TOPIC: This systematic review and meta-analysis evaluates whether semaglutide use, compared with non-GLP-1 receptor agonist therapies, is associated with non-arteritic anterior ischemic optic neuropathy (NAION).
CLINICAL RELEVANCE: NAION 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 PRISMA 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) and/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 GRADE.
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%CI, 0.59-10.15; I=99.34%; very low certainty). Time-stratified ORs at 1-3 years were likewise non-significant (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 one 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. 2 2 2
CONCLUSIONS: 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.
