# Absolute Risk Reduction for the Primary Kidney Composite Outcome with Finerenone Versus Placebo in the FIDELIO-DKD Trial: A Comprehensive Literature Synthesis

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### Background and Context

#### The Burden of Diabetic Kidney Disease and the Residual Risk Problem

Chronic kidney disease (CKD) arising from type 2 diabetes mellitus (T2DM) — commonly termed diabetic kidney disease (DKD) — represents one of the most consequential complications of the global diabetes epidemic. DKD develops in up to 40% of patients with T2DM, is the leading cause of end-stage kidney disease (ESKD), and is an independent risk factor for cardiovascular disease (PMC11214281). The coexistence of T2DM and CKD dramatically amplifies cardiovascular risk: patients with T2DM without kidney disease have a 10-year standardized cumulative all-cause mortality rate of approximately 11.5%, rising to 31.1% when kidney disease is also present (PMC12171220). The economic burden is correspondingly enormous; in the Netherlands alone, annual direct and indirect costs of dialysis range from €77,566 to €105,833 per patient, and total diabetes-related healthcare expenditure reached €1.3 billion in 2019 (PMC10685667).

For decades, the pharmacological cornerstone of DKD management was renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), which reduce albuminuria, slow eGFR decline, and lower cardiovascular risk. However, even with maximally tolerated RAS inhibition, a substantial residual risk of CKD progression and cardiovascular events persists. Landmark trials RENAAL and IDNT demonstrated that losartan and irbesartan, respectively, reduced composite kidney endpoints by 16–20%, yet participants still experienced 19.6% and 14.2% incidences of kidney failure, respectively (PMC12549410). The phenomenon of "aldosterone breakthrough" — in which serum aldosterone levels return to pre-treatment concentrations after weeks to months of ACEi or ARB therapy — occurs in up to 40% of patients, sustaining MR overactivation despite RAS blockade (PMC10299719, PMC11214281). The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors added a second pillar of cardiorenal protection, with trials such as CREDENCE (canagliflozin, HR 0.70 for the primary composite), DAPA-CKD (dapagliflozin, HR 0.61), and EMPA-KIDNEY (empagliflozin, HR 0.72) demonstrating substantial risk reductions (PMC9917247). Nevertheless, even with combined RAS blockade and SGLT2 inhibition, approximately 10% of patients in CREDENCE and DAPA-CKD still experienced CKD progression or kidney failure, underscoring persistent residual risk that demands additional therapeutic strategies (PMC11214281).

#### The FIDELIO-DKD Trial: Design, Population, and the Specific Question

It is within this context of persistent residual cardiorenal risk that finerenone — a third-generation, nonsteroidal, highly selective mineralocorticoid receptor antagonist (MRA) — was developed and evaluated. The FIDELIO-DKD trial (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease; NCT02540993) was the pivotal phase 3 randomized, double-blind, placebo-controlled, multicenter, event-driven trial designed specifically to evaluate finerenone's effect on kidney outcomes in patients with T2DM and predominantly advanced CKD (PMC12171220, PMC11214281, PMC9917247). The trial enrolled 5,734 adult participants who were receiving the maximum tolerated labeled dose of an ACEi or ARB. Eligible patients had either a UACR of 30–299 mg/g, an eGFR between 25 and <60 mL/min/1.73 m², and established diabetic retinopathy, or a UACR of 300–5,000 mg/g with an eGFR of 25 to <75 mL/min/1.73 m², reflecting a population with predominantly CKD stages 3–4 and severe albuminuria (PMC9917247, PMC12171220). The mean baseline eGFR was 44.3 mL/min/1.73 m² and the median baseline UACR was 852 mg/g (PMC12539649). Participants were randomized 1:1 to oral finerenone or matching placebo, on top of background RAS inhibition. In FIDELIO-DKD, participants with eGFR 25 to <60 mL/min/1.73 m² received finerenone 10 mg once daily with up-titration to 20 mg at month 1 if serum potassium was ≤4.8 mmol/L and eGFR was stable; those with eGFR ≥60 mL/min/1.73 m² received 20 mg once daily as the starting dose (PMC12539649, PMC11054947).

The user's question is precise and clinically important: what is the **absolute risk reduction (ARR)** for the **primary kidney composite outcome** of finerenone versus placebo, based strictly on the FIDELIO-DKD primary analysis? This question matters because relative risk reductions (hazard ratios) are the standard currency of trial reporting but can be misleading when baseline event rates differ across populations. The ARR — and its reciprocal, the number needed to treat (NNT) — translates the relative benefit into a clinically actionable metric that informs prescribing decisions, health-economic analyses, and guideline recommendations. The following sections synthesize the available evidence to answer this question with precision, while contextualizing the finding within the broader mechanistic, pharmacological, and clinical landscape.

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### Molecular and Mechanistic Pathways

#### MR Overactivation as a Driver of Cardiorenal Injury

The mineralocorticoid receptor is expressed not only in renal epithelial cells but also in cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, endothelial cells, podocytes, mesangial cells, macrophages, and other immune cells (PMC9408839, PMC10762446). Under physiological conditions, aldosterone binding to the MR in renal epithelial cells promotes sodium reabsorption and potassium excretion, maintaining extracellular volume and blood pressure homeostasis. However, in the pathological milieu of T2DM and CKD — characterized by hyperglycemia, oxidative stress, hemodynamic dysregulation, and elevated aldosterone levels — MR overactivation in non-epithelial tissues switches from a homeostatic regulator to a pathophysiological mediator (PMC12539649, PMC9408839).

