From FLOW to REMODEL: Understanding Semaglutide in CKD, With Katherine Tuttle, MD

Chronic kidney disease (CKD) in the setting of type 2 diabetes represents one of the most high-risk clinical scenarios in medicine, driven not only by progression to kidney failure but by a substantial burden of cardiovascular morbidity and premature death.

While recent therapeutic advances have improved outcomes, understanding how these treatments exert their benefits has remained a critical gap. The REMODEL trial was designed to address this question, offering a detailed mechanistic complement to landmark outcome data on semaglutide’s benefit in this patient population.

In an interview with HCPLive at the World Congress of Nephrology (WCN) in Yokohama, Japan, Katherine Tuttle, MD, explained that REMODEL builds on the success of the FLOW trial, which demonstrated significant reductions in kidney events, cardiovascular outcomes, and all-cause mortality with semaglutide, ultimately leading to the agent’s US Food and Drug Administration approval for this indication. While those findings established clinical efficacy, they did not fully explain the underlying biology. REMODEL, she explains, was specifically designed as a mechanistic “deep dive,” integrating advanced imaging, kidney biopsy, and transcriptomic analyses to uncover how these benefits are achieved.

The study confirmed key clinical findings, including a 40% reduction in albuminuria and stabilization of kidney function. Of note, functional MRI revealed significant reductions in kidney fat far exceeding overall weight loss as well as improved vascular health, reflected by decreased renal arterial resistance. Markers of fibrosis progression were halted in the treatment group, suggesting a protective structural effect.

Biopsy data provided further depth. Tuttle highlights a marked reduction in peri-glomerular immune cells, particularly natural killer T cells, alongside broad downregulation of fibroinflammatory pathways, pointing to a direct anti-inflammatory effect within the kidney microenvironment. Transcriptomic analyses additionally identified glomerular endothelial cells as a key site of regulation, supporting the concept of improved integrity of the glomerular filtration barrier and even evidence of repair, not just stabilization, over time.

She emphasizes that these results align closely with preclinical models, strengthening confidence in translational research approaches. Beyond individual findings, the study design itself represents a major advance, demonstrating that rigorous mechanistic trials can be successfully conducted in humans.

Looking ahead, Tuttle underscores the implications for precision medicine. While current therapies are broadly applied, variability in response remains a major challenge. By linking mechanistic signatures to treatment outcomes, REMODEL provides a framework for identifying responders and tailoring therapy. Ultimately, she suggests, this approach could shift care toward selecting the right treatment for the right patient at the right time, marking a significant step forward in the management of diabetic kidney disease.

Editors’ note: relevant disclosures for Tuttle include Eli Lilly and Company, Boehringer Ingelheim, Astra Zeneca, Gilead, Goldfinch Bio, Novo Nordisk, Travere Therapeutics, and Bayer.

References

1. Campbell P. Semaglutide 1.0 mg (Ozempic) Reduced Kidney Events 24% in FLOW Trial. HCPLive. March 5, 2024. Accessed March 31, 2026. https://www.hcplive.com/view/semaglutide-1-0-mg-ozempic-reduced-kidney-events-24-in-flow-trial

2. Brooks A. FDA Approves Semaglutide (Ozempic) for Type 2 Diabetes, Chronic Kidney Disease. HCPLive. January 28, 2025. Accessed March 31, 2026. https://www.hcplive.com/view/fda-approves-semaglutide-ozempic-type-2-diabetes-chronic-kidney-disease

3. Pruijm M, Belmar N, Bjornstad P, et al. REMODELing mechanistic trials for kidney disease: a multimodal, tissue-centered approach to understand the renal mechanism of action of semaglutide. Kidney International. doi:10.1016/j.kint.2025.10.005