Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease: Clinical Evidence and Potential Adverse Events Free

Spironolactone, eplerenone, and finerenone are MRAs available for clinical use in the United States. Spironolactone and eplerenone are first- and second-generation steroidal MRAs that improve clinical outcomes in individuals with severe congestive heart failure. However, early MRA CVD trials did not include individuals with advanced kidney disease (19–22). Finerenone is a nonsteroidal MRA that reduces CVD outcomes and slows CKD progression in individuals with DKD (Table 1) (23,24).

The mineralocorticoid receptor (MR) is present in many tissues including kidney, heart, fibroblasts, and myeloid cells. Aldosterone and cortisol are agonist ligands for the MR. When bound to the MR, aldosterone and cortisol recruit co-factors that increase pro-inflammatory and pro-fibrotic gene transcription. Overexpression of MR leads to oxidative stress, inflammation, and fibrosis, which ultimately contributes to progressive kidney and heart disease. Cortisol is converted to corticosterone in the kidney by 11-β hydroxysteroid dehydrogenase-2. Corticosterone has little affinity to the MR. Aldosterone is the primary hormone that binds to the MR in the kidney. By blocking the action of aldosterone, MRAs result in a gene transcription profile that attenuates aldosterone-mediated pro-inflammatory and pro-fibrotic signals (25).

Spironolactone is a nonselective steroidal MRA that also binds to the steroid hormone receptors, specifically glucocorticoid and progesterone receptors, in addition to the MR. Eplerenone is less potent but more selective for the MR than spironolactone. Both spironolactone and eplerenone have a greater affinity for the MR in the kidney than the MR in the heart. Finerenone is a potent and more selective MRA that does not bind to steroid hormone receptors. It has equal affinity to the MR in the heart and the MR in the kidney. Spironolactone has multiple active metabolites that significantly increase its half-life compared with eplerenone and finerenone. These properties reflect the differences in the observed side effect profiles of these medications (26,27).

Spironolactone has been known since 1999 to lower mortality in patients with advanced heart failure and reduced ejection fraction (19). The first proof-of-concept study evaluating the role of spironolactone on CVD outcomes in CKD was published in 2009 (28). In a study involving 112 subjects, Edwards et al. (28) showed that spironolactone 25 mg once daily resulted in significant improvements in left ventricular mass and aortic stiffness markers in patients with stage 2 or stage 3 CKD on RAAS inhibitors. Subsequently, in 2014, a systematic review by Chung et al. (29) that included 27 studies with 1,549 participants highlighted the paucity of data with steroidal MRAs for hard CVD end points in patients with CKD. A more recent post hoc analysis of participants enrolled in (TOPCAT) (the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trials) showed that spironolactone lowered the risk for major cardiac events or death across stages 1–3 CKD, but the risks of drug- related adverse events (AEs) were significantly higher in subgroups with lower estimated glomerular filtration rates (eGFRs) (30).

Over the past 2 decades, multiple small randomized controlled trials (RCTs) have reported improvement in proteinuria with steroidal MRAs. Currie et al. (31) reported on a meta-analysis of 21 studies involving 1,646 patients investigating renoprotective effects and risks of hyperkalemia in trials of steroidal MRAs in CKD. Steroidal MRAs added to RAAS inhibitors reduced proteinuria by 39%. At the same time, there was a threefold higher risk of withdrawal from the trial because of hyperkalemia in the intervention group. Death, CVD events, and hard kidney end points were not reported in sufficient numbers to allow for analysis. To date, there has not been a well-powered RCT assessing the impact of steroidal MRAs on DKD progression or hard kidney outcomes.

Early phase 2 studies of finerenone reported reductions in albuminuria similar to those with steroidal MRAs (32). The impact of finerenone on important kidney end points was evaluated in a phase 3 RCT published in 2020 (the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetes Kidney Disease [FIDELIO-DKD] study) (23). The trial included 5,674 patients with DKD on RAAS inhibitors with a urinary albumin-to-creatinine ratio (UACR) of 30–300 mg/g, eGFR of 25–60 mL/min/1.73 m², and diabetic retinopathy or a UACR of 300–5,000 mg/g and an eGFR of 25–75 mL/min/1.73 m². After a median follow-up of 2.6 years, a composite of kidney failure, 40% decline in eGFR, or death from renal cause was 18% lower in the finerenone group compared with placebo (hazard ratio [HR] 0.82, 95% CI 0.73–0.93). This study was followed by a phase 3 RCT published in 2021 that evaluated the impact of finerenone on CVD events in patients with DKD (the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease [FIGARO-DKD] study) (24). This trial included 7,352 patients with DKD treated with RAAS inhibitors who had a UACR of 30–300 mg/g and an eGFR of 25–90 mL/min/1.73 m² or a UACR of 300–5,000 mg/g and an eGFR ≥60 mL/min/1.73 m². After a median follow-up of 3.4 years, finerenone reduced the risk of death from CVD, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure by 13% (HR 0.87, 95% CI 0.76–0.98), with the benefit primarily driven by a lower incidence of hospitalization for heart failure. In the FIDELITY pooled efficacy and safety analysis of the FIDELIO-DKD and FIGARO-DKD results, Agarwal et al. (33) reported that the composite of CVD outcomes was lower by 14% and the composite of kidney outcomes was lower by 23% with finerenone compared with placebo across the wide spectrum of patients with DKD.

