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While reviewing patient cases with residents one morning, Joseph F. Rizzo III, MD, mentioned he recently cared for a patient who had taken semaglutide and developed severe optic neuropathy. One resident reported that she had just seen a patient in the emergency room with a similar history, presenting with the same eye condition. A week later, Rizzo saw yet another one of these patients.

“It seemed improbable that it would just be a coincidence,” Rizzo, director of Neuro-Ophthalmology Service at Massachusetts Eye and Ear, a teaching hospital of Harvard Medical School in Boston, told Medscape Medical News.

Eventually, Rizzo and several residents published research of patients at the clinic. It was the first study to show an association between the use of semaglutide and nonarteritic anterior ischemic optic neuropathy (NAION), according to the American Academy of Ophthalmology.

Weight-loss drugs are known to affect vision in a small subset of patients. Labeling for GLP-1 receptor agonists such as semaglutide and tirzepatide include warnings about the increased risk for diabetic retinopathy in patients with type 2 diabetes. The label for the combination of phentermine and topiramate warns of a risk for acute myopia and secondary angle-closure glaucoma, and the label for the combination of naltrexone and bupropion lists the risk for angle-closure glaucoma.

But which drug carries the lowest risk for vision complications remains a tricky question.

“Nobody has really done any true head-to-head comparisons of” the weight-loss drugs, said Mollie Cecil, MD, a spokesperson for the Obesity Medicine Association.

All weight-loss drugs have the potential to change the shape of the eye lens, which can cause transient blurring of vision. They also can worsen diabetic retinopathy due to a dramatic drop in blood sugar and increase the risk for blindness from NAION, said Rahul N. Khurana, MD, a spokesperson for the American Academy of Ophthalmology and an ophthalmologist at Northern California Retina Vitreous Associates in Mountain View, California.

“I don’t think we have enough data to say one drug is safer than the other,” he said.

A Shifting Vision of GLP-1 Receptor Agonists

Rizzo and his colleagues’ study published in JAMA Ophthalmology in July 2024 included nearly 2000 patients with type 2 diabetes or obesity. Those who took semaglutide had a four to seven times higher risk for NAION than those who did not take GLP-1 receptor agonists.

Rizzo said one limitation of the study was selection bias because patients were cared for at an eye hospital staffed by neuro-ophthalmologists, which was more likely to have patients with NAION. His team recently finished a nationwide study analyzing data on the same subject that has not yet been published, he said.

Numerous studies published since then have shown conflicting results, including a lower or higher risk for NAION than that reported in Rizzo’s research or no increase in risk.

After Rizzo’s study was published, the American Academy of Ophthalmology and other groups said further research was necessary to definitively say whether the drug causes NAION. The groups did not recommend that patients stop taking semaglutide unless they had a sudden loss of vision.

The use of GLP-1 receptor agonists has also been associated with other vision problems.

A recent study found patients with diabetes taking these drugs had a twofold higher risk for neovascular age-related macular degeneration than a matched cohort of patients who did not take a GLP-1 receptor agonist.

But the newer class of drugs may be safer for other patients, such as those who have obesity and do not have diabetes. A retrospective cohort study published earlier this year in Ophthalmology found the risk for primary open-angle glaucoma and ocular hypertension was significantly lower in this population of patients taking GLP-1 receptor agonists than in those taking other weight-loss medications, such as the combination of phentermine and topiramate.

“I don’t really think any of these are better for vision, although there is evidence that GLP-1 agents may be protective against glaucoma,” said Angelo Tanna, MD, vice chair of the Department of Ophthalmology at Northwestern University Feinberg School of Medicine in Chicago.

Older Drug, New Insights

Approved by the FDA in 1959 for the treatment of obesity, phentermine is the most commonly prescribed weight-loss drug in the US, according to a study published in January in JAMA Open Network.

Katherine Talcott, MD, a vitreoretinal surgeon at the Cole Eye Institute at the Cleveland Clinic in Cleveland, said some data suggest GLP-1 receptor agonists can worsen diabetic retinopathy. She and her colleagues had not seen a study on the effect of phentermine having the same effect, so they set out to do so in patients with overweight and obesity. Their study found phentermine was associated with a decreased future risk for a new diagnosis of diabetic retinopathy or the need for intravitreal anti-VEGF injections.

“It’s great that there’s an additive protective effect by being on the medicine,” she said.

However, phentermine is also associated with blurred vision and serious ocular side effects, with case reports of branch retinal artery occlusion, acute myopia and acute angle closure, and NAION.

Topiramate and Angle Closure

Tanna at Northwestern University said ocular adverse events associated with weight-loss drugs are rare but can have devastating consequences. Tanna co-authored a 2015 case report in the Journal of Glaucoma of bilateral angle closure in a woman who took the combination of phentermine and topiramate. He said he has seen a handful of cases of this rare reaction in patients taking topiramate, but this was the only case in which the drug was being used for weight loss.

A study analyzing the FDA Adverse Event Reporting System (FAERS) database found that topiramate was 30% more likely to be associated with reports of vision impairment than semaglutide.

Vision impairment included optic ischemic neuropathy, blindness, and reduced visual acuity.

Another study, published last year in Ophthalmology Glaucoma, identified topiramate with the most reports of angle-closure glaucoma in the FAERS database over a 20-years period.

A case report in 2014 also documented bilateral angle-closure glaucoma induced by topiramate several days after initiation of the drug. The combination of naltrexone and bupropion for weight loss also has been associated with this adverse event, along with bupropion alone for depression.

Choosing a Drug

Cecil said she considers several factors when deciding which weight-loss drug to prescribe, including a patient’s preexisting eye health.

“If you have somebody who has not yet developed peripheral vascular disease or diabetes, without compelling evidence I think that all weight-loss drugs would have about the same safety,” she said.

But insurance coverage and affordability are often the biggest drivers of her decisions.

“If I didn’t have to worry about insurance, I really would lean on the GLP-1s for most patients because they are safe, they are effective, and we are discovering more and more secondary benefits to them all the time, including decrease in cardiovascular disease,” Cecil said.

Rizzo said he does not discourage patients from taking semaglutide. But he urges caution for patients who have already lost vision for any reason.

“They have to make their own informed decision about whether they might be willing to accept what we believe is an increased risk,” he said.

Cecil noted that for patients with complicated chronic diseases, clinicians must be careful not to blame a drug when a patient develops an eye condition that may be related to their disease state.

“That’s one of the reasons why in obesity medicine, we talk so much about how important it is to really, truly have an individualized treatment plan,” she said.

Rizzo reported being a consultant for Life Biosciences, machineMD, and Viridian Therapeutics. Tanna reported being a consultant for Alcon, Ivantis, and Zeiss. Other sources reported having no relevant financial conflicts of interest.

Brenda Sandburg is a freelance journalist who has written about FDA policies, the biopharmaceutical industry, and legal issues for the Pink Sheet and American Lawyer Media.