Semaglutide Potentially Protective Against Nephrotoxicity Caused by Lithium

Semaglutide may have a protective effect on renal injury associated with lithium, new research shows.¹ Concomitant administration of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and lithium was not shown to increase nephrotoxicity, and lithium alone was found associated with increased renal adverse events.

The study included data on renal adverse events reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System between December 2003 and December 2024. Investigators computed reporting odds ratios (RORs) for terms renal impairment, renal failure, chronic kidney disease (CKD), end-stage renal disease (ESRD) and acute kidney injury (AKI) in association with lithium, semaglutide, or coreporting. These adverse events were chosen due to their documented association with lithium-induced nephrotoxicity.² Analysis was limited to reports that identified lithium or semaglutide as the primary suspect drug, in order to maintain attribution of the drug to the adverse event. Reporting odds ratio was defined as the odds of a renal adverse event occurring with a given drug relative to all other drugs in the database used. For a disproportionality signal, P < 0.05 was chosen for significance, and the lower bound for the information component was greater than 0; these selections reduced the likelihood of false positive findings.

Study author Roger McIntrye, MD, FRCPC, commented to Psychiatric Times that “as a clinician for 3 decades in the space of bipolar disorder, it has been absolutely heartbreaking to see patients having to stop lithium because of lithium-induced nephrotoxicity—especially when it's been the only drug that has saved their life.”

Lithium was found to be associated with significantly elevated reports of any renal adverse events. Concomitant administration of lithium with semaglutide did not show an increase in nephrotoxicity, while disproportionality estimates for each endpoint of renal adverse events with lithium were significant and exceeded thresholds. For lithium, the estimates were: renal impairment (ROR=4.98, P < 0.0001), renal failure (ROR=4.11, P < 0.0001), CKD (ROR=8.15, P < 0.0001), ESRD (ROR=9.55, P < 0.0001), and AKI (ROR=8.17, P < 0.0001). On the other hand, semaglutide showed inverse associations with renal impairment (ROR=0.54, P < 0.0001), renal failure (ROR=0.51, P < 0.0001), CKD (ROR=0.42, P < 0.0001), ESRD (ROR=0.25, P=0.0001), and the association with AKI was neutral (ROR=0.96, P=0.51). No semaglutide outcomes met the disproportionality threshold, and there were no reported cases of renal impairment, renal failure, CKD, or ESRD for coadministered lithium and semaglutide. Semaglutide’s known renal protective effects along with these findings indicate potential for semaglutide to mitigate risk or modify trajectory of nephrotoxicity caused by lithium.

McIntyre added that “this is one of the most important questions in psychopharmacology and psychiatry: trying to find a fit-for-purpose treatment for lithium-induced kidney injury, which is a major problem and barrier to prescription or continuation of a treatment that's the most life saving in bipolar disorder.”

Investigators noted these results may provide preliminary support for GLP-1 RAs as having a protective effect on lithium-associated renal injury.³ However, they pointed out that this database analysis is not able to establish causation and this sole study cannot be taken as evidence that GLP-1 RAs offer a true protective effect. The study notes that further research should be conducted on whether semaglutide or other incretin receptor agonists have nephroprotective effects in individuals taking lithium.

References

1. McIntyre RS, Kwan A. Potential protective role of GLP-1 receptor agonists and lithium-induced nephrotoxicity: a population-based observational study. CNS Spectr. Published online November 12, 2025. https://pubmed.ncbi.nlm.nih.gov/41220244/

2. Davis J, Desmond M, Berk M. Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification. BMC Nephrol. 2018;19(1):305.

3. J C, Me C, Mt C. Renoprotective mechanisms of glucagon-like peptide-1 receptor agonists. Diabetes Metab. 2025;51(3):101641.