REMODEL: Semaglutide Shows Secondary Kidney Signals Despite Null Coprimary Results

Once-weekly subcutaneous semaglutide did not significantly change coprimary MRI measures of kidney oxygenation, perfusion, or inflammation compared with placebo in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD), although several secondary measures differed, according to results of the REMODEL trial published in Nature Medicine.

REMODEL (NCT04865770) was designed as a mechanistic companion study to the phase 3 FLOW trial to identify kidney-specific mechanisms of action for the glucagon-like peptide-1 (GLP-1) receptor agonist. Investigators combined multiparametric MRI with paired kidney biopsies for histology, single-nucleus RNA sequencing, and spatial transcriptomics. The trial was funded by Novo Nordisk.

A total of 106 participants at 28 sites in 8 countries were randomized 2:1 to semaglutide titrated to 1mg once weekly or placebo for 52 weeks. The coprimary outcomes of cortical oxygenation, global kidney perfusion, and T1 mapping did not differ significantly between groups. Semaglutide was associated with a lower renal artery resistive index (estimated treatment ratio [ETR], 0.96; 95% CI, 0.93-0.99) and a higher cortical apparent diffusion coefficient (ETR, 1.05; 95% CI, 1.01-1.09), which the authors said indicated attenuation of fibrosis progression.

In exploratory analyses, semaglutide reduced the urinary albumin-to-creatinine ratio by 40% versus placebo, and perirenal and sinus fat volumes were 25% and 13% lower, respectively. Transcriptomic analyses identified glomerular endothelial cells as the most semaglutide-responsive cell populations. Serious adverse event rates were similar between groups, but discontinuation due to adverse events was more frequent with semaglutide (12.7% vs 2.9%). No biopsy-related serious adverse events occurred.

The investigators noted that the study was likely underpowered to detect modest chronic changes in oxygenation, that no formal hypothesis testing or multiplicity adjustment was planned, and that relationships among imaging, tissue, and clinical outcomes should be interpreted as associative rather than causal. Women made up 23.6% of participants. The authors concluded that kidney protection with semaglutide may involve reduced vascular resistance, prevention of fibrosis, and improved molecular programs supporting endothelial cell health.

Source: Tuttle KR, Bjornstad P, Smith C, et al. Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial. Nat Med. Published online October 1, 2026. doi:10.1038/s41591-026-04674-2