analyses within various healthcare systems will be important to ensure equitable access and guide reimbursement decisions.

While finerenone has firmly established its place in the management of CKD associated with T2D and is poised to make a significant impact in HFpEF/HFmrEF, its full therapeutic potential across the broader spectrum of cardiorenal diseases is an active and evolving area of investigation. Continued research will undoubtedly refine its role and further solidify its position in the armamentarium against these prevalent and burdensome conditions.

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