Kidney Compass: REMODEL Trial Provides Mechanistic Rationale for Semaglutide in CKD

At the World Congress of Nephrology 2026 in Yokohama, Japan, growing attention is being paid not just to whether therapies improve outcomes in chronic kidney disease, but how they work at a mechanistic level. In this episode of Kidney Compass, host Brendon Neuen, MBBS, PhD, spoke with David Cherney, MD, PhD, about the REMODEL trial, a mechanistic study designed to better understand the kidney-protective effects of semaglutide in patients with type 2 diabetes and chronic kidney disease.

As Cherney explained during the discussion, REMODEL was conceived as a companion to the landmark FLOW trial, which demonstrated significant reductions in cardiorenal outcomes with semaglutide. While FLOW established clinical efficacy, Cherney emphasized that REMODEL was designed to answer a different question: why these benefits occur. Both he and Neuen highlighted that prior analyses suggested the observed kidney protection could not be fully explained by traditional risk factor improvements such as glycemic control, weight loss, or blood pressure reduction.

To address this, Cherney described how REMODEL incorporated a range of advanced imaging and biomarker-based endpoints. The primary outcome focused on MRI-derived measures of kidney oxygenation, while secondary endpoints included albuminuria, kidney function, and a suite of mechanistic markers such as fibrosis, intrarenal fat, and inflammatory pathways. A subset of participants also underwent paired kidney biopsies, allowing for direct assessment of cellular and molecular changes within the kidney.

According to Cherney, the trial did not demonstrate an effect on kidney oxygenation, but did reveal several other important mechanistic signals. He noted that semaglutide led to a reduction in perirenal and hilar fat, a finding that Neuen highlighted as particularly intriguing given emerging hypotheses around the role of local adiposity in kidney injury. Cherney also pointed to improvements in markers of fibrosis and inflammation, including changes in endothelial cell biology and reductions in inflammatory cell populations, suggesting a direct intrarenal effect.

The conversation explored these findings in greater depth, with Neuen raising the possibility that perirenal fat may contribute to kidney injury through both mechanical and inflammatory mechanisms. In response, Cherney outlined multiple potential pathways, including physical compression of renal structures and the metabolic activity of adipose tissue driving cytokine-mediated injury. Both emphasized that these hypotheses warrant further investigation but may represent an underappreciated contributor to disease progression.

Clinically, Cherney reported that semaglutide reduced albuminuria by approximately 40%, reinforcing its potential as a kidney-protective therapy. He also presented subgroup analyses from the REMODEL trial showing consistent effects regardless of baseline use of SGLT2 inhibitors. Neuen noted that this finding aligns with broader evidence suggesting additive and complementary mechanisms between these drug classes, supporting their combined use in high-risk patients.

Looking ahead, both speakers emphasized the broader implications of these findings. Cherney suggested that the mechanisms observed in REMODEL, particularly those related to inflammation and endothelial dysfunction, are likely not specific to diabetes and may extend to non-diabetic kidney disease. He also stressed the importance of reframing semaglutide as a kidney-directed therapy, independent of its effects on glucose or weight, a point Neuen reinforced as critical for both clinicians and patients.

Editors’ note: Relevant disclosures for Neuen include AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and others. Relevant disclosures for Cherney include Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Abbvie, Janssen, AMGEN, Bayer, , Gilead, CSL-Behring, Otsuka, Novartis, GSK, and others.