One in 8 American adults reports using a glucagon-like peptide 1 receptor agonist (GLP-1RA) medication, and prescriptions continue to increase due to these drugs’ effectiveness in reducing cardiovascular mortality and treating diabetes and obesity.¹ GLP-1RAs improve blood glucose control and aid in weight loss by promoting insulin release, inhibiting glucagon secretion, slowing gastric emptying, and promoting neurohormonal satiety.² However, GLP-1 receptors are expressed throughout the human body and are not limited to pancreatic and gastrointestinal cell types. For example, GLP-1R expression in the cardiovascular and central nervous systems is thought to, at least in part, mitigate risk of myocardial infarction, stroke, and neurodegenerative impairments.² Due to these benefits, this class of medications is currently being investigated in clinical trials for Alzheimer disease and Parkinson disease.

The anti-inflammatory and antioxidant effects of GLP-1RAs observed in other organ systems may prevent damage in ocular tissues, leading to reduced risk of nonexudative age-related macular degeneration (AMD), exudative AMD, and primary open-angle glaucoma (POAG) compared to other diabetic medications (Figure 1).³ Extensively publicized reports of ocular adverse events, such as nonarteritic anterior ischemic optic neuropathy (NAION), have been challenging to assess due to confounding health factors and conflicting evidence. Given the vision-threatening concerns and widespread use of GLP-1RAs, some suggest candid patient conversations and closer follow-up may be warranted. Collectively, numerous retrospective and large database studies have identified potential benefits of GLP-1RA in ocular disease, indicating a need for prospective trials to more definitively identify protective effects and integrate this medication class into the ophthalmology toolbox.

Glaucoma

Multiple retrospective large database studies have demonstrated that GLP-1RAs reduce the risk of POAG compared with insulin and other diabetes medications.^3-5 Proposed mechanisms include both intraocular pressure (IOP)–lowering effects and IOP-independent effects.⁶

GLP-1 receptor-positive cells have been identified in human retinal ganglion cells (RGCs), which could suggest a direct protective effect of these medications at the site of damage. An additional study demonstrated that acute IOP increase causes supportive glial cells to become proinflammatory and neurotoxic. This effect is blocked by GLP-1RA, which  prevents optic nerve axonopathy.^7-9 GLP-1 signaling has been shown to promote microglia-mediated expression of neurotrophic factors, such as brain-derived neurotrophic factor and nerve growth factor, to promote neuronal survival and inhibit stress pathways in neurodegenerative conditions.^10,11

Regarding IOP-lowering mechanisms, GLP-1RAs have been shown to inhibit sodium-potassium ATPase in the choroid plexus, decreasing cerebrospinal fluid secretion and lowering intracranial pressure. It is postulated these medications may similarly reduce IOP by inhibiting sodium-potassium ATPase–mediated aqueous humor secretion by the ciliary body.^9,12 Additionally, GLP-1RAs activate nitric oxide (NO) synthase expressed in Schlemm’s canal and the trabecular meshwork, increasing NO production to reduce trabecular meshwork contraction, improving aqueous outflow.¹³ More research is needed to delineate the effects of GLP-1RAs in the various glaucoma subtypes, including neovascular glaucoma.

Diabetic Retinopathy and Diabetic Eye Disease

Typically thought of as a retinal microvascular disease, diabetic retinopathy (DR) is also a retinal neurodegenerative process.^14-17 GLP-1RAs decrease RGC damage by preventing mitophagy in diabetic rat models and, in vitro, demonstrating the neuroprotective effects of these medications on the retina.¹⁸

There have been mixed results from published clinical studies. One large electronic database study showed there was a significantly increased risk of diabetic macular edema following GLP-1RA initiation compared to sodium-glucose cotransporter 2 inhibitors (SGLT2i).¹⁹ A separate meta-analysis of 4 major clinical trials suggested prolonged use of GLP-1RA was associated with an elevated risk of rapidly worsening DR.²⁰ However, a retrospective single-institution study showed that although other anti-diabetic medications (such as sodium-glucose cotransporter 2 inhibitors) were associated with a lower risk of sight-threatening DR, GLP-1RAs were not shown to confer any increased DR risk, clinical worsening, or increased intervention in DR.^21,22

