Clinical Review | Ophthalmology
Ophthalmic Complications Linked to Semaglutide and Tirzepatide: Implications for Diabetes Management
Time to read: 06:56
Time to listen: 12:35
Published on MedED: 3 February 2025
Originally Published: 11 January 2025
Source: JAMA Ophthalmology
Type of article: Clinical Research Summary
MedED Catalogue Reference: MCECS015
Category: Ophthalmology
Cross-reference: Endorcrine Disorders
Keywords: ophthalmology, NAION, GLP-agonists, Type 2 Diabetes
Originally Published in JAMA Ophthalmology, 31 January, 2025. This is a summary of the clinical study and in no way represents the original research. Unless otherwise indicated, all work contained here is implicitly referenced to the original author and trial. Links to all original material can be found at the end of this summary. Access the Disclaimer
Key Take Away
While this study was unable to conclusively establish a causal link between semaglutide or tirzepatide and ophthalmic complications, clinicians are urged to adopt a cautious approach, particularly in patients at higher risk for optic nerve disorders, and remain vigilant for visual symptoms in these individuals.
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Study Context | Objectives | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References
Semaglutide and tirzepatide, both GLP-1 receptor agonists, are effective treatments for Type 2 Diabetes and obesity. Semaglutide mimics the action of GLP-1, helping to lower blood sugar levels and promote weight loss, while Tirzepatide, a dual GLP-1 and GIP receptor agonist, has shown similar benefits, with additional weight loss and improvements in HbA1c levels, depending on the dosage. The most common side effects for both medications are typically mild and include nausea, vomiting, and diarrhoea.1,2
However, growing concerns have emerged regarding potential ophthalmic complications associated with these therapies. In the SUSTAIN 6 trial—a 2-year cardiovascular outcomes study that is part of the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial programme—a link between semaglutide and an increased risk of diabetic retinopathy (DR) complications was revealed. Specifically, patients treated with semaglutide had a 76% higher rate of DR complications compared to those on a placebo.3
This phenomenon, often attributed to the rapid improvement in glycaemic control, raised concerns about the potential for early worsening of DR, a known issue with insulin therapy. These findings align with observations from other studies, such as a 2024 paper by Wai et al., which reported a higher rate of progression of proliferative diabetic retinopathy (PDR) and new-onset diabetic macular oedema (DME) in patients using GLP-1 agonists compared to those on SGLT-2 inhibitors.4
Further evidence has emerged from a large-matched cohort study of 16,827 patients, which indicated a higher risk of non-arteritic anterior ischemic optic neuropathy (NAION) in patients prescribed semaglutide compared to those on other diabetes medications .5
Against this background, this current study was prompted after the lead researcher noted a case of NAION in a patient treated with semaglutide just one day after starting therapy.
The stated outcome of this study was to report on the "…..ophthalmic complications associated with the use of semaglutide or tirzepatide."1
Study Design
This was a retrospective case series.
Researchers identified ophthalmic complications associated with semaglutide or tirzepatide use in patients initially seen in community settings. Members of NANOSnet, a listserv with over 800 members of the North American Neuro-Ophthalmology Society, were requested to report similar incidences and a search of the National Registry of Drug-Induced Ocular Side Effects was included
Demographic data collected included patient sex, age decade, drug use, duration, vascular risk factors, optic nerve swelling (unilateral/bilateral), symptoms on awakening, pain presence, and cup-disc ratio. No race or ethnicity data were gathered due to its irrelevance to the study's outcomes.
Of the nine patients, the following were reported:
While the study was notably small, these findings highlight a potential risk of optic neuropathy associated with GLP-1 receptor agonists, particularly in patients experiencing rapid glycaemic reduction.
The recurrence of symptoms upon re-exposure to semaglutide, in one case, suggested a possible direct toxic or idiosyncratic reaction to the drug.
Moreover, the presence of optic disc oedema and visual field defects raises concerns regarding optic nerve vulnerability in the context of rapid metabolic shifts which may accompany these medications.
