Review of Hyperkalemia Profile for Mineralocorticoid Receptor Antagonist in Patients with Chronic Kidney Disease and Type 2 Diabetes

Abstract

Background

Type 2 diabetes (T2D) frequently coexists with chronic kidney disease (CKD), magnifying the risk of both cardiovascular and renal complications. Although therapies targeting the renin-angiotensin-aldosterone system (RAAS) slow CKD progression and reduce cardiovascular events, they also raise the risk of hyperkalemia. Finerenone, a newer nonsteroidal mineralocorticoid receptor antagonist (MRA), offers potent cardiorenal protection with relatively low hyperkalemia risk.

Summary

We conducted a narrative review of randomized controlled trials published up to September 2024, which evaluated spironolactone, eplerenone, or finerenone in populations with T2D, CKD, or heart failure. Studies that reported explicit data on hyperkalemia incidence, severity, and management were included. The findings were synthesized narratively with the consideration of heterogeneity in study population and hyperkalemia definition. Evidence from spironolactone and eplerenone trials underscores the survival benefits of steroidal MRAs in heart failure patients but also demonstrates a notable hyperkalemia risk, especially in patients with advanced CKD. Finerenone, studied in FIDELIO-DKD, FIGARO-DKD, and subsequently pooled in FIDELITY, demonstrated robust efficacy in reducing cardiovascular and kidney outcomes. It was associated predominantly with mild-to-moderate hyperkalemia, which stabilized with regular monitoring. The incidence of severe events and therapy discontinuations due to hyperkalemia were low. A risk‐prediction model from FIDELITY further stratified patients by hyperkalemia risk, revealing consistent relative hyperkalemia risk of finerenone across all strata.

Key Messages

Hyperkalemia remains a pivotal challenge when prescribing MRAs in patients with T2D and CKD, often leading to underutilization of these lifesaving agents. However, finerenone’s safety profile, combined with diligent potassium surveillance and proactive management strategies (e.g., dietary guidance, potassium binders, use of diuretics), enables sustained cardiorenal benefits. Future research should explore real-world applicability of these trial findings and further refine risk-based treatment algorithms to optimize outcomes in this high-risk population.

Plain Language Summary

People with type 2 diabetes (T2D) and chronic kidney disease (CKD) benefit from heart- and kidney-protecting medicines (RAAS-blocking therapies), but these can raise blood potassium to unsafe levels. Older drugs like spironolactone and eplerenone often cause higher potassium, which may force doctors to stop them early. A newer option, finerenone, also lowers heart and kidney risks but usually causes less severe potassium increases. With regular blood checks, diet changes, and potassium binders if needed, most people can stay on finerenone and continue getting its life-saving benefits.

Introduction

Type 2 diabetes (T2D) and chronic kidney disease (CKD) are highly prevalent conditions that often coexist [1], amplifying each other’s adverse risk on cardiovascular and renal outcomes [2]. Guideline-directed medical therapy in this population typically includes renin-angiotensin-aldosterone system inhibitors, aimed at slowing CKD progression and reducing cardiovascular events [3]. More recently, nonsteroidal mineralocorticoid receptor antagonists (MRAs), such as finerenone, have become an essential addition to these regimens due to their potent cardiorenal protective effects [4]. However, patients with T2D, particularly those with concurrent CKD, face an increased risk of hyperkalemia [5, 6]. This risk is multifactorial, stemming from impaired potassium excretion, renal tubular dysfunction (e.g., type 4 renal tubular acidosis), and the use of RAAS inhibitors, which reduce potassium excretion in the distal nephron [5, 6]. Furthermore, declining kidney function exacerbates potassium imbalance, making hyperkalemia a frequent and clinically significant challenge in the management of these patients [7]. In particular, hyperkalemia remains a major barrier to the use of lifesaving therapies in this population not only prompting dose reductions or treatment discontinuation but also discouraging clinicians from initiating these therapies in the first place – ultimately compromising cardiorenal protection.

