REMODEL Trial Identifies Potential Mechanisms of Semaglutide’s Kidney-Protective Effects

A new randomized, placebo-controlled study published in Nature Medicine provides further insight into the kidney effects of semaglutide in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). The 52-week REMODEL trial evaluated once-weekly subcutaneous semaglutide 1 mg versus placebo in 106 participants, using multiparametric kidney MRI, biopsy, histology and molecular profiling to investigate potential kidney-specific mechanisms.

The study was designed as a mechanistic companion to the FLOW trial, in which once-weekly semaglutide 1 mg reduced the risk of the primary kidney outcome by 24% in people with T2D and CKD. REMODEL was designed to investigate kidney-specific mechanisms that may contribute to semaglutide’s effects beyond changes in glycemia and body weight.

Study Population and Baseline Characteristics

REMODEL (NCT04865770) included 106 participants with T2D and CKD who were randomized 2:1 at 28 sites across eight countries between April 2021 and October 2023. Of these, 71 received semaglutide and 35 received placebo. The mean age was 65.3 years, mean creatinine-based eGFR was 51.1 mL/min/1.73 m², and median UACR was 187.3 mg/g. Women accounted for 23.6% of participants. Semaglutide was titrated to 1 mg once weekly during the 52-week treatment period.

Reduced Renal Vascular Resistance and Fibrosis-Related Changes

The three coprimary MRI outcomes, kidney oxygenation measured by R2*, global kidney perfusion and tissue inflammation assessed by T1 mapping, did not differ significantly between semaglutide and placebo after 52 weeks. However, several secondary outcomes showed significant changes.

The renal artery resistive index (RARI) decreased with semaglutide, with an estimated treatment ratio of 0.96 (95% CI, 0.93–0.99; P=0.008), indicating reduced renal vascular resistance. Cortical apparent diffusion coefficient (ADC) was also higher with semaglutide (ETR, 1.05; 95% CI, 1.01–1.09; P=0.005), while delta ADC showed an estimated treatment difference of 61.49 (95% CI, 11.40–111.58; P=0.016). The investigators interpreted these findings as consistent with attenuation of progressive kidney fibrosis.

Semaglutide was also associated with lower kidney-associated fat. After 52 weeks, perirenal fat volume was 25% lower and sinus fat volume was 13% lower than with placebo. These reductions were greater in relative terms than the approximately 5% mean body-weight reduction with semaglutide versus placebo, raising the possibility that organ-specific fat loss may contribute to kidney effects.

Albuminuria Decreased While Kidney Function Was Maintained

Twenty-four-hour urine creatinine clearance was higher with semaglutide, with an estimated treatment difference of 12 mL/min (95% CI, 0.7–23.3; P=0.038). UACR was 40% lower with semaglutide, with an estimated treatment ratio of 0.60 (95% CI, 0.41–0.88; P=0.008).

eGFR estimates numerically favored semaglutide, but their confidence intervals crossed zero. Treatment differences were 3.4 mL/min/1.73 m² for creatinine-based eGFR, 2.9 mL/min/1.73 m² for creatinine-cystatin C eGFR and 2.3 mL/min/1.73 m² for cystatin C-based eGFR. These findings support maintenance of kidney function rather than a statistically demonstrated improvement in eGFR.

Biopsy and Molecular Analyses Point Toward Endothelial Effects

In the biopsy subgroup, an exploratory analysis found that the fractional intimal area of the most diseased arterioles was 10% lower with semaglutide than placebo (95% CI, −18.9 to −1.0; P=0.032). Histological assessment also showed less periglomerular inflammatory infiltration after treatment.

Fifty-three kidney biopsy samples underwent single-nucleus RNA sequencing, with 22 paired samples contributing to treatment-response analysis. Glomerular endothelial-cell populations were among the most responsive cell populations, with many genes associated with metabolic stress, inflammation and fibrosis downregulated compared with placebo after 52 weeks. Exploratory spatial transcriptomics further identified fewer immune cells in proximity to glomerular endothelial cells after semaglutide treatment.

Multifaceted Kidney Effects and Study Limitations

Taken together, the REMODEL findings suggest that semaglutide’s kidney effects may involve multiple interconnected processes, including reduced renal vascular resistance, attenuation of fibrosis-related changes, reduction in kidney-associated fat and alterations in glomerular endothelial-cell molecular programs.

However, these relationships are associative rather than proof of causality. The exploratory design limited power for some imaging analyses, no multiplicity adjustment was applied, and the study was not powered for post hoc subgroup analyses. Additional limitations included under-representation of women, the relatively small number of biopsy samples available for spatial transcriptomics, and the absence of direct GFR and renal plasma-flow measurements using reference clearance methods.

Safety Profile

Serious adverse events occurred at similar rates between the treatment groups. Permanent discontinuation because of adverse events occurred in 12.7% (9/71) of semaglutide-treated participants compared with 2.9% (1/35) of placebo-treated participants. No serious biopsy-related adverse events were reported. The REMODEL trial was funded by Novo Nordisk A/S.

Overall, REMODEL provides a detailed tissue-level and functional perspective on potential kidney-specific effects of semaglutide. Although its three coprimary MRI outcomes were not significantly different between treatment groups, the secondary and exploratory imaging, clinical, histological and molecular findings provide mechanistic evidence for further investigation of how GLP-1 receptor agonism may influence kidney structure and function in people with T2D and CKD.

Reference

Tuttle KR, Bjornstad P, Smith C, et al. Effects of semaglutide on kidney disease in type 2 diabetes: a randomized placebo-controlled trial. Nature Medicine. Published October 1, 2026.

A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People with Type 2 Diabetes and Chronic Kidney Disease (the REMODEL Trial) (REMODEL), ClinicalTrials.gov ID NCT04865770