Semaglutide and the Risk of Nonarteritic Ischemic Optic Neuropathy: A Systematic Review and Certainty of Evidence Meta-Analysis.

TOPIC: This systematic review and meta-analysis evaluates whether semaglutide use, compared with non-glucagon-like peptide-1 receptor agonist (GLP-1 RA) receptor agonist therapies, is associated with nonarteritic anterior ischemic optic neuropathy (NAION). CLINICAL RELEVANCE: Nonarteritic anterior ischemic optic neuropathy is a rare, vision-threatening optic neuropathy whose major risk factors overlap with populations prescribed semaglutide, making clarification of any associated risk clinically important for treatment decisions and patient counseling. METHODS: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was prospectively registered (PROSPERO CRD420251107346). Seven databases and Google Scholar were searched from inception to August 20, 2025. Eligible studies enrolled adults, compared semaglutide with non-GLP-1 RA users, and reported NAION as a distinct outcome with extractable odds ratios (ORs) or adjusted hazard ratios (aHRs). Two reviewers independently performed study selection, data extraction, and Newcastle-Ottawa risk of bias assessment. Random-effects models pooled ORs and aHRs. Prespecified subgroup analyses examined treatment indication. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Six observational studies (n = 4 831 654) met inclusion. In pooled OR analyses, semaglutide was not associated with a statistically significant increase in NAION compared with non-GLP-1 RA comparators (OR = 2.44; 95% confidence interval [CI], 0.59-10.15; I = 99.34%; very low certainty). Time-stratified ORs at 1 to 3 years were likewise nonsignificant (very low certainty). Compared with SGLT2 inhibitors, the pooled OR was 0.72 (95% CI, 0.38-1.35; I = 81.59%; very low certainty). In adjusted time-to-event analyses, the pooled aHR was 1.63 (95% CI, 0.88-2.39; I = 67.15%; low certainty). Exclusion of 1 influential study shifted the estimate (aHR = 1.92; 95% CI, 1.03-2.81; low certainty), indicating fragility. By indication, pooled aHRs were 1.70 (95% CI, 1.10-2.64; low certainty) for type 2 diabetes and 0.47 (95% CI, 0.19-1.13; moderate certainty) for obesity/overweight. Time-stratified aHRs were insufficient for meta-analysis. CONCLUSION: Across observational studies comparing semaglutide with non-GLP-1 RA therapies, pooled adjusted evidence does not demonstrate a consistent overall increase in NAION risk. However, estimates are limited by substantial heterogeneity, residual confounding, outcome misclassification, and fragility, resulting in low to very low certainty. Apparent indication-based differences should be interpreted cautiously and may reflect underlying disease-related risk rather than a drug-specific effect. Causality cannot be established, and further well-designed studies with standardized NAION ascertainment are needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.