Comparative Risk of Nonarteritic Anterior Ischemic Optic Neuropathy Among Glucagon-Like Peptide-1 Receptor Agonists: An Integrated Safety and Mechanistic Analysis

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Abstract

[AIMS] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for Type 2 diabetes (T2DM) and obesity, but emerging evidence links them to nonarteritic anterior ischemic optic neuropathy (NAION). Whether this risk differs across agents and the underlying mechanisms remains unclear. We aimed to compare the risks of NAION associated with different GLP-1RAs and to explore the potential molecular mechanisms underlying this adverse reaction. [MATERIALS AND METHODS] A network meta-analysis was performed to quantitatively compare the differences in NAION risk. Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) were used for validation. Network toxicology was further applied to identify central hub targets and signalling pathways. Molecular docking was conducted to evaluate the binding capacity of GLP-1RAs to central hub targets. [RESULTS] The network meta-analysis revealed significant differences in NAION risk across GLP-1RAs. Compared with non-GLP-1RA treatments, semaglutide showed the highest risk (HR = 1.538, 95% CI: 1.305-1.816), followed by liraglutide (HR = 1.251, 95% CI: 1.080-1.450). FAERS pharmacovigilance analysis suggested a strong disproportionate signal for semaglutide (ROR = 94.534, 95% CI: 83.093-107.552) and a statistically significant but weaker signal for liraglutide (ROR = 4.519, 95% CI: 2.617-7.802). Network toxicology identified CASP3 as the central hub target, and pathway enrichment analysis revealed that the underlying mechanisms were primarily related to Alzheimer's disease, neurodegeneration pathways, and lipid and atherosclerosis pathways. Molecular docking suggested that semaglutide and liraglutide had high binding affinity to CASP3. [CONCLUSIONS] The combined strategy of network meta-analysis, pharmacovigilance, network toxicology and molecular docking provides insights into possible risk differences and potential mechanisms, and may guide future research on the safety profile of GLP-1RAs.

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