Don’t Miss a Beat: CONFIDENCE Trial and Combination T2D, CKD Therapy at Heart in Diabetes 2025

In this episode of Don’t Miss a Beat, hosts Muthiah Vaduganathan, MD, MPH, a cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, and Steve Greene, MD, an advanced heart failure specialist at Duke University School of Medicine, review key findings and clinical implications of data from the CONFIDENCE trial.

Recorded on-site at the 9th Annual Heart in Diabetes Conference in Philadelphia, Pennsylvania, the episode breaks down the potential of combination initial therapy with finerenone plus empagliflozin in patients with both chronic kidney disease (CKD) and type 2 diabetes. Of note, the data were also presented at the 62nd European Renal Association (ERA 2025) Congress in Vienna, Austria.

Vaduganathan begins by acknowledging that Greene has pioneered much of the movement for rapid sequence implementation in heart failure, specifically referencing the STRONG-HF trial and describing how the concept of rapid sequence implementation has now made its way into CKD as the field explores the potential benefits of starting 2 drugs at once versus sequential monotherapy.

Vaduganathan posits that a trial similar to STRONG-HF may be necessary in the context of CKD but acknowledges the value CONFIDENCE provides as the largest currently available combination initiation therapy clinical trial in this patient population. He goes on to explain the design of CONFIDENCE, a phase 2 trial that enrolled 800 patients with CKD and type 2 diabetes who were randomized in a 1:1:1 ratio to receive empagliflozin monotherapy, finerenone monotherapy, or combination therapy with simultaneous initiation.

The primary endpoint was relative change in the log-transformed mean urinary albumin-to-creatinine ratio (UACR) from baseline to 180 days, which Vaduganathan explains has been accepted by the FDA as a validated surrogate of kidney disease progression. Greene expresses his agreement about the feasibility of this approach and inquires about some of the key findings Vaduganathan presented at Heart in Diabetes.

Findings published in the New England Journal of Medicine showed at day 180, the reduction in the UACR with combination therapy was 29% greater than that with finerenone alone (least-squares mean ratio of the difference in the change from baseline, 0.71; 95% confidence interval [CI], 0.61 to 0.82; P <.001) and 32% greater than that with empagliflozin alone (least-squares mean ratio of the difference in the change from baseline, 0.68; 95% CI, 0.59 to 0.79; P <.001).

Of note, neither agent, alone or in combination, led to unexpected adverse events, an aspect of the findings Greene emphasized as being especially important due to concerns over the potential side effects of starting combination therapy.

Looking ahead, Vaduganathan describes widespread interest in designing true combination pills that also help simplify issues like polypharmacy, additionally alluding to ongoing trials seeking to understand if these drugs can be given together as combination pills and benefit patients, both in the prevention and treatment of CKM conditions.

Check out this episode of Kidney Compass on CONFIDENCE, recorded at ERA with primary investigator Rajiv Agarwal, MD, MS: Kidney Compass: CONFIDENCE Trial at ERA 2025, with Rajiv Agarwal, MD, MS

Relevant disclosures for Vaduganathan include Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others. Relevant disclosures for Greene include Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, and others.

References

Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. New England Journal of Medicine. Published online June 5, 2025. doi:10.1056/nejmoa2410659