Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial

Abstract

Background: Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo in FIDELIO-DKD.

Methods: This post hoc safety analysis defined hyperkalemia as ≥mild or ≥moderate based on serum potassium concentrations of >5.5 or >6.0 mmol/L, respectively, assessed at all regular visits. Cumulative incidences of hyperkalemia were based on the Aalen-Johansen estimator using death as competing risk. A multivariate Cox proportional hazards model identified significant independent predictors of hyperkalemia. Restricted cubic splines assessed relationships between short-term post-baseline changes in serum potassium or eGFR and subsequent hyperkalemia risk. During the study, serum potassium levels guided drug dosing. Patients in either group who experienced ≥mild hyperkalemia had the study drug withheld until serum potassium was ≤5.0 mmol/L; then the drug was restarted at the 10 mg daily dose. Placebo-treated patients underwent sham treatment interruption and downtitration.

Results: Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex, β-blocker use, and finerenone assignment. Diuretic or sodium-glucose cotransporter-2 inhibitor use reduced risk. In both groups, short-term increases in serum potassium and decreases in eGFR were associated with subsequent hyperkalemia. At month 4, the magnitude of increased hyperkalemia risk for any change from baseline was smaller with finerenone than with placebo.

Conclusions: Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.

Keywords: chronic kidney disease; diabetic nephropathy; hyperkalemia; mineralocorticoid receptor antagonist; randomized controlled trials.

Figure 1.

Potassium management algorithm in FIDELIO-DKD. ^aIf eGFR is stable (i.e., ≤30% decrease since last available measurement). ^bUptitration visits were performed at 4 weeks ±7 days after any treatment interruption >7 days and after any uptitration. ^cRegular study visits were scheduled at month 1, month 4, and every 4 months thereafter. ^dIf treatment interruption ≤7 days.

Figure 2.

Cumulative incidence of elevated serum [K⁺]. (A) Shows time to treatment-emergent serum [K⁺] >5.5 mmol/L. (B) Shows time to treatment-emergent serum [K⁺] >6.0 mmol/L. ^aCumulative incidence calculated by Aalen–Johansen estimator using all-cause death as a competing risk. ^bIncidence calculated as n/N over 2.6 years’ median follow-up. ^cPatients at risk must have both a baseline and postbaseline treatment-emergent value and the baseline value must be below the threshold.

Figure 3.

Multivariate analysis of time to any serum [K⁺] >5.5 mmol/L. ^aUACR is modeled as a continuous variable; 1 unit change in log₂ UACR denotes doubling of UACR. 95% CI, 95% confidence interval; Ref, reference category.

Figure 4.

Short-term changes in serum [K⁺] and eGFR and the future risk of hyperkalemia ([K⁺] >5.5 mmol/L). (A) Changes in serum [K⁺] from baseline to month 1. (B) Changes in serum [K⁺] from baseline to month 4. (C) Changes in eGFR from baseline to month 1. (D) Changes in eGFR from baseline to month 4. 95% CI, 95% confidence interval; HR, hazard ratio.