In the kidney, MR overactivation promotes glomerular hypertrophy, glomerulosclerosis, and vascular damage through multiple downstream mechanisms, including enhanced reactive oxygen species (ROS) production, inflammatory cell infiltration, and activation of pro-fibrotic signaling pathways. MR overactivation results in renal injury through the MR-Rac1 pathway, causing glomerular hyperfiltration, and promotes differentiation of macrophages and T lymphocytes into pro-inflammatory phenotypes, driving chronic inflammation that damages target organs (PMC9968798). The resulting cascade of glomerular inflammation and fibrosis accelerates albuminuria and progressive eGFR decline. In the vasculature, MR overactivation promotes smooth muscle cell proliferation, endothelial dysfunction through reduced nitric oxide bioavailability, and vascular stiffness, contributing to elevated cardiovascular risk in DKD (PMC9408839, PMC10762446).

A particularly important pathophysiological concept is the phenomenon of aldosterone breakthrough during chronic RAS inhibition. Despite ACEi or ARB therapy, plasma aldosterone levels return to pre-treatment concentrations in approximately 40% of patients after several weeks to months, sustaining MR-mediated injury even in the context of otherwise optimized pharmacotherapy (PMC10299719, PMC11214281). This observation provides the mechanistic rationale for adding an MRA to background RAS blockade: the two drug classes target complementary nodes in the RAAS cascade, with RAS inhibitors reducing angiotensin II-mediated effects and MRAs blocking the downstream aldosterone-MR signaling that persists despite upstream inhibition.

#### Finerenone's Distinct Mechanism of MR Antagonism

Finerenone's mechanism of action differs fundamentally from that of steroidal MRAs (spironolactone, eplerenone) in ways that have direct clinical consequences. Structurally, finerenone is a nonsteroidal compound whose bulky molecular architecture induces a unique MR conformational change that prevents recruitment of transcriptional coregulators, blocking downstream pro-inflammatory and pro-fibrotic gene expression — distinguishing it from steroidal MRAs, which act as partial agonists for cofactor recruitment at high concentrations (PMC11214281, PMC10299719, PMC10762446).

The pharmacological consequences of this distinct binding mode are several. First, finerenone exhibits high MR potency (IC50 approximately 17–18 nM) and high selectivity for the MR over androgen, progesterone, glucocorticoid, and estrogen receptors (IC50 >10,000 nM for each), eliminating sex hormone-related adverse effects (PMC12171220, PMC12335729). Second, finerenone demonstrates a relatively balanced tissue distribution between the heart and kidney, in contrast to spironolactone and eplerenone which preferentially accumulate in the kidney, hypothesized to underlie its dual cardiorenal protection and lower propensity for hyperkalemia (PMC12171220).

#### Anti-Inflammatory and Anti-Fibrotic Mechanisms Underlying Renal Protection

The renal protective effects of finerenone are mediated through both hemodynamic and non-hemodynamic pathways, with the latter increasingly recognized as the dominant mechanism for long-term kidney protection. In preclinical models, finerenone consistently reduced markers of renal inflammation and fibrosis across multiple experimental systems. In the DOCA-salt rat model of cardiorenal end-organ damage, finerenone reduced renal mRNA expression of PAI-1, MCP-1, osteopontin, and MMP-2 and attenuated histologically confirmed renal fibrosis; in mouse models of ischemia-reperfusion-induced CKD, finerenone promoted macrophage polarization from M1 to M2 phenotype by increasing IL-4 receptor expression (PMC9408839, PMC10762446).

The clinical translation of these anti-fibrotic mechanisms is reflected in the temporal pattern of benefit observed in FIDELIO-DKD. In FIDELIO-DKD, Kaplan-Meier curves for the composite cardiovascular outcome separated early (at approximately 6 months), while curves for the composite kidney outcome diverged later (at approximately 20–24 months), consistent with slower anti-fibrotic remodeling (PMC9408839, PMC9917247). This temporal dissociation supports the concept that finerenone's early benefits are partly mediated by natriuresis, modest blood pressure reduction, and rapid anti-inflammatory effects, while its sustained kidney protection reflects progressive attenuation of MR-driven fibrosis and structural remodeling. The mean systolic blood pressure reduction in FIDELIO-DKD was approximately −2.1 mmHg with finerenone versus +0.9 mmHg with placebo at month 12, confirming that the predominant mechanism of cardiorenal benefit is non-hemodynamic (PMC9408839, PMC9917247).

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### Dose-Response and Pharmacokinetics

#### Dose Selection and Titration in FIDELIO-DKD

The dosing strategy for finerenone in FIDELIO-DKD was guided by eGFR at screening and serum potassium at month 1. Patients with eGFR 25 to <60 mL/min/1.73 m² received an initial dose of 10 mg once daily, with up-titration to 20 mg once daily at month 1 if serum potassium was ≤4.8 mmol/L and eGFR was stable. Patients with eGFR ≥60 mL/min/1.73 m² received 20 mg once daily as the starting dose. The target dose was 20 mg once daily for all patients (PMC12539649, PMC11054947). This eGFR-stratified dosing approach was designed to balance efficacy (which is dose-dependent, as demonstrated in the phase IIb ARTS-DN trial) against the risk of hyperkalemia, which increases with higher doses and lower eGFR.

