GLP-1 receptor agonists and ocular safety- Pharmacokinetic insights into ischemic optic neuropathy and diabetic retinopathy risk: A review.
Practitioners should consider individual patient ocular risks when prescribing GLP-1 receptor agonists, particularly high-exposure formulations like semaglutide and orforglipron.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This review evaluated associations between GLP-1 receptor agonists and the risk of developing non-arteritic anterior ischemic optic neuropathy (NAION) or diabetic retinopathy (DR). The review reported hazard ratios for NAION ranging from 1.29 to 7.64 and for DR from 0.42 to 1.76. It emphasized the need for formulation-specific postmarketing ocular surveillance for agents like semaglutide and orforglipron.
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.
Background
This paper addresses the ocular safety concerns associated with GLP-1 receptor agonists, particularly regarding NAION and DR. Prior knowledge indicated that while GLP-1 RAs are effective for managing type 2 diabetes and obesity, their effects on ocular health were unclear. This review is significant as it synthesizes existing data to evaluate the risk of ocular complications linked to these medications.
Methods
The review involved a search of PubMed through June 2026 for human clinical trials, observational studies, and meta-analyses reporting quantitative ocular outcomes. It included pharmacokinetic data and regulatory prescribing information. The focus was on evaluating the associations between GLP-1 RAs and ocular risks.
Results
The review reported hazard ratios for NAION ranging from 1.29 to 7.64 and for DR from 0.42 to 1.76. High-exposure subcutaneous semaglutide was noted as having the most consistent signal for NAION. The worsening of DR was associated with rapid reductions in HbA1c, particularly reductions of at least 2%.
Interpretation
The findings suggest that while there is a statistically significant association between certain GLP-1 RAs and ocular risks, the clinical significance may vary. The evidence indicates a need for caution with high-exposure formulations, particularly semaglutide, but does not support class-wide prescribing restrictions. Limitations such as the lack of direct evidence for NAION risk and the narrative nature of the review may confound the conclusions.
Key findings
- Hazard ratios for NAION ranged from 1.29 to 7.64.
- Hazard ratios for diabetic retinopathy ranged from 0.42 to 1.76.
- The most consistent NAION signal involved high-exposure subcutaneous semaglutide.
- Semaglutide 7.2 mg has an estimated Css of approximately 230 nmol/L.
- Preliminary NAION threshold at a steady-state concentration (Css) of approximately 30-55 nmol/L.
Limitations
- Narrative review, no direct evidence of NAION risk.
- Lacks standardized ophthalmic endpoints.
- Observational data may not establish causality.
- Potential for publication bias in reviewed studies.