Semaglutide and Non-arteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Narrative Synthesis

Background/Objective: Recent observational studies report conflicting evidence on whether semaglutide use is associated with non-arteritic anterior ischemic optic neuropathy (NAION). This systematic review synthesizes available evidence and critically evaluates bias and confounding. Case Report: PubMed, Embase, and the Cochrane Library were searched through December 2025 for observational studies assessing semaglutide and NAION. Two reviewers independently screened records, extracted data, and assessed study quality using the Newcastle-Ottawa Scale. Owing to substantial clinical and methodological heterogeneity, results were synthesized narratively. Discussion: Nine large retrospective cohort studies, encompassing more than 3 million patients, and one major regulatory review were included. Findings were sharply divided. Four studies reported statistically significant increased risk, with hazard ratios ranging from 1.76 to 4.28. Four studies found no significant association, while one suggested a protective effect (odds ratio 0.36). All studies were of moderate quality and exhibited high risk of bias in cohort comparability. Notably, studies using broad or untreated comparators consistently reported elevated risk, whereas studies employing active comparators with similar metabolic risk profiles generally found no association. Conclusion: Current evidence does not support a causal relationship between semaglutide and NAION. The divergent findings are most plausibly explained by confounding by indication: patients prescribed semaglutide tend to have more severe diabetes, obesity, and cardiovascular disease, all independent risk factors for NAION. Even under the highest reported relative risk estimates, the absolute risk remains very low and is outweighed by well-established cardiovascular and renal benefits of semaglutide. Definitive clarification will require prospective studies with standardized ophthalmologic adjudication and measurement.