Semaglutide is a glucagon-like peptide-1 agonist (GLP-1 agonist) that is FDA-approved for the treatment of type 2 diabetes and weight loss.1 Over the past few years, semaglutide has become an increasingly powerful tool in the treatment of type 2 diabetes and then evolved into a popular weight-loss solution.
In fact, over the past 5 years, a 40-fold increase in the use of semaglutide medications has occurred in the US.2 Like most medications, the substantial benefit of semaglutide is not without some risk.
This article will introduce the semaglutide medications, approved uses, possible adverse effects—including the possibility of worsening of diabetic retinopathy resulting from a rapid decrease in blood glucose and the potential risk of non-arteritic ischemic optic neuropathy (NAION)—as well as address surgical considerations.
Understanding GLP-1 agonists
GLP-1 agonists stimulate insulin production by the pancreas and reduce glucagon secretion. The result is slowed gastric emptying and reduced appetite leading to weight loss and improved glycemic control.3
Semaglutide has several advantages over other available type 2 diabetes treatment options, such as lower risk of hypoglycemia, cardiovascular benefits, promoting weight loss, and the option of a weekly dosage regimen.3
Examples of GLP-1 agonists include:
- Exenatide
- Liraglutide
- Albiglutide
- Tirzepatide
- Semaglutide
- Dulaglutide
An overview of semaglutide medications
The three FDA-approved semaglutide medications are Ozempic, Rybelsus, and Wegovy. Ozempic and Rybelsus are approved for the treatment of type 2 diabetes, while Wegovy is approved for the management of health complications caused by obesity such as cardiovascular events.
All three medications are recommended to be used in conjunction with diet and exercise to improve glycemic control and weight. Of note, Ozempic and Wegovy are weekly injections while Rybelsus is a daily tablet.
Table 1: Overview of semaglutide medications.4-7
| Semaglutide | Indication | Dosage | FDA Approval |
|---|---|---|---|
| Ozempic | Treatment of type 2 diabetes, especially in those with increased cardiovascular risk | Once weekly injection | 2017 |
| Rybelsus | Treatment of type 2 diabetes | Daily tablet | 2019 |
| Wegovy | Weight loss in the prevention or management of weight-related medical conditions, especially cardiovascular events | Once weekly injection | 2021 |
Table 1: Adapted from Novo Nordisk and US Food & Drug Administration.
While Wegovy is the only of the three approved for weight-loss management, the other two are often used “off-label” for that purpose. The number of off-label prescriptions for Ozempic and Rybelsus has doubled in the past 2 years due to its efficacy and popularity.8 According to pharmaceutical company Novo Nordisk, over 25,000 people are starting Wegovy per week in 2024, and over 500,000 Ozempic prescriptions are ordered per week.8
As seen in Table 2, the half-life of GLP-1 agonists varies between different medications within this class.9 The side effects of GLP-1 agonists are primarily gastrointestinal (GI), secondary to its effect on slowing down the GI tract to elongate the feeling of satiety, which can cause nausea, vomiting, and diarrhea, and may lead to kidney injury, as well as rapid weight loss.10
Table 2: GLP-1 agonists and their half-lives.9
| GLP-1 Agonist | Half-Life |
|---|---|
| Exenatide (Byetta) and Extended-Release Exenatide (Bydureon) | 2.4 hours |
| Liraglutide (Victoza) | 13 hours |
| Dulaglutide (Trulicity) | 90 hours |
| Albiglutide (Tanzeum) | 120 hours |
| Semaglutide (Ozempic) | 160 hours |
Table 2: Adapted from Biopharma PEG.