The phase IIb ARTS-DN trial (n=823 patients with T2DM and DKD on RAS inhibitors) demonstrated a dose-dependent UACR reduction across 1.25–20 mg/day finerenone, with a 38% UACR reduction at 20 mg/day (PMC10762446). These phase II data directly informed the dose selection and titration algorithm used in FIDELIO-DKD.

#### Pharmacokinetic Profile and Clinical Implications

Finerenone undergoes hepatic phase 1 metabolism via cytosolic enzymes, with subsequent biliary excretion of metabolites, minimizing reliance on renal clearance — a critical pharmacokinetic advantage in patients with CKD (PMC12335729). The absence of active metabolites supports a predictable pharmacokinetic profile, and hyperkalemia can be managed through dose reduction, temporary discontinuation, dietary modifications, and routine monitoring (PMC12335729).

Strong CYP3A4 inhibitors (ketoconazole, ritonavir, grapefruit juice) are contraindicated with finerenone; strong or moderate CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St. John's Wort) should be avoided due to markedly reduced finerenone plasma concentrations (PMC10311906, PMC11054947).

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### Clinical Evidence and Implications

#### The FIDELIO-DKD Primary Analysis: Absolute Risk Reduction for the Kidney Composite Outcome

The primary endpoint of FIDELIO-DKD was a composite of time to first occurrence of kidney failure (defined as ESKD [initiation of chronic dialysis for ≥90 days or kidney transplantation] or sustained decrease in eGFR to <15 mL/min/1.73 m²), a sustained decrease of at least 40% in eGFR from baseline over at least 4 weeks, or death from renal causes. This composite was chosen to capture the full spectrum of clinically meaningful kidney disease progression, from early functional decline (≥40% eGFR reduction) to irreversible kidney failure and renal death.

**The primary analysis result, reported consistently across multiple sources in the provided literature, is as follows:** In FIDELIO-DKD, finerenone significantly reduced the primary composite kidney outcome (kidney failure, sustained ≥40% eGFR decline, or renal death) compared with placebo — occurring in 17.8% of finerenone-treated patients versus 21.1% of placebo-treated patients over a median follow-up of 2.6 years — with a hazard ratio of 0.82 (95% CI 0.73–0.93; P=0.001), representing an 18% relative risk reduction (PMC12171220, PMC11214281, PMC9917247, PMC11054947).

The **absolute risk reduction (ARR)** is calculated directly from the event rates: 21.1% − 17.8% = **3.3 percentage points** (approximately 3.3 events per 100 patients treated over the median 2.6-year follow-up period). This ARR of 3.3% translates to a **number needed to treat (NNT) of approximately 30** (1/0.033 ≈ 30.3) to prevent one primary kidney composite event over the trial's median follow-up duration of 2.6 years. These figures are derived directly from the event rates reported in the primary FIDELIO-DKD analysis (PMC12171220, PMC11214281). It is important to note that this NNT is calculated over the specific follow-up period of the trial; the NNT over a longer treatment duration would be expected to decrease (i.e., fewer patients would need to be treated to prevent one event) as the cumulative event rates diverge further over time.

The FIDELITY pooled analysis (n=13,026; median follow-up 3.0 years) reported a 23% relative risk reduction in the kidney composite (HR 0.77; 95% CI 0.67–0.88; P<0.001) with event rates of 5.5% versus 7.1%, using a more stringent ≥57% eGFR decrease threshold (PMC11214281, PMC9917247). These FIDELITY figures are not directly comparable to the FIDELIO-DKD primary analysis because they use a different (more stringent) kidney composite endpoint and a different (pooled) population, but they provide important context for understanding the magnitude of relative benefit across the spectrum of CKD severity.

#### Decomposition of the Primary Composite: Individual Components

Understanding which components of the primary composite drove the overall benefit is essential for interpreting the clinical significance of the ARR. In FIDELIO-DKD, the risk of a sustained ≥40% decline in eGFR was reduced with finerenone (HR 0.81; 95% CI 0.72–0.92), representing a key contributor to the primary composite benefit (PMC12171220). The risk of ESKD specifically was reduced by 36% in FIGARO-DKD (HR 0.64; 95% CI 0.41–0.995; P=0.046) and by 20% in the FIDELITY pooled analysis (HR 0.80; 95% CI 0.64–0.99; P=0.040) (PMC12171220, PMC11214281). Renal death was extremely rare in both arms of FIDELIO-DKD, occurring in very few patients in each group, and did not contribute meaningfully to the primary composite event rate (PMC12470496).

The meta-analysis by Chen et al. (2026), which pooled 7 RCTs including 33,455 patients, confirmed that finerenone significantly reduced the HR for the primary composite outcome (HR 0.81; 95% CI 0.76–0.87; P<0.00001; I²=13%), the ≥57% eGFR threshold composite (HR 0.76; 95% CI 0.70–0.83; I²=0%), kidney failure (HR 0.82; 95% CI 0.74–0.91; I²=0%), and ESKD (HR 0.87; 95% CI 0.77–0.99; I²=46%) (PMC12851658). The consistency of these findings across multiple trials and meta-analyses, with low heterogeneity for most endpoints, strengthens confidence in the primary FIDELIO-DKD result.