Finerenone, unlike spironolactone and eplerenone, selectively blocks the mineralocorticoid receptor without the steroidal side effects [8]; thus, it is hypothesized to be a safer alternative with a lower hyperkalemia risk, particularly in patients with advanced renal dysfunction or with higher baseline potassium. Given the importance of maintaining patients on renin-angiotensin-aldosterone system inhibitor and nonsteroidal MRA therapy to achieve optimal clinical benefits, clinicians need to vigilantly monitor serum potassium, perform risk assessment for hyperkalemia, and employ proactive management strategies – including dietary counseling, use of potassium binders, and dose adjustments – to minimize the occurrence of severe hyperkalemia and reduce unnecessary therapy discontinuation [9]. Therefore, addressing hyperkalemia helps optimize treatment strategies and ensure the safe use of therapies in this vulnerable population [10]. The purpose of this article is to summarize evidence from clinical trials for the risk of hyperkalemia and provide a potential risk stratification tool for hyperkalemia leveraging a recent analysis from the FIDELITY trial.

Methods

A narrative review was conducted by searching PubMed for articles published up to August 2024 that examined hyperkalemia in patients with T2D, CKD, or heart failure (HF) receiving one of 3 MRAs (spironolactone, eplerenone, and finerenone). Spironolactone and eplerenone were selected as they are the most commonly prescribed steroidal MRAs. Finerenone was included as the only FDA-approved nonsteroidal MRA with a labeled indication for reducing the risk of kidney function decline and cardiovascular events in patients with T2D and CKD, supported by robust evidence from large-scale randomized clinical trials. Additional indications in HFpEF and HFmrEF are anticipated. The database search used multiple combinations of relevant keywords, including “hyperkalemia,” “chronic kidney disease,” “CKD,” “type 2 diabetes,” “T2D,” “heart failure,” “mineralocorticoid receptor antagonists,” “MRAs,” “finerenone,” “spironolactone,” and “eplerenone”. List of references from retrieved publications was also screened manually to identify any studies that may have been missed during the initial database search.

Studies were considered eligible if they were randomized controlled trials (RCTs), published in English, and provided explicit data on hyperkalemia incidence, severity, and/or management in patients with CKD, T2D, or HF who were receiving MRAs (spironolactone, eplerenone, or finerenone). Although the primary focus was on T2D and CKD, some HF trials were also included to illustrate the risk of hyperkalemia for these 3 medications in a broader patient population. Articles were excluded if they were non-human or non-clinical studies. For all included trials, data on the study design, patient characteristics, and hyperkalemia outcomes were extracted. Given the heterogeneity among trials in terms of patient population, definition of hyperkalemia, and follow-up duration, the findings were synthesized narratively rather than through a formal statistical comparison. The final set of trials included were BARACK-D, SPin-D, RALES, EMPHASIS-HF, ATHENA-HF, TOPCAT, FIDELIO-DKD, FIGARO-DKD, FIDELITY, FINEARTS, and ARTS-HF, which collectively informed the hyperkalemia risk and management strategies in patients with T2D, CKD, and HF receiving MRAs.

Results: Findings on Hyperkalemia in Clinical Trials

Summary of Clinical Trials and Their Findings

Spironolactone

The BARACK-D trial [11] was a phase 3, prospective, randomized, open, blinded endpoint study designed to assess whether adding low-dose spironolactone to standard care provided mortality and cardiovascular benefits over standard care alone for individuals with stage 3b CKD treated in primary care (Table 1). Unlike the RALES trial, which demonstrated clear survival benefits in patients with heart failure with reduced ejection fraction, BARACK-D did not show a statistically significant reduction in cardiovascular events, highlighting the limitations of steroidal MRAs in moderate-to-advanced CKD populations without overt HF. Compared to controls (13.4%), more participants in the spironolactone group (24.7%) developed hyperkalemia, defined as serum potassium ≥5.5 mmol/L. Most cases of hyperkalemia were mild (potassium 5.5–5.9 mmol/L) in both arms, but 11% of these episodes reached potassium levels ≥6 mmol/L, necessitating treatment suspension or dose adjustment. In total, 8.0% (n = 54) of spironolactone recipients discontinued the drug because of hyperkalemia. Among those who developed hyperkalemia, the average baseline estimated glomerular filtration rate (eGFR) was 41.9 mL/min/1.73 m² (standard deviation [sd] 7.08), whereas it was 43.9 mL/min/1.73/m² (sd 6.92) among those who did not develop hyperkalemia.