AKI is associated with a high risk of mortality, kidney failure, CVD events, prolonged hospitalization, and hospital readmissions (34). Medications may cause AKI by reducing kidney perfusion or by promoting inflammation and damage. MRAs lower intraglomerular pressure and may initially lower the glomerular filtration rate (GFR). This initial drop in GFR is largely reversible but can lead to AKI when renal perfusion is impaired because of other mechanisms such as during acute illnesses or periods of hypovolemia (35).

Glomerular hyperfiltration is an early occurrence in DKD. It leads to intraglomerular hypertension and hypertrophy, which in turn plays an important role in DKD progression. Interventions to reduce glomerular hyperfiltration result in lowering of GFR (and consequent rise in serum creatinine) from the expected intraglomerular hemodynamic changes. In clinical trials involving a low-protein diet, intensive blood pressure control (36,37), RAAS inhibitors (8,9), or SGLT2 inhibitors (10,11)—interventions that are expected to lower intraglomerular pressure—the initial lowering of GFR was typically <30% and consistently followed by slowing of GFR decline after a few weeks of intervention. This short-term lowering of GFR provides long-term benefits for kidney function. MRAs also lead to a reduction in GFR soon after their initiation that stabilizes a few weeks into treatment. Therefore, an initial drop in eGFR of <30% that is observed soon after MRA initiation should not be considered an AE.

Evaluating the true AKI risk with MRAs is difficult because the definition of AKI has not been consistent in clinical trials, and MRA-related AKI is rarely reported in meta-analyses of clinical trials conducted in patients with CKD (29,31,38–40).

The landmark Randomized Aldactone Evaluation Study (RALES) randomized 1,663 patients with severe heart failure and left ventricular ejection fraction (LVEF) <35% to spironolactone 25 mg or placebo (19). Twenty percent of participants had diabetes, and 95% were receiving RAAS inhibitors. Patients with advanced kidney disease, defined as an eGFR <30 mL/min/1.73 m² and serum creatinine >2.5 mg/dL, were excluded from the study. The frequency of kidney and urological AEs (termed urinary system disorders) was similar in the two groups and occurred in 11% of participants on spironolactone and 12% of those on placebo. AKI was not reported as an AE (19). Further evaluation of the RALES data by Vardeny et al. (22) revealed worsening renal failure (WRF) in 17% of the spironolactone group versus 7% of the placebo group. WRF was defined as a 30% reduction in GFR 12 weeks after randomization. However, WRF was associated with an increased adjusted risk of death in the placebo group (HR 1.9, 95% CI 1.3–2.6) but not in the spironolactone group (HR 1.1, 95% CI 0.79–1.5). An initial decline in eGFR was noted at 4 weeks in the spironolactone group, and there was no significant difference in eGFR between the two groups by 6 months. In a study by Mehdi et al. (41) involving 81 individuals with diabetes, hypertension, and albuminuria, participants on lisinopril 80 mg daily—double the conventional maximum dose—were randomized to an add-on placebo, losartan, or spironolactone. The incidence of a transient increase in serum creatinine ≥50% from baseline was similar in all three groups, suggesting that spironolactone did not lead to a worsening of kidney function in a setting of maximum RAAS blockade. A retrospective observational study of patients with heart failure revealed that the addition of spironolactone to standard therapy for heart failure resulted in a 12% increased risk of AKI compared with loop diuretics alone (42). A recent study using spontaneous report data to capture drug-related AEs identified spironolactone along with furosemide and trimethoprim-sufamethoxazole as three agents that needed to be used carefully and monitored closely in patients at risk for AKI (43).

The Eplerenone Post-Acute Myocardial Infarction Health Failure Efficacy and Survival Study (EPHESUS) randomized 6,642 patients with acute myocardial infarction and LVEF ≤40% receiving standard of care treatments to eplerenone or placebo (44). Diabetes was present in 32% of participants, and 86% were receiving RAAS inhibitors. AKI was not reported as an AE in the primary study. However, further evaluation of these data by Rossignol et al. (20) revealed statistically significant early WRF in 17% of the eplerenone group versus 15% of the placebo group (P = 0.02). Early WRF was defined as a reduction in eGFR ≥20% at 1 month. Early WRF was associated with worse CVD outcomes independent of baseline kidney function. However, like the spironolactone group in RALES, the eplerenone group retained its cardiovascular benefit despite a statistically significant difference in early WRF.

