High-Dose Semaglutide Preserves Kidney Function, Reduces Inflammation in Obesity Without Diabetes

A post hoc analysis of the phase 3 STEP UP trial found that semaglutide 7.2 mg and 2.4 mg were each associated with significant increases in estimated glomerular filtration rate measured by the creatinine-cystatin C equation (eGFRcre-cys) compared with placebo at 72 weeks in adults with obesity who did not have diabetes.

The findings, which were presented at at the American Diabetes Association (ADA) Scientific Sessions 2026 in New Orleans, Louisiana, by Peter Rossing, MD, PhD, showed both semaglutide doses also produced significantly greater reductions in high-sensitivity C-reactive protein (hsCRP) versus placebo, suggesting a measurable reduction in systemic inflammation alongside the observed renal benefit.

The analysis adds to a growing body of evidence examining the renal and inflammatory effects of GLP-1 receptor agonist therapy in populations beyond T2D, with methodological attention paid to a key limitation of standard eGFR measurement in the setting of substantial weight loss.

Why eGFRcre-cys Matters in Weight Loss Trials

Standard creatinine-based eGFR (eGFRcre) is subject to confounding by reductions in muscle mass that accompany significant weight loss, a recognized limitation when assessing kidney function changes in obesity trials. Investigators used both the CKD-EPI 2021 creatinine equation and the combined creatinine-cystatin C equation to characterize eGFR changes, with the latter considered less susceptible to weight loss-related muscle mass reduction.

At week 72, eGFRcre ratios to baseline were similar across all three groups, with few participants shifting eGFR category, a pattern the investigators attributed in part to the confounding effect of lean mass loss on creatinine-based estimates. In contrast, eGFRcre-cys increased significantly with both semaglutide 7.2 mg and 2.4 mg versus placebo (estimated treatment difference [ETD] at week 72, 3.31 mL/min/1.73 m2; 95% CI, 1.63–5.00; P <.001 and 3.21 mL/min/1.73 m2; 95% CI, 1.08–5.33; P = .001, respectively), and more participants in both active treatment groups shifted to the eGFRcre-cys ≥90 mL/min/1.73 m2 category by week 72.

STEP UP Trial Design and Kidney Outcome Findings

The STEP UP trial randomly assigned adults with obesity but without diabetes to once-weekly subcutaneous semaglutide 7.2 mg (n = 1005), semaglutide 2.4 mg (n = 201), or placebo (n = 201). The present post hoc analysis assessed changes in eGFRcre, eGFRcre-cys, eGFR category shifts, and hsCRP from baseline to week 72 using observed values from the on-treatment period.

At baseline, approximately two-thirds of participants across all groups had normal kidney function, defined as eGFRcre ≥90 mL/min/1.73 m2 (67.3%, 70.6%, and 69.7% in the semaglutide 7.2 mg, 2.4 mg, and placebo groups, respectively). Baseline mean eGFRcre values were 99.0 mL/min/1.73 m2, 100 mL/min/1.73 m2, and 99.2 mL/min/1.73 m2 across the 3 groups.

Regarding hsCRP, both semaglutide groups demonstrated significantly greater median reductions from baseline versus placebo at week 72 (estimated treatment ratio [ETR], 0.42; 95% CI, 0.36–0.50; P <.001 for 7.2 mg vs placebo and 0.47; 95% CI, 0.38–0.58; P <.001 for 2.4 mg vs placebo), reflecting reduced systemic inflammation. The difference between the 2 semaglutide doses for hsCRP reduction was not statistically significant (ETR, 0.90; 95% CI, 0.77–1.05; P = .24).

Semaglutide Mechanism and Renal Relevance in Obesity

Semaglutide is a GLP-1 receptor agonist approved at 2.4 mg weekly (Wegovy, Novo Nordisk) for chronic weight management in adults with obesity or overweight with ≥ 1 weight-related comorbidity, and at lower doses (Ozempic) for glycemic management and cardiovascular risk reduction in T2D.

Most recently, the US Food and Drug Administration approved higher dose semaglutide injection 7.2 mg to be used along with a reduced calorie diet and increased physical activity to help adults with obesity lose weight and keep it off, provided they have tolerated the 2.4 mg dosage for ≥ 4 weeks and additional weight reduction is clinically indicated. The approval was based on the results from the STEP UP trial program.

GLP-1 receptors are expressed in the kidney, and preclinical and clinical data have suggested potential renoprotective effects of GLP-1 receptor agonism independent of glucose lowering, including reductions in intraglomerular pressure and inflammation. In populations with obesity but without T2D, the renal implications of sustained GLP-1 receptor agonist therapy have been less extensively characterized, making data from STEP UP of potential interest for understanding the drug class's broader organ-level effects.

References

1. Rossing P, Jacobsen CSF, HjelmesÆth J, et al. High-Dose Semaglutide Is Associated with Preservation of Kidney Function in People Living with Obesity without Diabetes. Presented at American Diabetes Association (ADA) Scientific Sessions 2026 in New Orleans, Louisiana, June 5-8, 2026.

2. Górriz JL, Soler MJ, Navarro-González JF, et al. GLP-1 receptor agonists and diabetic kidney disease: a call of attention to nephrologists. J Clin Med. 2020;9(6):1853.

3. Brooks A. FDA Approves Higher Dose Semaglutide (Wegovy HD) Injection 7.2 mg for Obesity. HCPLive. March 19, 2026. Accessed June 5, 2026. https://www.hcplive.com/view/fda-approves-higher-dose-semaglutide-wegovy-hd-injection-7-2-mg-for-obesity