Semaglutide and Associated Ophthalmic Risks

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Article initiated by:
Sanjana Jaiswal
All contributors:
Elizabeth Arogundade, Megha Yadav, MD, Andrew Go Lee, MD, Sanjana Jaiswal
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Semaglutide and associated Ophthalmic risks

Semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist commonly used to lower blood glucose levels in diabetics and to prevent cardiovascular complications. Since its approval by the US FDA for chronic weight management in 2021, the use of Semaglutide has significantly increased in clinical practice. However, recent studies have raised concerns about potential adverse outcomes. This article aims to summarize ‘Semaglutide and associated Ophthalmic risks’ to aid in making informed decisions while prescribing Semaglutide to patients.

Background

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). It is primarily used for the treatment of type 2 diabetes mellitus (T2DM) and, more recently, at higher doses for the treatment of obesity. Both of these conditions - Diabetes and obesity are reaching epidemic proportions and often coexist, posing a significant risk for morbidity and mortality.[1] Semaglutide offers better glucose control, clinically significant weight loss, and cardiovascular benefits, making it increasingly valuable for high-risk patients. [2]

Its Use and Recent FDA Approval

Semaglutide, marketed as Ozempic (by Novo Nordisk), was approved by the US Food and Drug Administration (FDA) in December 2017 for treating T2DM and later in December 2022 for obesity (under the brand name Wegovy, typically at higher doses). [3] Consequently, between 2021 and 2023, the weekly prescriptions of Semaglutide and other GLP-1 RAs in the United States grew by approximately 60%. [4][5]

Concerns about Ocular Complications of Semaglutide

While these outcomes are promising, recent clinical trials, such as the SUSTAIN (Semaglutide Unabated Sustainability study for T2DM treatment), have raised concerns about the worsening of diabetic retinopathy (DR) and risk of NAION associated with semaglutide use. [1][5][6][7]

Mechanism of Action

Semaglutide acts as a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, stimulating insulin secretion in response to high blood sugar.[1][8] It also suppresses hepatic gluconeogenesis by inhibiting glucagon release, thus effectively lowering blood glucose levels. [1]

Semaglutide promotes weight loss by slowing gastric emptying and reducing hunger and food cravings. Thus, it increases fullness and satiety and improves control of eating through its effects on neutral pathways. [8][9]

As a synthetic GLP-1 agonist, it resists rapid degradation by the enzyme dipeptidyl peptidase-8 4 (DPP-4), ensuring prolonged therapeutic effects. [8]

Indications and Uses

Diabetes

Semaglutide is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). [10]

Recommended Dosage and form:

Semaglutide is available as a subcutaneous injection in the form of prefilled multidose pens, including Ozempic® and Wegovy®. [11][12]

Strengths of Ozempic: 2 mg/3 mL, 4 mg/3 mL, and 8 mg/3 mL

The starting dose is 0.25 mg once weekly for 4 weeks, followed by an increase to 0.5 mg once weekly. [12]

Obesity/Chronic weight management

It is indicated as an adjunct to reduced calorie intake and increased physical activity in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) who have at least one weight-related comorbidity. [8]

Recommended Dosage and form:

Available in single-use, prefilled pens. [8]

The dose is 2.4 mg injected subcutaneously once weekly, administered on the same day each week, with or without meals. [8]

Adverse Effects of Semaglutide

General

The most common adverse reaction of Semaglutide is gastrointestinal side effects. It is contraindicated in pregnant women and patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2. [8]

Diabetic Retinopathy(DR)

Data showing a connection between semaglutide and DR emerged during the phase-3 trials i.e., the SUSTAIN and PIONEER program. [1][13] There is a potential risk of worsening diabetic retinopathy in patients treated with semaglutide, especially among those who have pre-existing retinopathy. Rapid improvements in glucose control may be the contributing mechanism for this risk. Studies have reported findings, indicating that tight glucose control could worsen pre-existing retinopathy. [1]

Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)

Recent retrospective analyses found semaglutide to be associated with an increased risk of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION).[5] A cohort study involving 16,827 patients indicated a higher incidence of NAION in those treated with semaglutide compared to those using non-GLP-1 receptor agonist medications. This risk appears most pronounced within the first year of semaglutide use, suggesting a potential drug-induced effect. The presence of GLP-1 receptor in the human optic nerve and the enhanced sympathetic nervous system activity induced by GLP-1 receptor agonists may increase the susceptibility to NAION. [5]