Table 1.

Summary for the included clinical trials

Clinical trial	Primary outcome	Inclusion and exclusion criteria	Definition of hyperkalemia
BARACK-D (2024)	Low-dose spironolactone for mortality and cardiovascular benefits in stage 3b CKD	Inclusion: stage 3b CKD (eGFR ∼30–44 mL/min/1.73 m2), receiving standard care in primary care setting	Hyperkalemia defined as serum potassium ≥5.5 mmol/L. Most episodes were mild (5.5–5.9 mmol/L), though 11% reached ≥6.0 mmol/L, requiring treatment modification. Discontinuation due to hyperkalemia occurred in 8% of the spironolactone arm
		Exclusion: hyperkalemia at baseline (≥5.5 mmol/L), other standard trial exclusions
SPin-D (2019)	Safety, tolerability and preliminary efficacy of spironolactone in maintenance hemodialysis	Inclusion: patients on maintenance hemodialysis	The primary safety endpoints were hyperkalemia (potassium >6.5 mEq/L)
		Exclusion: serum potassium ≥6.5 mEq/L or unscheduled dialysis for hyperkalemia within 3 months; potassium ≥6.0 mEq/L within 2 weeks prior to baseline
RALES (1999)	Survival benefits of spironolactone in severe HF	Inclusion: NYHA class III–IV HF, ejection fraction ≤35%, receiving standard therapy	Hyperkalemia defined as serum potassium >5.5 mmol/L, leading to dose adjustment or discontinuation
		Exclusion: serum potassium >5.0 mmol/L, creatinine >2.5 mg/dL, or recent MI
EMPHASIS-HF (2011)	Reduction in hospitalizations and death in mild HF with eplerenone	Inclusion: NYHA class II HF, ejection fraction ≤30%, receiving standard therapy	Hyperkalemia defined as serum potassium >5.5 mmol/L, requiring intervention
		Exclusion: serum potassium >5.0 mmol/L, creatinine >2.5 mg/dL
ATHENA-HF (2017)	Effects of high-dose spironolactone in acute HF	Inclusion: patients with acute HF, elevated natriuretic peptides, and receiving guideline-directed medical therapy	Hyperkalemia defined as serum potassium >5.5 mmol/L, with no cases of severe hyperkalemia (>6.0 mEq/L) observed during the 96-h treatment period
		Exclusion: serum potassium >5.0 mmol/L, severe renal dysfunction
TOPCAT (2014)	Impact of spironolactone on HF with preserved ejection fraction	Inclusion: HF with preserved ejection fraction, aged ≥50 years, elevated BNP or hospitalization for HF in the last 12 months	Hyperkalemia defined as serum potassium ≥5.5 mmol/L, associated with higher mortality risk
		Exclusion: serum potassium >5.0 mmol/L, eGFR <30 mL/min/1.73 m2
FIDELIO-DKD (2020)	Reduction in kidney outcomes with finerenone	Inclusion: CKD (eGFR 25–75 mL/min/1.73 m2) and T2D, albuminuria, receiving RAASi	Hyperkalemia defined as serum potassium > 5.5 mmol/L, requiring dose adjustment or discontinuation
		Exclusion: serum potassium >4.8 mmol/L, significant liver disease
FIGARO-DKD (2021)	Reduction in cardiovascular events with finerenone	Inclusion: CKD (eGFR 25–90 mL/min/1.73 m2) and T2D, albuminuria, receiving RAASi	Hyperkalemia defined as serum potassium >5.5 mmol/L, leading to dose adjustment or discontinuation
		Exclusion: serum potassium >5.5 mmol/L, significant liver disease
FIDELITY (2022)	Pooled analysis of cardiovascular and kidney outcomes in FIDELIO-DKD and FIGARO-DKD	Inclusion: CKD and T2D, meeting the inclusion criteria of either FIDELIO-DKD or FIGARO-DKD trials	Hyperkalemia defined as serum potassium >5.5 mmol/L, with higher incidence in finerenone group; serious hyperkalemia requiring hospitalization was rare
		Exclusion: criteria based on individual trial protocols
FINEARTS-HF (2024)	Finerenone in HF with mildly reduced or preserved EF	Eligibility requirements included stabilized HF in either inpatients or outpatients who were at least 40 years of age, had a LVEF of 40% or more (including those with prior LVEF less than 40%), evidence of structural heart disease and elevation of natriuretic peptides	Hyperkalemia defined according to standard cutoff (e.g., >5.5 mmol/L). Although ≥6.0 mmol/L occurred in ∼3% of finerenone users, there were no hyperkalemia-related deaths and few hyperkalemia-related hospitalizations (0.5%)
ARTS-HF (2016)	Efficacy and safety of finerenone in patients with worsening chronic HF	Inclusion: HFrEF with diabetes mellitus and/or CKD, aged ≥18 years, receiving guideline-directed medical therapy	Hyperkalemia defined as serum potassium ≥5.6 mmol/L
		Exclusion: serum potassium > 5.0 mmol/L, eGFR <30 mL/min/1.73 m2