#### The Secondary Cardiovascular Composite Outcome in FIDELIO-DKD

Although the user's question focuses specifically on the primary kidney composite, the secondary cardiovascular composite outcome of FIDELIO-DKD is clinically inseparable from the kidney findings and provides important context for the overall benefit-risk assessment. The secondary cardiovascular composite in FIDELIO-DKD (CV death, nonfatal MI, nonfatal stroke, or HF hospitalization) occurred in 13.0% of finerenone-treated patients versus 14.8% of placebo-treated patients (HR 0.86; 95% CI 0.75–0.99; P=0.03) (PMC13163276, PMC11214281).

#### UACR Reduction as a Surrogate Marker of Kidney Protection

A critical secondary finding of FIDELIO-DKD was the early and sustained reduction in UACR with finerenone. At 4 months, finerenone produced approximately a 31% greater reduction in UACR compared to placebo in FIDELIO-DKD, and this difference was maintained throughout the remainder of the trial (PMC12171220, PMC9917247). This early UACR reduction is clinically significant as a validated surrogate marker for long-term kidney outcomes. The antiproteinuric effect of finerenone is not merely a biomarker of benefit but is mechanistically linked to the long-term kidney protection observed in the trial, consistent with the known relationship between albuminuria reduction and slowing of CKD progression across multiple therapeutic interventions.

#### FIGARO-DKD: Complementary Evidence from a Broader CKD Population

FIGARO-DKD (n=7,437; median follow-up 3.4 years) enrolled a population with mean baseline eGFR of approximately 67.8 mL/min/1.73 m² and median baseline UACR of 308 mg/g; its primary cardiovascular composite occurred in 12.4% of finerenone-treated versus 14.2% of placebo-treated patients (HR 0.87; 95% CI 0.76–0.98; P=0.03), driven primarily by a 29% reduction in HF hospitalization (HR 0.71; 95% CI 0.56–0.90) (PMC12171220, PMC11214281).

The secondary kidney composite in FIGARO-DKD (kidney failure, sustained ≥40% eGFR decline, or renal death) occurred in 9.5% of finerenone-treated versus 10.8% of placebo-treated patients (HR 0.87; 95% CI 0.76–1.01), which did not reach statistical significance (PMC12171220). Finerenone also reduced UACR by 32% at 4 months in FIGARO-DKD (PMC12171220). ESKD was reduced by 36% in FIGARO-DKD (HR 0.64; 95% CI 0.41–0.995; P=0.046) and by 20% in the FIDELITY pooled analysis (HR 0.80; 95% CI 0.64–0.99; P=0.040) (PMC12171220, PMC11214281).

#### The FIDELITY Pooled Analysis: Comprehensive Evidence Across the CKD Spectrum

The FIDELITY prespecified pooled analysis combined individual patient-level data from FIDELIO-DKD and FIGARO-DKD (n=13,026; median follow-up 3.0 years) to provide more robust estimates of finerenone's efficacy and safety across the full spectrum of CKD severity in patients with T2DM. The FIDELITY analysis showed robust evidence of both cardiovascular and kidney protection with finerenone versus placebo, including a 30% risk reduction in doubling (>57% reduction) of serum creatinine and a 20% relative risk reduction of the composite kidney outcome (5.5% vs. 7.1%, HR 0.77; 95% CI 0.67–0.88; P<0.001). In addition, there was a 14% risk reduction in the composite cardiovascular outcome (12.7% vs. 14.4%; HR 0.86; 95% CI 0.78–0.95; P=0.0018), primarily driven by a reduction in HF hospitalization (PMC11214281). The primary kidney composite in FIDELITY (kidney failure, sustained ≥57% decrease in eGFR, or renal death) was thus reduced by 23% with finerenone (HR 0.77; 95% CI 0.67–0.88; P<0.001), with event rates of 5.5% versus 7.1% (PMC11214281, PMC9917247).

The FIDELITY analysis confirmed that finerenone's benefits were consistent across key subgroups. In the FIDELITY analysis, approximately 6.7% of participants were receiving SGLT2 inhibitors and approximately 7.2% were receiving GLP-1 receptor agonists at baseline; cardiorenal benefits were consistent irrespective of baseline HbA1c, insulin use, history of heart failure, atrial fibrillation, ASCVD, or systolic blood pressure quartile (PMC12539649). Blood pressure reduction was modest (mean 2.5 mmHg systolic), confirming that the cardiorenal benefits are not primarily mediated by antihypertensive effects (PMC11214281).

#### Subgroup Analyses and Special Populations

Several prespecified and post-hoc subgroup analyses of FIDELIO-DKD have provided additional insights into the consistency and magnitude of finerenone's kidney benefit. A post-hoc analysis of FIDELIO-DKD restricted to the 4,619 participants (81.4%) meeting CREDENCE eligibility criteria showed finerenone reduced the CREDENCE-equivalent cardiorenal composite by 26% (HR 0.74; 95% CI 0.63–0.87), comparable to the 30% reduction with canagliflozin in CREDENCE (PMC9917247). This analysis is important because it addresses the concern that the 18% relative risk reduction in FIDELIO-DKD might appear smaller than the 30% reduction in CREDENCE due to differences in endpoint definitions and patient populations rather than true differences in drug efficacy.

