CONFIDENCE Trial Insights on CKD Combination Therapy, With Rajiv Agarwal, MD, MS

The treatment paradigm for chronic kidney disease (CKD) is rapidly evolving, as clinicians move from a single-drug approach to a more complex, multi-therapy strategy. Over the past several years, the introduction of SGLT2 inhibitors, finerenone, and semaglutide alongside traditional RAAS blockade has created both new opportunities and new uncertainty around how best to deploy these therapies.

In an interview with HCPLive at World Congress of Nephrology (WCN) in Yokohama, Japan, Rajiv Agarwal, MD, MS, said this expanding toolkit has raised a critical question as to whether therapies should be introduced sequentially or started together. While clinicians have historically taken a stepwise approach titrating one agent at a time, he notes that this process can take up to a year, time during which ongoing kidney and cardiovascular damage may continue.

In response, the CONFIDENCE trial was designed to evaluate whether simultaneous initiation of combination therapy could accelerate benefit without compromising safety. He explains that this was the first adequately powered study to assess starting therapies such as finerenone and SGLT2 inhibitors at the same time. While prior studies evaluated add-on strategies, they did not address the safety and efficacy of concurrent initiation.

Concerns going into the trial included the potential for hypotension, acute kidney injury, and hyperkalemia, particularly given the hemodynamic effects of these agents. The findings, however, demonstrated that combination therapy could achieve meaningful reductions in albuminuria both safely and effectively.

A pair of additional analyses from CONFIDENCE presented at WCN offer further insight into patient response. The first examined differences by sex and age, revealing that women experienced approximately 20% greater reductions in urinary albumin-to-creatinine ratio compared with men. Agarwal noted that older patients also demonstrated enhanced responses, with each decade of age associated with a roughly 10% greater likelihood of benefit. Of note, these gains were not accompanied by increased safety concerns, challenging assumptions about treating higher-risk populations.

The second analysis addressed early declines in estimated glomerular filtration rate (eGFR), a common concern when initiating these therapies. Agarwal emphasizes that these initial dips are typically reversible and not predictive of long-term harm. Rather than discontinuing treatment, clinicians should monitor patients closely, particularly if eGFR declines exceed 30%, and adjust contributing factors such as volume status or concomitant medications.

Ultimately, he underscores that multimodal therapy represents the future of CKD management. Early and sustained use of combination treatment, he suggests, has the potential to significantly reduce cardiovascular events and extend patient survival.

Editors’ note: Relevant disclosures for Agarwal include Akebia Therapeutics, Alnylam, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim, Intercept, Novartis, and others.

References

1. Campbell P. CONFIDENCE: SGLT2i and Finerenone Effective, Safe to Initiate Simultaneously in CKD. HCPLive. June 5, 2025. Accessed April 2, 2026. https://www.hcplive.com/view/confidence-sglt2i-and-finerenone-effective-safe-to-initiate-simultaneously-in-ckd

2. Agarwal R. Effect of Simultaneous Initiation of Finerenone and Empagliflozin on Urinary Albumin-to-creatinine Ratio by Age and Sex in the CONFIDENCE Trial. Presented at World Congress of Nephrology (WCN) in Yokohama, Japan, March 28-31, 2026.

3. Agarwal R. Estimated Glomerular Filtration Rate, Systolic Blood Pressure, and Urinary Albumin-to-creatinine Ratio — Unravelling the Interplay in Combination: Findings From the CONFIDENCE Trial. Presented at World Congress of Nephrology (WCN) in Yokohama, Japan, March 28-31, 2026.