Although clear protective benefits in diabetic retinopathy development and impact on disease progression remain under investigation, GLP-1RAs have been shown to reduce complications from chronic diabetes, such as retinal vein occlusion and cardiovascular disease.^23,24

Age-Related Macular Degeneration

Nonexudative age-related macular degeneration (AMD) is a complex and multifaceted disease caused by inflammation, lipid deposition, and oxidative stress, leading to drusen deposition and retinal pigment epithelium (RPE) damage.²⁵ This damage culminates in geographic atrophy or disruption of Bruch’s membrane, leading to severe vision loss and, in some cases, neovascularization. In agreement with the profound anti-inflammatory effects of GLP-1RAs, a recent study demonstrated a protective effect of these medications against the development of non-exudative AMD compared with other diabetes and lipid-lowering medications.³

GLP-1RAs have also been shown to alter cellular metabolism to mitigate oxidative stress, which is thought to play a pivotal role in AMD pathogenesis.²⁶ It is also feasible that reduction in AMD risk factors such as obesity, cardiovascular disease, and hyperlipidemia with GLP-1RAs could further provide benefit by reducing systemic inflammation and vascular risk factors.^27-30 GLP-1RAs were also associated with reduced hazard in exudative AMD compared with insulin, aspirin, and statins.³

Future studies are needed to determine whether this class of medications inhibits progression from nonexudative to neovascular or late atrophic stages of AMD.

Adverse Effects

Aside from the debated increased risk of DR progression, a separate complication that has garnered widespread attention is the purported association of semaglutide with an increased risk of NAION, a vision-threatening condition.³¹ However, a causal relationship has not been established.³² Furthermore, subsequent large retrospective studies have demonstrated no effect of GLP-1RA on the increased risk of ischemic optic neuropathy.^33,34 However, these studies are limited by the inability to identify NAION with electronic health record coding with absolute certainty.

One potential mechanism could be increased prevalence of NAION risk factors in patients starting GLP-1RA or that sudden and rapid decline in blood glucose could increase the risk of diabetic papillopathy or worsened DR.^31,35-37 Prospective trials are needed to further explore this potential adverse event and worsened DR, which is the central premise of the ophthalmic FOCUS trial that is expected to release results in 2026. Otherwise, current recommendations are for patients to be screened for baseline diabetic retinopathy before initiating GLP-1RA and participate in personalized risk discussions.

Clinical Recommendations and Future Research

Numerous retrospective studies have outlined the potential benefits of GLP-1RA on ocular disease; however, this must be balanced with additional studies suggesting ophthalmic complications from this medication class. Prospective trials are needed to further define potential protective effects of these medications in glaucoma and AMD. Additionally, with equivocal findings in DR and NAION, discussing personalized ocular risk of starting GLP-1RA in patients is key, and considering increased follow-up frequency after medication initiation may be warranted. GP

Rachel Chapman is the founder and chief executive officer of EyeSentry, a startup working on glaucoma risk assessment tools for primary care, and is a fourth-year medical student at the University of Central Florida College of Medicine. Reach her at ra513791@ucf.edu.

Kevin Allan, MD, PhD, is a PGY-2 ophthalmology resident at the Cole Eye Institute at Cleveland Clinic in Cleveland, Ohio. He reports no disclosures. Reach him at allank2@ccf.org.

Katherine E. Talcott, MD, FASRS, is a retina surgeon and associate residency program director at the Cole Eye Institute at Cleveland Clinic. She reports consultancy to 4DMT, Alimera, AbbVie, Apellis, Bausch + Lomb, EyePoint Pharmaceuticals, Genentech, Harrow, Outlook, Regeneron, and Zeiss; Speaking fees from Astellas, Genentech, and Zeiss; and research support from Regeneron and Zeiss. Reach her at talcotk@ccf.org.

Mary Qiu, MD,, is a glaucoma and cataract surgeon who is on the faculty at the Cole Eye Institute at Cleveland Clinic. She is a consultant for AbbVie and W.L. Gore; a consultant and medical advisory board member of Nova Eye Medical; and a member of the medical advisory board for LEP Biomedical. Reach her at mary.qiu@gmail.com.

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