GLP-1 receptor agonists and ocular safety- Pharmacokinetic insights into ischemic optic neuropathy and diabetic retinopathy risk: A review.

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes mellitus and obesity, but their expanding use has raised concerns about ocular safety. This narrative review aimed to evaluate associations between individual GLP-1 RAs and the risk of developing non-arteritic anterior ischemic optic neuropathy (NAION) or diabetic retinopathy (DR), with particular emphasis on whether pharmacokinetic exposure and formulation explain within-class heterogeneity. PubMed was searched through June 2026, without a lower date limit, for human clinical trials, observational studies, and meta-analyses reporting quantitative ocular outcomes; reference lists, regulatory prescribing information, and pharmacokinetic data were also reviewed. Reported hazard ratios ranged from 1.29 to 7.64 for NAION and from 0.42 to 1.76 for DR. The most consistent NAION signal involved high-exposure subcutaneous semaglutide, whereas findings for oral semaglutide, liraglutide, dulaglutide, exenatide, and tirzepatide were absent, inconsistent, or weaker. DR worsening was likewise most evident with high-bioavailability subcutaneous semaglutide, but appeared more closely related to rapid, large reductions in glycated hemoglobin (HbA1c), particularly reductions of at least 2%, than to a class-specific retinal effect. Observational exposure patterns supported a preliminary, hypothesis-generating NAION threshold at a steady-state concentration (Css) of approximately 30-55 nmol/L. Semaglutide 7.2 mg, with an estimated Css of approximately 230 nmol/L, and highly bioavailable oral orforglipron warrant formulation-specific postmarketing ocular surveillance, although direct evidence of NAION risk remains unavailable. Current evidence does not support class-wide prescribing restrictions. An individualized approach considering patient-specific ocular risk, agent, formulation, and dose is more appropriate, while prospective studies with standardized ophthalmic endpoints are needed to establish causality and validate pharmacokinetic and pharmacogenomic risk parameters.