Risk of Hyperkalemia With Empagliflozin, Finerenone, or Both: Secondary Analysis of the CONFIDENCE Randomized Trial

Background: Hyperkalemia is common with renin-angiotensin system inhibitor (RASi) therapy, frequently leading to treatment interruption and potentially curtailing cardiovascular and kidney benefits. Sodium-glucose cotransporter 2 inhibitors might mitigate the risk of hyperkalemia with RASis. Objectives: This prespecified secondary analysis of the CONFIDENCE trial aimed to investigate the impact of empagliflozin, finerenone (a nonsteroidal mineralocorticoid receptor antagonist), and their combination on hyperkalemia, and whether hyperkalemia mediates albuminuria reduction in high-risk patients with chronic kidney disease and type 2 diabetes with albuminuria. Methods: In this double-blind, randomized, controlled trial, CONFIDENCE, patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate: 30-90 mL/min/1.73 m ²), and albuminuria (urine albumin-to-creatinine ratio [UACR]: 100-5,000 mg/g) on stable doses of RASis were randomized 1:1:1 to empagliflozin, finerenone, or both. The primary outcome was change in UACR from baseline to Day 180. Mean changes in potassium were estimated using linear mixed models. Logistic regression models assessed the risk of moderate (serum potassium >5.5 mmol/L) and severe (serum potassium >6.0 mmol/L) hyperkalemia. Causal mediation analysis was used to ascertain the impact of hyperkalemia on mean UACR change at Day 180. Results: Patients developing hyperkalemia had lower estimated glomerular filtration rate, higher potassium, and more severe albuminuria at baseline. Hyperkalemia events accumulated over the 180 days of the trial in all 3 groups. There were few treatment discontinuations. Randomization to finerenone was associated with increase in serum potassium. No difference was seen between combination treatment and finerenone in mean change in serum potassium (P = 0.91) or the odds of developing hyperkalemia (P = 0.85). Overall, hyperkalemia occurred in 113 patients (14.5%): 40 of 265 (15.1%) with combination therapy, 48 of 255 (18.8%) with finerenone, and 25 of 259 (9.7%) with empagliflozin. Hyperkalemia was not in the causal pathway of UACR reduction at Day 180. Conclusions: Over 180 days, the combination of empagliflozin and finerenone did not significantly mitigate the risk of hyperkalemia. The treatment effect was maintained regardless of development of hyperkalemia.