GLP-1 Drugs Linked to Small but Worrying Increase in Wet AMD Risk

Researchers speculate that GLP-1 drugs can enhance VEGF expression, thereby stimulating angiogenesis. Photo: Carolyn Majcher, OD. Click image to enlarge. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), in widespread use to treat diabetes and obesity, have also demonstrated off-label benefits for a multitude of conditions, including cardiovascular disease, hypertension, Parkinson’s, Alzheimer’s and some addictive disorders. Their neuroprotective effects are even thought to extend to the optic nerve. However, many researchers are concerned about potential ocular adverse effects with continued use of these medications, most notoriously the controversy about a potential increased risk of ischemic optic neuropathy that has generated several research papers—often contradictory—since last summer.In that environment of uncertainty comes a new study published last Thursday in JAMA Ophthalmology demonstrating that more than twice as many patients with diabetes exposed to GLP-1 agonists developed neovascular age-related macular degeneration (wet AMD) compared with those in a matched cohort of similar patients who were unexposed.1 The reported hazard ratio was 2.21, and the absolute risk difference was 0.11%.“These findings suggest clinicians should be aware of the potential ocular complications associated with GLP-1 RA use and are encouraged to report any suspected adverse events to postmarketing pharmacovigilance systems to facilitate safety tracking and raise public awareness,” the study authors wrote in their paper.This population-based, retrospective cohort study was conducted from January 2020 to November 2023, with a follow-up period of three years. The researchers used comprehensive administrative health and demographic data from patients in Ontario, in the context of a universal public health care system. A total of 46,334 patients who used GLP-1 drugs for at least six months were 1:2 propensity score matched to 92,668 control participants with diabetes with no exposure. Among these 139,002 matched patients, mean patient age was 66.2, and 46.6% were women.Over a mean follow-up period of 2.4 years, 0.2% of the GLP-1 receptor agonist  cohort progressed to wet AMD compared with only 0.1% of control participants, resulting in an increased hazard for wet AMD of 2.21 for the GLP-1 RA cohort. The study team proposed that GLP-1 receptor blockade via GLP-1 RAs stimulates the cytokine CXCL12, which may enhance VEGF expression, resulting in elevated wet AMD risk.The researchers noted that further research is needed to elucidate the exact pathophysiological mechanisms involved and to understand the trade-offs between the benefits and risks of GLP-1 receptor agonists. They emphasized that their study did not stratify by the type of GLP-1 RA prescribed. As such, their findings should not be generalized to specific brand-name drugs. Their analysis was also not able to account for the dose, route of administration or frequency of administration of GLP-1 RAs, given that this information was not regularly reported in the databases used.1A commentary also published in JAMA Ophthalmology remarked that this study “suggests as many as one in 1,000 GLP-1 RA users could progress to wet AMD over unexposed patients; if this risk was carried over millions of users, those affected could end up being a sizable group of patients.”2The commentary author also highlighted that the study focused on patients with diabetes who were older than 66 years and observed these patients for up to three years. Although not impossible, he found it unlikely that a person would progress from no AMD to wet AMD within three years. These findings would suggest there was an already at-risk group of patients with non-neovascular AMD within the cohort. He concluded that future work should focus on controlling for the baseline level of AMD to determine if it is, in fact, this subgroup driving the results seen.“GLP-1 RAs have had a tremendous role in the care of patients with diabetes and now those needing additional help with weight management,” he wrote. “While certainly not outweighing the good these medications offer, prescribing physicians need to keep in mind the real and serious ocular adverse events that may occur.”2Click here and here for the journal sources. 1. Shor R, Mihalache A, Noori A, et al. Glucagon-like peptide-1 receptor agonists and risk of neovascular age-related macular degeneration. JAMA Ophthalmol. June 5, 2025. [Epub ahead of print].2. VanderBeek BL. Should we be concerned about glucagon-like peptide-1 receptor agonists? JAMA Ophthalmol. June 5, 2025. [Epub ahead of print].