Semaglutide Carries Potential Risk of Worsening Diabetic Retinopathy

Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) injectable used in the treatment of type 2 diabetes.¹ GLP-1 agonists stimulate glucose-dependent insulin release, inhibit hepatic glucagon production, and delay gastric emptying in response to increasing blood glucose levels. In the SUSTAIN-6 trial, semaglutide showed a statistically significant 26% risk reduction in major adverse cardiovascular events (MACE) when compared to placebo.² In addition to cardiovascular benefits, semaglutide also showed a statistically significant average weight loss up to 10.8 pounds and lowered average A1c by 1%.² These advantages make semaglutide and other GLP agonists a preferred agent for treatment for patients with type 2 diabetes, atherosclerotic cardiovascular disease (ASCVD), and obesity.¹

Despite demonstrating numerous benefits, semaglutide has also been linked to an increased incidence of diabetic retinopathy (DR), which was initially reported in the SUSTAIN-6 trial.² DR is a common microvascular complication affecting the eyes that can occur as diabetes progresses. Hyperglycemia is a contributing risk factor to DR because the increase in blood glucose can lead to osmotic stress and inflammation. If left untreated, it can eventually lead to blindness.

Although it was not designed to assess the incidence of DR, the SUSTAIN-6 trial showed a statistically significant increased risk of new onset or worsening DR, with 3% incidence in the semaglutide group as compared to 1.8% in the placebo group.² It is worth noting that many patients who experienced retinal complications had preexisting retinopathy at baseline and no correlation was found in patients without diabetic retinopathy at baseline. Other GLP-1 RAs that have shown cardiovascular benefits are liraglutide and dulaglutide. In the LEADER trial, no statistically significant difference was found between liraglutide and placebo with respect to incidence of diabetic retinopathy.³

In light of these findings, a number of observational studies have been conducted on the potential relationship between GLP1-RAs and DR. One such study, conducted by Dauner and Farley, investigated this by using the FDA Adverse Event Reporting System (FAERS) database.⁴ Researchers used a composite of 12 different terms to identify adverse events related to DR and used proportional reporting ratio (PRR) to identify specific GLP1-RAs with signals for the composite outcome. Although their findings showed no signal correlating the GLP1-RA drug class to the composite outcome, they did observe that semaglutide had a signal for the composite outcome. Additionally, 3 other GLP1-RAs had signals for some of the 12 individual components of the composite outcome.

It is important to note that this study has some limitations. The increased reports of DR with semaglutide use in the FAERS database does not prove causation. For example, it could simply be that semaglutide is prescribed more frequently than other GLP-1 agonists, or alternatively, prescribers who are aware of the possible link between semaglutide and DR may be more likely to report it compared to those who are unaware.Another risk of using the FAERS database is that data may not be entirely accurate, duplicate reports may have been submitted for a single incident, and data may be missing.⁵ 

It has been hypothesized that this transient worsening in DR is due to the rapid A1c lowering effect of semaglutide.⁶ Over 40 weeks, the SUSTAIN-FORTE trial showed the potential increased benefit of a 2 mg dose of semaglutide, which lowered A1c by 2.1%. The 1 mg dose lowered A1c by 1.9%.⁷

The FOCUS trial seeks to further investigate the long-term effects of semaglutide on DR in patients with type 2 diabetes.⁸ This clinical trial will measure the presence of early treatment diabetic retinopathy level progression in 1500 patients with an A1c between 7% and 10%. Patients will administer either 1 mg of semaglutide or placebo subcutaneously every week. The time frame of the trial will be 5 years and is estimated to be completed in early 2027.⁸

While DR has been identified as a potential adverse effect of semaglutide, there remains a positive benefit-risk profile when used accordingly with the FDA-approved prescribing information. According to the American Diabetes Association guidelines, patients who have been newly diagnosed with type 2 diabetes should have a comprehensive eye exam at the time of diagnosis.⁹ After the initial exam, subsequent eye exams should be conducted annually. In patients who have recently been initiated on semaglutide, especially those with a prior history of retinopathy, prescribers should be vigilant and closely monitor for signs of new or worsening retinopathy.¹⁰

References

1. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S111-S124. doi:10.2337/dc21-S009

2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141

3. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827

4. Dauner DG, Farley JF. Comparing the use of individual and composite terms to evaluate adverse drug event disproportionality: a focus on glucagon-like peptide-1 receptor agonists and diabetic retinopathy. Expert Opinion on Drug Safety. 2021;20(4):475-480. doi:10.1080/14740338.2021.1887136

5. FAERS Public Dashboard - EUA - FAQ. Accessed August 3, 2021. https://fis.fda.gov/extensions/FPD-FAQ/FPD-FAQ.html

6. Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889-897. doi:10.1111/dom.13172

7. Frías JP, Auerbach P, Bajaj HS, et al. Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. The Lancet Diabetes & Endocrinology. 2021;0(0). doi:10.1016/S2213-8587(21)00174-1

8. Novo Nordisk A/S. Long-Term Effects of Semaglutide on Diabetic Retinopathy in Subjects With Type 2 Diabetes. clinicaltrials.gov; 2021. Accessed July 22, 2021. https://clinicaltrials.gov/ct2/show/NCT03811561

9. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes—2021 | Diabetes Care. Accessed July 24, 2021. https://care.diabetesjournals.org/content/44/Supplement_1/S151

10. Safi SZ, Qvist R, Kumar S, Batumalaie K, Ismail ISB. Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets. Biomed Res Int. 2014;2014:801269. doi:10.1155/2014/801269