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January Blog - GLP1s and risk of retinopathy

By Courtney Cameron posted 25 days ago

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Diabetic Retinopathy
Prepared by: Emily Short, PharmD, PGY-1 Pharmacy Resident, Boston Medical Center
What is diabetic retinopathy?
Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus and is one of the most common causes of vision loss worldwide among individuals aged 25 to 74 years.1 In 2021, the Centers for Disease Control and Prevention (CDC) estimated about 9.6 million people across the United States had been diagnosed with diabetic retinopathy, of which 1.84 million have vision-threatening DR.2 The development of DR in patients with diabetes occurs largely due to chronic hyperglycemia, which may lead to altered neuronal function, increased retinal blood flow and retinal blood vessel pressure, structural changes of the retina, and oxidative stress.3 Besides hyperglycemia, other risk factors that place patients at higher risk include hypertension, microvascular complications, such as diabetes-related nephropathy and neuropathy, dyslipidemia, and pregnancy.4
How do glucagon-like peptide 1 receptor agonists (GLP-1RA) potentially lead to diabetic retinopathy?
While speculative, the potential contribution of GLP-1RA to DR development is linked to their ability to rapidly decrease glucose levels upon initiation.5 The sudden lower concentration of glucose within the plasma creates a pressure gradient, causing water to move from the interstitium to the lower-pressure space within blood vessels. The smaller-sized blood vessels in the eye, being more sensitive to water retention, are at an elevated risk of endothelial damage when subjected to a rapid change in this osmotic gradient. This theory is called the osmotic hypothesis.
However, there are numerous recognized failings in this theory, including that serum osmolality gradients are more guided by serum sodium than serum glucose.5 Additionally, the osmotic gradient does not readily explain the neovascularization and retinal features of diabetic retinopathy.
Another theory of DR pathophysiology relates to the risks of retinopathy upon insulin initiation.5 Insulin is thought to work synergistically with, and may even upregulate the actions of, vascular endothelial growth factor (VEGF) as an anabolic hormone itself. This theory may explain why insulin is associated with worsening in individuals who have pre-existing retinopathy where VEGF may already be playing a predominant role. These mechanisms are thought also to relate to the upregulation of reactive oxygen species (ROS) within the retinal endothelial cells, resulting in further damage. Supporters of this theory further indicate that diabetic retinopathy is more prevalent in patients with type 1 diabetes, where insulin is required for management, as opposed to patients with type 2 diabetes, who may be treated with oral hypoglycemic agents that are not statistically associated with an increase in retinopathy.
What data is available regarding diabetic retinopathy associated with GLP-1 receptor agonist use?
An association of treatment with GLP-1RA receptor agonists and DR was originally reported in the SUSTAIN-6 trial, which demonstrated a statistically significant increase in risk of new or worsening DR, with 3% incidence in the semaglutide group versus 1.8% in the placebo group (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02).6 
Although the findings regarding DR in SUSTAIN-6 were statistically significant, other potential contributing factors exist. Of note, the majority (83.5%) of participants who developed DR complications within the trial were reported to have DR at baseline. It also must be considered that SUSTAIN-6 was not designed nor adequately powered to assess DR incidence. Furthermore, although all GLP-1RAs carry the potential for causing DR secondary to rapid glucose lowering, observations of new or worsening DR within primary literature thus far have been isolated to the SUSTAIN-6 trial.
The safety of GLP-1RAs regarding the development of DR is supported by the LEADER trial, which demonstrated no statistically significant difference in rates of DR in those receiving liraglutide compared to placebo.7 Several recent analyses also support the safety of GLP-1 receptor agonists. A 2020 meta-analysis of six placebo-controlled GLP-1RA cardiovascular outcome trials reporting prespecified retinopathy outcomes found no association between GLP-1RA use and DR. Curiously, this analysis did note a relationship between retinopathy and average HbA1c reduction - a 0.1% reduction in HbA1c was associated with 6%, 14%, or 8% increased risk for DR at the three months, one year, and throughout overall follow-up, respectively. However, the trials included in the meta-analysis were not powered to assess DR and had inconsistent criteria for evaluating retinopathy.8
Another 2023 meta-analysis among 93 studies comparing GLP-1 RAs to placebo, insulin, or oral antidiabetic medicine found GLP-1RA use was associated with increased risk of both early and late-stage DR, although these results barely reached statistical significance with 95% confidence intervals of 1.01 to 1.68 and 1.01 to 1.66, respectively. However, upon further investigation, the statistically significant finding proves to be attributable solely to albiglutide, as shown below. Notably, albiglutide was discontinued by the manufacturer in 2017 due to a lack of prescribing.9
Individual GLP-1 RA comparisons.
Recommendations and future directions:
The 2024 American Diabetes Association guidelines recommend patients with type 2 diabetes have a comprehensive eye exam at the time of diagnosis and annually thereafter.10 Similarly, patients with type 1 diabetes should receive a dilated eye exam within 5 years after diagnosis and annually thereafter. Patients with preexisting diabetes should be counseled on the risk of new or worsening diabetic retinopathy associated with pregnancy, as applicable. 
With limited quality evidence available thus far, the association of GLP-1RAs with the development of DR remains somewhat unclear. Fortunately, there may be more insight in the near future - the FOCUS trial, with anticipated completion in November 2027, is currently underway to evaluate the long-term effects of semaglutide on DR.11 In the meantime, it remains pertinent to consider patient-specific factors that may increase their risk of DR when deciding if a GLP-1RA is the optimal choice of therapy. 
1. Leasher JL, Bourne RR, Flaxman SR, et al. Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010 [published correction appears in Diabetes Care. 2016 Nov;39(11):2096]. Diabetes Care. 2016;39(9):1643-1649. doi:10.2337/dc15-2171
2. Centers for Disease Control and Prevention. Prevalence of Diabetic Retinopathy (DR). Vision and Eye Health Surveillance System (VEHSS). Reviewed June 13, 2023. Available at:
3. Frank RN. Diabetic retinopathy. N Engl J Med. 2004;350(1):48-58. doi:10.1056/NEJMra021678
4. Zhang L, Krzentowski G, Albert A, Lefebvre PJ. Risk of developing retinopathy in Diabetes Control and Complications Trial type 1 diabetic patients with good or poor metabolic control. Diabetes Care. 2001;24(7):1275-1279. doi:10.2337/diacare.24.7.1275
5. Jingi AM, Tankeu AT, Ateba NA. et al. Mechanism of worsening diabetic retinopathy with rapid lowering of blood glucose: the synergistic hypothesis. BMC Endocr Disord 17, 63 (2017).
6. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141
7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827
8. Bethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC. HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression. Diabetes Care. 2021;44(1):290-296. doi:10.2337/dc20-1815
9. Kapoor I, Sarvepalli SM, D'Alessio D, Grewal DS, Hadziahmetovic M. GLP-1 receptor agonists and diabetic retinopathy: A meta-analysis of randomized clinical trials. Surv Ophthalmol. 2023;68(6):1071-1083. doi:10.1016/j.survophthal.2023.07.002
10. American Diabetes Association Professional Practice Committee. 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes—2024. Diabetes Care 2024;47 (Suppl. 1):S231–S243 
11. [Internet]. Bethesda (MD): National Library of Medicine (US). 2019 May 8- . Identifier NCT03811561NCT00287391, A Research Study to Look at How Semaglutide Compared to Placebo Affects Diabetic Eye Disease in People With Type 2 Diabetes (FOCUS). Available at: