Finerenone plus empagliflozin does not mitigate hyperkalemia risk

Combining empagliflozin with finerenone falls short of alleviating the risk of hyperkalemia, according to the results of the CONFIDENCE trial.

“Our prespecified secondary analysis of the CONFIDENCE trial confirms that baseline potassium, estimated glomerular filtration rate (eGFR), and finerenone-containing regimens were key determinants of hyperkalemia,” the investigators said.

“However, we found no evidence that adding empagliflozin to finerenone reduces mean change in serum potassium levels or the incidence of moderate or severe hyperkalemia during the 180-day duration of the trial,” they added.

In CONFIDENCE, patients with type 2 diabetes, chronic kidney disease (eGFR, 30‒90 mL/min/1.73 m²), and albuminuria (urine albumin-to-creatinine ratio [UACR], 100‒5,000 mg/g) on stable doses of renin-angiotensin system inhibitors (RASi) were randomly allocated 1:1:1 to receive empagliflozin alone, finerenone alone, or both. Change in UACR from baseline to day 180 served as the primary outcome.

The investigators used linear mixed models to estimate mean changes in potassium and logistic regression models to assess the risk of moderate (serum potassium >5.5 mmol/L) and severe (serum potassium >6.0 mmol/L) hyperkalemia. They also determined the influence of hyperkalemia on mean UACR change at day 180 using causal mediation analysis.

Hyperkalemia

Participants who developed hyperkalemia were found to have lower eGFR, higher potassium, and more severe albuminuria at baseline. In all three groups, hyperkalemia events amassed over 180 days. Few treatment discontinuations occurred. [J Am Coll Cardiol 2026;87:772-784]

Treatment with finerenone correlated with an increase in serum potassium. No difference was observed in mean change in serum potassium (p=0.91) or the likelihood of hyperkalemia development (p=0.85) between finerenone monotherapy and combination treatment.

Of the patients, 113 (14.5 percent) developed hyperkalemia: 40 of 265 (15.1 percent) in the combination therapy group, 48 of 255 (18.8 percent) in the finerenone monotherapy group, and 25 of 259 (9.7 percent) in the empagliflozin monotherapy group. Notably, hyperkalemia was not in the causal pathway of UACR reduction at day 180.

“The findings of this analysis further delineate the determinants of hyperkalemia in high-risk patients with type 2 diabetes and chronic kidney disease as baseline potassium, baseline eGFR, and treatment with finerenone-containing regimens,” the investigators said. [J Am Soc Nephrol 2022;33:225-237] 

“Importantly, our data indicate that hyperkalemia, when it occurred, was not in the causal pathway of reduction in albuminuria,” they added.

A causal pathway is possible, as patients who are more adherent to therapy have a higher likelihood of developing hyperkalemia and appear to receive more kidney-protective benefit, as shown by a greater UACR reduction. However, the current analysis did not find any mediation.

“These data underscore the critical need for proactive and careful management of hyperkalemia to ensure the continued and optimal use of beneficial treatments, thereby preserving their substantial cardiovascular and kidney-protective effects in this vulnerable patient population,” the investigators said.

Hyperkalemia is common among patients treated with RASi and often leads to treatment interruption and potential reduction in cardiovascular and kidney benefits, according to the investigators.