GLP-1 agonists may increase risk of neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in older adults. It is characterized by the progressive deterioration of central high-resolution vision, which is essential for daily activities, such as reading and driving. AMD primarily occurs in two forms: atrophic (dry) and neovascular (wet). The atrophic form is responsible for 85%–90% of AMD cases, but neovascular age-related macular degeneration (nAMD) is responsible for 90% of severe vision loss.1 Glucagon-like peptide-1 receptor agonists (GLP-1 RAs, e.g., semaglutide) are widely used in the treatment of diabetes and obesity, but little is known about their long-term ocular effects. Ocular adverse effects have been reported with GLP-1 RAs, including diabetic retinopathy and nonarteritic anterior ischemic optic neuropathy.1 It has been postulated that the rapid reduction in blood glucose levels triggered by GLP-1 RAs leads to a hypoxic state of the retina that promotes abnormal angiogenesis. As the underlying pathogenesis of nAMD involves abnormal and excessive angiogenesis, Toronto-based researchers aimed to evaluate the risk of developing nAMD associated with the use of GLP-1 RAs in patients with diabetes.1The population-based, retrospective cohort study used comprehensive administrative health and demographic data from patients in Ontario, collected by the Institute for Clinical Evaluative Sciences from universal public healthcare system databases. The study was conducted from January 2020 to November 2023, with a follow-up period of up to three years. The study included patients aged 66 years or older with a diagnosis of diabetes and a minimum follow-up period of 12 months following initial diabetes diagnosis. Patients were excluded if they had incomplete Ontario Health Insurance Plan or Ontario Drug Benefit data, were exposed to GLP-1 RAs for less than six months or were diagnosed with nAMD before or at the time of diagnosis of diabetes.1A total of 1,119,517 patients with diabetes were eligible for the study. The investigators created a 1:2 matched cohort of 139,002 patients, including 46,334 patients who were exposed to GLP-1 RAs for at least six months and 92,668 unexposed matched patients. Systemic comorbidities that were associated with any kind of AMD and socioeconomic status were used to calculate propensity scores. The primary outcome was the incidence and time to development of nAMD during the follow-up period (mean 2.4 years).1Results showed the following:Of the 139,002 matched patients, the mean age was 66.2 years and 46.6% were women.The predominant GLP-1 RA used was semaglutide (97.5%), followed by lixisenatide (2.5%).The incidence of newly diagnosed nAMD was higher among the cohort exposed to GLP-1 RAs compared to the unexposed cohort. Cox proportional hazard models, both unadjusted (crude) and adjusted, estimated hazard ratios for nAMD development of > 2.0 among patients exposed to GLP-1 RAs (exposed, 0.2% vs unexposed, 0.1%; difference, 0.1%; crude: HR, 2.11; 95%CI, 1.58–2.82; adjusted: HR, 2.21; 95%CI, 1.65–2.96).Longer durations of exposure to GLP-1 RAs were associated with a higher risk of nAMD. Risk was highest (more than 3 times as high) among patients with the longest exposure to GLP-1 RAs.Increased age and a history of a cerebrovascular accident were also associated with a substantially increased risk of nAMD in the adjusted model (age: HR, 1.12; 95% CI, 1.07–1.18; cerebrovascular accident: HR, 1.96; 95%CI, 1.15–3.34).1The authors conclude that in this cohort study, GLP-1 RA use by patients with diabetes was associated with a two-fold higher risk of new onset nAMD compared with similar patients with diabetes who did not receive a GLP-1 RA. They believe these findings expand upon the growing body of literature raising concerns regarding the potential ocular safety of GLP-1 RAs in patients with diabetes. However, they caution that their results demonstrate associations rather than cause and effect. Further research is needed to determine the exact pathophysiologic mechanisms involved, whether there is a true cause and effect relationship, and to understand the trade-offs between the benefits and risks of GLP-1 RAs in older adults with diabetes.1An accompanying commentary indicates that the results of this study suggest that as many as one in 1,000 GLP-1 RA users with diabetes could progress to nAMD compared with unexposed patients. If this risk was carried over millions of users, a sizable group of patients could end up being affected. However, it is unknown which patients are at highest risk of progressing to nAMD and this needs to be further studied. Researchers also need to determine if this adverse effect appears only in patients with diabetes or if those using GLP-1 RAs for weight management or other indications are also at risk. Semaglutide has been suggested to be the drug most associated with ocular adverse events and 97% of patients included in this study’s GLP-1 RA cohort were using semaglutide. Further research should assess whether other drugs in the GLP-1 RA class are less likely to cause ocular adverse events. The commentary concludes that prescribers need to keep in mind the real and serious ocular adverse events that may occur with GLP-1 RAs.2ReferencesShor R, Mihalache A, Noori A, et al. Glucagon-like peptide-1 receptor agonists and risk of neovascular age-related macular degeneration. JAMA Ophthalmol 2025. Published online June 5, 2025. (accessed June 5, 2025).VanderBeek BL. Should we be concerned about glucagon-like peptide-1 receptor agonists? JAMA Ophthalmol 2025. Published online June 5, 2025. (accessed June 5, 2025).

GLP-1 agonists may increase risk of neovascular age-related macular degeneration

Register for free access or login.

Related Topics

Business Topic