Hyperkalemia with Mineralocorticoid Receptor Antagonist Use in People with CKD

• aldosterone
• chronic kidney disease
• diabetic nephropathy
• hyperkalemia

With the recent publication of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) (1) and the Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) (2) studies and with the recent approval of finerenone by the Food and Drug Administration (FDA) (3) and at least two other novel nonsteroidal mineralocorticoid receptor antagonists under robust development (aparenone and exarenone), a constructive consideration of the balance between benefit and risk and an update of mineralocorticoid receptor antagonists are highly appropriate. We believe that a consideration of the salient differences with respect to both clinical efficacy and serious adverse events of mineralocorticoid receptor antagonists (both first and second generation steroidal mineralocorticoid receptor antagonists and the recently approved novel nonsteroidal mineralocorticoid receptor antagonists in both the CKD and heart failure with reduced ejection fraction space) will aid clinicians as mineralocorticoid receptor antagonists assume an increasingly important niche in the clinical practice of nephrology. Several caveats are appropriate. Both FIDELIO-DKD and FIGARO-DKD enrolled mainly diabetic and albuminuric patients with CKD (diabetic nephropathy), but we do not yet have evidence for efficacy in nonalbuminuric patients with diabetic kidney disease (which make up about 50% of patients) and diabetic nephropathy. We propose that the operative mechanism of action blocking inflammation and fibrosis may be applicable to nondiabetic CKD. Indeed, the FIND-CKD study (NCT05047263) investigating finerenone in nondiabetic CKD was initiated in September 2021 and is expected to be completed in November 2025. Of importance, the FIND-CKD study is enrolling proteinuric (urinary albumin-creatinine ratio [UACR] of ≥200 but <3500 mg/g) patients with CKD. In summary, we should be cautious in extrapolating widely from FIDELIO-DKD and FIGARO-DKD while we await completion of the FIND-CKD study and, hopefully, additional studies of nonproteinuric CKD in both diabetic and nondiabetic patients.

It is well established that renin-angiotensin-aldosterone system inhibitor (RAASi) and, subsequently, mineralocorticoid receptor antagonist–provoked hyperkalemia constitute an over-riding concern and indeed a constraint with their widespread prescription (4,5). Hyperkalemia is one of the most common reasons for down-titrating or discontinuing RAASis, thus potentially depriving patients of the reno- and cardioprotective benefits of these agents. Indeed, the discontinuation or the use of submaximal RAASi doses in response to hyperkalemia was associated with worse cardiorenal outcomes and higher mortality in a recent analysis of >1.7 million individuals (6).

Regretfully, what constitutes clinically relevant hyperkalemia and its perception are obtuse and frequently misleading, and consequently, they must be honed and refined (7). Hyperkalemia is not a bimodal term; it is overly simplistic to assume the stance that hyperkalemia either constitutes a complication or, alternatively, does not. Rather, there are gradations of risk, and indeed, recent clinical studies have used cut points to more accurately assess the frequency and severity of hyperkalemia as a complication of RAASis, mineralocorticoid receptor antagonists, and indeed, SGLT2is (1,2).

The incidence of hyperkalemia in FIDELIO-DKD depended on the definition used. There were 516 (18%) versus 255 (9%) hyperkalemia events reported by the local investigators (irrespective of definition) in patients receiving finerenone versus placebo, respectively. The number of serious hyperkalemia events was 44 (1.6%) versus 12 (0.4%); the number of hospitalizations due to hyperkalemia was 40 (1%) versus eight (0.3%), and the number of permanent discontinuations due to hyperkalemia was 64 (2%) versus 25 (0.9%) in patients receiving finerenone versus placebo. Importantly, there were no deaths attributable to hyperkalemia.

Although the overall number of patients affected by any degree of hyperkalemia in FIDELIO-DKD was not negligible, the mitigation strategies applied in the study protocol resulted in only a very small number of patients discontinuing the study regimen or experiencing severe adverse effects, and no patients died as a result of hyperkalemia. These mitigation strategies included the exclusion of patients with baseline serum potassium concentration >4.8 mEq/L from study participation, a prespecified strict monitoring schedule, and predefined steps for discontinuation and reinitiation of the study drug in the face of hyperkalemia events. Finerenone’s FDA label specifies a similar mitigation regimen to be followed, indicating a conscious effort to minimize the risk of hyperkalemia (in contrast to the practice followed in the wake of the Randomized Aldactone Evaluation Study [RALES]; vide infra).

