Nonsteroidal mineralocorticoid receptor antagonist in diabetic kidney disease: mechanistic insights and clinical integration

Article information

Korean J Nephrol. 2026;.j.krcp.26.233

Publication date (electronic) : 2026 July 2

doi : https://doi.org/10.23876/j.krcp.26.233

Hye Yun Jeong¹, Eun Young Lee^,2, On behalf of the Korean Diabetic Kidney Disease Study Group

¹Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea

²Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital and Soonchunhyang University College of Medicine, Cheonan, Republic of Korea

Correspondence: Eun Young Lee Division of Nephrology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital and Soonchunhyang University College of Medicine, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Republic of Korea. E-mail: eylee@schmc.ac.kr

Received 2026 May 13; Accepted 2026 May 25.

Abstract

Introduction

Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide, imposing a substantial clinical and socioeconomic burden [1,2]. Despite the widespread use of current standard therapies, including renin-angiotensin system (RAS) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors, a considerable proportion of patients continue to experience progressive kidney function decline and are at high risk of cardiovascular events [3]. This persistent residual risk highlights the limitations of current treatment strategies and underscores the need for additional therapeutic approaches targeting complementary disease mechanisms.

In this context, increasing attention has been directed toward the mineralocorticoid receptor (MR) as a pivotal therapeutic target in DKD. Beyond its classical role in electrolyte and volume regulation, MR signaling has been implicated in pathways contributing to both renal and cardiovascular injury [4,5]. These insights have led to the development of nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), which offer greater receptor selectivity and an improved safety profile compared with traditional steroidal agents [6,7].

Among ns-MRAs, finerenone has been the most extensively studied, with large-scale trials demonstrating consistent renal and cardiovascular benefits across a broad spectrum of CKD in patients with type 2 diabetes (T2D) [8,9]. These findings have led to the incorporation of ns-MRAs into contemporary clinical guidelines and have expanded the therapeutic landscape for DKD management.

In this review, we summarize the pathophysiological rationale for targeting MR signaling in DKD and the clinical evidence supporting their use. We also discuss safety considerations, emerging agents, and the potential of combination therapy.

Pathophysiological basis and pharmacological rationale for nonsteroidal mineralocorticoid receptor antagonists

Aldosterone is a key contributor to the initiation and progression of DKD, independent of blood pressure [10,11]. Experimental studies show that aldosterone promotes inflammatory responses, endothelial dysfunction, glomerular fibrosis, and tubular damage [12]. Although angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are standard treatments, they frequently do not achieve full aldosterone suppression, a phenomenon termed ‘aldosterone escape,’ observed in 20%–40% of patients and linked to faster kidney function decline [13]. This residual risk highlights a need for strategies that directly target the mechanisms underlying progressive cardiorenal disease.

Chronic overactivation of the MR is a fundamental pathogenic mechanism in DKD (Fig. 1) [14–16]. MR signaling in both epithelial and non-epithelial cells contributes to maladaptive inflammatory and fibrotic processes [17]. In renal epithelial cells, excessive MR activation augments sodium reabsorption, promoting volume expansion and intraglomerular pressure, which accelerate albuminuria [5,18]. These perturbations secondarily impose increased preload and afterload on the heart, contributing to myocardial stress [19].

Figure 1.

MR overactivation in cardiorenal disease.

Schematic showing how MR overactivation contributes to the kidney and heart. In renal epithelial cells, MR activation promotes sodium reabsorption, volume expansion, hypertension, and increased intraglomerular pressure, while in podocytes it induces cytoskeletal disruption and loss of slit diaphragm integrity. In the vascular system, MR activation in vascular smooth muscle cells (VSMCs) and fibroblasts leads to oxidative stress, vascular stiffening, and fibrosis. In immune cells, it enhances inflammatory cell recruitment and profibrotic signaling, and in cardiomyocytes, it contributes to hypertrophy. Together, these mechanisms drive the progression of cardiorenal disease.

MR, mineralocorticoid receptor.

