GLP-1 Receptor Agonists and Narrow-Therapeutic-Index Drug Failure: A FAERS Disproportionality Analysis

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying and cause rapid weight loss, which may alter the exposure to co-administered oral drugs with a narrow therapeutic index (NTI).To assess the disproportionate reporting of failure and toxicity of NTI and critical-efficacy oral drugs co-reported with semaglutide or tirzepatide. We performed a disproportionality analysis of all public quarterly files of the US FDA Adverse Event Reporting System (FAERS), Q4 2017–Q2 2026, following READUS-PV. Index drugs were levothyroxine, oral contraceptives, warfarin, lithium, and antiepileptics; non-oral contraceptives were used as a negative control. We estimated crude and adjusted reporting odds ratios (aROR) against SGLT2 and DPP-4 inhibitor comparators and information components (IC025); a signal required a lower 95% CI above 1 and IC025 > 0. We also assessed Ω interaction, Weibull time to onset, nine sensitivity analyses, and individual lithium toxicity cases. Of 12,469,961 deduplicated reports, 28,208 listed an index drug with a GLP-1 RA (7,435) or a comparator (20,773). No failure outcome was observed, including levothyroxine failure (aROR 0.94, 95% CI 0.82–1.09) and oral contraceptive failure (aROR 1.15, 0.66–2.00). Lithium toxicity was the only outcome that met all signal criteria (73 cases; aROR 3.10, 1.94–4.95; IC025 0.23; Ω025 0.24), with both semaglutide (aROR 2.61) and tirzepatide (aROR 5.78); vomiting was co-reported in 26 of the 73 cases. It persisted without literature-based reports (aROR 2.21, 1.33–3.65) but was not significant in reports received before June 2025 (aROR 1.46, 0.79–2.70). Levothyroxine toxicity was modestly increased (aROR 1.54, 1.08–2.20) without meeting signal criteria. GLP-1 RAs were not associated with disproportionate reporting of NTI drug failure. Lithium toxicity was a consistent signal, compatible with reduced lithium clearance during gastrointestinal fluid loss. Lithium levels and thyroid function in levothyroxine users should be monitored when GLP-1 RAs are initiated or escalated. These hypothesis-generating findings require confirmation in clinical data.