Does Semaglutide Use Increase the Risk of Urinary Stone Disease?
Key Highlights
- Retrospective cohort of 30,954 adults initiating semaglutide or metformin.
- No significant difference in incident urinary stone disease
- Semaglutide group showed greater BMI reduction compared with metformin group
- Results do not support prior findings suggesting an elevated stone risk with glucagon-like peptide-1 receptor agonist therapy.
In a large retrospective cohort analysis presented at the American Society of Nephrology Kidney Week 2025, researchers assessed whether semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), affects the risk of incident urinary stone disease compared with metformin. The findings suggest no statistically significant association between semaglutide use and new-onset urinary stones, offering reassurance for clinicians prescribing GLP-1RAs to patients with obesity or type 2 diabetes.
Obesity is a well-established risk factor for urinary stone disease, driven by insulin resistance, altered urinary pH, and increased excretion of lithogenic solutes such as calcium and uric acid. GLP-1RAs, including semaglutide, are known to improve insulin sensitivity and promote weight loss, both of which might theoretically lower stone risk. However, prior data from the Veterans Health Administration unexpectedly suggested a higher incidence of stones among GLP-1RA users,2 prompting the need for confirmation in broader populations.
Using electronic health records from the Apollo dataset, investigators identified approximately 66 million patients with new prescriptions for semaglutide or metformin between January 2016 and December 2023. After high-dimensional propensity score matching, 15,477 matched pairs (n = 30,954) were included in the final analysis. Eligible patients had been treated for at least three months with either medication. The primary outcome was an incident diagnosis of urinary stone disease, defined by ICD-10 diagnostic or procedural codes.
The study population had a mean (SD) age of 51.8 (13.3) years for semaglutide users and 51.4 (15.9) years for metformin users; approximately 70% were female, and one-third had diabetes. The baseline BMI was higher in the semaglutide group (36.9 vs 35.8). Mean follow-up was 780 days for semaglutide and 1041 days for metformin.
During follow-up, no significant difference in urinary stone events was observed between groups (HR, 0.94; 95% CI, 0.83–1.06; P = .3). Among the subset of patients with BMI data (n = 5953), semaglutide users demonstrated a greater mean BMI reduction compared with metformin users (–1.7; 95% CI, –1.9 to –1.6; P < .001), consistent with the known metabolic effects of GLP-1RA therapy.
While the retrospective design and reliance on administrative data limit causal inference, the large sample size and propensity-matched design strengthen the validity of results.
“These findings do not demonstrate a statistically significant association between semaglutide use and incident urinary stone disease,” the authors concluded.
Future studies are needed to explore whether specific patient subgroups, such as those with prior nephrolithiasis or extreme obesity, experience different risk patterns.
References
- Ganesan C, Kim SH, Chang TC, Conti S, Leppert J, Pao AC. GLP-1 receptor agonist semaglutide and risk of incident urinary stone disease. Presented at: American Society of Nephrology Kidney Week; November 5–9, 2025; Houston, Texas. doi:10.1681/ASN.20253gqh8bva
- Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nature Medicine. Jan. 20, 2025. DOI: 10.1038/s41591-024-03412-w