Is Ozempic (semaglutide) safe for a patient with diabetic retinopathy?

Ozempic Safety in Diabetic Retinopathy

Ozempic (semaglutide) can be used in patients with diabetic retinopathy, but requires significant caution, mandatory pre-treatment ophthalmologic assessment, and slow dose titration—particularly in patients with pre-existing proliferative diabetic retinopathy, poor baseline glycemic control (HbA1c >9%), or concurrent insulin use. 1, 2, 3

Understanding the Risk

The concern with semaglutide and diabetic retinopathy is not a direct drug effect on the eye, but rather stems from rapid and sustained reductions in blood glucose that can temporarily worsen retinopathy—a phenomenon well-documented with aggressive insulin therapy. 1, 4

• In the SUSTAIN 6 cardiovascular outcomes trial, diabetic retinopathy complications occurred in 3.0% of semaglutide-treated patients versus 1.8% with placebo over 2 years. 3
• The absolute risk increase was substantially higher among patients with pre-existing diabetic retinopathy (8.2% vs 5.2%) compared to those without known retinopathy (0.7% vs 0.4%). 3
• GLP-1R expression is minimal in normal human eyes and was not detected in eyes with advanced proliferative diabetic retinopathy, supporting an indirect mechanism. 5
• The risk appears predominantly in patients with prior proliferative retinopathy, poor baseline glycemic control, and rapid HbA1c reduction (>1.0% decrease). 2, 6, 4

Mandatory Pre-Treatment Requirements

Before initiating semaglutide, you must complete the following assessments:

• Comprehensive dilated ophthalmologic examination if not performed within the last 12 months, specifically documenting retinopathy status and whether proliferative disease is present. 1, 2
• Assess renal function (eGFR) due to risk of acute kidney injury with volume depletion from GI side effects. 1
• Screen for personal or family history of medullary thyroid cancer or MEN2 (absolute contraindications). 1, 3
• Document baseline HbA1c to identify high-risk patients (HbA1c >9%). 2

Risk Mitigation Protocol

Dose Titration Strategy

• Start at 0.25 mg subcutaneously once weekly and titrate slowly with weekly dose increments (0.25 mg → 0.5 mg → 1.0 mg → 1.7 mg as tolerated). 1
• This gradual approach minimizes both GI side effects and the rapidity of glycemic improvement that drives retinopathy worsening. 2, 7

Concomitant Medication Adjustments

For patients on insulin or sulfonylureas with well-controlled baseline HbA1c:

• Reduce total daily insulin dose by 20% when starting semaglutide to slow the rate of glycemic improvement. 2
• Reduce sulfonylurea dose by 50% in patients with well-controlled baseline HbA1c. 2
• These adjustments are critical to prevent the rapid HbA1c drops that mediate retinopathy worsening. 4

Monitoring During Treatment

• Close glucose monitoring during the first 4-8 weeks, especially if on insulin, sulfonylureas, or glinides. 1
• Consider more frequent ophthalmologic monitoring (every 6 months rather than annually) in high-risk patients with pre-existing retinopathy. 2
• Monitor for GI symptoms (nausea, vomiting, diarrhea) and assess for volume depletion, as dehydration can precipitate acute kidney injury. 1, 7
• Patients with a history of diabetic retinopathy should be monitored for progression per FDA labeling. 3

Special Populations Requiring Extra Caution

Patients with Proliferative Diabetic Retinopathy

• The American College of Cardiology recommends exercising caution and considering alternative GLP-1 receptor agonists or SGLT2 inhibitors first in patients with proliferative diabetic retinopathy. 2
• If semaglutide is chosen despite proliferative disease, implement all risk mitigation strategies above and ensure close ophthalmologic follow-up. 2

Elderly Patients (>60 years)

• Additional caution is warranted due to higher risk of volume depletion, orthostatic hypotension, and increased fall risk from dizziness or hypoglycemia. 1
• Instruct patients to hold medication if unable to maintain hydration during nausea episodes. 1

Balancing Risks and Benefits

The cardiovascular benefits of semaglutide are substantial and may outweigh retinopathy risks in many patients:

• Semaglutide reduces major adverse cardiovascular events by 13% and new/worsening nephropathy by 36%. 2
• The number needed to treat (NNT) for cardiovascular benefit is 43, while the number needed to harm (NNH) for retinopathy worsening is 77. 6
• For the broader GLP-1RA class, NNT for cardiovascular benefit is 77 versus NNH of 1000 for retinopathy. 6

Critical Pitfalls to Avoid

• Do not initiate semaglutide without recent ophthalmologic assessment in patients with diabetes, as you cannot risk-stratify appropriately. 1, 2
• Avoid aggressive dose escalation in patients with established retinopathy or poor baseline glycemic control. 2
• Do not overlook concomitant insulin/sulfonylurea dose reductions, as the combination of medications can drive rapid glycemic improvement. 2
• Recognize that the retinopathy risk is mechanism-based (rapid glucose lowering), not a direct drug toxicity, which informs your mitigation strategy. 1, 4

Contradictory Evidence Note

While the SUSTAIN 6 trial showed increased retinopathy complications 3, one case report described resolution of proliferative diabetic retinopathy with semaglutide therapy 8, and another case report documented new-onset diabetic retinopathy with GLP-1RA therapy 9. The preponderance of evidence from large trials supports the association with worsening retinopathy in high-risk patients, making the pre-treatment assessment and risk mitigation strategies essential. 6, 4