We hypothesized that semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and treatment currently U.S. Food and Drug Administration (FDA) approved to reduce worsening of kidney disease and kidney failure may protect against lithium-induced nephrotoxicity.

Renal adverse events (AEs) reported to the FDA Adverse Event Reporting System (FAERS) between December 2003 and December 2024 were analyzed using the validated OpenVigil 2.1 platform. Reporting odds ratios (RORs) were computed for the MedDRA terms renal impairment, renal failure, chronic kidney disease (CKD), end-stage renal disease (ESRD), and acute kidney injury (AKI) in association with lithium, semaglutide, and their co-reporting. A disproportionality signal was considered statistically significant when p < 0.05, and the lower bound of the information component (IC025) was greater than 0.

Lithium was associated with significantly elevated reporting odds across all renal AEs, with each outcome exceeding statistical signal thresholds (p < 0.0001, IC025 > 0). In contrast, semaglutide demonstrated inverse associations for renal impairment, renal failure, CKD, and ESRD (RORs = 0.25–0.54), and a neutral association for AKI (ROR = 0.96); however, none met the criteria for a disproportionality signal (IC025 < 0). Co-reported use of lithium and semaglutide did not yield a significant signal for any renal outcome, including AKI (ROR = 5.81, p = 0.015, IC025 < 0).

This observation, provides impetus to conduct adequate, thorough, mechanistic, clinical, and observational studies to determine whether semaglutide (and/or other incretin receptor agonists) could possibly mitigate the risk for, and/or modify the trajectory of, lithium-induced nephrotoxicity.