Safety Signals of GLP ‐1 Receptor Agonists: A Multi‐Method Pharmacovigilance Analysis of FAERS (2018–2025) With Sensitivity‐Stratified Prioritisation, Notoriety‐Bias Assessment, and Cross‐Database Validation

BACKGROUND: GLP-1 receptor agonists (GLP-1 RAs) are widely prescribed for type 2 diabetes and obesity, but their post-marketing safety profile-particularly psychiatric, vascular, neoplastic and rare ophthalmic events-remains incompletely characterised and is vulnerable to confounding by indication, secondary-suspect attribution and notoriety bias. METHODS: We analysed 32 quarterly FAERS files (2018Q1-2025Q4): 288408 unique GLP-1 RA reports versus 11 319 150 non-GLP-1 RA reports. Disproportionality used four methods (reporting odds ratio [ROR]; proportional reporting ratio [PRR]; Bayesian Confidence Propagation Neural Network information component, lower 95% bound [BCPNN IC025]; Multi-item Gamma Poisson Shrinker empirical Bayes lower 5th-percentile bound [MGPS EB05]; signal = ≥ 3 of 4). The top 30 ROR-ranked signals were stratified by primary-suspect (PS) sensitivity. Triangulation included active-comparator, intra-class psychiatric comparison, interrupted time-series assessment of reporting around the 2023 EMA announcement, Weber-effect evaluation with Cochran-Armitage trend testing, and external validation in JADER. RESULTS: Of 22 059 PT-class pairs, 544 met the ≥ 3-of-4 criterion. PS-stratification retained 21 of the top 30 signals and demoted 9 as secondary-suspect-driven (e.g., capillaritis ROR 18.6 → 0.27; heart sounds 84.3 → 0.55). PS-stable headline signals were dominated by gastrointestinal/hepatobiliary effects: cyclic vomiting syndrome (ROR 64.8; semaglutide-dominant), gallbladder injury (84.2), impaired gastric emptying (45.1), plus liraglutide-concentrated medullary thyroid cancer (41.1) and semaglutide-concentrated optic ischaemic neuropathy (26.5). Only semaglutide carried a class-level suicidal-ideation signal (ROR 2.30). Interrupted time series detected no level (p = 0.39) or slope change (p = 0.75) at the 2023 EMA announcement; psychiatric time-to-onset (median 47 days) aligned with early GI reactions. Sixteen of 17 priority signals (94.1%) replicated in JADER. As disproportionality analyses, these are hypothesis-generating safety signals and cannot establish incidence, relative risk, or causality.