LVEF, left ventricular ejection fraction.

The Spironolactone in Dialysis (SPin-D) trial [12] assessed the safety, tolerability, and preliminary efficacy of various spironolactone doses compared with placebo in patients on maintenance hemodialysis. The proportion of patients and event rate for hyperkalemia incidence were nominally higher for patients randomized to spironolactone 50 mg per day (32.0% [8 of 25]) compared with lower dosages (14.8–17.6%) in both the intention-to-treat and as-treated analyses.

The RALES trial [13] investigated the effects of spironolactone in patients with severe HF (NYHA class III or IV). The study showed significant survival benefits, reducing mortality rates among participants treated with spironolactone compared with placebo (relative risk [RR], 0.68; 95% confidence interval [CI] 0.59–0.78; p < 0.001). Despite excluding patients with baseline serum potassium levels above 5.0 mmol/L and implementing regular monitoring and dose adjustments, approximately 2% of patients in the spironolactone group (vs. 1% in placebo group) developed serious hyperkalemia, leading to treatment discontinuation in some cases (three individuals in the spironolactone group) [2].

The ATHENA-HF trial [14] assessed the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone. Importantly, only 1 patient in the group receiving usual care and 0 in the group taking high-dose spironolactone experienced serum potassium levels between 5.5 and 5.9 mEq/L, and no one had a potassium concentration of more than 6.0 mEq/L during the 96 h of study treatment.

In the TOPCAT trial [15], patients randomized to spironolactone had a significantly higher risk of developing hyperkalemia (serum potassium ≥5.5 mmol/L) compared to the placebo group (hazard ratio [HR] = 3.21; 95% CI: 2.46–4.20; p < 0.001). Factors that were associated with an increased risk of incident hyperkalemia included assignment to spironolactone, lower eGFR, higher potassium levels, the presence of diabetes, and lower hemoglobin levels at baseline. Additionally, the combination of spironolactone with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker further increased the risk of hyperkalemia.

