What is the mechanism by which Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), may increase the risk of blindness?

Mechanism of Vision Loss with GLP-1 Receptor Agonists

GLP-1 receptor agonists can cause blindness primarily through rapid reduction in blood glucose levels leading to worsening of diabetic retinopathy, particularly in patients with pre-existing retinopathy. 1

Primary Mechanisms of Vision Loss

1. Rapid Glycemic Reduction and Diabetic Retinopathy

• GLP-1 RAs can cause rapid and substantial reductions in blood glucose levels, which paradoxically can worsen diabetic retinopathy in the short term 1
• This phenomenon is most pronounced in patients with:
  • Pre-existing proliferative retinopathy
  • Long-standing poor glycemic control followed by rapid improvement
  • Significant baseline retinopathy before starting treatment

2. Potential Risk of NAION (Non-Arteritic Anterior Ischemic Optic Neuropathy)

• Recent evidence suggests GLP-1 RAs, particularly semaglutide, may be associated with increased risk of NAION 2
• The relative risk increase ranges from nonsignificant to fourfold, though absolute numbers remain low 2
• This may be related to hemodynamic changes induced by GLP-1 RAs in predisposed patients with an optic "disc-at-risk" 2

Specific Ocular Adverse Events

Real-world data from the FDA Adverse Event Reporting System shows:

• Blurred vision and visual impairment are commonly reported adverse events 3
• Some ocular adverse events occur as early as 10 days after treatment initiation 3
• Semaglutide and lixisenatide show statistically significant associations with ocular adverse events 3

Risk Factors and Vulnerable Populations

Patients at highest risk include those with:

• Pre-existing proliferative diabetic retinopathy 1
• Rapid A1C reduction after starting GLP-1 RA therapy 1
• Anatomical risk factors such as "disc-at-risk" configuration 2
• Longer duration of diabetes 1

Monitoring and Prevention

To mitigate vision loss risk:

• Baseline eye examination should be performed prior to initiating GLP-1 RAs, especially semaglutide 1
• Regular ophthalmologic follow-up is essential, particularly for high-risk patients 4
• Consider slower titration of GLP-1 RAs in patients with established retinopathy 1
• Assess retinopathy status when intensifying glucose-lowering therapies with GLP-1 RAs 1

Long-Term Outcomes

Interestingly, recent cohort studies suggest:

• While GLP-1 RAs may increase the risk of incident diabetic retinopathy (HR 1.07), they may actually reduce the risk of severe complications in patients with pre-existing retinopathy 5
• Lower rates of vitreous hemorrhages (HR 0.74), neovascular glaucoma (HR 0.78), and blindness (HR 0.77) have been observed in patients with pre-existing diabetic retinopathy who use GLP-1 RAs 5

The mechanism of GLP-1 RA-associated vision loss is complex, involving both direct effects on retinal vasculature and indirect effects through rapid glycemic control. The risk appears highest during initial treatment phases, particularly in patients with pre-existing retinopathy, underscoring the importance of ophthalmologic monitoring when starting these medications.