Glucagon-Like Peptide-1 Receptor Agonists and Neovascular Age-Related Macular Degeneration in Type 2 Diabetes: A Review of Emerging Clinical Evidence

Abstract

Abstract Purpose of Review Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in the management of type 2 diabetes mellitus (T2DM) because of their established glycaemic, weight, cardiovascular, and kidney benefits. Recent observational evidence has raised questions regarding a possible association between GLP-1RA exposure and neovascular age-related macular degeneration (nAMD). This review critically evaluates the emerging direct clinical evidence, considers relevant pharmacovigilance and diabetic retinal disease data, and examines biological mechanisms that may plausibly link GLP-1RA therapy with retinal and choroidal homeostasis. Recent Findings Direct clinical evidence regarding GLP-1RA exposure and nAMD is heterogeneous. A population-based cohort of older adults with diabetes reported an increased incidence of nAMD among predominantly semaglutide-exposed patients, with an adjusted hazard ratio of 2.21. Subsequent studies have not consistently reproduced this finding: one national cohort reported a lower incidence of nAMD among GLP-1RA users, whereas two large active-comparator analyses found no significant increase in nAMD risk, including a multi-database study of semaglutide using both new-user and self-controlled designs. Differences in population characteristics, comparator selection, confounding adjustment, ophthalmic surveillance, exposure definition, and outcome ascertainment likely contribute to the discordant findings. Pharmacovigilance reports, diabetic retinopathy studies, and mechanistic evidence involving oxidative stress, inflammation, endothelial function, and angiogenic signalling provide supportive context but remain secondary to nAMD-specific clinical evidence and do not establish causality. Summary Current evidence does not establish a causal association between GLP-1RA therapy and nAMD or demonstrate a consistent class-wide increase in risk. Smaller agent-specific or population-specific effects cannot yet be excluded. Available evidence does not support withholding otherwise indicated GLP-1RA therapy, instituting GLP-1RA-specific nAMD screening, or modifying established nAMD management solely on the basis of treatment exposure. Future studies should incorporate detailed drug exposure, longitudinal metabolic data, imaging-confirmed AMD phenotypes, ophthalmic surveillance, and assessment of latency and susceptible subgroups.