Eplerenone

A recent meta-analysis of 19 RCTs published between 2002 and 2021 evaluated the effects of eplerenone in patients with CKD, demonstrating consistent reductions in albuminuria and systolic blood pressure [16]. While these surrogate markers are associated with slowed CKD progression, the analysis did not assess clinical outcomes directly, and thus evidence supporting eplerenone’s efficacy in altering long-term kidney or cardiovascular outcomes in CKD remains limited. In a pooled analysis of 10 articles involving 4,176 patients, the total risk of hyperkalemia (≥5.5 mmol/L) in the eplerenone group was higher by 70% (RR = 1.70, 95% CI: 1.35–2.13, p ≤ 0.0001) compared to placebo, and no significant heterogeneity was identified in these subgroup trials (chi² = 1.90, p = 0.99, I² = 0%). Seven articles (n = 3,394) indicated the difference in risk of hyperkalemia (≥6.0 mmol/L) between the eplerenone treatment groups and the control group (RR = 1.61, 95% CI: 1.06–2.44, p = 0.02).

The EMPHASIS-HF trial [17] evaluated eplerenone compared to placebo in patients with mild HF. A serum potassium level >5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (p < 0.001). A serum potassium level above 6.0 mmol/L occurred in 33 of 1,336 patients (2.5%) in the eplerenone group and 25 of 1,340 patients (1.9%) in the placebo group (p = 0.29) [3]. Subgroup analyses of this trial showed that there was an increase in the incidence of potassium >5.5 mmol/L with eplerenone in patients with diabetes, 63 (14.1%) versus 33 (8.5%) on placebo (p = 0.01), and there was an increase in the incidence of potassium >5.5 mmol/L with eplerenone in patients with CKD (i.e., an eGFR <60 mL/min/1.73 m²), 70 (16.6%) versus 43 (9.3%) on placebo (p = 0.002).

In a recently published study that pooled individual patient data from the RALES and EMPHASIS-HF trials [18], hyperkalemia (potassium levels >5.5 mmol/L) occurred more frequently in patients treated with MRAs compared to those receiving placebo (HR 2.22; 95% CI: 1.80–2.72). This risk was notably higher in patients who experienced a decline in eGFR to <30 mL/min/1.73 m², with a HR of 5.56 (95% CI: 1.68–18.37), compared to those who did not have such a decline (HR: 2.08; 95% CI: 1.68–2.58). The interaction between treatment and eGFR decline was not statistically significant (p interaction = 0.07).

Finerenone

In the FIGARO-DKD trial [19], which enrolled patients with earlier stages of CKD associated with T2D, finerenone substantially reduced the risk of cardiovascular events. While hyperkalemia (serum potassium >5.5 mmol/L) was observed more frequently in the finerenone group (10.8%) compared to placebo (5.3%), these events remained generally manageable, and hospitalizations for hyperkalemia remained rare (0.6% vs. 0.1%). Only 1.2% of patients receiving finerenone discontinued therapy due to hyperkalemia, indicating that with appropriate monitoring, most patients can continue treatment and achieve its cardiovascular benefits.

The FIDELIO-DKD trial [20] evaluating kidney outcomes in patients with CKD and T2D showed finerenone’s protective effects on renal function while maintaining a manageable safety profile. Although hyperkalemia rates were higher with finerenone (18.3% vs. 9.0% in the placebo group), permanent discontinuations due to hyperkalemia were infrequent (2.3% vs. 0.9%).

The FIDELITY analysis is a pooled analysis of FIGARO-DKD and FIDELIO-DKD [21]. Although hyperkalemia (serum potassium >5.5 mmol/L) was more common with finerenone (14.0%) than with placebo (6.9%), most episodes were mild to moderate and could be effectively managed with appropriate monitoring and dose adjustments. Notably, severe hyperkalemia events requiring hospitalization remained low (0.9% with finerenone vs. 0.2% with placebo), and no fatal hyperkalemia events occurred. Permanent discontinuation due to elevated potassium was also infrequent (1.7% with finerenone vs. 0.6% with placebo). Importantly, the mean increase in serum potassium stabilized after the fourth month of treatment, suggesting that routine potassium surveillance is sufficient to maintain long-term safety. The mean increase in serum potassium in the finerenone group was modest – rising by 0.21 mmol/L at month 4 and stabilizing at 0.20 mmol/L by month 12, compared with a stable 0.02 mmol/L increase in the placebo group at both time points (per FIDELITY supplemental data). Furthermore, finerenone was associated with a lower incidence of investigator-reported hypokalemia (1.1% vs. 2.3% with placebo), suggesting its potential advantage in preventing electrolyte imbalances on both the lower and higher end of the potassium spectrum.

