GLP-1 Receptor Agonists Demonstrate Increased Risk of Neovascular Age-Related Macular Degeneration in Diabetes

Individuals with diabetes that are exposed to glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) could face a 2-fold higher risk of incident neovascular age-related macular degeneration (nAMD) development compared with similar individuals with diabetes that were unexposed to GLP-1 treatment, according to findings published by investigators in JAMA Ophthalmology.¹

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Causes, Signs, and Symptoms of nAMD

Age-related macular degeneration (AMD) impacts the central area of the retina in the eye, known as the macula, and is a progressive deterioration of high-resolution vision, which is crucial for daily activity. AMD is reported as the leading cause of irreversible blindness in older adults residing in Western populations and accounts for 8.7% of all cases of blindness in the US.^1,2

Commonly, individuals develop the more severe condition, nAMD, if they do not recognize the initial signs and symptoms of AMD. Neovascular is the wet form of the disease and is responsible for 90% of severe vision loss, as it involves abnormal vascular growth and macular damage. Signs and symptoms of nAMD include blurred vision, difficulty seeing at a distance or doing detailed work, blind spots developing in the line of sight, difficulty distinguishing between colors and edges, and straight lines appearing wavy. Oftentimes, the development of nAMD is linked to hypoxia, oxidative stress, lipid metabolism issues, and inflammation.^1,2

GLP-1s Role in nAMD Development

GLP-1s are crucial for maintaining glucose balance and promoting a feeling of fullness caused by the release of L cells in the distal intestine and the binding to its G-protein-coupled receptor, which has since been found in other tissues, such as the retina.¹

Recent research, specifically a retrospective matched cohort study, indicated a notably higher risk of nonatretic anterior ischemic optic neuropathy (NAION) in individuals with diabetes using semaglutide (Ozempic, WeGovy; Novo Nordisk). This observation has led to the hypothesis that the rapid reduction in blood glucose levels caused by GLP-1s might create a hypoxic state in the retina, potentially fostering abnormal blood vessel growth. Given that the development of nAMD involves similar abnormal blood vessel proliferation, the researchers conducted a population-based study that investigated the potential link between systemic GLP-1 exposure and the incidence of nAMD.¹

Trial Design and Results

This retrospective cohort study was conducted from January 2020 to November 2023 with a 3-year follow-up, including investigated data from Ontario, Canada, which was provided by the Institute for Clinical Evaluative Sciences. Data analysis was performed between August and October 2024 and included individuals with diabetes aged 66 years and older with at least 12 months of follow-up after their initial diabetes diagnosis. From over 1.1 million eligible individuals, a 1:2 matched cohort of 139,002 individuals was established, comprising 46,334 individuals exposed to GLP-1s and 92,668 unexposed matched patients. The study authors noted that propensity scores were calculated based on systemic comorbidities associated with AMD and socioeconomic status.¹

Among 139,002 propensity-score-matched patients (46,334 exposed to GLP-1 RAs, primarily semaglutide, and 92,668 unexposed), 0.2% of individuals using GLP-1s developed nAMD compared to 0.1% of non-users. Additionally, this includes individuals with increased age and a history of cerebrovascular accident also contributing to the risk.¹

The findings suggest that diabetic individuals using GLP-1s had twice the risk of developing nAMD compared to similar diabetic patients not on GLP-1s. However, further research is needed to fully understand the underlying biological mechanism and to weigh the benefits of GLP-1s against their potential risks.¹

“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 post-marketing pharmacovigilance systems to facilitate safety tracking and raise public awareness,” the study authors concluded in a news release.¹

REFERENCES

1. Shor R., Mihalache A., Noori A., JAMA Ophthalmol. Glucagon-Like Peptide-1 Receptor Agonists and Risk of Neovascular Age-Related Macular Degeneration. June 5, 2025. Accessed June 6, 2025. doi:10.1001/jamaophthalmol.2025.1455

2. Roche. Understanding neovascular age-related macular degeneration. Updated June 6, 2025. Accessed June 6, 2025. https://www.roche.com/stories/neovascular-age-related-macular-degeneration