An exploratory subgroup analysis of the FIDELITY dataset focused on the 890 participants (7%) with stage 4 CKD (eGFR <30 mL/min/1.73 m²) at baseline. In the 890 FIDELITY participants (7%) with stage 4 CKD (eGFR <30 mL/min/1.73 m²), finerenone reduced the kidney composite risk by 37% at year 2 (HR 0.63; 95% CI 0.42–0.95; P=0.026), but this benefit was not sustained beyond 2 years; the chronic eGFR slope was significantly better with finerenone (−1.8 vs. −3.2 mL/min/1.73 m² per year; difference 1.39; 95% CI 0.48–2.30; P=0.04) (PMC10278789). These findings suggest that finerenone provides cardiovascular benefits and slows eGFR decline even in stage 4 CKD, but the long-term kidney composite benefit may be attenuated by the severity of irreversible kidney damage in this population.

A prespecified subgroup analysis of FIDELIO-DKD examining the effect of concomitant SGLT2 inhibitor use (4.6% of the total FIDELIO-DKD population) found that finerenone improved UACR reduction by 25% in patients receiving concomitant SGLT2 inhibitors, and fewer hyperkalemia events were observed in finerenone-treated patients with versus without concomitant SGLT2 inhibitor use (8.1% vs. 18.7%) (PMC11214281, PMC9917247).

A Chinese subgroup analysis of FIGARO-DKD (n=325; median follow-up 3.3 years) demonstrated that finerenone significantly reduced the key secondary kidney composite (≥40% eGFR decline) in Chinese patients (HR 0.48; 95% CI 0.29–0.79; P=0.0029), with a NNT of 7 at month 36; finerenone also reduced UACR by 39% versus placebo at month 4 and improved the chronic eGFR slope (−3.57 vs. −5.83 mL/min/1.73 m² per year; difference 2.25; 95% CI 0.75–3.76) (PMC12074935).

#### Real-World Evidence and Cost-Effectiveness

A Dutch cost-effectiveness analysis using the FINE-CKD Markov model demonstrated that finerenone yielded 9.40 life years and 7.05 QALYs per patient versus 9.18 life years and 6.85 QALYs for standard of care, with total lifetime costs of €93,248 versus €99,384 (saving €6,136 per patient), driven primarily by a reduction in dialysis costs (−€7,935) offsetting higher medication costs (+€3,545); dominance was confirmed in 82.5% of simulations with a 93.1% probability of cost-effectiveness at the Dutch willingness-to-pay threshold of €20,000 per QALY (PMC10685667). These findings underscore that the 3.3% ARR for the primary kidney composite in FIDELIO-DKD translates into meaningful long-term economic value, primarily through prevention of costly dialysis.

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### Safety Profile and Adverse Events

#### Hyperkalemia: The Primary Safety Concern

Hyperkalemia is the most clinically important adverse effect of finerenone and the primary safety concern in patients with CKD, who already have impaired renal potassium excretion. In FIDELIO-DKD, hyperkalemia-related adverse events occurred in 18.3% of finerenone-treated patients versus 9.0% of placebo-treated patients, with permanent treatment discontinuation due to hyperkalemia in 2.3% versus 0.9%, respectively (PMC12171220, PMC11214281). These discontinuation rates are substantially lower than those observed in trials of dual RAS blockade, despite FIDELIO-DKD having no protocol restrictions on dietary potassium or potassium supplements (PMC11214281, PMC9917247).

In FIGARO-DKD, hyperkalemia rates were 10.8% with finerenone versus 5.3% with placebo; in the FIDELITY pooled analysis, rates of hyperkalemia leading to permanent treatment discontinuation were 1.7% with finerenone versus 0.6% with placebo (PMC11214281, PMC9917247). The lower hyperkalemia rate in FIGARO-DKD compared to FIDELIO-DKD is consistent with the known relationship between eGFR and hyperkalemia risk: lower eGFR impairs renal potassium excretion and amplifies the potassium-retaining effect of MR blockade.

Compared to steroidal MRAs, finerenone's hyperkalemia burden is substantially lower. An indirect post-hoc comparison found that the proportion of patients with serum potassium ≥5.5 mmol/L was 12% with finerenone versus 35% with spironolactone plus patiromer and 64% with spironolactone without patiromer; treatment discontinuation due to hyperkalemia was 0.3% with finerenone versus 7% and 23% for spironolactone with and without patiromer, respectively (PMC12171220, PMC12709536).

#### Monitoring Protocol and Dose Adjustment

The serum potassium monitoring protocol used in FIDELIO-DKD and FIGARO-DKD provides a practical framework for clinical use. Serum potassium was assessed at baseline, at 1 month after treatment initiation, at month 4, and at 4-monthly intervals thereafter. Finerenone was temporarily withheld for serum potassium >5.5 mmol/L and restarted at the 10 mg dose when potassium returned to ≤5.0 mmol/L. RAS inhibitor dose reduction was not permitted in the trial protocol, and finerenone was continued without dose adjustment for serum potassium 5.0–5.5 mmol/L (PMC11214281, PMC12171220). The current FDA prescribing information recommends initiating finerenone only in patients with serum potassium ≤5.0 mEq/L, with dose titration from 10 mg to 20 mg at 4 weeks if potassium is ≤4.8 mEq/L, maintenance of the current dose if potassium is >4.8 to ≤5.5 mEq/L, and temporary discontinuation if potassium exceeds 5.5 mEq/L (PMC12171220, PMC12709536).

