medwireNews: The risk for new-onset neovascular age-related macular degeneration (nAMD) in patients with diabetes more than doubles with use of glucagon-like peptide (GLP)-1 receptor agonists for 6 months or more versus no use, suggests a study in JAMA Ophthalmology.
“The pertinence of our findings is underscored by the dramatic increase in GLP-1 [receptor agonist] use, both in patients with diabetes and those with obesity without diabetes,” observe Rajeev Muni (St Michael’s Hospital, Toronto, Ontario, Canada) and colleagues.
They assessed population-based data from the Ontario ICES administrative health database on a cohort of Canadian patients aged at least 66 years with a diabetes duration of at least 1 year. The team found that over 3 years of follow-up, 0.2% of 46,334 patients exposed to GLP-1 receptor agonist treatment for 6 months or longer were newly diagnosed with nAMD versus 0.1% of 92,668 patients with no exposure to GLP-1 receptor agonists, with a significant hazard ratio (HR) for nAMD of 2.11 with GLP-1 receptor agonist use.
The increased associated risk with GLP-1 receptor agonist treatment remained even after adjustment for factors such as age, sociodemographic characteristics, and medical comorbidities, with an HR of 2.21 and an absolute risk difference of 0.11%.
“Although the risk of nAMD development was low in both exposed and unexposed patients with diabetes, risk was highest (more than 3 times as high) among those with the longest exposure to GLP-1 [receptor agonists],” Muni et al comment.
Specifically, among patients taking GLP-1 receptor agonists for more than 30 months, the adjusted HR was a significant 3.26 compared with unexposed participants, whereas the HRs among patients who received the therapy for 6–18 months and 18–30 months were a significant 2.11 and a nonsignificant 0.94, respectively.
The mean age of the patients was 66.2 years, and 53.4% were men. Semaglutide was the most predominant GLP-1 receptor agonist, used by 97.5% of the cohort, although the researchers point out that their analysis “did not stratify by the type of GLP-1 receptor agonist prescribed, and as such, our findings should not be generalized to specific brands of GLP-1 [receptor agonists].”
In addition to GLP-1 receptor agonist use, other significant risk factors for nAMD included advanced age and history of cerebrovascular accident, significantly increasing the risk by 12% and 96%, respectively.
The study authors say that their findings expand on concerns raised in the literature “regarding the potential ocular safety of systemic GLP-1 [receptor agonist] use in patients with diabetes,” but add that “it is also important to note that these findings demonstrate associations rather than cause and effect.”
Possible underlying mechanisms for the association include the induction of a temporary hypoxic state as a result of rapid systemic reduction in glucose levels caused by GLP-1 receptor agonists including in the retina, or choroidal neovascularization or enhanced vascular endothelial growth factor expression due to increases in the chemokine CXCL12.
“The complex pathophysiological mechanisms underlying these findings remain poorly understood and require further research,” they conclude.
In a linked commentary, Brian VanderBeek, from the Scheie Eye Institute in Philadelphia, Pennsylvania, USA, points out that the study findings suggest that as many as “1 in 1000 GLP-1 [receptor agonist] users could progress to nAMD over unexposed patients; if this risk was carried over millions of users, those affected could end up being a sizeable group of patients.”
However, the commentator points out that which patients might be at risk remains one of the unanswered questions. Acknowledging that “it seems unlikely that a person would progress from no AMD to nAMD within 3 years,” he therefore proposes the possibility that “there was an already at-risk group of patients with non-neovascular AMD within the cohort.”
VanderBeek recommends that future research “should focus on controlling for the baseline level of AMD to determine if it is, in fact, this subgroup driving the results seen.”
He adds that further study is also needed to determine if this is an adverse effect only in patients with diabetes or if those using GLP-1 receptor agonists for weight management or other indications are similarly at risk.
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JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.1455
JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.1599
