Association of Glucagon-Like Peptide-1 Receptor Agonists With Optic Nerve and Retinal Adverse Events: A Population-Based Observational Study Across 180 Countries

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are important therapeutic options for type 2 diabetes and obesity; however, concerns about ophthalmic safety persist. This study examined associations between GLP-1 RAs and ocular adverse events (AEs). Global observational pharmacovigilance study. We searched the US FAERS database (via OpenVigil 2.1) and WHO's VigiBase (via VigiAccess) for optic nerve and retinal AEs associated with semaglutide and tirzepatide, covering the period from their respective approval dates-December 2017 for semaglutide and May 2022 for tirzepatide-through September 2024. In FAERS, all other drugs were compared, while in VigiBase, metformin, empagliflozin, dulaglutide, and insulin served as controls. Disproportionality metrics included reporting odds ratios (RORs) with 95% confidence intervals. Semaglutide and tirzepatide accounted for 76,444 cases (0.59%) in FAERS (n=12,936,341) and 118,639 cases (0.34%) in VigiBase (n>35,000,000). Semaglutide showed significantly higher odds of ischemic optic neuropathy (ION) (FAERS: ROR=11.12, 95%CI=8.15-15.16; VigiBase: ROR=68.58, 95%CI=16.75-280.67), diabetic retinopathy (DR) (FAERS: ROR=17.28, 95%CI=13.62-21.91; VigiBase: ROR=7.81, 95%CI=5.60-10.90), as well as retinal/vitreous detachment, retinal/vitreous hemorrhage, and retinal tear (FAERS: ROR=2.44-5.89, 95%CI=1.70-8.97, all p<0.001, IC025=0.49, compared to all other drugs. VigiBase: ROR=5.49-20.91, 95%CI=2.71-90.11, all p≤0.0001, IC025≥0.53, compared to metformin). Unique to VigiBase were macular edema (ROR=3.87, 95%CI=1.89-7.92), macular hole (ROR=20.90, 95%CI=2.65-165.01), and papilledema (ROR=6.97, 95%CI=2.53-19.17) (all p≤0.004, IC025≥0.27, compared to metformin). Sensitivity analyses using empagliflozin and dulaglutide revealed significant associations with ION and DR, while vitreous detachment and hemorrhage were significant when compared to dulaglutide. Additionally, when insulin was used as a comparator, semaglutide showed a higher ROR for ION (ROR=9.84, 95%CI=4.25-22.81, P<0.0001, IC025=0.42). However, tirzepatide was only significantly associated with DR in FAERS. Given the widespread use of semaglutide, its association with ocular AEs highlight the need for global pharmacovigilance and post-marketing surveillance.