#### Other Adverse Events and Safety Considerations

Beyond hyperkalemia, the overall safety profile of finerenone in FIDELIO-DKD was favorable. Acute kidney injury was similar between finerenone and placebo groups in FIDELIO-DKD (HR 0.96; 95% CI 0.74–1.25; P=0.76) (PMC12171220). Finerenone's nonsteroidal structure confers high selectivity for the MR and minimizes off-target effects on androgen, progesterone, estrogen, and glucocorticoid receptors, resulting in a lower incidence of sex hormone-related adverse effects such as gynecomastia compared to steroidal MRAs like spironolactone (PMC12171220, PMC12335729). In contrast to steroidal MRAs such as spironolactone, which increase cortisol levels and HbA1c, finerenone's high receptor selectivity is associated with a more neutral metabolic profile (PMC12539649).

A meta-analysis of four RCTs (n=14,875) found no association between finerenone and overall tumor risk, but identified a potential signal for urinary tract malignancies (Peto OR 1.69; 95% CI 1.07–2.67), limited by small sample size and short follow-up (PMC11456546).

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### Unresolved Controversies and Disagreements

#### Relative vs. Absolute Benefit: Contextualizing the 18% Relative Risk Reduction

A persistent controversy in the interpretation of FIDELIO-DKD concerns the apparent discrepancy between the 18% relative risk reduction for the primary kidney composite with finerenone and the 30% relative risk reduction observed with canagliflozin in CREDENCE. This comparison has generated the impression that MR antagonism with finerenone is inferior to SGLT2 inhibition for cardiorenal protection in DKD. However, as discussed in the clinical evidence section, this discrepancy is largely attributable to key differences in trial design rather than true differences in drug efficacy (PMC9917247). The CREDENCE primary endpoint included a sustained ≥57% decrease in eGFR (equivalent to doubling of serum creatinine), while FIDELIO-DKD used the less stringent ≥40% threshold; patients with HFrEF were eligible in CREDENCE but excluded from FIDELIO-DKD; and the baseline characteristics of the two populations differed in important ways. When the FIDELIO-DKD data were reanalyzed using the CREDENCE endpoint definition in the "CREDENCE-like" subgroup (n=4,619), finerenone reduced the cardiorenal composite by 26% (HR 0.74; 95% CI 0.63–0.87), a magnitude comparable to the 30% reduction with canagliflozin (PMC9917247). This analysis substantially mitigates the concern about relative inferiority of finerenone versus SGLT2 inhibitors for kidney protection.

A network meta-analysis of 18 RCTs (n=51,496) found that SGLT2 inhibitors were associated with a stronger effect on renal outcomes and HF hospitalization compared to finerenone (RR 1.29; 95% CI 1.13–1.47 for renal outcomes; RR 1.31; 95% CI 1.07–1.61 for HHF), while finerenone and SGLT2 inhibitors were comparable in their effects on MACE reduction (PMC11214281). The ongoing CONFIDENCE trial (NCT05254002) is the first prospective randomized trial directly comparing finerenone plus empagliflozin versus each monotherapy, and its results will provide definitive evidence on the additive or synergistic effects of combination therapy.

#### The Systematic Review and Meta-Analysis by Finerenone vs. Placebo on Renal Outcomes (2025)

A systematic review and meta-analysis published in 2025 (PMC12470496) pooling three RCTs encompassing up to 19,027 participants reported non-significant pooled relative risks for kidney failure (RR 0.86; 95% CI 0.35–2.13), ESKD (RR 0.82; 95% CI 0.54–1.23), and sustained ≥40% eGFR decline (RR 0.97; 95% CI 0.50–1.88), with GRADE certainty rated as low for all primary renal outcomes and high heterogeneity for the ≥40% eGFR outcome (I²=73.9%; P=0.0216) (PMC12470496).

This apparent contradiction with the statistically significant primary FIDELIO-DKD result requires careful interpretation. The meta-analysis pooled data from trials with fundamentally different primary endpoints, patient populations, and follow-up durations. The high heterogeneity for the ≥40% eGFR decline outcome reflects the fundamental incompatibility of pooling these trials for kidney-specific endpoints. The wide confidence intervals in the meta-analysis reflect the small number of included trials and the heterogeneity of the pooled population, not a genuine absence of kidney benefit. The primary FIDELIO-DKD analysis — which was specifically designed and powered to detect kidney outcomes in a high-risk DKD population — remains the definitive evidence base for finerenone's kidney-protective effects, and its statistically significant result (HR 0.82; 95% CI 0.73–0.93; P=0.001) should not be dismissed on the basis of this meta-analysis.

#### Hyperkalemia Risk: Manageable or Clinically Significant?

A second area of controversy concerns the clinical significance of finerenone-associated hyperkalemia. The meta-analysis by PMC12470496 found that finerenone was associated with a significantly higher risk of hospitalization for hyperkalemia (pooled RR 4.57; 95% CI 1.07–19.48; I²=22%), indicating a meaningfully elevated relative risk, though the confidence interval was wide and the prediction interval (0.65–32.30) reflected substantial uncertainty about the magnitude of effect across settings (PMC12470496). The absolute rates of hyperkalemia-related hospitalization in the pivotal trials were low, and the clinical consensus, reflected in multiple guidelines (ADA, KDIGO, ESC, ESH), is that finerenone's hyperkalemia risk is manageable with appropriate patient selection (baseline potassium ≤5.0 mEq/L), structured monitoring, and dose adjustment, and does not outweigh the substantial cardiorenal benefits demonstrated in FIDELIO-DKD and FIGARO-DKD (PMC12171220, PMC12709536, PMC11214281).

