GLP-1 Drugs and Macular Degeneration

 GLP-1 receptor agonists are being linked to a long list of benefits besides weight loss and diabetes, as evidence suggests they can lower the risk of conditions ranging from cancer and addiction to suicidal ideation, stroke, and more. But eye health has been an outlier, with research offering conflicting data about whether the medications make certain ocular diseases more or less likely.

What about age-related macular degeneration (AMD), which affects an estimated 19.8 million Americans age 40 and over? Some studies suggest GLP-1 drugs might reduce risk, but there are also hints that they could make progression to advanced AMD more likely. In any case, absolute risk remains small.

"In truth, it's all still a mystery," said Abhimanyu Ahuja, MD, of Casey Eye Institute at Oregon Health & Science University in Portland, who led a recent study examining links between GLP-1 drugs and AMD.

"Our large database study and others have suggested there's an association with a decreased risk of AMD in patients who take GLP-1 agonists," he told MedPage Today. However, "these findings are observational. So while the association appears very strong and consistent, the biological mechanism and whether the relationship is causal remain unknown."

Protective Effects Seen in Risk of AMD Itself

For their study, published in JAMA Ophthalmology, Ahuja and colleagues retrospectively tracked two groups of 45,704 matched patients age 55 and older (78% women), all with obesity but no diabetes. Those who took GLP-1 agonists had an 84% reduced risk of developing nonexudative (dry) AMD at 5 years, an 87% reduced risk at 7 years, and a 91% reduced risk at 10 years compared with those who took other weight-loss drugs.

The authors noted that reduction of inflammation in patients taking GLP-1 drugs could explain their lower risk of AMD. Weight reduction could also play a role, they wrote, although obesity hasn't been consistently linked to AMD risk.

"There may also be secondary effects through improved vascular health, reduced oxidative stress, or metabolic regulation, though these remain speculative for now," study co-author Alfredo Paredes III, a medical student with Florida Atlantic University Schmidt College of Medicine in Boca Raton, told MedPage Today.

A similarly designed study in patients with both obesity and diabetes, published in Retina, also linked GLP-1 drugs to lower risk of AMD than seen with alternative therapies (15% reduced risk of dry AMD and 20% less risk of exudative or wet AMD, the advanced form).

For now, "I am not recommending that patients take GLP-1 agonists to prevent AMD," Paredes said. "However, if a patient asks whether GLP-1 agonists are harmful [in terms of] AMD specifically, this data suggests that they likely are not."

But GLP-1 Drugs Could Also Boost AMD Progression

Other research presents a less optimistic picture. Another recent study published in JAMA Ophthalmology found that adults age 66 and older with diabetes taking GLP-1 receptor agonists -- primarily semaglutide (Ozempic, Wegovy, and Rybelsus) -- for at least 6 months had more than double the adjusted risk of developing advanced AMD over 3 years compared with matched non-users (adjusted HR 2.21). Those who used the drugs for more than 30 months had an even higher risk (adjusted HR 3.62).

The absolute risks were small, however, at 0.2% versus 0.1% in non-users.

And other data point in the opposite direction. The Retina study linked GLP-1 drugs in patients with early or intermediate AMD to a 27% lower risk of progression to wet AMD.

Global View: 'There's Limited Information'

Andrew Morgenstern, OD, of Walter Reed National Military Medical Center in Bethesda, Maryland, told MedPage Today that he doesn't view the research regarding GLP-1 drugs and AMD as "conflicting."

Instead, "there's limited information," said Morgenstern, who co-wrote a report about the medications for the American Optometric Association. "We're very much in the early phases of learning about not just GLP-1 drugs and their relationship to age-related macular degeneration, but their relationship to all conditions throughout the body. We're still in the learning phase of what these drugs do."

If there is a benefit to the drugs in AMD, he said, it seems likely to have to do with normalizing blood chemistry. "You're getting better, less leaky, and more nutritious blood flow to [the affected] area of the eye, which reduces the risk of development of the disease."

It's harder to explain why the drugs may boost risk of progression to wet AMD, he said. It's possible that they're "causing some sort of chemical imbalance that the body is not loving, and the body is reacting as a result of it."

What Now? Monitor Patients Closely

Morgenstern emphasized the need for appropriate monitoring. "Anybody starting this drug should have an annual dilated, comprehensive eye exam," he said. "And anybody on these drugs with risk factors may want to have more frequent exams based on clinical appearance, patient health, and doctor discretion."

Morgenstern and Ahuja said randomized controlled trials are needed to definitively answer questions about GLP-1 drugs and AMD. "Our work provides sufficient motivation to conduct a randomized clinical trial to test that potential," Ahuja said. However, "this would be challenging, as it would require a large population of patients and long follow-up."

For now, Griffin Christenson, OD, in private practice in Hudson, Wisconsin, told MedPage Today, "we aren't at a stage yet where we can be touting this as some sort of a silver bullet. The research needs to be done. But there's at least enough here to say this deserves a closer look."

Disclosures

Ahuja, Paredes, Morgenstern, and Christenson reported no disclosures.

https://www.medpagetoday.com/spotlight/aao-amd/118743