BACKGROUND AND OBJECTIVES: Recent observational studies have reported conflicting evidence regarding an association between glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, and nonarteritic anterior ischemic optic neuropathy (NAION). We aimed to synthesize the pooled evidence assessing the association between GLP-1RA use and NAION risk.
METHODS: Embase, Medline, and Cochrane CENTRAL databases were searched from inception to April 5, 2025. Observational studies and randomized controlled trials comparing NAION risk in GLP-1RA users with non-GLP-1RA users were included. Title/abstract and full-text screening were conducted in duplicate by 2 independent reviewers. Discrepancies were resolved through discussion or adjudication by a third reviewer. Risk of bias was assessed using the Risk of Bias In Nonrandomized Studies of Interventions (ROBINS-I) tool, and the certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation framework. Pooled relative risks (RRs) were estimated using Bayesian random-effects models, incorporating half-normal, between-study, and weakly informative priors. The RR with 95% credible interval (CrI) was computed to analyze the development of NAION associated with GLP-1RA exposure.
RESULTS: Five studies were included in the primary analysis, encompassing 1,593,554 patients (682,456 semaglutide users and 911,098 non-GLP-1RA users). Semaglutide use was associated with a high probability of increased risk of NAION compared with non-GLP-1RA use (RR: 2.52, 95% CrI [1.56, 4.72],: 57.8%, P(RR > 1): 99.9%). This association was particularly pronounced among patients with diabetes (RR: 2.41, 95% CrI [1.57, 4.10],: 47.2%, P(RR > 1): 99.9%). The overall incidence of NAION across 5 studies and 7 comparisons, encompassing 1,460,760 patients (semaglutide: 1,108,542; dulaglutide: 326,282; and exenatide: 25,936) and 272 NAION events (semaglutide: 198; dulaglutide: 54; and exenatide: 20) was 85 cases per 100,000 GLP-1RA users (95% CrI [29, 263],: 98.8%, P(incidence >0.00001): 100%). The incidence of NAION across 1,108,542 semaglutide users was 118 cases per 100,000 (95% CrI [32, 451],: 98.8%, P(incidence >0.00001): 100%). Leave-one-out sensitivity analyses consistently supported these findings. I I I I2 2 2 2
DISCUSSION: Low-to-moderate certainty evidence indicates that semaglutide significantly increases risk of NAION relative to non-GLP-1RAs, particularly among patients with diabetes. These findings warrant further investigation and should inform clinical risk-benefit discussions.
