REMODEL: Mechanistic Insights Into Semaglutide in CKD, With Petter Bjornstad, MD

The treatment landscape for chronic kidney disease (CKD) has evolved rapidly in recent years, with therapies now demonstrating meaningful benefits across kidney, cardiovascular, and metabolic outcomes. While large outcome trials have established efficacy, the understanding of the underlying mechanisms behind these protective effects has been limited.

The emergence of mechanistic studies such as the REMODEL trial marks a pivotal step toward answering that question, offering a deeper, biology-driven understanding of treatment effects in CKD. At the World Congress of Nephrology (WCN) 2026 Meeting in Yokohama, Japan, Petter Bjornstad, MD, executive director of the UW Medicine Diabetes Institute, professor of pediatrics and medicine, and the Raisbeck Endowed Chair of Diabetes Research at the University of Washington, presented an overview of REMODEL, including its framework and key outcomes, during a High Impact Clinical Trial session.

The rapid rise of GLP-1 RAs, including semaglutide, has transformed their role from glucose-lowering agents into foundational therapies used across endocrinology, cardiology, and nephrology. Their demonstrated benefits in weight reduction, cardiovascular risk, and kidney outcomes have driven widespread adoption and growing interest in their systemic effects.

In this context, mechanistic studies are increasingly important, helping to clarify the biological pathways that may underlie these broad clinical benefits. Bjornstad notes REMODEL stands out as a first-of-its-kind phase 3 mechanistic trial that integrates advanced imaging, tissue analysis, and biomarker discovery within the rigorous framework of a registration study. He emphasizes that this design serves as a “blueprint” for future trials, demonstrating that complex mechanistic investigations incorporating multiparametric MRI, kidney biopsy, and molecular profiling can be successfully conducted at scale across global sites.

From a mechanistic standpoint, he explains that the findings point to a central role for microvascular and endothelial health. Using functional MRI, the study demonstrated reduced renal vascular resistance, suggesting improved blood flow within the kidney. These findings were reinforced by biopsy data, which revealed gene expression patterns consistent with healthier endothelial cell function and enhanced intercellular communication.

Bjornstad situates these findings within the broader evidence base established by outcome trials, noting that the mechanistic insights from REMODEL help contextualize why GLP-1 RAs confer both renal and cardiovascular protection. He highlights that endothelial cells are present throughout the body, and improvements in vascular health may underpin the systemic benefits observed with these therapies.

The study also revealed reductions in fat surrounding and within the kidney, alongside consistent signals of vascular improvement across imaging, histology, and biomarker analyses. He underscores that this multidimensional validation strengthens confidence in the findings and enhances clinicians’ ability to interpret clinical trial outcomes.

Despite these advances, Bjornstad cautions that much remains to be understood. Ongoing analyses aim to further define the role of GLP-1 receptor expression and refine understanding of treatment response and residual risk. He also points to the growing pipeline of mechanistic trials as an encouraging trend, emphasizing that such studies are essential not only for understanding therapeutic effects, but also for identifying why some patients continue to progress despite treatment.

Editors’ Note: Bjornstad reports relevant disclosures with AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli-Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma, and others.

References

1. Cherney DZI, Belmar N, Bjornstad P, et al. Rationale, design and baseline characteristics of REMODEL, a mechanism-of-action trial with semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant. 2025;40(11):2182-2192. doi:10.1093/ndt/gfaf114

2. Brooks A. FDA Approves Semaglutide (Ozempic) for Type 2 Diabetes, Chronic Kidney Disease. HCPLive. January 28, 2026. Accessed March 28, 2026. https://www.hcplive.com/view/fda-approves-semaglutide-ozempic-type-2-diabetes-chronic-kidney-disease