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From Weight Loss to Vision Loss: A Potential Risk of Semaglutide

August 1, 2024 . 8 views . View Full Issue (Volume 13, Issue 6) . Print this page

By: Sariah Grant, PharmD Candidate c/o 2027

           In June 2021, the Food and Drug Administration approved Novo Nordisk’s semaglutide, marketed under the brand name Wegovy. It was approved for adults facing obesity and other weight-related conditions.1 Initially developed for the management of type 2 diabetes mellitus (T2D), semaglutide’s use has expanded significantly due to its efficacy in promoting weight loss.Wegovy and other semaglutide brand names, including Ozempic and Rybelsus,have quickly become staples in weight-loss therapy.2

 Several factors have contributed to semaglutide’s success, including its effectiveness in treating diabetes and, more recently, its efficacy in reducing body weight.2 According to the Centers for Disease Control and Prevention (CDC), over 70% of Americans face obesity or issues with being overweight.3 It is an issue that can no longer be treated lightly. Given the associated health risks, intervention is needed as a preventative measure. The FDA recognizes obesity as a serious health crisis linked to major health issues including heart disease, stroke, diabetes, and an increased risk of certain types of cancer.1

Despite the clinical benefits of semaglutide, researchers at Harvard Medical School have identified a potential risk associated with the drug’s use, specifically linking it to the development of non-arteritic anterior ischemic optic neuropathy (NAION).4 This eye disease is characterized by vision loss, which may influence decisions regarding the prescription and use of semaglutide.5

Semaglutide Mechanism and Uses

Semaglutide mimics an incretin hormone, which causes a decrease in blood sugar levels.6 This hormone is produced in the intestines after specific nutrients enter the pathway and neural impulses indicate food intake. Semaglutide is classified as a glucagon-like peptide 1 receptor (GLP-1) agonist. GLP-1 agonists work by stimulating the release and secretion of insulin from the pancreatic islets when glucose levels are elevated, usually after eating. It also suppresses the release of glucagon, which raises blood sugar levels. Additionally, semaglutide decreases appetite, promotes satiety, and decreases how much one desires to eat.6

            The Semaglutide Treatment Effect in People with Obesity (STEP) program was a series of randomized phase 3 clinical trials aimed to evaluate the safety and efficacy of the 2.4 mg dose of semaglutide used for weight-loss.6 The STEP program revealed that only 7.6% of participants did not see greater than a 5% average weight loss after taking subcutaneous semaglutide for 12 weeks. These results indicate that semaglutide has a high average weight loss efficacy.6

Understanding NAION

Non-arteritic anterior ischemic optic neuropathy (NAION) is an ophthalmic condition characterized by acute vision lossand is the second most common type of optic neuropathy in adults.4,5 It occurs due to impaired blood flow, resulting in ischemia and subsequent damage to the optic nerve head.7 The exact etiology of this ischemia is unclear. However, a well-accepted proposed risk factor is a congenitally small optic nerve head structure. This anatomical variation increases the likelihood of crowding of axons within the protective layer of the optic nerve, known as the dural sheath. Such crowding may cause vascular compression and edema, ultimately leading to ischemia. Other believed risk factors include obstructive sleep apnea, nocturnal systemic hypotension, hypertension, being over 50, hypercholesterolemia, diabetes mellitus, and the use of certain medications.7

Clinical manifestations of NAION are characterized by acute, painless, unilateral vision loss, usually noticed upon waking.5 This vision loss may include altitudinal vision loss, and/or color-blindness. Upon eye examination, the patient’s optic disc appears swollen due to edema. Currently, there is no effective therapy for NAION. Several treatments have been attempted, but most have been inadequately studied.5

The Risk of NAION for Patients on Semaglutide

A retrospective cohort study was conducted by Boston researchers at Harvard Medical School to determine if semaglutide treatment is associated with an increased risk of nonarteritic anterior ischemic optic neuropathy (NAION).4 The study collected data on patients with NAION diagnoses from a centralized registry at Harvard’s Massachusetts Eye and Ear teaching hospital. Researchers collected data on variables such as age, sex, race, diseases, and conditions, mainly focusing on type 2 diabetes and overweight or obesity statuses. The data spanned from December 1, 2017, to November 30, 2023, covering the period of semaglutide’s approval for type 2 diabetes and weight loss, as well as tracking patient outcomes. Any occurrence of NAION reported prior to the start date was excluded, as were any patients younger than 12 years of age, per FDA age requirements for semaglutide.4 Researchers designed a propensity score-matched cohort study to compare patients who took semaglutide with those who took non-GLP-1 receptor agonist drugs for type 2 diabetes and weight loss. The cohorts were matched based on similar covarying factors including sex, age, obesity, obstructive sleep apnea, systemic hypertension, type 2 diabetes, hyperlipidemia, etc.4

