Global Study Links GLP-1 Drugs to Various Optic Nerve, Retinal AEs

New evidence links GLP-1 receptor agonists—a rapidly growing drug class for type 2 diabetes and obesity—to increased risk of ocular adverse events on an international scale. Until more studies are completed to clarify the mechanisms behind these associations, clinicians should be mindful of these risks in GLP-1 users. Photo: Novo Nordisk. Click image to enlarge. Given the recent influx of evidence suggesting a connection between the popular diabetes and weight loss drug, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and various ocular adverse events, a new study aimed to investigate this potential association on a global scale. Its findings, published recently in the American Journal of Ophthalmology, revealed a notable correlation between semaglutide, the most commonly prescribed GLP-1 RA, and increased incidents of ischemic optic neuropathy, diabetic retinopathy and several other retinal and vitreous issues. The study drew data from two major sources: the US FDA Adverse Event Reporting System (FAERS) and WHO’s VigiBase. It encompassed reports filed from December 2017 to September 2024, marking the respective approval dates of two GLP-1 RAs, semaglutide and tirzepatide. Both drugs were evaluated for their association with optic nerve and retinal adverse events and compared with metformin, empagliflozin, dulaglutide and insulin.Findings showed that within the 12,936,341 cases reported in FAERS, semaglutide and tirzepatide contributed to 76,444 cases (0.59%). In WHO’s VigiBase, which documented over 35 million cases, these drugs accounted for 118,639 instances (0.34%). Semaglutide was notably associated with high risks of ischemic optic neuropathy and diabetic retinopathy; in FAERS, the reporting odds ratio for ischemic optic neuropathy was 11.12; for diabetic retinopathy, it was 17.28. In VigiBase, these ratios were 68.58 and 7.81, respectively. The drug was also linked with significant increases in retinal/vitreous detachment, retinal/vitreous hemorrhage and retinal tears. Moreover, while exclusive to VigiBase, semaglutide users also demonstrated a higher risk of macular edema, macular hole and papilledema.In contrast with semaglutide, tirzepatide showed limited associations with ocular adverse events. In FAERS, this GLP-1 RA showed a notable connection with diabetic retinopathy, but its effect was not as prominent in other conditions when compared to other drugs like insulin. “This discrepancy may arise from tirzepatide’s unique dual GLP-1 and GIP receptor agonist mechanism and lower GLP-1 receptor affinity, affecting ocular vascular and metabolic responses differently than semaglutide,” the authors explained in their AJO report. “Differences in receptor binding and pharmacodynamics could explain this observation, but further investigation is needed to determine whether the differences stem from drug properties, population characteristics or both.”The authors also disclosed their inability to establish causality for the association between semaglutide and ocular AEs, noting that the biological mechanisms remain unclear. “Although GLP-1 receptors in the retina, ganglion cells and central nervous system play a neuroprotective role by suppressing neuroinflammation—suggesting no direct causality—the rapid normalization of glycemic control and weight loss may disrupt pre-existing vascular stability, potentially increasing the risk of NAION,” they wrote. “Our sensitivity analysis with exenatide suggests that NAION may be unique to semaglutide, indicating a mechanism beyond transient glucose reductions associated with GLP-1 RAs.”The growing compendium of research exposing the ocular risks associated with GLP-1 RAs is concerning as the popularity of these drugs continues to rise, though more prospective studies are still needed to clarify the mechanisms behind these associations. The study authors conclude by advising, “Until further evidence emerges, healthcare providers should be mindful of potential ocular risks in GLP-1 RA users.”Click here for the journal source. Lakhani M, Kwan ATH, Mihalache A, et al. Association of glucagon-like peptide-1 receptor agonists with optic nerve and retinal adverse events: a population-based observational study across 180 countries. Am J Ophthalmol. May 8, 2025. [Epub ahead of print].