Using the FIDELITY dataset, a practical risk‐prediction tool to identify patients with T2D and CKD with a higher risk of developing treatment‐emergent hyperkalemia (serum potassium >5.5 mmol/L) was introduced. Using a stepwise Cox model of baseline variables in the placebo arm, seven independent predictors (elevated baseline serum potassium, prior medical history of hyperkalemia, lack of sodium glucose transporter 2 [SGLT2] inhibitor use, high albuminuria, low hemoglobin, no thiazide use, and lower eGFR) were combined into an integer risk score, which was then validated in the finerenone arm. The model showed good discrimination (C‐index ≥0.72) and was well calibrated for hyperkalemia risk at 2 years. Hyperkalemia incidence increased incrementally across low‐, intermediate‐, and high‐risk groups; however, the relative increase in the risk for hyperkalemia with finerenone versus placebo remained consistent across these strata (p value for interaction 0.38). Specifically, the HR was 2.58 (95% CI: 1.92–3.49), 2.73 (2.31–3.23), and 2.26 (1.91–2.67) in the low‐risk (T1), intermediate‐risk (T2), and high‐risk (T3) group, respectively. Moreover, finerenone continued to confer cardiovascular and kidney benefits regardless of hyperkalemia risk category.

The FINEARTS-HF trial evaluated finerenone in patients with HF and mildly reduced or preserved ejection fraction [22] and met its primary endpoint by demonstrating a reduction in the composite outcome of cardiovascular death and HF events. Although potassium levels above 6.0 mmol/L occurred in 3.0% of patients in the finerenone group (versus 1.4% with placebo), no hyperkalemia-related deaths were reported, and hyperkalemia-related hospitalizations remained uncommon (0.5% with finerenone vs. 0.2% with placebo). Moreover, finerenone was associated with a lower incidence of hypokalemia (potassium <3.5 mmol/L) compared to placebo, underscoring its generally well-tolerated and manageable safety profile in this patient population. However, this trial did not report hyperkalemia profile for patients with CKD and T2D.

The ARTS-HF study [23] was a randomized, double-blind, phase 2b trial designed to evaluate the efficacy and safety of different doses of finerenone compared with eplerenone in patients with worsening chronic heart failure with reduced ejection fraction who also had T2D and/or CKD. The study observed that 4.3% of the entire study population (including both finerenone and eplerenone groups) experienced hyperkalemia (serum potassium concentrations ≥5.6 mmol/L) at any time during the study. The incidence of hyperkalemia was similar between the finerenone and eplerenone groups, indicating that finerenone, even at higher doses, did not significantly increase the risk of hyperkalemia compared to eplerenone. Specifically, finerenone showed lower or comparable incidences of hyperkalemia across most dosage groups when compared to eplerenone, with only the 15→20 mg finerenone group showing a higher incidence of serum potassium concentrations >6.0 mmol/L (1.9% vs. 0.5% in the eplerenone group). The data suggest that when finerenone is initiated at lower doses (2.5–10 mg), the incidence of hyperkalemia (serum potassium levels ≥5.6 mmol/L) is comparable to, or even lower than, that seen in the eplerenone group. Across the lower finerenone doses, the incidence of hyperkalemia ranged from 3.6% to 3.8%, which is similar to the incidence observed in the eplerenone group (4.7%). However, when finerenone was initiated at a higher dose (15 mg), the incidence of hyperkalemia was higher (6.3%) compared to eplerenone. Notably, severe hyperkalemia (serum potassium levels >6.0 mmol/L) occurred in 1.9% of patients in the higher dose finerenone group, while it was only 0.5% in the eplerenone group, with no cases of severe hyperkalemia reported in the lower finerenone dose groups.

