Can Glucagon-like peptide-1 (GLP-1) receptor agonists cause blindness?

Can GLP-1 Receptor Agonists Cause Blindness?

GLP-1 receptor agonists do not directly cause blindness, but they are associated with worsening of diabetic retinopathy complications in patients with pre-existing retinopathy, primarily due to rapid glucose reduction rather than a toxic drug effect. 1, 2 Importantly, recent large-scale real-world data show that among patients with established diabetic retinopathy, GLP-1 RAs are actually associated with reduced rates of sight-threatening complications including blindness. 3

Understanding the Retinopathy Risk

The concern about GLP-1 RAs and vision stems from two distinct mechanisms:

Rapid Glycemic Improvement Effect

• Rapid improvement in glucose control has been associated with temporary worsening of diabetic retinopathy, a phenomenon well-documented with any intensive glucose-lowering therapy, not unique to GLP-1 RAs. 2
• The FDA label for semaglutide notes that in a 2-year cardiovascular outcomes trial, diabetic retinopathy complications occurred in 3.0% of OZEMPIC-treated patients versus 1.8% with placebo. 2
• The absolute risk increase was substantially larger among patients with pre-existing diabetic retinopathy at baseline (8.2% vs 5.2%) compared to those without known retinopathy (0.7% vs 0.4%). 2

Real-World Outcomes Data

Recent large-scale evidence provides important context:

• In a cohort of 185,066 patients with type 2 diabetes, GLP-1 RA use was associated with a modest increase in incident diabetic retinopathy (HR 1.07,95% CI 1.03-1.11). 3
• However, among 32,695 patients with pre-existing diabetic retinopathy, GLP-1 RAs were associated with significantly lower rates of sight-threatening complications: vitreous hemorrhage (HR 0.74), neovascular glaucoma (HR 0.78), and blindness (HR 0.77). 3
• No increased risk of progression to proliferative diabetic retinopathy or diabetic macular edema was observed. 3

Nonarteritic Ischemic Optic Neuropathy (NAION) Concerns

Recent case reports and pharmacovigilance data have raised concerns about NAION:

• A case series reported 7 patients with NAION and 1 with bilateral papillitis associated with semaglutide or tirzepatide use, though causality could not be established. 4
• Pharmacovigilance databases show disproportionate reporting of ischemic optic neuropathy with semaglutide (FAERS: ROR 11.12; VigiBase: ROR 68.58). 5
• However, a large cohort study found no statistically significant difference in NAION risk (HR 1.26,95% CI 0.94-1.70). 3
• The mechanism, if causal, remains unclear and may relate to rapid glucose correction rather than direct drug toxicity. 4, 6

Clinical Risk Stratification and Monitoring

Before Starting GLP-1 RA Therapy

• Assess retinopathy status when intensifying glucose-lowering therapies such as GLP-1 RAs. 1
• Obtain baseline eye examination before starting GLP-1 RA therapy. 1
• Patients with a history of diabetic retinopathy should be monitored for progression. 2

Monitoring Schedule Based on Retinopathy Status

For patients WITHOUT retinopathy:

• If no retinopathy is present and glycemia is well controlled, screening every 1-2 years may be considered. 1

For patients WITH any level of diabetic retinopathy:

• Dilated retinal examinations should be repeated at least annually. 1
• More frequent monitoring is necessary when starting GLP-1 RAs in patients with established retinopathy. 1

Risk Mitigation Strategy

• Consider more gradual improvement in glycemic control in patients with established retinopathy to minimize the risk of worsening. 1
• Optimize blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy. 1

Clinical Decision-Making Algorithm

For patients with NO diabetic retinopathy:

• GLP-1 RAs can be initiated with standard monitoring
• The absolute risk of developing retinopathy complications is very low (0.7% vs 0.4% with placebo) 2
• Follow routine diabetic eye screening guidelines 1

For patients with ESTABLISHED diabetic retinopathy:

• GLP-1 RAs should NOT be withheld, as they reduce sight-threatening complications and blindness 3
• Implement more gradual glucose reduction to minimize early worsening 1
• Increase ophthalmologic monitoring frequency (at least annually, consider more frequent initially) 1, 2
• Ensure blood pressure and lipid control are optimized 1

For patients with recent acute retinopathy complications:

• Consider delaying GLP-1 RA initiation until retinopathy is stabilized
• If cardiovascular or renal benefits are urgently needed, proceed with very gradual titration and close ophthalmologic follow-up 1

Important Caveats

• The cardiovascular and renal benefits of GLP-1 RAs with proven efficacy (liraglutide, semaglutide, dulaglutide) are substantial and should be weighed against the modest and primarily transient retinopathy risk. 7
• The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. 2
• Pharmacovigilance data showing associations with various ocular adverse events are subject to reporting bias and cannot establish causation. 5, 8
• The protective effects against sight-threatening complications in patients with established retinopathy suggest that withholding GLP-1 RAs due to retinopathy concerns may actually worsen long-term visual outcomes. 3