Other Ocular Adverse Effects

There is a reported increase in the risk of new-onset macular edema in patients treated with semaglutide compared with placebo. [11][14] As per the SUSTAIN-6, there is a 76% higher risk of retinopathy-related complications (blindness, vitreous hemorrhage, necessity of photocoagulation, and use of intravitreal agents) in the semaglutide treatment group as compared to placebo.[12][14]

Clinical recommendations

The rapid HbA1c reduction linked to semaglutide might contribute to complications like DR as per current understanding. [11] [14]Patients should be informed of the potential associated risk of developing eye diseases with semaglutide.

Key Guidelines:

  1. Consider performing dilated fundoscopy before starting semaglutide therapy in diabetic or other at-risk patients and to diagnose and treat concomitant diabetic retinopathy (DR) simultaneously.
  2. Consider down-titrate insulin therapy or stop sulphonylurea to reduce the risk of acute DR worsening.
  3. For severe DR, initiate retinopathy treatment before or alongside glucose-lowering therapy, expecting a typically transient worsening though. [1][15]
  4. Early detection of DR onset/progression and, eventually, specific treatment is crucial. Thus, screen for DR at T2DM diagnosis and annually, while also taking into account individual metabolic control and baseline DR conditions. [16]
  5. Guidelines on DR management are the same as for patients receiving other antidiabetic agents, including anti-VEGF agents.
  6. Consider discussing with patients with or at risk of NAION the possible association of semaglutide therapy and visual loss.
  7. A cautious approach is essential, particularly with coexisting insulin treatment and advanced disease stages.[1]


References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cigrovski Berkovic M, Strollo F. Semaglutide-eye-catching results. World J Diabetes. 2023;14(4):424-434. doi:10.4239/wjd.v14.i4.424
  2. ↑ Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol. 2021;20(1):189. doi:10.1186/s12933-021-01366-8
  3. ↑ Commissioner O of the. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. June 21, 2021. Accessed August 22, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
  4. ↑ Semaglutide Medications | novoMEDLINKTM. novoMEDLINK. Accessed August 13, 2024. https://www.novomedlink.com/semaglutide/medicines.html, https://www.novomedlink.com/semaglutide/medicines.html
  5. ↑ 5.0 5.1 5.2 5.3 Hathaway JT, Shah MP, Hathaway DB, et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmology. 2024;142(8):732-739. doi:10.1001/jamaophthalmol.2024.2296
  6. ↑ Saw M, Wong VW, Ho IV, Liew G. New anti-hyperglycaemic agents for type 2 diabetes and their effects on diabetic retinopathy. Eye (Lond). 2019;33(12):1842-1851. doi:10.1038/s41433-019-0494-z
  7. ↑ Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomized, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. doi:10.1016/S2213-8587(17)30013-X
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Chao AM, Tronieri JS, Amaro A, Wadden TA. Semaglutide for the treatment of obesity. Trends Cardiovasc Med. 2023;33(3):159-166. doi:10.1016/j.tcm.2021.12.008
  9. ↑ Gabery S, Salinas CG, Paulsen SJ, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5(6):e133429, 133429. doi:10.1172/jci.insight.133429
  10. ↑ Kommu S, Whitfield P. Semaglutide. In: StatPearls. StatPearls Publishing; 2024. Accessed August 13, 2024. http://www.ncbi.nlm.nih.gov/books/NBK603723/
  11. ↑ 11.0 11.1 11.2 Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): a new weight loss drug for chronic weight management. J Investig Med. 2022;70(1):5-13. doi:10.1136/jim-2021-001952
  12. ↑ 12.0 12.1 12.2 Mahapatra MK, Karuppasamy M, Sahoo BM. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes. Rev Endocr Metab Disord. 2022;23(3):521-539. doi:10.1007/s11154-021-09699-1
  13. ↑ Smits MM, Van Raalte DH. Safety of Semaglutide. Front Endocrinol (Lausanne). 2021;12:645563. doi:10.3389/fendo.2021.645563
  14. ↑ 14.0 14.1 14.2 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
  15. ↑ Aiello LP, DCCT/EDIC Research Group. Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):17-23. doi:10.2337/dc13-2251
  16. ↑ Introduction: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S1-S2. doi:10.2337/dc20-Sint
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