The CONFIDENCE trial investigated the efficacy of dual Empagliflozin & Finerenone therapy in compound CKD-T2D patients compared to Finerenone monotherapy in hyperkalemia prevention. The results suggested that dual therapy did not significantly mitigate hyperkalemia risk compared to solitary Finerenone administration.¹

Methodology

The CONFIDENCE trial was a double-blind, randomised, controlled study that enrolled patients with T2D, CKD, and albuminuria.¹˒² All participants were on stable doses of a renin-angiotensin system inhibitor. Patients were randomised 1:1:1 to receive empagliflozin, finerenone, or a combination of both for 180 days. This secondary analysis investigated the mean changes in serum potassium from baseline and the risk of developing moderate or severe hyperkalemia.¹

Results

Overall, hyperkalemia occurred in 113 patients (14.5%). The incidence was 18.8% in the finerenone group, 15.1% in the combination therapy group, and 9.7% in the empagliflozin group. The addition of empagliflozin to finerenone did not result in a statistically significant reduction in the odds of developing hyperkalemia compared to finerenone alone (p=0.85). Similarly, there was no significant difference in the mean change in serum potassium between the combination and finerenone-only arms (p=0.91).

Key determinants for developing hyperkalemia were identified as higher baseline serum potassium, lower baseline eGFR, and treatment with a finerenone-containing regimen. A causal mediation analysis demonstrated that the development of hyperkalemia was not in the causal pathway for the primary trial outcome of Albumin:Creatinine ratio reduction. Despite the incidence of hyperkalemia, adverse events leading to treatment discontinuation were infrequent and occurred at similar rates across all groups (3.5–5.0%).

In Practice

This analysis from the CONFIDENCE trial indicates that while combination therapy with empagliflozin and finerenone provides greater albuminuria reduction, it does not lessen the risk of hyperkalemia associated with finerenone. The findings underscore the importance of continued, diligent monitoring of serum potassium for patients on finerenone-containing regimens, as recommended in clinical guidelines. The reno-protective benefits of these therapies appear to be maintained irrespective of the development of hyperkalemia, reinforcing the value of proactive management to allow patients to remain on these beneficial treatments.

Next Steps

The authors noted that further studies are needed to assess whether the continuation of therapy in patients with manageable hyperkalemia leads to better long-term outcomes.

This study was funded by Bayer AG.

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References

1. Agarwal R, Green JB, Heerspink HJL, et al. Risk of Hyperkalemia With Empagliflozin, Finerenone, or Both: Secondary Analysis of the CONFIDENCE Randomized Trial. JACC. 2026;87(7):772-784. https://doi.org/10.1016/j.jacc.2025.10.049

2. Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N Engl J Med. 2025;393:533-543. https://doi.org/10.1056/NEJMoa2410659