Ocular complications from glucagon-like peptide-1 receptor agonists: Clinical evidence, potential mechanisms, and clinical recommendations.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)-central to type 2 diabetes mellitus (T2DM) management owing to their comprehensive benefits (glycemic control, weight reduction, cardiovascular benefits, and renal protection)-exhibit a concerning ocular safety profile. Clinical trial data, notably from SUSTAIN-6, revealed a higher incidence of diabetic retinopathy (DR) complications with semaglutide, particularly in patients with preexisting DR and rapid HbA1c reduction, reflecting early worsening. Conversely, the REWIND and LEADER trials reported no significant increase in DR risk, suggesting variability among agents and the potential influence of glycemic trajectory. Observational studies and meta-analyses provide mixed findings: some suggest increased DR progression risk in vulnerable populations, while others indicate a lower risk than insulin therapy. Beyond DR, recent pharmacoepidemiologic studies and pharmacovigilance reports have implicated GLP-1 RAs-especially semaglutide-in nonarteritic anterior ischemic optic neuropathy (NAION), leading the European Medicines Agency to classify NAION as a very rare adverse effect and prompting regulatory scrutiny. Conversely, real-world data suggest possible protective associations with other retinal disorders, including reduced incidence of neovascular age-related macular degeneration and diabetic macular edema, although findings remain inconsistent. The mechanistic pathways involve rapid metabolic shifts, vascular dysregulation, and potentially direct effects on retinal or optic nerve tissue. While GLP-1 RAs confer substantial systemic benefits, their ocular risks appear concentrated in high-risk subgroups. Individualized prescribing, baseline ophthalmic assessment, and interdisciplinary monitoring are essential until ongoing prospective trials clarify their long-term ocular impact.