Glucagon-like Peptide-1 Receptor Agonists and Risk of Nonarteritic Anterior Ischemic Optic Neuropathy: Systematic Review and Meta-Analysis

Clinical Snapshot

Key Findings

• P Value: P(RR > 1): 99.9%

• Effect Size: RR 2.52 for semaglutide versus non-GLP-1RA users

• Primary Outcome: NAION incidence in GLP-1RA users versus non-users

• Nnt Or Sensitivity: Incidence rate: 118 cases per 100,000 semaglutide users (95% CrI [32, 451])

• Confidence Interval: 95% CrI [1.56, 4.72]

Clinical Application

Requires enhanced ophthalmological surveillance and patient counselling regarding NAION risk Relevant to PBS-subsidised GLP-1RAs; aligns with TGA post-market surveillance requirements and RACGP diabetes management guidelines requiring comprehensive risk assessment Patients with diabetes or obesity considering GLP-1RA therapy, particularly semaglutide

Abstract

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], I2: 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], I2: 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], I2: 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], I2: 98.8%, P(incidence >0.00001): 100%). Leave-one-out sensitivity analyses consistently supported these findings. 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.

References

1. 1.Dhivagaran, T., Butt, F., Arunasalam, L., Bae, I., Mikhail, D., Tao, B. K., Xie, J. S., Balas, M., Popovic, M., & Margolin, E. (2026). Glucagon-like Peptide-1 Receptor Agonists and Risk of Nonarteritic Anterior Ischemic Optic Neuropathy: Systematic Review and Meta-Analysis. Neurology. https://doi.org/10.1212/WNL.0000000000214864