Beyond the epithelial compartment, MR activation in non-epithelial cells plays a critical role in the progression of both renal and cardiac injury [5,17,20]. MR activation in podocytes disrupts slit diaphragm integrity, resulting in proteinuria. In the vascular endothelium, dysregulated MR signaling induces oxidative stress and vascular stiffening, impairing renal autoregulation [21]. Furthermore, MR activation in immune cells amplifies inflammatory cell recruitment and profibrotic mediators like transforming growth factor beta [20]. These combined processes result in renal interstitial fibrosis and myocardial stiffening, accelerating the progression toward overt cardiorenal dysfunction.

The ns-MRAs offer advantages over steroidal MRAs, exhibiting greater receptor selectivity and a more balanced distribution between renal and cardiac tissues, with minimal off-target activity [22]. Through selective inhibition of MR-dependent transcriptional activity, ns-MRAs modulate key inflammatory and oxidative stress pathways [23]. Their favorable safety profile, characterized by a lower incidence of hyperkalemia, supports their use in high-risk patients with T2D with CKD [24].

Nonsteroidal mineralocorticoid receptor antagonists in type 2 diabetes with chronic kidney disease: evidence and clinical outcomes

The 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend ns-MRAs for patients with T2D, estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m², and persistent albuminuria despite maximally tolerated RAS inhibition (Grade 2A) [25]. The American Diabetes Association (ADA) 2026 Standards of Care also reinforces their use to reduce CKD progression and cardiovascular events [26]. These recommendations are supported by high-quality evidence from pivotal clinical trials demonstrating the efficacy and safety of ns-MRAs in reducing both kidney and cardiovascular outcomes in patients with T2D with CKD.

Early clinical trials, such as ARTS-DN, showed that finerenone effectively reduced albuminuria with a lower risk of hyperkalemia than steroidal MRAs. These findings led to the pivotal phase 3 trials, FIDELIO-DKD and FIGARO-DKD, which assessed cardiorenal outcomes across the DKD spectrum. In FIDELIO-DKD, involving patients with advanced albuminuric CKD, finerenone reduced the primary composite kidney outcome (kidney failure, sustained ≥40% eGFR decline, or renal death) by 18% compared to placebo. Although hyperkalemia was more frequent, treatment discontinuation remained low (2.3%), confirming its clinical feasibility [9]. Conversely, FIGARO-DKD focused on earlier-stage CKD, where finerenone significantly decreased the primary cardiovascular composite outcome by 13% [8]. Finally, the pooled FIDELITY analysis of over 13,000 participants confirmed consistent cardiorenal benefits across various CKD severities [27]. These effects were notably independent of baseline SGLT2 inhibitor or glucagon-like peptide-1 receptor agonist (GLP-1 RA) use, supporting finerenone’s broad clinical utility in T2D with CKD management.

Subgroup analyses from major trials provide strong evidence for finerenone’s efficacy in Asian populations, including Koreans (Table 1). In FIDELIO-DKD, where Asians comprised 23.4% of the cohort, finerenone reduced the risk of the composite kidney outcome more prominently in Asian patients (hazard ratio [HR], 0.70) compared to the rest-of-world (ROW; HR, 0.88). Although investigator-reported hyperkalemia was more frequent in Asians, laboratory-defined rates were similar across regions, suggesting the influence of local practice patterns rather than ethnic differences [28]. The pooled FIDELITY analysis (22% Asian, with Korea as a third contributor) reinforced these findings, showing significantly greater reductions in eGFR-related kidney outcomes in Asians [29]. Further support comes from the FIGARO-DKD Chinese subgroup [30] and the CONFIDENCE trial, the latter of which demonstrated that finerenone plus empagliflozin produced superior urine albumin-to-creatinine ratio (UACR) reductions compared to monotherapy, with particularly pronounced effects in Asian participants [31]. Collectively, these data confirm that finerenone provides consistent cardiorenal protection and manageable safety in Asian patients, establishing its role as a key therapeutic pillar for DKD in Korea.

Table 1.