One proposed mechanism of this particular effect is that rapid glycaemic correction could induce optic nerve swelling, leading to compartment-like pressure effects and subsequent infarction, as seen in NAION. This is consistent with prior observations suggesting that optic nerve swelling may precede NAION, particularly in individuals with predisposing anatomical factors.
Given these concerns, clinicians prescribing GLP-1 receptor agonists should be vigilant for visual symptoms, particularly in patients with pre-existing optic nerve compromise or those undergoing rapid glycaemic reductions. Regular ophthalmologic monitoring may be warranted for high-risk individuals.
Clinical Note
In response to emerging reports of potential associations between GLP-1 receptor agonists and optic neuropathy, the American Academy of Ophthalmology (AAO) has issued a statement advising clinicians and patients to be aware of potential visual complications.
While the AAO has not recommended discontinuing semaglutide or tirzepatide outright, they advise patients experiencing vision loss to seek immediate medical attention and consult their prescribing physician regarding potential medication adjustments.
Limitations
The researchers indicated several limitations, including that the retrospective uncontrolled case series is limited by its lack of a control group, potential selection bias, and reliance on historical data, which may lead to incomplete or inaccurate information and reduced ability to establish causality. Because the study was initiated after a single case of NAION associated with semaglutide, there is a risk of confirmation bias.
Conclusion
In conclusion, while a causal link between semaglutide or tirzepatide use and ophthalmic complications could not be established in this case series, the potential association with rapid hyperglycemia correction warrants further investigation.
Hypotheses suggest that the drugs' effect on glucose levels, rather than direct toxicity, may contribute to the reported complications. Future controlled studies and postmarketing surveillance are essential to clarify the relationship between incretin-based therapies and optic neuropathies.
Until these findings are confirmed, clinicians should take a cautious approach, particularly in patients at higher risk for optic nerve disorders, and remain vigilant for visual symptoms in these individuals.
Importance of this study for South Africa
The prevalence of type 2 diabetes (T2DM) in South Africa is alarmingly high, with estimates suggesting that 12–15% of adults are affected. 7, 8
Non-arteritic anterior ischaemic optic neuropathy (NA-AION) is a major cause of sudden, unilateral, painless vision loss, particularly in individuals over the age of 50. Indeed NA-AION is the second leading cause of permanent optic nerve-related vision loss in adults.9
Both T2DM and blindness due to optic neuropathies place a significant burden on South Africa's healthcare system and communities.
Preventable blindness is a global public health problem. South Africa is at risk of falling short of the UN SDG goals for 2030 unless immediate and effective interventions are implemented to tackle the rising diabetes epidemic.
Medications like semaglutide and tirzepatide are now available in South Africa. Semaglutide, sold under the trade name Ozempic ™ by Novo Nodisk, has been in the country for some time. Tirzepatide, marketed as Mounjaro and distributed under license by Aspen from Eli Lilly, is newly released and has been available since December 2024. Both of these GLP-1 receptor agonists offer promising therapeutic benefits for managing T2DM and obesity, but they also present potential risks for ophthalmic complications, such as NA-AION.10,11
Given the increasing use of these drugs, healthcare practitioners must be aware of the associated risks. As more patients are prescribed these therapies, clinicians must stay vigilant and prepared to manage any ocular side effects, ensuring timely intervention and appropriate monitoring.
Access the Study
Katz BJ, Lee MS, Lincoff NS, et al. Ophthalmic Complications Associated With the Antidiabetic Drugs Semaglutide and Tirzepatide. JAMA Ophthalmol. Published online January 30, 2025. doi:10.1001/jamaophthalmol.2024.6058
Conflict of Interest, Funding and Support
Role of the Funder/Sponsor
The study's funder had no role in the design, data collection, data analysis, data interpretation, or writing of the report.
Conflict of Interest Disclosures
Full declaration available online
Funding/Support
Funding/Support: This study was supported by an unrestricted grant from Research to Prevent Blindness Inc. to the Department of Ophthalmology and Visual Sciences, University of Utah and the Department of Ophthalmology, University of West Virginia.
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References
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