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### Limitations of the Evidence Base

The evidence base for finerenone's kidney-protective effects, while robust, has several important methodological and generalizability limitations that must be acknowledged.

**Trial population selection and generalizability.** FIDELIO-DKD enrolled patients who were already receiving maximally tolerated RAS inhibition with serum potassium ≤4.8 mmol/L at screening — a highly selected population that may not reflect the broader DKD population in routine clinical practice — and both pivotal trials required a minimum eGFR of 25 mL/min/1.73 m², leaving a gap in evidence for patients with more advanced CKD below this threshold (PMC12539649, PMC12171220, PMC10762446).

**Short follow-up duration relative to disease trajectory.** The median follow-up of 2.6 years in FIDELIO-DKD is relatively short for a progressive chronic disease like DKD, and may not capture the full long-term benefit of finerenone on hard kidney endpoints such as ESKD. The ARR of 3.3% over 2.6 years would be expected to increase with longer follow-up as the cumulative event rates diverge further, and the NNT of approximately 30 would decrease accordingly. The cost-effectiveness analysis confirmed that cost savings from finerenone increase over time, with the largest incremental cost reductions occurring in the first 10 years (PMC10685667).

**Low baseline SGLT2 inhibitor use.** Only approximately 4.6–6.7% of participants in FIDELIO-DKD and FIGARO-DKD were receiving SGLT2 inhibitors at baseline, limiting the evidence base for the contemporary triple combination of RAS inhibitors, SGLT2 inhibitors, and finerenone (PMC12539649, PMC11214281). Contemporary clinical practice increasingly involves combination therapy with RAS inhibitors, SGLT2 inhibitors, and finerenone, but the evidence base for this triple combination is currently limited to subgroup analyses and the phase 2 CONFIDENCE trial (PMC9917247, PMC11214281). The CONFIDENCE trial (n=818) demonstrated that finerenone plus empagliflozin combination therapy achieved a 52% reduction in UACR from baseline at 180 days, exceeding either monotherapy, but as a phase 2 trial with a surrogate primary endpoint and 6-month follow-up, these results are insufficient to establish long-term hard kidney outcome benefits of the combination (PMC12747910).

**Racial and ethnic underrepresentation.** Only 4.7% and 3.5% of FIDELIO-DKD and FIGARO-DKD participants, respectively, identified as Black, thus limiting the generalizability of these data by race/ethnicity (PMC12539649). The Chinese subgroup analysis of FIGARO-DKD (n=325) suggested potentially larger absolute kidney benefits in Asian patients with higher baseline albuminuria, but this finding requires confirmation in larger, dedicated studies (PMC12074935).

**Industry funding and potential conflicts of interest.** The pivotal FIDELIO-DKD and FIGARO-DKD trials, as well as the FIDELITY pooled analysis, were funded by Bayer, the manufacturer of finerenone. While the trials were conducted with rigorous double-blind, placebo-controlled designs and independent adjudication of outcomes, industry funding introduces the potential for publication bias and selective reporting that cannot be fully excluded, as noted by independent reviewers of the evidence base (PMC12470496, PMC11214281). Independent replication of the FIDELIO-DKD findings in investigator-initiated trials would strengthen confidence in the results.

**Surrogate endpoint concerns.** The ≥40% eGFR decline component of the primary composite endpoint, while validated as a surrogate for kidney failure in multiple analyses, is not itself a hard clinical outcome. The FDA and regulatory agencies have accepted this endpoint as a valid surrogate for kidney failure based on epidemiological evidence, but the relationship between eGFR decline and subsequent ESKD may vary across different patient populations and disease etiologies (PMC12470496, PMC9917247).

**Real-world implementation challenges.** The controlled trial environment — with protocolized monitoring, high adherence, and close biochemical surveillance — differs substantially from routine clinical practice, where variability in patient behavior, comorbidities, and healthcare system factors may influence both effectiveness and safety (PMC13163276, PMC12539649). Real-world data from the FINE-REAL observational study (NCT05348733) are being collected to address this gap, but results were not yet available at the time of the literature search (PMC12539649, PMC11054947).

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### Conclusions and Future Directions

#### What the Evidence Supports

The FIDELIO-DKD primary analysis provides clear, statistically robust evidence that finerenone, added to maximally tolerated RAS inhibition, significantly reduces the primary composite kidney outcome (kidney failure, sustained ≥40% eGFR decline, or renal death) in adults with T2DM and CKD (eGFR 25–75 mL/min/1.73 m²). The primary analysis result is unambiguous: the primary composite kidney outcome occurred in **17.8% of finerenone-treated patients versus 21.1% of placebo-treated patients** (HR 0.82; 95% CI 0.73–0.93; P=0.001), yielding an **absolute risk reduction of 3.3 percentage points** and a **number needed to treat of approximately 30** over the median 2.6-year follow-up period (PMC12171220, PMC11214281). This ARR is clinically meaningful and translates into substantial long-term economic value through prevention of costly dialysis, as demonstrated by the Dutch cost-effectiveness analysis showing finerenone to be a dominant treatment strategy (PMC10685667).