Of note, major drug warnings come along with semaglutide. The list includes risk of thyroid C-cell tumors, pancreatitis, gallbladder disease, kidney disease, hypoglycemia, and hypersensitivity.4 Suicidal tendency is also listed as an additional risk with Wegovy.4
Key clinical trials on the safety and efficacy of GLP-1 agonists
Several key clinical trials were completed to investigate the efficacy and adverse effects of GLP-1 agonists. The main study objectives were cardiovascular outcome and glycemic control, but diabetic retinopathy was a secondary factor.11
LEADER
Trial Name: LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results)
Conclusions: The LEADER trial studied patients with diabetes type 2 at high risk for cardiovascular disease to determine the effect of treatment with liraglutide versus placebo on the incidence of cardiovascular events. Results showed that subjects receiving treatment with liraglutide not only had more significant reductions in hemoglobin A1C (HbA1c) but also a reduced risk of cardiovascular events (myocardial infarction, stroke, heart failure).12
REWIND
Trial Name: REWIND (Researching Cardiovascular Events with a Weekly INcretin in Diabetes)
Conclusions: The REWIND trial investigated dulaglutide’s effect on adverse cardiovascular outcomes in people with type 2 diabetes at high risk for adverse cardiovascular events. Subjects received either weekly injections of dulaglutide or placebo and were followed for a median of 5.4 years. The study concluded that dulaglutide reduced incidence of ischemic stroke but did not reduce incidence of hemorrhagic stroke or reduce stroke severity.13
PIONEER-6
Trial Name: PIONEER-6 (Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes)
Conclusions: The PIONEER-6 trial assessed cardiovascular risk associated with once-daily oral semaglutide in subjects at high risk for adverse cardiovascular events.11 The objective was to ensure an adequate safety profile for oral semaglutide, and results showed that there was no increased cardiovascular risk associated with the medication over the placebo.14
EXSCEL
Trial Name: EXSCEL (EXenatide Study of Cardiovascular Event Lowering)
Conclusions: The EXSCEL trial evaluated the effect of once-weekly exenatide injection on outcomes of cardiovascular death, stroke, or myocardial infarction in subjects with type 2 diabetes. The results showed no significant difference in the adverse cardiovascular outcomes between the treated and placebo groups.15
HARMONY
Trial Name: HARMONY (Effect of Albiglutide When Added to Standard Blood Glucose Lowering Therapies on Major Cardiovascular Events in Subjects with Type 2 Diabetes)
Conclusions: The HARMONY trial investigated the safety and efficacy of once-weekly albiglutide in preventing cardiovascular death, stroke, or myocardial infarction in subjects with type 2 diabetes. Results showed that albiglutide was superior to the placebo in reducing the risk of cardiovascular events, and therefore, the investigators suggest incorporating GLP-1 agonists into a strategy to reduce cardiovascular risk in type 2 diabetics.16
SUSTAIN-6
Trial: SUSTAIN-6 (Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes)
Conclusions: The SUSTAIN-6 trial investigated the cardiovascular safety of once-weekly semaglutide injection in subjects with type 2 diabetes and a high risk of adverse cardiovascular events. Results showed that the risk for cardiovascular death, myocardial infarction, and stroke was significantly reduced in subjects receiving semaglutide treatment.17
Impact of semaglutide on diabetic retinopathy
A meta-analysis was performed of the studies above to determine the correlation between reduction of HbA1c and worsening or development of diabetic retinopathy.11 While semaglutide has been a game-changer for many diabetic patients due to its significant and rapid results, these recent studies point to semaglutide as having the greatest risk of worsening diabetic retinopathy.11
The SUSTAIN-6 trial, examining treatment with semaglutide, was the only study with a statistically significant worsening of diabetic retinopathy.11 The SUSTAIN-6 trial found that retinopathy occurred in 3% of patients treated with semaglutide versus 1.8% with placebo. For patients without a known history of diabetic retinopathy, the absolute risk increase was 0.7% with semaglutide vs. 0.4% in the placebo.3
The analysis also confirmed that semaglutide was found to have the most significant HbA1c decrease noted at the 3-month, 1-year, and end-point marks of the GLP-1 agonists investigated.11
Potential mechanism of action
The proposed mechanism for worsening of retinopathy is the rapid, intense lowering of blood glucose by semaglutide before retinal microvascular adjustment can occur.18 Similar effects have been seen in diabetic patients with a history of bariatric surgery, initiation of intense insulin treatment, and after pregnancy.18,19 In those cases, the worsening was temporary.18 Long-term monitoring of affected semaglutide patients will be needed to confirm if a comparable course is observed.
An ongoing clinical trial, called FOCUS, is investigating the ophthalmic effects of semaglutide. This study will investigate not only worsening of diabetic retinopathy but other potential ophthalmic complications or benefits. This study is planned to last for 5 years and be completed in December of 2026.20
Other ocular effects of semaglutide
Though the primary concern is worsening of preexisting retinopathy, other ocular structures could be affected by semaglutide. In a review of all reported adverse effects from Ozempic, 2,109 adverse events were reported, and 140 of them were ocular in nature.21
Macular edema was rare, noted in four cases, diabetic retinopathy was noted in 23 cases, and the most common ocular effect was blurred vision, which occurred in 47 cases.21 Changes in lens thickness resulting in refractive error shift and blurred vision can be induced by rapid blood sugar fluctuation. This usually subsides as the blood sugar stabilizes a few months after starting the medication.21
Research on NAION and semaglutide
Just recently, in July 2024, Hathaway et al. published research suggesting a higher risk of NAION in patients prescribed semaglutides for type 2 diabetes or obesity than counterparts treated with non-GLP-1 agonists. The retrospective study could not prove causality but found a difference in the 36-month cumulative incidence of NAION.22
In the type 2 diabetes cohort, the cumulative incidence was 8.9% for those treated with semaglutide and 1.8% for those treated with non-GLP-1 agonists.22 The greatest risk of NAION was during the first year of treatment and the proposed mechanism is that GLP-1 agonists induce sympathetic nervous system activity which alters optic nerve head perfusion.22
Patients should be counseled on this increased risk, especially those who have comorbid NAION risk factors like hypertension, hypercholesterolemia, cardiovascular disease, sleep apnea, history of smoking, or crowded “disc at risk” optic nerve anatomy.