Asian subgroup evidence for finerenone in DKD

Consistent with the robust cardiorenal outcomes seen in T2D with CKD, the clinical value of ns-MRAs is further strengthened by their proven efficacy in mitigating heart failure, a frequent and severe complication in the DKD population [32]. While steroidal MRAs like spironolactone and eplerenone are established in heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status [33–36], the ns-MRA finerenone has recently expanded this evidence base [37]. In the FINEARTS-HF trial, finerenone significantly reduced cardiovascular death and worsening heart failure in patients with mildly reduced or preserved ejection fraction, showing consistent benefits across diabetes status [38]. Furthermore, a prespecified subgroup analysis of the FIDELIO-DKD trial demonstrated that finerenone improved both renal and cardiovascular outcomes on top of optimized RAS blockade, with consistent benefits regardless of a history of heart failure [39]. These data support finerenone as a cardiorenal protective therapy, reinforcing its role as a fundamental pillar in the management of high-risk DKD patients.

Safety considerations of potassium and estimated glomerular filtration rate monitoring with nonsteroidal mineralocorticoid receptor antagonists

As MRAs can raise serum potassium, careful patient selection and monitoring are essential. In FIDELIO-DKD and FIGARO-DKD, only patients with serum potassium ≤4.8 mmol/L after optimized RAS inhibition were enrolled, and potassium was checked periodically thereafter. Finerenone was continued if potassium remained ≤5.5 mmol/L and temporarily withheld if it exceeded this level, with treatment resumed once potassium returned to ≤5.0 mmol/L. Following a similar selection and monitoring strategy in clinical practice is recommended to replicate the favorable safety profile observed in these trials, supporting the safe integration of ns-MRAs into comprehensive DKD management [25].

As observed with other kidney-protective therapies, an acute decline in eGFR may occur shortly after initiation of finerenone. Notably, a prespecified FIDELITY pooled analysis [40] showed that although a substantial proportion of patients experienced acute eGFR changes within the first month, the cardiovascular and kidney benefits of finerenone remained consistent across all categories of early eGFR change, and these acute declines did not affect its long-term efficacy or safety for cardiorenal outcomes. Accordingly, the ADA 2026 Standards of Care specifically recommend periodic monitoring of both serum potassium and eGFR in patients with CKD and diabetes receiving ns-MRAs, with routine assessments at treatment initiation and at clinically appropriate intervals thereafter to detect and manage potential renal function changes and electrolyte disturbances [26].

Other nonsteroidal mineralocorticoid receptor antagonists in diabetic kidney disease

While finerenone is the only ns-MRA with proven large-scale cardiorenal outcomes, other agents are expanding the therapeutic landscape. Esaxerenone, approved in Japan, has shown significant albuminuria reduction in T2D patients, though its cardioprotective effects (N-terminal pro-B-type natriuretic peptide [NT-proBNP] reduction) may be attenuated in this population [41]. Ocedurenone (KBP-5074) demonstrated consistent blood pressure lowering in stage 3b/4 CKD patients across diabetes status with a low incidence of severe hyperkalemia [42]. Innovative approaches include balcinrenone (AZD9977), designed for co-administration with SGLT2 inhibitors. While phase 2b data showed its combination with dapagliflozin significantly reduced UACR in CKD patients [43], results in heart failure cohorts were less consistent [44]. Additionally, apararenone (MT-3995) is being explored for its metabolic benefits in nonalcoholic steatohepatitis alongside its antialbuminuric effects [45,46]. The expanding ns-MRA pipeline may enable more individualized treatment of T2D with CKD according to CKD stage and coexisting cardiorenal comorbidities. Ultimately, these developments will further strengthen the multimodal approach to DKD management, complementing current standard therapies.

Combination therapy with nonsteroidal mineralocorticoid receptor antagonists

While finerenone provides clear cardiorenal benefits, interest in combination therapy to achieve synergistic protection is growing. The CONFIDENCE trial evaluated the co-initiation of finerenone and empagliflozin in T2D with CKD patients on optimized RAS blockade. The combination therapy led to significantly greater UACR reductions than either monotherapy, with early additive effects and a safety profile—including hyperkalemia rates—comparable to monotherapy [47]. These results support combining ns-MRAs with SGLT2 inhibitors as a feasible and potent kidney-protective strategy.

Although no independent randomized controlled trials have yet been dedicated solely to the co-administration of finerenone and GLP-1 RA, emerging data from the CONFIDENCE trial support this synergistic potential. A recent analysis demonstrated that the simultaneous initiation of finerenone and empagliflozin significantly reduces albuminuria regardless of baseline GLP-1 RA use, with no additional safety concerns [48]. While these integrated effects reinforce the clinical utility of a ‘4-pillar’ treatment framework, further prospective studies are warranted to evaluate the long-term impact of this combination on clinical endpoints, including cardiovascular outcomes and the progression to end-stage kidney disease (Fig. 2).

