Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy: Notoriety Bias or True Ocular Toxicity?

Objective: To determine whether the semaglutide-NAION association reflects true toxicity or reporting bias. Research design and methods: We performed temporal disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data (2018Q1-2026Q2) to detect reporting anomalies and class-level spillover, and GLP1R cis-eQTL drug-target Mendelian randomization (MR) of NAION-relevant ocular phenotypes to test causal effects of GLP1R activation on semaglutide-relevant ocular toxicity. Results: Semaglutide ROR was 116.8 (95% CI 106.8-127.7). FAERS rates rose from below 8 per 10,000 annually (2018-2023) to 52 (2024), 177 (2025), and 203 (2026H1) after July 2024 publication, while comparators remained stable. Median time to onset was 246 days (Weibull {beta} = 1.09), a random-type profile inconsistent with cumulative toxicity. These anomalies were complemented by GLP1R-targeted MR evidence: no causal effect of genetically proxied GLP1R activation (all P [≥] 0.11), while confirming glucose-lowering (P = 7.6E-6). Conclusions: Pharmacovigilance and genetic evidence converge to show that the semaglutide-NAION signal reflects notoriety bias rather than toxicity.