Common Diabetes Treatment May Cause Neovascular Age-Related Macular Degeneration

Results from a recent population-based cohort study have indicated that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may increase the risk of developing neovascular age-related macular degeneration (nAMD) in patients with diabetes.1

GLP-1 RAs are one of the most beneficial treatments for type 2 diabetes; it increases glucose transporter expression in pancreatic cells, which facilitate glucose movement across the cell membrane. The medication also introduces pancreatic cells to secrete insulin in response to increased glucose content. GLP-1 RAs are one of the most widely used treatments in the world for diabetes and obesity.2

However, GLP-1 RAs have also exhibited adverse events. In two major phase 3a trials, GLP-1 RAs were associated with a higher risk of diabetic retinopathy (DR) and a .8% higher proportion of DR cases compared to placebo. Additionally, recent studies have posited that rapidly lowering blood glucose because of GLP-1 RAs may lead to a hypoxic state in the retina, promoting further abnormal angiogenesis.1

“Given that the underlying pathogenesis of nAMD involves abnormal and excessive angiogenesis, we aimed to evaluate this hypothesis by investigating an association between systemic exposure to GLP-1 RAs and the incidence of nAMD using data from a population-based study,” Reut Shor, MD, department of ophthalmology and vision sciences, University of Toronto, and colleagues wrote.1

Shor and colleagues collected data on adult patients ≥66 years with diabetes from 2020-2023. Patients who were followed up for <12 months or were diagnosed with nAMD before or at the time of diabetes diagnosis were excluded. A total of 1,069,140 patients with diabetes were collected – of these, 72,755 (6.8%) had been exposed to GLP-1 RAs for ≥6 months. 996,385 patients (93.2%) had no prior exposure.1

Of the individuals exposed to GLP-1 RAs, 93 patients (.2%) were newly diagnosed with nAMD by the end of the study. By comparison, 88 patients with no prior GLP-1 RA experience were newly diagnosed with nAMD. Univariable Cox proportional analysis indicates that patients with diabetes exposed to GLP-1 RAs had a substantially higher incidence of diagnosis than those who were not (.2% versus .1%; difference, .1%; 95% CI, .08%-.12%; hazard ratio [HR], 2.11; 95% CI, 1.58-2.82).1

In addition to GLP-1 RAs, the study also indicated that increased age and a history of cerebrovascular accident were associated with a significantly increased risk of nAMD (age: HR, 1.12; 95% CI, 1.07-1.18; cerebrovascular accident: HR, 1.96; 95% CI, 1.15-3.34).1

Shor and colleagues noted that these results are consistent with the growing body of literature questioning the safety and efficacy of GLP-1 RAs, the use of which has been dramatically increasing in recent years. However, they do indicate a few limitations, including a lack of stratification by GLP-1 RA prescription type, inability to account for dose, route of administration, or frequency of administration of GLP-1 RAs, and an inability to account for other variables like smoking and sun exposure.1

In a related editorial, Brian VanderBeek, MD, MPH, department of ophthalmology, University of Pennsylvania Perelman School of Medicine, supports the research, stating that these findings are critical to contextualize the potential risks of mis- or overusing GLP-1 RAs.3

“GLP-1 RAs have had a tremendous role in the care of patients with diabetes and now those needing additional help with weight management,” VanderBeck wrote. “However, the adage that ‘there is no such thing as a free lunch’ remains true. 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.”3

References

1. Shor R, Mihalache A, Noori A, et al. Glucagon-like peptide-1 receptor agonists and risk of neovascular age-related macular degeneration. JAMA Ophthalmology. Published online June 5, 2025. doi:10.1001/jamaophthalmol.2025.1455

2. Lee S, Lee DY. Glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes. Ann Pediatr Endocrinol Metab. 2017;22(1):15-26. doi:10.6065/apem.2017.22.1.15

3. VanderBeek BL. Should We Be Concerned About Glucagon-Like Peptide-1 Receptor Agonists? JAMA Ophthalmol. Published online June 05, 2025. doi:10.1001/jamaophthalmol.2025.1599