It has been more than 15 months since European regulators raised concerns about nonarteritic anterior ischemic optic neuropathy (NAION), sometimes described as an “eye stroke,” as a very rare potential adverse effect of semaglutide.

To date, US labels for the semaglutide products Ozempic and Wegovy (Novo) do not contain information about NAION.

Attorneys representing plaintiffs in product liability cases contend that the lack of such information puts US clinicians and patients at a disadvantage.

Adding a warning to the label would make clinicians and patients more likely to consider the potential risk for NAION when making prescribing decisions, argues Jonathan Orent, JD, of the law firm Motley Rice.

Orent is co-lead attorney in federal multidistrict litigation (MDL) involving allegations of NAION associated with GLP-1 drugs. Cases have also been filed involving Eli Lilly’s dual GLP-1/GIP tirzepatide (Mounjaro and Zepbound) although the European Medicines Agency’s current warning applies only to semaglutide.

Speaking at a Science Day meeting in federal court in Philadelphia, Orent summarized earlier testimony from expert witnesses supporting the plaintiffs.

NAION, a rare condition, may affect about 1 in 10,000 people. However, experts for the plaintiffs testified that if GLP-1s were to double the risk, it could become more consequential, particularly among patients with smaller-than-average optic discs who use the drugs for several years. Clinicians and patients need a signal to prompt more consideration of NAION, Orent argued.

“Those are the kind of things that warning labels can provide. And that’s why it’s important for doctors to be aware of what the likelihood of a patient to stay on a drug is,” Orent said.

No firm timelines have been set for decisions in the NAION litigation, known as MDL-3163, or in related litigation, MDL-3094, involving allegations of gastroparesis and other gastrointestinal injuries.

US product information for semaglutide and tirzepatide includes warnings about the potential for severe gastrointestinal adverse reactions.

US District Court Judge Karen Marston, JD, Eastern District of Pennsylvania, is overseeing both MDLs. As of October, MDL-3163 included 247 cases involving alleged eye injuries, up from 29 in January. Over the same period, the number of cases in MDL-3094 rose from 3063 to 4025.

What Should Clinicians Tell Patients?

The litigation and publicity surrounding these drugs may prompt patients and clinicians to more carefully weigh the rare potential risk for NAION when making decisions about GLP-1s, said Rudrani Banik, MD, associate professor of ophthalmology at the Icahn School of Medicine at Mount Sinai, New York City.

However, she said, people should not stop taking GLP-1 drugs because of these reports but should discuss any concerns with their physicians.

“The whole conversation should be about raising awareness but not causing panic,” Banik told Medscape Medical News.

Ophthalmologists should also keep the reports of NAION in mind when treating patients taking GLP-1 drugs, she said.

“We need to ask more questions, probe, and maybe have a discussion with the prescribing doctor about whether the patient’s a good candidate,” for a GLP-1, Banik said.

Banik is not involved in the litigation. As a neuro-ophthalmologist, she frequently sees patients with NAION and posted a video on Instagram explaining to patients and fellow clinicians the concerns surrounding GLP-1 drugs.

In a joint consensus statement issued in May, the American Academy of Ophthalmology Board of Trustees and the North American Neuro-Ophthalmology Society noted that research findings on NAION in patients taking GLP-1 drugs have been mixed. Some studies have suggested a small increased risk, whereas others found no association.

The groups also noted that most patients with NAION have the so-called “disc at risk,” or a small or crowded optic disc with a tiny or absent cup, which may predispose the optic nerve to ischemia.

Clinicians and the Courts

Attorneys representing Eli Lilly and Novo said at the Science Day hearing that top medical organizations in ophthalmology have not concluded that causation exists between GLP-1 drugs and NAION. They also noted how medical conditions that people who take GLP-1 drugs commonly have, such as diabetes and sleep apnea, may increase risk for NAION.

Both companies have disclosed in investor filings that they face numerous product liability lawsuits involving GLP-1 drugs. Eli Lilly said, in its most recent filing that domestic cases are also pending in state courts in Delaware, Indiana, and New Jersey, as well as internationally in Israel and Canada.

Most US federal lawsuits have been coordinated or consolidated for pretrial proceedings in two federal MDLs before Judge Marston, according to Eli Lilly’s most recent quarterly filing with the US Securities and Exchange Commission.

Unlike a class action, an MDL centralizes similar federal lawsuits before one judge for coordinated pretrial proceedings. This allows for more efficient handling of a collection of individual lawsuits, said D. Theodore Rave, JD, professor at The University of Texas at Austin School of Law, who has published research on MDLs.

MDL designation does not establish the validity of the plaintiffs’ claims. But the rising number of cases does indicate that many lawyers think they might win in court and thus are willing to invest in these cases, Rave said.

“It doesn’t mean that they’re winners,” said Rave, speaking of MDLs in general. “They still have to be litigated, but it does mean that there are enough lawyers out there who think that they might be winners that they’re willing to invest in it.”

“Plaintiffs’ lawyers don’t work for free,” he said of MDLs in general. “They’re all working on a contingency fee basis, where they front the costs, expecting that they will be paid something at the end of the day if and when the cases settle.”

‘Crowded Disc’ Risk — Explained in Bagel Terms

MDLs can require federal judges to consider highly technical scientific questions. Courts may schedule a Science Day hearing to allow each side to present an overview of the relevant science.

At the recent Science Day hearing on the NAION MDL, Leonard Levin, MD, PhD, professor in the Departments of Ophthalmology & Visual Sciences and Neurology & Neurosurgery at the McGill University, Montréal, Canada, explained that NAION appears more likely to occur when there is crowding at the optic nerve head, or disc, where nerve fibers come together.

Speaking for the plaintiffs, Levin likened variations in optic disc anatomy to two styles of bagels: New York and Montréal. A Montréal bagel has a larger hole in the middle, whereas the denser New York bagel has a smaller hole, said Levin. A person with a small cup to disc ratio, analogous to the New York bagel, may be at greater risk for injury if edema sets off a domino effect, he said.

“Even the beginnings of optic nerve ischemia. It doesn’t have to be a lot. Because once it starts, it’s like you triggered it off,” Levin said. “You start having that edema, you start getting a crowded optic nerve, there’s minimal space, more ischemia, more edema. And that results in a loss of vision.”

Speaking for Novo Nordisk, Prem Subramanian, MD, PhD, chief of neuro-ophthalmology at the University of Colorado Anschutz in Aurora, disagreed with placing too much emphasis on a small cup to disc ratio.

Research has suggested that perhaps 30% of people have a crowded optic nerve, he said.

“I actually don’t like the term ‘disc at risk’ because I don’t want to tell 30% of my patients that they’re at risk for developing NAION when, in fact, it’s a really rare condition,” he said.

“So, I look at it a little bit differently, just saying that that’s one of the things that we’ve identified in the majority of people who get the condition, but not that the majority of people who have that will ever develop NAION.”

Subramanian noted how difficult this uncertainty could be to explain to patients who had permanently lost vision from NAION, for which there is currently no treatment.

“Every single patient asks me, ‘Why did I get NAION?’ And I express to them that I am the second most frustrated person in the room regarding this diagnosis because I cannot tell them why their NAION occurred. I can only tell them what we know might have been associated with it and might have led to it,” he said.

Banik and Rave reported no relevant financial disclosures.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She has covered medical research and healthcare policy for more than 20 years.