Do Ozempic/Wegovy and the like increase risk of sudden vision loss?

Popular weight loss and diabetes medications called GLP-1 agonists and a recent JAMA study.

There is not a day I practice medicine anymore that I’m not fielding questions about GLP-1 medications like Ozempic and Wegovy, Mounjaro and Zepbound. Many people have had tremendous success controlling their type 2 diabetes and/or losing weight while consequently reducing the burden of their other comorbid conditions. Some have had side effects that are significant, and rarely some have experienced more serious adverse effects. I could write an entire Substack about these medications. They are very much in demand. But I want to quickly address one specific question that has been coming up frequently - can these medications cause vision loss? I’ve been asked this a bunch of times lately, and you’ll see why below.

I do not push these GLP-1 agonist meds like Wegovy/Ozempic/semaglutide and Zepbound/Mounjaro/tirzepatide… but I do prescribe them for weight loss when patients have done their research, understand and accept risks and benefits, have had minimal success with other weight loss strategies, or want this option for the treatment of type 2 diabetes. These meds really do work, and the list of collateral benefits just seems to keep growing. There are proven benefits and FDA approvals for diabetes and obesity treatment, with growing evidence for potential benefits with respect to cardiovascular disease, fatty liver, polycystic ovarian syndrome, depression, addiction, cancer reduction when compared with insulin, and even Parkinson’s Disease. Side effects should not be trivialized and often include gastrointestinal problems like nausea, diarrhea, vomiting, constipation, muscle mass loss, and several other more rare adverse events (like those listed at the bottom of this Mounjaro health care provider page).

So what’s this news about vision loss? It started with a study published in JAMA Ophthalmology in July 2024 that investigated whether semaglutide (brand name Ozempic and Wegovy) increased the risk of nonarteritic anterior ischemic optic neuropathy (NAION).

What is NAION besides a hard acronym to remember? Local Penn Ophthalmology defines this term:

Non-arteritic anterior ischemic optic neuropathy (NAION) is a potentially debilitating condition that occurs from a lack of sufficient blood flow to the optic nerve. The exact cause is not fully understood. NAION causes damage to the optic nerve - the cable that connects the brain to the eye and carries millions of nerve fibers and blood vessels.

Although sometimes there can be total blockage of a blood vessel that feeds the optic nerve, it is believed to be more commonly caused by inadequate flow to one half of the nerve. If the optic nerve's nutrient and oxygen supply is cut off, nerve tissue is damaged, resulting in vision loss.

People with NAION usually have no warning before vision loss occurs. Most patients notice a loss of vision in one eye upon waking in the morning with no pain. Some people notice a dark area or shadow in their vision that affects the upper or lower half of their visual field. Other symptoms include loss of contrast and light sensitivity.

Terrifying stuff. If this happened to me while I was taking a medicine that might be associated with an increased risk, I would be pretty upset, too. But did the JAMA study from this summer conclusively prove this association? According to the American Academy of Ophthalmology and the North American Neuro-Ophthalmology Society the answer is - we need more research.

The problem is that this study was a retrospective cohort study.

A retrospective cohort study is generally considered to have moderate authority in the hierarchy of evidence-based medicine, ranking below randomized controlled trials but above case-control studies and case reports. However, its validity and power can vary significantly depending on factors such as sample size, the quality of data collection, the ability to control for confounding variables, and the presence of selection bias. This means that while it can provide valuable insights and generate hypotheses, its findings often require confirmation through more rigorous prospective studies or randomized controlled trials.

What were the key findings anyway?

The study found an increased risk of NAION in semaglutide users compared to non-users:

• For people with type 2 diabetes there was a possible 4X risk of NAION. For the biostatisticians out there, that’s a hazard ratio (HR) of 4.28 (95% CI: 1.62, 11.29)

• For people with obesity/overweight a 7X risk was observed. HR = 7.64 (95% CI: 2.21, 26.36)

Four-fold and seven-fold increases are scary. If you need a quick review of relative versus absolute risks, might I suggest my ninja tricks for statistical analysis.

So, what were the absolute risks of NAION over a cumulative 36 months?

• Type 2 diabetes: 8.9% for semaglutide users vs 1.8% for non-users

• Obesity/overweight: 6.7% for semaglutide users vs 0.8% for non-users

• The risk was highest in the first 12 months of follow-up and declined thereafter.

But what are the caveats and disclaimers here? Why is this medication still available under FDA approval? Here are several important limitations and potential confounding factors:

• Confounding by indication: Semaglutide is often prescribed to patients with higher cardiovascular risk, who may also have a higher baseline risk of NAION. This could lead to bias towards showing a harmful effect of semaglutide.

• Residual confounding: Despite controlling for several risk factors, unadjusted or incompletely controlled factors (e.g., smoking, intensity of antihypertensive therapy, severity of sleep apnea, diabetes duration and severity) could influence the results.