Management of Hyperkalemia in Patients with Kidney Disease

In patients with CKD, hyperkalemia management hinges on identifying and addressing underlying risk factors – most notably reduced excretory capacity, metabolic acidosis, constipation, diabetes, and the use of RAAS inhibitors. Initial steps include verifying that elevated potassium levels are not due to pseudohyperkalemia and measuring serum potassium regularly – particularly after initiating or titrating RAAS inhibitors. Dietary counseling is recommended to tailor potassium intake to the patient’s degree of renal impairment; mild-to-moderate CKD often tolerates standard potassium intake unless hyperkalemia is otherwise unexplained, whereas advanced CKD requires restricting high-potassium foods. Metabolic acidosis correction with oral sodium bicarbonate (if serum bicarbonate <22 mmol/L) can help shift potassium intracellularly and enhance renal potassium excretion. Loop diuretics may be added or uptitrated in hypervolemic CKD patients to augment urinary potassium excretion with careful volume and creatinine monitoring. Short courses of traditional potassium-binding resins – such as sodium or calcium polystyrene sulfonate – are used acutely, although they lack robust long-term safety data. Newer binders like patiromer and sodium zirconium cyclosilicate, while not universally available, have demonstrated efficacy for chronic hyperkalemia, allowing patients to maintain life-saving RAAS blockade by stabilizing serum potassium. Ultimately, treatment must be individualized, balancing the cardiorenal benefits of RAAS inhibitors against the risk of hyperkalemia and leveraging diet, bicarbonate therapy, diuretics, and potassium binders when needed to achieve safe and effective potassium control.

Regarding a management algorithm, clinicians should initiate or continue RAAS inhibitors (± finerenone) and regularly monitor serum potassium and eGFR – at baseline, 1–4 weeks, and after any dose change. If K⁺ remains below 5.0 mmol/L, therapy can be maintained at the current dose. Should K⁺ rise to 5.0–5.4 mmol/L, closer monitoring and dietary advice are recommended. If K⁺ reaches 5.5 mmol/L or higher, the RAAS inhibitor should be temporarily held or dose-reduced while identifying triggers (e.g., metabolic acidosis, overuse of potassium supplements) and considering potassium binders (patiromer or sodium zirconium cyclosilicate) along with diuretic adjustments. Re-challenging therapy is appropriate once potassium levels stabilize.

Discussion

T2D coexisting with CKD is associated with accelerated cardiovascular and renal complications, necessitating therapies that comprehensively target these overlapping risks. Among these, MRAs have consistently demonstrated cardiorenal benefits by blocking the deleterious effects of aldosterone on blood pressure, cardiac remodeling, and kidney function. While spironolactone and eplerenone have shown survival benefits in patients with HF, their use in CKD has primarily demonstrated reductions in albuminuria and blood pressure – surrogate markers of disease progression – rather than definitive improvements in long-term kidney outcomes. They also increase the risk of hyperkalemia, necessitating careful monitoring to prevent serious adverse effects.

Recent clinical trials have illuminated both the promise and the challenges of MRA therapy across various patient populations. Spironolactone and eplerenone confer mortality and morbidity benefits but pose notable hyperkalemia risk. In contrast, finerenone, a nonsteroidal MRA, has demonstrated robust cardiorenal protective effects in patients with T2D and CKD, with a more favorable safety profile regarding steroid-related adverse events. More recently, in the FINEARTS-HF trial, finerenone also significantly reduced the risk of the composite endpoint of worsening HF events and cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction – despite only ∼40% of participants having diabetes and ∼50% having eGFR <60 mL/min/1.73 m² – highlighting its broader therapeutic potential beyond the diabetic CKD population. Furthermore, the FIND-CKD Study, a study of finerenone in addition to standard of care on the progression of kidney disease in patients with non-diabetic CKD, is ongoing and will investigate the effects of finerenone in adults with CKD without diabetes [24]. The results from this trial will also be illuminating. Notably, finerenone was approved in July 2025 to treat patients with HF with left ventricular ejection fraction ≥40% based on phase 3 data from the FINEARTS-HF trial [22, 25]. However, these data were published after the predefined literature cutoff for this review and are therefore not included. While finerenone does increase the incidence of hyperkalemia compared with placebo, most cases were mild or moderate, suggesting that effective potassium monitoring and dose adjustments typically maintain therapy continuity without undermining its clinical benefits.