The FIDELIO-DKD study randomized 5,734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. All patients were treated with the maximum tolerated dose of an RAAS inhibitor (23). Both groups had similar eGFRs at the beginning of randomization. The finerenone group was noted to have a greater decline in eGFR slope versus the placebo group during the first 4 months (−3.18 vs. −0.73 mL/min/1.73 m². Thereafter, the mean change in eGFR slope was less for the finerenone group than for the placebo group (−2.66 vs. −3.97 mL/min/1.73 m²) (23). In the FIDELITY pooled data analysis, there was no difference in AKI or hospitalization for AKI between finerenone and placebo (33). A recent meta-analysis showed that dual therapy with an RAAS inhibitor and an MRA is associated with an increased risk of AKI. However, this risk was mitigated if a nonsteroidal MRA was used (45).

Heterogeneity in AKI definitions and variability in AKI reporting in clinical trials create a barrier to understanding AKI risk with MRA treatment (Table 2). A standardized definition for AKI in clinical trials is essential to inform our understanding of patient characteristics that increase risks for MRA-induced AKI events. It is also worth noting that most MRA trials excluded patients with severe kidney disease.

The Kidney Disease Improving Global Outcomes (KDIGO) 2024 clinical practice guidelines for DKD recommend baseline assessment and regular monitoring of serum creatinine while using RAAS inhibitors or MRAs (46). We recommend checking serum creatinine at baseline and within 2–4 weeks of initiating MRAs in DKD. For patients on long-term therapy, checking serum creatinine every 3–6 months is reasonable; however, more frequent monitoring may be considered in patients with a high risk of hemodynamic instability. Minor elevations of serum creatinine (up to 30% from baseline) would be expected because of changes in intraglomerular hemodynamics. A greater rise in serum creatinine merits careful evaluation and possible change in clinical management. This may include reduction in the dose or withholding of MRAs, evaluation for intravascular volume depletion or hypotension, and evaluation for renal artery stenosis in selected patients.

Hyperkalemia is one of the most important adverse effects of MRAs, especially for patients with CKD receiving RAAS inhibitors. Aldosterone inhibits endocytosis of epithelial sodium channels (ENaC) in the apical membrane of principal cells of the collecting duct. Increase in ENaC activity leads to sodium reabsorption and concomitant potassium excretion. By blocking aldosterone’s binding to cytosolic MRs, MRAs promote ENaC endocytosis and thereby lower sodium reabsorption and urinary potassium excretion (47).

While both nonsteroidal and steroidal MRAs may cause hyperkalemia, there is growing evidence that nonsteroidal MRAs may have a lower predilection for hyperkalemia compared with steroidal MRAs. In a randomized phase 2 trial that compared finerenone (2.5–10 mg/day), spironolactone (25–50 mg/day), and placebo in individuals with heart failure with reduced ejection fraction and stage 3 CKD, mean increases in serum potassium concentration over 30 days were significantly lower with finerenone compared with spironolactone across all dose ranges. The increase in potassium with finerenone was similar to that of placebo for the 2.5-mg daily dose and only modestly higher than placebo for the 5-to 10-mg daily dose. The incidence of investigator-reported hyperkalemia was also lower with finerenone than spironolactone (5 vs. 13%) (48). In a much larger comparative post hoc analysis of finerenone and spironolactone in >900 individuals with resistant hypertension and moderate to advanced CKD (mean eGFR 35–37 mL/min/1.73 m²), Agarwal et al. (49) reported a lower risk for hyperkalemia in finerenone-treated participants. The incidence of hyperkalemia (potassium ≥5.5 mmol/L) during 12–17 weeks of treatment was 3% for placebo, 12% for finerenone, 35% for the combination of spironolactone and patiromer (a potassium binder in the colon), and 64% for spironolactone. Treatment discontinuation because of hyperkalemia was 0.3% for finerenone, 7% for the combination of spironolactone and patiromer, and 23% for spironolactone (49). Similarly, a recent systematic review and meta-analysis of RCTs involving patients with DKD showed that a nonsteroidal MRA added to an RAAS inhibitor has a lower risk of hyperkalemia than a steroidal MRA added to an RAAS inhibitor (twofold and fivefold higher risk of hyperkalemia compared with patients on RAAS monotherapy, respectively) (45).

The underlying mechanisms for lower hyperkalemia risk with finerenone compared with spironolactone are not fully elucidated. The differences in tissue distribution and plasma half-life may be contributing to the differential impacts of two agents on potassium homeostasis (49). Rodent studies show a balanced distribution of drug-equivalent concentrations in kidneys and heart for finerenone and a higher accumulation in kidneys compared with heart for spironolactone (50). Finerenone also has a relatively short half-life (2.2–2.8 hours), whereas active metabolites of spironolactone have long half-lives (>12 hours) (49). These factors may explain the lower and less sustained effect on potassium homeostasis with finerenone than with spironolactone.