Figure 2.

Targeting MR overactivation: clinical benefits of ns-MRAs.

(A) MR overactivation promotes organ damage in both the kidney and heart, leading to glomerular injury, fibrosis, kidney failure, cardiac remodeling, and heart failure. (B) Comparison of steroidal MRAs and ns-MRAs: steroidal MRAs are associated with off-target effects, whereas ns-MRAs exhibit improved selectivity and a more balanced cardiorenal distribution. (C) ns-MRAs confer cardiorenal protection, reducing cardiovascular events and mortality, as well as slowing eGFR decline and decreasing albuminuria.

CV, cardiovascular; eGFR, estimated glomerular filtration rate; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist.

Clinical use of finerenone

Based on robust evidence from randomized trials, recent guidelines increasingly support the use of finerenone in patients with T2D with CKD. The recently updated KDIGO 2026 draft guidelines [49] recommend that, in patients with T2D receiving RAS inhibitors who have persistent albuminuria and normal serum potassium levels, an SGLT2 inhibitor and an ns-MRA be initiated simultaneously. They also suggest adding a ns-MRA with proven kidney or cardiovascular benefit in individuals with diabetes, an eGFR ≥25 mL/min/1.73 m², normal serum potassium, and albuminuria (UACR ≥200 mg/g) despite maximally tolerated RAS inhibition, while the ADA 2026 guidelines advocate combined use of SGLT2 inhibitors and ns-MRAs in patients with T2D, UACR ≥100 mg/g, and eGFR of 30–90 mL/min/1.73 m² who are already receiving RAS inhibitors.

Although clinical trials have established efficacy, real-world effectiveness remains less well defined. In this context, the study by Yamanouchi et al. [50] showed that finerenone may improve the eGFR slope in patients with T2D with CKD, regardless of baseline eGFR and albuminuria levels; however, its small, predominantly Japanese cohort, short follow-up, and differences in background therapy may limit generalizability. Accordingly, caution is warranted when extrapolating these findings to broader clinical populations.

In addition, while prior trials focused primarily on patients with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF), the 2026 ADA guidelines recommend finerenone in individuals with diabetes and symptomatic stage C heart failure with an ejection fraction ≥40%. A recent retrospective real-world study [50] of patients with HFrEF or HFmrEF, diabetes, and CKD reported improvements in NT-proBNP levels and left ventricular remodeling without significant worsening of renal function or hyperkalemia. These findings complement the existing evidence for finerenone in HFmrEF/HFpEF and T2D with CKD populations and suggest a potential benefit in HFrEF. However, given the observational design and limited sample size, further studies are needed before these results can be applied widely in real-world practice.

The efficacy and safety of finerenone in type 1 diabetes patients with CKD remain uncertain. However, the FINE-ONE trial demonstrated that finerenone significantly reduced the UACR compared with placebo over 6 months [51]. The study enrolled adults aged ≥18 years with type 1 diabetes and CKD, defined by eGFR of 25 to 90 mL/min/1.73 m² and UACR of 200 to 5,000 mg/g. These findings highlight the potential of finerenone in this population, but large, long-term trials are warranted to confirm its efficacy and safety.

Conclusion

In summary, ns-MRAs offer a mechanistically complementary and evidence-based therapy to reduce residual kidney and cardiovascular risk in patients with T2D with CKD. Their incorporation as a distinct and synergistic layer of the multipronged therapeutic strategy addresses critical pathophysiologic pathways not targeted by existing glucose-lowering or hemodynamic therapies, establishing a comprehensive, multipronged approach to organ protection in high-risk populations.

Summary

1. Current clinical guidelines now position nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs) as a core component of guideline-directed therapy for patients with diabetic kidney disease with persistent albuminuria despite optimized renin-angiotensin system blockade.

2. In combination with established standard of care therapies, ns-MRAs constitute the essential therapeutic pillar addressing residual cardiorenal risk through direct modulation of inflammation and fibrosis, thereby completing a comprehensive, mechanism-based strategy for diabetic kidney disease management.

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