• Small sample size: The study included 555 semaglutide users and 1,134 non-users, resulting in wide confidence intervals that don't rule out smaller effects. For example, that 4X risk might be anywhere between 1.62X and 11.29X the risk. Kind of big differences in possible true risk, combined with the other uncertainties. I’ll keep going…

• Lack of dose-response analysis: The study couldn't explore whether higher doses or cumulative exposure led to greater risk, which could have strengthened causality arguments.

• Limited generalizability: The study was conducted in a specialized neuro-ophthalmology clinic, potentially reflecting a population with a higher propensity for eye disease.

• Temporal association: The front-loaded risk observed could be due to confounding by indication rather than a drug-induced effect. The NAION incidence decreased as time using the medicine increased.

You can see that while this study establishes a potential link between semaglutide and increased NAION risk, the results should be interpreted cautiously. It calls for further research to address these limitations and answer additional questions about the nature of the risk, potential drug class effects, and patient-specific risk factors. Indeed that’s what ophthalmologists themselves are calling for. I don’t see anything specifically about NAION on the Wegovy website for health care providers. I do see this general warning about a different eye problem:

Diabetic Retinopathy Complications in Patients with Type 2 Diabetes: In a trial of adult patients with type 2 diabetes, diabetic retinopathy was reported by 4.0% of Wegovy^® patients and 2.7% of placebo patients. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

Reading through the package insert for Wegovy, I also do not see any mention of NAION as a risk. I’m guessing this is because it did not show up in the prospective randomized controlled trials that led to FDA approval or it would have to be listed.

How do people know to ask about vision loss with these medications? Are they reading JAMA Ophthalmology?

In a separate blog analysis, posted on the AHA/ASA Stroke journal website, some of the media frenzy that has led many patients to ask their doctors questions in the office is highlighted:

The authors end their article by concluding that these findings suggest semaglutide may potentially increase the risk of NAION. These conclusions were immediately relayed by influential media such as the British Broadcasting Corporation (BBC), the Guardian, USA Today and Forbes, as well as news agencies such as Reuters.

Five days after the article was released, the American Academy of Ophthalmology (AAO) and the North American Neuro-Ophthalmology Society (NANOS) issued a joint press release, calling for caution in the interpretation of its results and stating that “this intriguing finding [suggesting a potential link between semaglutide treatment and NAION] should inspire more research that will help clarify if semaglutide does cause NAION”.

In less than a month, the article generated more views than the top 3 articles published in JAMA Ophthalmology in 2023 combined.

Remember that we don’t have conclusive proof of a cause and effect relationship yet. Instead there is an intriguing finding suggesting a potential link and should inspire more research.

But the qualified findings of the study are lost in the headlines. A lack of biostatistical fluency in the media leads to immediate patient concerns, and in some cases panic. That’s understandable. And cause and effect might yet be proven. But the swift solicitations from personal injury lawyers have already arrived. Notice the ALL CAPS and alarm:

CRITICAL FINDING: The results were alarming. Patients taking Ozempic or other semaglutide medications showed a four- to eight-times higher likelihood of developing nonarteritic anterior ischemic optic neuropathy (NAION). This condition is a severe form of optic neuropathy, second only to glaucoma in causing optic nerve-related blindness…

The drug's effectiveness in promoting weight loss led to widespread off-label use for weight management. However, this surge in popularity has been accompanied by a rise in lawsuits from users reporting severe side effects not initially disclosed by manufacturers…

Our dangerous drug team is actively participating in and closely monitoring these developments. Since Ozempic prescribing physicians and users were not adequately warned about these potential semaglutide side effects, our legal team is taking action to hold the drug manufacturers accountable.

If you or someone you know has suffered injuries from Ozempic or similar medications, we encourage you to reach out to our product liability lawyers for a free consultation to understand your legal rights.

There’s actually a slew of lawsuits as usual. This contributes to higher costs.

So what’s the nuanced view of this study that takes into account a reasonable degree of concern tempered by an appreciation of the limits and shortcomings of this NAION retrospective cohort study? I have added the risk of vision problems like NAION to my list of possible side effects I drop with patient education, but I’m also waiting for better proof just like the American Academy of Ophthalmology and the North American Neuro-Ophthalmology Society asked us to.

Once again, I could write an entire blog about GLP-1 meds, but as a family doc I prefer to keep the subjects broad, the approach to diabetes and overweight/obesity multifaceted, and the primary care approach to health not reliant on medications alone. Hopefully this post will add some nuance to any discussions people might have with their own docs about these GLP-1 medications, specifically considering risks to their vision, while giving pause to some and context for others.

I wish it were easier in medicine. It rarely is.

Take good care.