The evidence also supports the following conclusions: (1) finerenone's kidney-protective effects are mediated through both early hemodynamic mechanisms (natriuresis, modest blood pressure reduction, early UACR reduction) and longer-term anti-inflammatory and anti-fibrotic mechanisms; (2) the early UACR reduction of approximately 31% at 4 months is a validated surrogate marker of long-term kidney protection; (3) finerenone's benefits are consistent across key subgroups including patients with and without concomitant SGLT2 inhibitor or GLP-1 RA use, across eGFR and UACR categories, and regardless of baseline HbA1c or insulin use; (4) the safety profile is manageable with appropriate patient selection and structured potassium monitoring; and (5) finerenone is cost-effective and potentially cost-saving compared to standard of care in the Dutch healthcare system.

#### What the Evidence Does NOT Support

The evidence does not support the following conclusions: (1) that finerenone is superior to SGLT2 inhibitors for kidney protection — the available network meta-analyses suggest SGLT2 inhibitors have a stronger effect on renal outcomes and HF hospitalization, though the two drug classes are comparable for MACE reduction and have complementary mechanisms; (2) that finerenone's kidney benefits extend to patients with eGFR <25 mL/min/1.73 m², for whom evidence is limited to a small, non-randomized, retrospective case series of nine patients; (3) that the combination of finerenone plus SGLT2 inhibitors provides additive hard kidney outcome benefits beyond either monotherapy — this hypothesis is supported by preclinical data and the CONFIDENCE trial's UACR results, but has not been tested in an adequately powered outcomes trial; (4) that finerenone's kidney benefits are equivalent in non-diabetic CKD — the FIND-CKD trial is ongoing but has not yet reported results; and (5) that the 3.3% ARR observed over 2.6 years in FIDELIO-DKD will remain constant over longer treatment durations — the ARR is expected to increase with longer follow-up as cumulative event rates diverge.

#### Future Research Directions

Six concrete future research priorities emerge from the gaps identified in this synthesis:

**1. Long-term outcomes with combination therapy.** The CONFIDENCE trial (NCT05254002) has demonstrated superior UACR reduction with finerenone plus empagliflozin versus either monotherapy at 6 months, but a dedicated, adequately powered phase 3 outcomes trial evaluating the combination on hard kidney and cardiovascular endpoints over ≥3 years is urgently needed. The ongoing CONFIDENCE trial's 6-month surrogate endpoint data are insufficient to establish long-term hard outcome benefits of combination therapy.

**2. Finerenone in non-diabetic CKD.** The FIND-CKD trial is evaluating finerenone in adults with non-diabetic CKD with a primary endpoint of change in eGFR slope. Results from this trial will determine whether finerenone's kidney-protective effects extend beyond the T2DM-CKD population and could substantially broaden its clinical indication (PMC11214281, PMC10573495).

**3. Finerenone in type 1 diabetes-related CKD.** The FINE-ONE trial (NCT05901831) is the first phase 3 trial evaluating finerenone in adults with type 1 diabetes and CKD (UACR ≥200 mg/g or eGFR 25–90 mL/min/1.73 m²), with a primary endpoint of relative change in UACR at 6 months. If positive, finerenone could become the first registered treatment for type 1 diabetes-related CKD in nearly three decades.

**4. Finerenone in pediatric CKD.** The FIONA trial (NCT05196035) is evaluating finerenone in children aged 6 months to <18 years with CKD stages 1–3a and proteinuria, with primary endpoints of ≥30% reduction in UPCR from baseline to day 180 and percent change in UPCR from baseline to day 180 (PMC10956186). These trials will establish whether finerenone's antiproteinuric effects translate to the pediatric population, where RAAS blockade is currently the only proven intervention.

**5. Real-world effectiveness and safety.** The FINE-REAL observational study (NCT05348733) is collecting real-world data on treatment patterns, safety, and effectiveness of finerenone in routine clinical practice across multiple countries. These data will address the critical question of whether the benefits observed in the controlled trial environment translate to the more heterogeneous, less closely monitored real-world DKD population, and will provide insights into barriers to uptake and implementation.

**6. Biomarker-guided patient selection and precision medicine.** Future research should investigate whether specific biomarkers — including serum aldosterone levels, urinary biomarkers of inflammation and fibrosis (e.g., MCP-1, KIM-1, NGAL), or genetic markers of MR pathway activation — can identify patients most likely to benefit from finerenone and guide personalized treatment decisions. The observation that the kidney benefit in stage 4 CKD was attenuated beyond 2 years (PMC10278789) suggests that earlier initiation of finerenone — before irreversible nephron loss — may be critical for maximizing long-term kidney protection, and biomarker-guided early identification of high-risk patients could optimize the timing of treatment initiation.

In summary, the FIDELIO-DKD primary analysis provides definitive evidence that finerenone reduces the primary kidney composite outcome by an absolute 3.3 percentage points (NNT ≈ 30 over 2.6 years) in adults with T2DM and CKD on background RAS inhibition. This ARR, while modest in absolute terms, is clinically meaningful in the context of a high-risk population with limited therapeutic options, translates into long-term economic value through dialysis prevention, and is supported by a consistent mechanistic rationale and a manageable safety profile. Finerenone has earned its place as a fourth pillar of DKD pharmacotherapy alongside RAS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists, and ongoing trials will continue to define its optimal role in combination regimens and broader CKD populations.

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