Researchers tracked cumulative incidences of NAION using the Kaplan-Meier survival analysis, and the Cox proportional hazards regression model.4 The Kaplan-Meier survival analysis measures the fraction of living patients for a period after treatment.8 The study spanned from the time of the first prescription of semaglutide or non-GLP-1 treatment until the first event of NAION, death, or the end of the 36-month period.4 The Cox proportional hazard regression model, calculates the hazard ratio of an endpoint associated with a specific risk factor and the probability of the event to occur.9

The type 2 diabetes study included 710 patients.4 Among these, 17 patients on semaglutide were diagnosed with NAION, compared to only 6 in the non-GLP-1 treatment cohort. The Kaplan-Meier survival analysis determined a cumulative incidence of 8.9% (95% CI, 4.5%-13.1%) for the semaglutide group, compared to only 1.8% (95% CI, 0%-3.5%) for the non-semaglutide group after 36 months. The Cox proportional hazards regression model yielded a high hazard ratio of 4.28 (95% CI, 1.62-11.29) (P<.001), indicating a higher risk of NAION in the semaglutide cohort compared to the non-GLP-1 treatment cohort.4

The overweight or obesity study included 979 patients.4 Of these, 20 patients in the semaglutide treatment cohort developed NAION, compared to only 3 in the non-GLP-1 treatment cohort. At 36 months, the Kaplan-Meier survival analysis calculated a cumulative incidence of NAION of 6.7% (95% CI, 3.6%-9.7%) for the semaglutide treatment cohort, versus 0.8% (95% CI, 0%-1.8%) for the non-GLP-1 treatment cohort. Additionally, the Cox proportional hazard regression model resulted in a high hazard ratio of 7.64 (95% CI, 2.21-26.36) (P<.001), indicating a higher risk of NAION in the semaglutide cohort compared to the non-GLP-1 treatment group.4

Discussion

            The findings of both studies have led researchers to two key conclusions.4 First, patients taking semaglutide are at an increased risk of developing NAION.Second, there appears to be a higher chance of developing NAION among the overweight and obese cohort compared to the type 2 diabetes cohort. Although the results of the study seem conclusive, the researchers at Harvard Medical School acknowledge several limitations in their research. These limitations include that data was collected from an institution which specializes in ophthalmology, and thus may not be reflective of the generalized use of semaglutide. The study also does not factor any biases of semaglutide prescription to patients, does not confirm patient’s adherence to treatment, and is limited to data within the institution. Crucially, this data could not be conclusive as it does not assess risk reduction after discontinuing a medication or evaluate dose-dependent risk factors as required by the FDA.4

Conclusion

            Given the limitations in this study, further research is necessary to align with FDA risk assessment procedures.4 Until a more definitive study is conducted, it is recommended that patients should continue their medications as prescribed and consult with their healthcare providers regarding any concerns.4 However, if a future study confirms that there is an association between semaglutide and non-artertic anterior ischemic optic neuropathy, healthcare providers may need to reassess the prescribing of Ozempic, Rybelsus, and Wegovy, weighing both the potential risks and benefits.

References

  1. U.S. Food and Drug Administration. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. Published June 4, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
  2. U.S. Food and Drug Administration. Medications Containing Semaglutide Marketed for Type 2 Diabetes or Weight Loss. FDA. Published June 19, 2023. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or weight-loss
  3. Centers for Disease Control and Prevention. Overweight & Obesity. Published January 5,2023. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm
  4. 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.
  5. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond). 2015;29(1):65-79. doi: 10.1038/eye.2014.144
  6. Chao AM, Tronieri JS, Amaro A, Wadden TA. Clinical Insight on Semaglutide for Chronic Weight Management in Adults: Patient Selection and Special Considerations. Drug Des Devel Ther. 2022;16:4449-4461. doi: 10.2147/DDDT.S365416
  7. Bernstein SL, Johnson MA, Miller NR. Nonarteritic anterior ischemic optic neuropathy (NAION) and its experimental models. Prog Retin Eye Res. 2011;30(3):167-87. doi: 10.1016/j.preteyeres.2011.02.003
  8. Goel MK, Khanna P, Kishore J. Understanding survival analysis: Kaplan-Meier estimate. Int J Ayurveda Res. 2010;1(4):274-8. doi: 10.4103/0974-7788.76794.
  9. Abd ElHafeez S, D’Arrigo G, Leonardis D, Fusaro M, Tripepi G, Roumeliotis S. Methods to Analyze Time-to-Event Data: The Cox Regression Analysis. Oxid Med Cell Longev. 2021;2021:1302811. doi: 10.1155/2021/1302811
Published by Rho Chi Post

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