Although clinical trial results show a moderate risk for hyperkalemia with finerenone, the results need to be interpreted with caution because mitigation strategies to lower AEs in trials may not all be practical in routine clinical practice. Moura-Neto and Ronco (51) underscored this point in an editorial in which they noted an unexpected rise in hospitalizations and deaths associated with hyperkalemia after a widespread adoption of spironolactone for patients with severe heart failure after publication of RALES, which showed benefit in mortality reduction with only a minimal risk for hyperkalemia. Given this experience, it is prudent to follow mitigation strategies to lower hyperkalemia risk when starting finerenone or other MRAs (52). The latest KDIGO guideline for diabetes management in CKD recommends mitigation strategies and potassium monitoring after finerenone initiation, as summarized in Figure 2. These recommendations may be used for steroidal MRAs as well (46). In addition to these mitigation strategies, the use of novel potassium binders in patients prone to hyperkalemia are also likely to enable more patients with CKD and diabetes to benefit from MRAs.

Spironolactone is a potent nonselective steroidal MRA that binds to other steroid hormone receptors, resulting in dose-dependent anti-androgenic and progestogenic AEs such as impotence, gynecomastia, and breast pain (53). Eplerenone is more selective but less potent than spironolactone and is associated with a lower risk of sexual side effects (53). Finerenone is a potent, selective, nonsteroidal MRA that does not bind with other steroid hormone receptors.

A meta-analysis of 14 trials involving >3,000 participants showed that spironolactone was associated with an eightfold higher risk for gynecomastia compared with controls (54). There seems to be a dose-response relationship with sexual side effects, with the risk rising significantly with doses >100 mg/day (55).

Sexual side effects are an important cause for drug discontinuation. In TOPCAT, breast tenderness or enlargement led to permanent discontinuation of spironolactone in 2.5% of patients (56). The rates of gynecomastia and breast tenderness are lower with eplerenone than with spironolactone, with clinical trials in heart failure reporting a rate of 0.7–1.6% with eplerenone compared with 7–10% with spironolactone (57). In two RCTs in patients with heart failure, eplerenone was found to have rates of gynecomastia and impotence similar to those with placebo (21,44)

Interestingly, in a trial that compared varying doses of eplerenone, spironolactone, and placebo for hypertension management, a high 400 mg/day dose of eplerenone was associated with a small reversible increase in thyroid-stimulating hormone (58). However, the clinical significance of this finding is unclear.

Sexual side effects do not seem to be a concern with finerenone. In the FIDELITY pooled analysis involving >13,000 participants, reproductive and breast disorders were similar among finerenone and placebo groups. Gynecomastia was only noted in eight patients (0.1%) in the finerenone group versus 11 patients (0.2%) in the placebo group (33).

DKD is a major cause of kidney failure. There is a significant residual risk of kidney failure with DKD even in patients treated with an RAAS inhibitor or SGLT2 inhibitor. MRAs reduce the risk for kidney failure and CVD in individuals with DKD, but concerns regarding AKI, hyperkalemia, and sexual dysfunction may limit the use of MRAs in some patient groups. However, emerging data suggest that nonsteroidal MRAs such as finerenone have a lower risk for side effects and more direct evidence for cardiorenal benefits in DKD than steroidal MRAs. Because these agents are new, ongoing analysis of real-world data is expected to shed more light on the frequency of reported side effects and may identify other potential AEs. Close monitoring of kidney function and potassium levels in the first few weeks after drug initiation as well as judicious use of novel potassium binding agents in selected groups may enable more patients with DKD to benefit from MRAs. It is imperative for clinicians to implement all proven therapeutic measures to stem the global epidemic of kidney failure.

The authors acknowledge the medical writing support provided by Khaled Shelbaya, MBBCh, MPH, MMSc, of ILM Consulting Services, LLC, which was funded by Bayer US, LLC. The authors also acknowledge the editorial support, visualization, and graphical abstract development provided by Aqsa Dar, ScM, of ILM Consulting Services, LLC, which was also funded by Bayer US, LLC. ILM’s services complied with international guidelines for Good Publication Practice (GPP 2022).

Bayer US, LLC, paid for the medical writing support, publication management, and processing charges for this article.

No potential conflicts of interest relevant to this article were reported.

Both of the authors contributed to the conceptualization, writing, and reviewing of the manuscript and approved the final version for submission. Both authors are the guarantors of this work and, as such, had full access to all the data reported and take responsibility for the integrity of the data and the accuracy of the data analysis.