Hyperkalemia Risk with Finerenone: Results from the FIDELIO-DKD Trial
Authors: Agarwal Rajiv , Joseph Amer , Anker Stefan D. , Filippatos Gerasimos , Rossing Peter , Ruilope Luis M. , Pitt Bertram , Kolkhof Peter , Scott Charlie , Lawatscheck Robert , Wilson Daniel J. , Bakris George L. ,   on behalf of the FIDELIO-DKD Investigators
Published: November 2021

Significance Statement
Hyperkalemia is common after treatment with a mineralocorticoid receptor antagonist (MRA). In the FIDELIO-DKD randomized trial, the nonsteroidal MRA finerenone improved cardiorenal outcomes, but was associated with a twofold higher risk of hyperkalemia versus placebo, consistent across patient subgroups. Short-term increases in serum potassium and decreases in eGFR with finerenone or placebo were associated with subsequent hyperkalemia; at month 4, the magnitude of the increased hyperkalemia risk for any given change from baseline was smaller with finerenone than with placebo. Routine potassium monitoring, with temporary treatment interruption and dose reduction in the event of hyperkalemia, is necessary for the safe use of finerenone to protect the kidneys and cardiovascular system of patients with CKD and T2D.

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.