What are the considerations for using semaglutide (glucagon-like peptide-1 receptor agonist) in a patient with type 2 diabetes and a history of cardiovascular disease who has or is at risk for diabetic retinopathy?

Semaglutide and Diabetic Retinopathy: Risk Assessment and Management

Pre-Treatment Requirements

Before initiating semaglutide in any patient with type 2 diabetes and cardiovascular disease, obtain a comprehensive dilated eye examination if not performed within the last 12 months to document baseline retinopathy status. 1, 2

• The FDA label explicitly warns that diabetic retinopathy complications occurred more frequently with semaglutide (3.0%) compared to placebo (1.8%) in the SUSTAIN-6 trial 3
• The absolute risk increase is substantially higher among patients with pre-existing proliferative diabetic retinopathy (8.2% vs 5.2% placebo) compared to those without known retinopathy (0.7% vs 0.4% placebo) 3
• Patients with a history of proliferative diabetic retinopathy require particularly careful consideration, as this represents the highest-risk subgroup 1, 2

Understanding the Mechanism: Rapid Glycemic Improvement, Not Direct Drug Toxicity

The retinopathy risk with semaglutide appears related to the rapidity of A1C reduction rather than direct drug toxicity 2, 4:

• Meta-regression analysis demonstrates that decreases in A1C correlate with increases in diabetic retinopathy complications (log RR = -0.67 × ΔA1C, p=0.076) 4
• The risk is predominantly seen with A1C reductions >1.0% (RR 1.59,95% CI 1.09-2.32) and treatment duration >1 year (RR 1.56,95% CI 1.07-2.28) 4
• This phenomenon of "early worsening" with rapid glycemic control has been documented with any aggressive diabetes treatment, not just GLP-1 receptor agonists 2

Risk Mitigation Strategies During Initiation

Start at the lowest dose (0.25 mg weekly) and titrate slowly every 4 weeks to minimize the rapidity of glycemic improvement 1, 2:

• Slow titration mitigates both gastrointestinal side effects and rapid A1C drops that may worsen retinopathy 2
• For patients on insulin, reduce basal insulin dose by 20% when starting semaglutide to slow the rate of glycemic improvement 1, 2
• For patients on sulfonylureas with well-controlled baseline A1C, reduce sulfonylurea dose by 50% 1, 2

Balancing Cardiovascular Benefits Against Retinopathy Risk

The cardiovascular benefits of semaglutide (26% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke; HR 0.74,95% CI 0.58-0.95) typically outweigh the retinopathy risks in patients with established cardiovascular disease 2, 3:

• The number needed to treat (NNT) for cardiovascular benefit is 43, while the number needed to harm (NNH) for retinopathy worsening is 77 4
• Semaglutide also provides a 36% reduction in new or worsening nephropathy 2
• For patients with both cardiovascular disease and proliferative diabetic retinopathy, consider alternative GLP-1 receptor agonists (such as liraglutide) or SGLT2 inhibitors first 2

Recent Real-World Evidence Provides Reassurance

The most recent and highest-quality real-world evidence contradicts earlier trial findings, showing no increased risk and potentially protective effects 5, 6:

• A 2025 network study of 810,390 semaglutide users found no increased risk of proliferative diabetic retinopathy compared to dulaglutide (HR 0.81,95% CI 0.42-1.54), empagliflozin (HR 0.83,95% CI 0.53-1.30), or sitagliptin (HR 0.83,95% CI 0.45-1.55) 5
• Semaglutide showed lower risk of treatment-requiring diabetic retinopathy/diabetic macular edema compared to dulaglutide (HR 0.53,95% CI 0.31-0.91), sitagliptin (HR 0.46,95% CI 0.26-0.81), and glipizide (HR 0.55,95% CI 0.33-0.91) 5
• A separate 2025 study of 185,066 patients found no difference in sight-threatening diabetic retinopathy complications when comparing semaglutide to dulaglutide (HR 0.88,95% CI 0.70-1.11) 6

Monitoring Protocol

Establish more frequent ophthalmologic monitoring (every 6 months rather than annually) in high-risk patients during the first year of treatment 2:

• High-risk patients include those with pre-existing proliferative diabetic retinopathy, baseline A1C >9%, or concurrent insulin therapy 2
• Monitor home glucose closely for the first 4 weeks of therapy 1
• Educate patients to report any visual changes immediately 2

Clinical Decision Algorithm

For patients with type 2 diabetes, cardiovascular disease, and NO history of proliferative diabetic retinopathy:

• Proceed with semaglutide initiation after confirming recent eye examination 1, 2
• Use slow titration protocol starting at 0.25 mg weekly 1, 2
• Reduce insulin/sulfonylurea doses as outlined above 1, 2

For patients with type 2 diabetes, cardiovascular disease, and HISTORY of proliferative diabetic retinopathy:

• Consider alternative GLP-1 receptor agonists (liraglutide) or SGLT2 inhibitors first 2
• If semaglutide is chosen due to superior cardiovascular benefits, ensure ophthalmology co-management with 6-month follow-up 2
• Use the slowest possible titration schedule 2

For patients with type 2 diabetes, cardiovascular disease, and ACTIVE proliferative diabetic retinopathy:

• Prioritize SGLT2 inhibitors for cardiovascular risk reduction 2
• Defer semaglutide until retinopathy is stabilized with ophthalmologic treatment 2

Common Pitfalls to Avoid

• Do not skip the pre-treatment eye examination even if the patient reports "no vision problems"—asymptomatic retinopathy is common 1, 2
• Do not aggressively titrate semaglutide in patients with poor baseline glycemic control (A1C >9%) and pre-existing retinopathy 2
• Do not dismiss the cardiovascular benefits due to retinopathy concerns in patients without pre-existing proliferative disease—the real-world evidence is reassuring 5, 6
• Do not fail to reduce insulin/sulfonylurea doses when initiating semaglutide, as this contributes to rapid glycemic swings 1, 2