Lithium toxicity following a change from semaglutide to tirzepatide for weight loss management

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for weight management. Although generally well-tolerated, these agents may alter the pharmacokinetics of concurrently administered medications.

A 23-year-old male with schizoaffective disorder, bipolar type, developed lithium toxicity shortly after switching from semaglutide to tirzepatide. While taking semaglutide, the patient was started on lithium and titrated to 1800 mg nightly, corresponding to a level of 0.9 mEq/L. Four days after his first dose of tirzepatide, he reported early symptoms of potential lithium toxicity, which progressed significantly after the second dose. Symptoms corresponded to a 15-hour post-dose level of 1.7 mEq/L, despite no changes in renal function, hydration status, or other concurrent medications. Management with intravenous fluids was sufficient, and lithium dose reduction prevented future toxicity.

Application of the Drug Interaction Probability Scale suggests a probable interaction between tirzepatide and lithium. The interaction might be mediated through delayed gastric emptying or other pharmacokinetic changes. Limited reports of GLP-1-modulating agents associated with lithium toxicity have been published and may be an underrecognized phenomenon. To date, no pharmacokinetic studies have been published evaluating this potential drug-drug interaction. Although many other medications seem to be at risk for decreased absorption, tirzepatide may enhance the absorption of lithium.

Clinicians should be vigilant when initiating or switching GLP-1-modulating agents in patients receiving lithium. Pharmacokinetic studies are needed to clarify the mechanism of this interaction. Until more is known, increased monitoring of lithium levels is warranted, with initiation of a GLP-1-modulating agent, a dose change, or switching to another agent.