What are the considerations for prescribing semaglutide (glucagon-like peptide-1 receptor agonist) to patients with proliferative diabetic retinopathy?

Semaglutide and Proliferative Diabetic Retinopathy

Exercise caution when prescribing semaglutide to patients with a history of proliferative diabetic retinopathy, as the American College of Cardiology explicitly lists this as a consideration that may prompt use of alternative agents. 1

Risk Assessment and Mechanism

The FDA label for semaglutide confirms that diabetic retinopathy complications occurred more frequently in semaglutide-treated patients (3.0%) compared to placebo (1.8%) in cardiovascular outcome trials. 2 The absolute risk increase was substantially larger among patients with pre-existing diabetic retinopathy at baseline (8.2% vs 5.2% placebo) compared to those without known retinopathy history (0.7% vs 0.4% placebo). 2

The mechanism appears related to the rapidity of A1C reduction rather than a direct drug effect—rapid improvement in glucose control has been associated with temporary worsening of diabetic retinopathy. 2, 3, 4 Meta-regression analysis demonstrates that decreases in A1C correlate with increases in diabetic retinopathy complications, particularly when A1C drops exceed 1.0% (RR 1.59). 5

Pre-Treatment Requirements

Before initiating semaglutide in any patient:

• Obtain a comprehensive dilated eye examination if not performed within the last 12 months to assess retinopathy status and stratify risk. 3, 6, 4
• Document the presence and severity of any diabetic retinopathy, as this directly impacts risk stratification. 3, 4
• Discuss the potential risk of retinopathy complications and document informed consent, particularly in patients with pre-existing proliferative retinopathy. 3

Decision Algorithm for Patients with Proliferative Diabetic Retinopathy

If proliferative diabetic retinopathy is present:

1. Consider alternative GLP-1 receptor agonists or other drug classes first (such as SGLT2 inhibitors for cardiovascular risk reduction), as the American College of Cardiology guidelines specifically list proliferative retinopathy as a consideration for alternative agents. 1

2. If semaglutide is chosen despite proliferative retinopathy (e.g., for compelling cardiovascular indications where the 13% reduction in major adverse cardiovascular events may outweigh risks): 3

   • Reduce concomitant insulin dose by 20% at initiation to slow the rate of glycemic improvement. 3, 6
   • Reduce sulfonylurea dose by 50% if applicable. 6
   • Avoid aggressive A1C reduction—titrate semaglutide more gradually than standard protocols. 3

Monitoring Protocol

For patients with proliferative retinopathy on semaglutide:

• Increase ophthalmologic monitoring frequency to every 6 months rather than annually during the first year of therapy. 3
• Dilated retinal examinations should be repeated at least annually thereafter if retinopathy remains stable. 4
• More frequent examinations by an ophthalmologist are required if retinopathy is progressing or becomes sight-threatening. 4

For patients without baseline retinopathy:

• Baseline eye examination before starting therapy. 4
• If no retinopathy develops and glycemia is well controlled, screening every 1-2 years may be considered. 4

Risk-Benefit Context

The number needed to harm for worsening retinopathy with semaglutide is 77, while the number needed to treat for preventing major adverse cardiovascular events is 43. 5 In patients with established cardiovascular disease and proliferative retinopathy, the cardiovascular benefits may outweigh optic nerve risks, but this requires close collaboration with ophthalmology. 3, 5

Critical Pitfalls to Avoid

• Do not initiate semaglutide without recent ophthalmologic assessment—the risk is highest in patients with unrecognized proliferative retinopathy. 3, 6
• Do not allow rapid A1C reduction in patients with established retinopathy—this is the primary modifiable risk factor. 3, 2
• Do not assume all GLP-1 receptor agonists carry equal risk—semaglutide and dulaglutide specifically require caution with proliferative retinopathy, while this concern is less prominent with other agents in the class. 1, 5