CONFIDENCE: SGLT2i and Finerenone Effective, Safe to Initiate Simultaneously in CKD

Simultaneous initiation of finerenone (Kerendia) and empagliflozin (Jardiance) is well-tolerated and was associated with a greater reduction in urinary albumin to creatinine ratio (UACR) than either therapy alone among patients with chronic kidney disease (CKD) and type 2 diabetes, according to the CONFIDENCE trial.

Presented at the 62nd European Renal Association (ERA 2025) Congress, results help to confirm the safety and efficacy of combination therapy, which is currently being adopted in management of chronic kidney disease.

“The CONFIDENCE study delivers clinical evidence that simultaneous initiation of finerenone and empagliflozin led to an early and additive reduction in UACR of 52% in patients with chronic kidney disease and type 2 diabetes, which was significantly greater than with either treatment alone,” said Rajiv Agarwal, MD, Professor Emeritus of Medicine, Indiana University School of Medicine and VA Medical Centre in Indianaoplis.2 “Given that UACR is an important mediator of kidney and cardiovascular outcomes, these findings provide key insights to clinicians when considering how to optimize disease management, supporting the early combined use of finerenone and an SGLT-2 inhibitor for a positive impact on patient outcomes.”

The new era of combination therapy in CKD in type 2 diabetes, often referred to as a pillared approach, has gone from science fiction to real-world practice in the last decade. What began with revelations surrounding the nephroprotective benefits of SGLT2 inhibitors has evolved into and now, the field sits poised with 4 foundational classes of therapy with proven benefits: RAASi, SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal mineralocorticoid receptor agonists. However, given the independent development of these classes and agents, many have questions surrounding the potential safety and efficacy of a combination approach.1,2,3,4

The CONFIDENCE trial was launched in 2022 to examine the safety and efficacy of simultaneous initiation of empagliflozin and finerenone, which received approval for CKD in type 2 diabetes in 2023 and 2021, respectively. The primary efficacy outcome for the trial was the relative change in mean UACR from baseline to 180 days.1

For inclusion in the trial, patients were required to have type 2 diabetes with HbA1c levels less than 11%, an eGFR between 30 and 90 ml/min/1.73m2 of body surface area, and albuminuria, defined as a UACR between 100 and 5000 mg.1

Per trial protocol, patients were randomized in a 1:1:1 ratio to empagliflozin alone, finerenone alone, or combination therapy with simultaneous initiation. Of note, finerenone was initiated at 20 mg per day when the eGFR was 60 ml/min/1.73m2 or greater and at 10 mg per day when the baseline eGFR was less than 60 ml/min/1.73m2. According to investigators, randomization was stratified according to the eGFR and UACR measurements at screening.1

A total of 1664 participants were enrolled in the trial from 143 sites in 14 countries. Of these, 818 were randomized to a treatment group and entered the double-blind period of the trial. Investigators limited the total number of patients included in the full analysis to 800 patients as 4 participants underwent randomization in error and had not taken at least one dose of a trial drug and 14 participants from a single site were excluded because of violations of the Good Clinical Practice guidelines that were not related to the conduct of this trial. Of the 800 participants included in the efficacy analyses, 269 received combination therapy, 264 received finerenone, and 267 received empagliflozin.1

Upon analysis, use of a combination approach was associated with a least-squares mean ratio of the change in UACR from baseline to day 180 of 0.48 (95% CI, 0.44 to 0.54) in the combination therapy group. Relative to monotherapy approaches, the reduction in UACR seen with combination therapy was 29% greater than 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).1

Investigators pointed out UACR was also measured 30 days after stopping the trial medication at 180 days. In these analyses, UACR increased from the end of t4eatment to the end of follow-up with least-squares mean ratios of 1.63 (95% CI, 1.49 to 1.78) in the combination-therapy group, 1.45 (95% CI, 1.32 to 1.59) in the finerenone group, and 1.44 (95% CI, 1.32 to 1.58) in the empagliflozin group.1

Safety analyses of the trial suggested there were no unexpected adverse events with either agent alone or in combination. Investigators pointed out less than 5% of patients experienced adverse events leading to discontinuation. Serious adverse events were observed in 7.1% of the combination therapy group, 6.1% of the finerenone group, and 6.4% of the empagliflozin group. Of note, 1 participant from each study group discontinued the trial due to hyperkalemia.1

“The CONFIDENCE data mark an important milestone in our mission to improve care for people living with chronic kidney disease associated with type 2 diabetes,” said Michael Devoy, MBBS, chief medical officer at Bayer’s Pharmaceuticals Division.2 “The findings suggest that a proactive simultaneous initiation can deliver a substantial early and additive UACR reduction, which is associated with kidney and cardiovascular protection. We are excited to share these important results with physicians, as they demonstrate that early combined use of finerenone and an SGLT2-inhibitor has the potential to improve long-term outcomes for millions of patients worldwide.”

References:

1. Agarwal R, Green JB, Heerspink HJ, et al. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. The New England Journal of Medicine. Published online June 5, 2025. doi: 1056/NEJMoa2410659

2. Bayer. Simultaneous treatment start with Finerenone and SGLT-2-inhibitor demonstrated positive data in patients with CKD associated with type 2 diabetes. Simultaneous treatment start with Finerenone and SGLT-2-inhibitor demonstrated positive data in patients with CKD associated with type 2 diabetes . Published June 5, 2025. Accessed June 5, 2025. https://www.bayer.com/media/en-us/simultaneous-treatment-start-with-finerenone-and-sglt-2-inhibitor-demonstrated-positive-data-in-patients-with-ckd-associated-with-type-2-diabetes/

3. Eli Lilly and Company. US FDA approves Jardiance® for the treatment of adults with chronic kidney disease | Eli Lilly and Company. Eli Lilly and Company. Published September 22, 2022. Accessed June 5, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-jardiancer-treatment-adults-chronic-kidney

4. Center for Drug Evaluation and Research. FDA approves drug to reduce risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes. FDA. Published online July 8, 2021. Accessed June 5, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease