How do GLP-1 receptor agonists affect ocular health?

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are being increasingly prescribed for both patients with diabetes and overweight/obesity. Although GLP-1 RAs are currently just approved for type 2 diabetes, they are also being used to attenuate weight gain in patients with type 1 diabetes. Drugs such as semaglutide 0.25 to 1.0 mg (Ozempic; Novo Nordisk), semaglutide 1.0 to 2.4 mg (Wegovy; Novo Nordisk), and tirzepatide 0.25 to 1.5 mg (Mounjaro; Lilly) are often prescribed in type 2 diabetes because they are associated with statistically significant reductions in body weight, as well as reductions in cardiorenal risk.¹ Widespread shortages of these agents have been reported due to their increasing popularity for weight loss, including a newer indication for tirzepatide for overweight and obesity in patients without diabetes (identical to Mounjaro but relabeled as Zepbound).² More recently, some of these drugs have been shown to improve other outcomes such as sleep apnea, dementia risk, and COVID-associated mortality during the pandemic. It is presumed that these additional benefits may be due to improved metabolic function (insulin sensitivity and inflammatory dyslipidemia) as well as reduced body weight.³ Let’s take a look at some of these findings, as well as consider some potential impacts on ocular health.

GLP-1 RAs have multiple mechanisms of action, including reductions in both appetite/gastric emptying and glucagon secretion, as well as briefly heightened insulin secretion, all of which synergistically reduce blood glucose levels and body mass index (BMI).⁴ Third-generation agents such as semaglutide and tirzepatide are more potent than first- and second-generation drugs such as exenatide, liraglutide, and dulaglutide. Hemoglobin A_1C (HbA_1C) reductions with these newer GLP-1 drugs have been linked to increased risk of diabetic retinopathy (DR) progression, particularly for patients who experience a rapid, more than 2-point drop in HbA_1C and have preexisting non-proliferative diabetic retinopathy (NPDR).⁵ One of these agents, semaglutide, was recently associated with a significant increase in the risk of non-arteritic anterior ischemic optic neuropathy,⁶ and I have previously reported a case of diabetic papillopathy (an anterior ischemic optic neuropathy variant) associated with GLP-1 use and rapid reduction in HbA_1C in this column.⁷

Results of a 2024 study by Malhotra et al found that 2 years of tirzepatide use in patients with polysomnography confirmed obstructive sleep apnea syndrome (OSAS) reduced the apnea-hypopnea index score (AHI = number of apneic plus hyponeic events lasting at least 10 seconds with 4% or more reduction in oxygen saturation per hour of sleep) by about 50% compared with baseline.⁸ More than 250 tirzepatide-naive subjects with a BMI greater than 30 (mean = 35.6) had a mean AHI at study entrance of 37.4 events/hour, which decreased to a mean of 18.8 events/hour (P < .001). Mean weight loss was 16.5 pounds. Prior observational evidence has shown reductions in AHI with weight loss in general, and the effect seen with tirzepatide in this trial exceeds that found in other analyses, suggesting that improved insulin sensitivity, blood glucose, and inflammation may have contributed to the apnea benefit in addition to weight loss alone. OSAS has been linked to increased risk of major adverse cardiovascular events such as heart attack, congestive heart failure, and stroke, as well as major eye diseases such as DR and age-related macular degeneration (including suboptimal response to anti-VEGF therapy). Therefore, a drug regimen that improves OSAS severity should also be of interest to eye doctors.

Results of another recent study found that semaglutide reduced risk of neuropsychiatric disorders over 12 months, including cognitive deficit and dementia, when compared with other common diabetes medications such as sitagliptin and glipizide. The analyzed cohort included more than 1 million patients from the US TriNetX collaborative network of electronic health records.⁹ Additionally, a proteomic study of more than 13,000 subjects with type 2 diabetes recently showed significant reductions in multiple inflammatory proteins linked to Alzheimer disease (AD) with use of the first-generation GLP-1 drug exenatide.¹⁰ A presentation at the 2024 Alzheimer’s Association International Conference also showed that the second-generation GLP-1 agonist liraglutide used for 12 months reduced cognitive decline by 18% compared with placebo in subjects with mild AD. Exploratory secondary analysis in this randomized controlled trial also demonstrated nearly 50% less volume loss in several areas of the brain, including frontal, temporal, parietal, and total gray matter, as measured by magnetic resonance imaging.¹¹ Results of another retrospective study found that semaglutide use was associated with reduced risk of AD diagnosis in patients with type 2 diabetes by 40% to 70% when compared with a host of other diabetes medications, including insulin, metformin, dipeptidyl-peptidase-IV inhibitors, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, and even other GLP-1 analogs.¹² Multiple clinical trials are now underway evaluating both semaglutide and tirzepatide in patients with mild cognitive impairment.

Multiple case reports linking GLP-1 use to worsening DR have been reported, though systematic analyses have differed on this point.¹³ Meta-analysis of DR outcomes from cardiovascular outcomes trials showed that progression risk was directly proportionate to the magnitude of HbA_1C reduction.¹⁴ The consensus now is that GLP-1 agonists, such as exogenous insulin itself, may be associated with worsening DR when mean glucose levels drop precipitously and rapidly (glycemic re-entry retinopathy).^15,16 Optometrists and ophthalmologists alike should be vigilant in patients with sudden, large reductions in HbA_1C or increases in glucose time-below-range using a continuous glucose monitor (percentage of glucose readings <= 70 mL), especially in patients with preexisting moderate or worse NPDR. The pleiotropic effects of this class of agents nearly guarantees we will be managing patients who use them over the coming years.

References:

1. Marx N, Husain M, Lehrke M, Verma S, Sattar N. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation. 2022;146(24):1882-1894. doi:10.1161/CIRCULATIONAHA.122.059595

2. Whitley HP, Trujillo JM, Neumiller JJ. Special report: Potential strategies for addressing GLP-1 and dual GLP-1/GIP receptor agonist shortages. Clin Diabetes. 2023;41(3):467-473. doi:10.2337/cd23-0023

3. Yazıcı D, Yapıcı Eser H, Kıyıcı S,et al. Clinical impact of glucagon-like peptide-1 receptor analogs on the complications of obesity. Obes Facts. 2023;16(2):149-163. doi:10.1159/000526808

4. Kong MW, Yu Y, Wan Y, Gao Y, Zhang CX. Glucagon-like peptide-1 receptor agonists: exploring the mechanisms from glycemic control to treatment of multisystemic diseases. World J Gastroenterol. 2024;30(36):4036-4043. doi:10.3748/wjg.v30.i36.4036

5. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141

6. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol. 2024;142(8):732-739. doi:10.1001/jamaophthalmol.2024.2296

7. Chous AP. Optic disk swelling in an asymptomatic patient with diabetes. Optometry Times. November 12, 2021. Accessed December 17, 2024. https://www.optometrytimes.com/view/optic-disk-swelling-in-an-asymptomatic-patient-with-diabetes

8. Malhotra A, Grunstein RR, Fietze I, et al; SURMOUNT-OSA Investigators. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. doi:10.1056/NEJMoa2404881

9. De Giorgi R, Koychev I, Adler AI, et al.12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study. eClinicalMedicine. 2024;74:102726. Published online July 10, 2024. doi:10.1016/j.eclinm.2024.102726

10. Koychev I, Reid G, Nguyen M, et al. Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial. Alzheimers Res Ther. 2024;16(1):212. doi:10.1186/s13195-024-01573-x

11. GLP-1 drug liraglutide may protect against dementia. News release. Alzheimer’s Association International Conference. July 30, 2024. Accessed December 17, 2024. https://aaic.alz.org/releases-2024/glp-drug-liraglutide-may-protect-against-dementia.asp

12. Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement. Published online October 24, 2024. doi:10.1002/alz.14313

13. Wang T, Hong JL, Gower EW, et al. Incretin-based therapies and diabetic retinopathy: real-world evidence in older US adults. Diabetes Care. 2018;41(9):1998-2009. doi:10.2337/dc17-2285

14. 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

15. Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116(7):874-886. doi:10.1001/archopht.116.7.874

16. Zoungas S, Arima H, Gerstein HC, et al; Collaborators on Trials of Lowering Glucose (CONTROL) group. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431-437. doi:10.1016/S2213-8587(17)30104-3