An additional and compelling consideration is relevant. The hyperkalemia management protocol in FIDELIO-DKD did not include the use of novel potassium binders (both patiromer and SZC), the use of which has become commonplace and which predictably enable the continuation of RAASis even when they cause hyperkalemia. Their use could thus further mitigate the hyperkalemia that might occur with the application of finerenone in clinical practice.

Many recent comparisons have failed to account for the over-riding importance of the role of concomitant medications. In both the FIDELIO-DKD and FIGARO-DKD studies, RAASis were administered at the guideline-mandated maximally tolerated doses. In contrast, comparator trials have not imposed similar requirements. Consequently, differences in concomitant renin-angiotensin-aldosterone system blockade constitute a glaring, albeit frequently ignored, additional variable for provoking hyperkalemia; hence, inadvertently, we are comparing “apples and oranges.” It is worth remembering when compiling and reviewing this routine care data that evidence-based use of finerenone is as an add-on to maximally tolerated RAASi.

Recently, several authors have sounded the alarm over the prospect of an increase in hyperkalemia after finerenone is used in routine care settings (8). These authors refer to observations made in the immediate aftermath of RALES, which disclosed a substantial increase in hyperkalemia-associated hospitalizations (9). These hyperkalemia occurrences were attributable to the use of spironolactone without preselection of patients or mitigation strategies. Furthermore, the incidence of hyperkalemia should be lower with finerenone than with spironolactone on the basis of their mechanism of action and pharmacokietics. It is noteworthy that finerenone has a short half-life when compared with spironolactone, and metabolites of spironolactone have been found to persist in the urine as long as 2 weeks after therapy.

Confirmation of less hyperkalemia occurring with finerenone as compared with spironolactone is supported by evidence from head-to-head comparison of the two agents in patients in a randomized, controlled, phase 2 trial (10). Finerenone (5–10 mg/d) was compared with placebo and open-label spironolactone (25 or 50 mg/d) in 392 patients with heart failure with reduced ejection fraction and moderate CKD. Finerenone was at least as effective as spironolactone 25 or 50 mg/d in decreasing biomarkers of hemodynamic stress, but it was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04–0.30 and 0.45 mmol/L, respectively; P<0.001 to P=0.01) and lower incidences of hyperkalemia (5% and 12%, respectively; P=0.05).

Notwithstanding the desire for larger trials with longer follow-up comparing finerenone with spironolactone, such a trial is unlikely to be ever conducted. Consequently, we caution against hesitating to utilize a novel drug, such as finerenone, while demanding evidence that most likely will never materialize. We should instead focus on incorporating finerenone into clinical practice along with other recently added novel reno- and cardioprotective interventions to ensure the best outcomes for our patients with CKD. The combination of finerenone with an SGLT2i is particularly intriguing because experimental studies have suggested potentially additive benefits at low dose, whereas their effects on hyperkalemia in clinical trials have been the opposite. The efficacy and safety of such a combination regimen will need to be examined in larger clinical trials.

The recent publication of FIDELIO-DKD and FIGARO-DKD and the approval of finerenone by the FDA suggest that novel nonsteroidal mineralocorticoid receptor antagonists may constitute an important advancement in the treatment paradigm for diabetic CKD, further expanding our therapeutic armamentarium and offering the prospect to improve the outcomes of our patients. Several lines of evidence suggest that the severity and magnitude of hyperkalemia are less frequent and less severe than that provoked by older steroidal mineralocorticoid receptor antagonists. We contend that prescribing novel nonsteroidal mineralocorticoid receptor antagonists, when coupled with appropriate laboratory monitoring after mineralocorticoid receptor antagonist initiation, and judicious treatment with novel potassium binders when warranted will enable sustained long-term treatment of patients with CKD in clinical practice, with a consequent improvement in cardiorenal outcomes and a reduction in mortality.

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