A key step forward was the development of risk prediction models, such as that derived from the FIDELITY analysis, which help clinicians stratify patients based on information that can be feasibly and routinely collected in a clinical visit. Providers can intensify monitoring strategies and adopt proactive interventions by identifying individuals at higher hyperkalemia risk. For example, dietary counseling may be recommended to limit excessive potassium intake, metabolic acidosis can be corrected with sodium bicarbonate, and loop diuretics may be optimized to enhance potassium excretion. In persistent or recurrent hyperkalemia, newer potassium binders such as patiromer and sodium zirconium cyclosilicate could allow for continued MRA therapy by stabilizing serum potassium.

Although the primary focus of our review is on T2D and CKD, some HF trials were also included to illustrate the risk of hyperkalemia for MRAs in a broader patient population. It is important to note that most of the safety data originate from RCTs with protocol-driven follow-up, which may not fully capture real-world complexities. Patients in routine clinical practice often present with multiple comorbidities, limited resources for frequent laboratory testing, and variability in adherence, all of which might influence hyperkalemia risk. Future studies and registries should thus investigate the long-term adherence and real-world effectiveness of finerenone and other MRAs under less controlled conditions, clarifying whether the favorable balance of benefits and risks translates beyond trial populations.

It is also worth noting that aldosterone synthase inhibitors represent an emerging therapeutic approach for CKD by directly suppressing aldosterone production. A phase 2 trial of vicadrostat in 586 patients with CKD and albuminuria demonstrated a reduced urine albumin to creatinine ratio of 37–40% compared to placebo [26]. While 14% of participants experienced hyperkalemia, most participants with hyperkalemia did not require medical intervention (86%). The EASi-KIDNEY trial is currently enrolling and will assess the safety and cardiorenal efficacy of vicadrostat combined with empagliflozin, including separate analyses for patients with and without diabetes [26]. This trial will be useful in determining the clinical utility of aldosterone synthase inhibitors and their integration into CKD treatment paradigms.

In conclusion, hyperkalemia remains a significant concern when prescribing MRAs to individuals with T2D and CKD, but the accumulating evidence suggests that finerenone can safely and effectively confer meaningful cardiorenal protection under appropriate monitoring protocols. By personalizing treatment to each patient’s risk profile and integrating adjunctive measures in clinical practice to mitigate potassium elevations, clinicians can maximize the potential of MRAs without compromising safety, ultimately improving outcomes in a vulnerable patient population. These measures facilitate adherence, reduce hyperkalemia-related complications, and enhance survival.

Acknowledgments

The authors would like to acknowledge the medical writing support provided by Mohamed Ali, PharmD, MSc, of ILM Consulting Services, LLC, which was funded by Bayer US, LLC. The authors would also like to acknowledge the editorial support, visualizations, 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).

Conflict of Interest Statement

The authors, J.B.K. and A.M.D., do not have any conflicts of interest to declare with respect to this article.

Funding Sources

Bayer US, LLC., funded the article processing charge for this article. Bayer US, LLC., also funded ILM Consulting Services, LLC., for medical writing support and publication management.

Author Contributions

The author contributed to the writing and reviewing of each draft and reviewing and approving the final draft for submission. J.B.K. and A.M.D.: conceptualization and writing – review and editing.

Funding Statement

Bayer US, LLC., funded the article processing charge for this article. Bayer US, LLC., also funded ILM Consulting Services, LLC., for medical writing support and publication management.