In the obesity cohort, cumulative incidence was 6.7% and 0.8%, respectively.22 The pathological mechanism requires further investigation but the authors propose GLP-1 agonist activation of the sympathetic nervous system and expression of GLP-1 receptors in the optic nerve may affect or alter perfusion thereby increasing risk of NAION.22
Potential neuroprotective effects of GLP-1 agonists
Other research suggests GLP-1 agonists could have a neuroprotective effect that may reduce the risk of glaucoma, retinal disease, and systemic neuro-degenerative diseases like Alzheimer’s disease and Parkinson's disease.
Preclinical research has demonstrated that GLP-1 agonists may prevent ganglion cell degeneration, maintain the blood-retinal barrier and vascular tone, maintain mitochondrial integrity, which can reduce oxidative stress, and reduce neuro-inflammation through activation of anti-inflammatory cytokines.23 Since these are preclinical findings, this area requires more, longer-term research.
Patient recommendations for the ocular effects of semaglutide
Before starting a semaglutide, a patient should have a baseline diabetic eye examination at initiation or within 12 months prior. Those patients with a history of diabetic retinopathy should have sooner follow-ups if they are starting semaglutide to monitor for progression as the body undergoes rapid blood glucose change (every 3 months rather than 6 months, for example).
If there is an indication of progressing retinopathy, then exams should be performed even more frequently. If worsening or sight-threatening retinopathy is present, retina specialist referral may be warranted sooner than is typical to err on the side of caution due to the risk that rapid deterioration could occur.
The standard treatments for diabetic retinopathy, like anti-VEGF injection, laser photocoagulation, and vitrectomy, are still indicated in these patients without reservation.19,24
Surgical considerations associated with GLP-1 agonists
The most common ophthalmic procedures done include cataract, glaucoma, and vitreoretinal surgeries, all of which require some level of anesthesia, ranging from topical and regional, to monitored anesthesia care (MAC) and general anesthesia. MAC is defined as having an anesthesiologist or a certified registered nurse anesthetist present to monitor patient safety and minimize patient discomfort while patients go under anesthesia.
A 1999 study on 1,006 cataract surgeries found that patients on systemic hypertensives, with pulmonary disease, renal disease, cancer, and patients under the age of 60 were more likely to require intervention, and therefore requiring MAC.25
Many medications are stopped or adjusted prior to a patient's entry for surgery. Blood-thinning medications are typically stopped to prevent excessive bleeding. Diabetes medications such as insulin and metformin are adjusted to prevent both hyperglycemia and hypoglycemia. With the recent increase in the use of GLP-1 agonists, ophthalmologists must be aware of the associated surgical guidelines.
New ASA guidelines on GLP-1 agonists
On June 29, 2023, the American Society of Anesthesiologists (ASA) released guidelines recommending that patients going into elective surgeries hold their use of GLP-1 agonists either on the day of surgery if taken daily, or a week before surgery.26
The ASA Task Force on Preoperative Fasting had reviewed the literature and determined that the “risk of regurgitation and pulmonary aspiration of gastric contents” was high enough to warrant stopping medication and monitoring for GI symptoms before the procedure.26
The current literature review shows evidence that a significant increase in residual gastric contents was found in patients taking weekly GLP-1 agonists compared to patients who do not.27
While the ASA does give guidelines on the timing of stopping medications depending on dosing schedules, there are currently no studies to support these guidelines nor give insight into exactly how efficacious these guidelines are at minimizing adverse post-operative GI effects.26
Current research on GLP-1 agonists and surgery
Gariani et al. and Putzu et al. also note that “theoretically, three to five half-lives would be necessary to withhold to restore gastric motility, [and that] this could translate into more than 4 weeks” of no treatment, which could put patients at increased risk of hyperglycemia on top of the increased risk of complications associated with further delayed surgery.28
Given that some GLP-1 agonists need to be stopped as early as a week in advance due to their long half-life, surgeons and patients need to consider how to best manage blood sugar levels during this period. The ASA does recommend that if GLP-1 agonists are “held for longer than the dosing schedule, [to] consider consulting an endocrinologist for bridging the antidiabetic therapy to avoid hyperglycemia.”26
Some studies, such as one by Dixit et al., even suggest that GLP-1 agonist use has no significantly increased risk of post-operative aspiration, though they cite potential confounders such as unknown duration since last taken medication and unknown adherence to the prescribed therapy.29
Ultimately, more studies would need to better assess the effectiveness of different anti-diabetic treatments during this pre-operative period in managing blood sugar while also minimizing intra- and post-operative complications.
In conclusion
Despite its cautions with retinopathy, semaglutide is still a highly recommended medication. Due to substantial improvement in HbA1c, weight loss, and decreased risk of renal and cardiovascular complications, the medication is still a powerful tool in diabetes and obesity management.
It just needs to be recommended along with increased vigilance and management with an optometrist or ophthalmologist.
