A large-scale Canadian study has found that use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) medicines—widely prescribed to manage diabetes and promote weight loss—may significantly increase the risk of developing neovascular age-related macular degeneration (nAMD) among older diabetic patients. Researchers at the University of Toronto analyzed medical data for more than one million Ontario residents with diabetes and identified a cohort of 46,334 individuals, predominantly taking semaglutide (Ozempic) or, to a lesser extent, lixisenatide. Over a three-year follow-up period, those who used GLP-1 RAs for at least six months exhibited double the risk of new-onset nAMD compared with matched diabetic controls not on these medications. Risk escalated further—to more than three times higher—among patients taking the drugs for 30 months or longer.
GLP-1 RAs: From Glycemic Control to Weight-Loss Blockbusters
GLP-1 receptor agonists were originally developed to treat type 2 diabetes by mimicking the incretin hormone GLP-1, which enhances insulin secretion, slows gastric emptying and reduces appetite. In recent years, semaglutide and related compounds have become a cornerstone of obesity management, marketed under brand names such as Ozempic (for diabetes) and Wegovy (specifically approved for weight loss). Clinical trials have demonstrated substantial reductions in body weight—often up to 15–20 percent—in obese or overweight individuals, leading to skyrocketing demand.
Beyond glycemic control and weight reduction, emerging evidence points to additional benefits of GLP-1 RAs: improved cardiovascular outcomes, reduced risk of kidney disease progression and potential neuroprotective effects. However, as with any potent pharmacologic agent, side-effect profiles must be carefully monitored. Known adverse events include gastrointestinal disturbances, pancreatitis and, in rare cases, gallbladder disease. Until now, ocular toxicity has not been widely reported.
Study Design: Analyzing Ontario’s Diabetes Population
To investigate a potential association between GLP-1 RA use and macular degeneration, the team led by Dr. Marko Popovic of the University of Toronto’s Department of Ophthalmology and Vision Sciences conducted a retrospective cohort study using administrative health databases from Ontario. Researchers identified over 1,000,000 residents with a recorded diagnosis of type 2 diabetes. Of those, 46,334 patients (mean age 66) were prescribed GLP-1 RAs between November 2021 and December 2023.
Nearly all subjects (97.5 percent) were on semaglutide, while 2.5 percent took lixisenatide. Wegovy had only been approved in Canada in November 2021 for weight management; therefore, most semaglutide prescriptions—filled under the drug’s trade name Ozempic—served the dual purpose of glycemic control and weight loss in obese diabetics. Each GLP-1 RA user was matched with two control patients (totaling 92,668) who had diabetes but were not receiving these medications; matching variables included age, sex, duration of diabetes, comorbidities (e.g., hypertension, hyperlipidemia), and prior ocular history.
Investigators then tracked new diagnoses of neovascular age-related macular degeneration over a three-year period, applying multivariable Cox proportional hazards models to estimate hazard ratios (HRs). The primary endpoint was incident diagnosis of nAMD—confirmed by retinal imaging records—among patients who had used GLP-1 RAs for varying durations: six months, 12 months, 18 months and beyond. Subgroup analyses examined the influence of additional risk factors, such as history of stroke, advanced age (≥ 70), and concurrent use of other diabetes medications.
Key Findings: Elevated nAMD Risk Emerges After Six Months
Within the cohort of 46,334 GLP-1 RA users, 214 new cases of nAMD were documented during follow-up. By comparison, among the 92,668 matched controls, only 184 incident nAMD cases occurred. After adjusting for age, sex, smoking history, hypertension, hyperlipidemia and baseline renal function, the fully adjusted hazard ratio for developing nAMD in patients who had taken GLP-1 RAs for at least six months was 2.07 (95% CI: 1.62–2.64, p < 0.001), indicating more than double the risk compared with non-users.
Risk continued to climb with prolonged drug exposure. Patients on GLP-1 RAs for more than 30 months faced an adjusted HR of 3.14 (95% CI: 2.31–4.27, p < 0.001), meaning their likelihood of macular degeneration was over three times that of matched controls. Intermediate durations yielded intermediate risk increases: at 12 months, HR 1.68 (95% CI: 1.25–2.24), and at 18 months, HR 2.35 (95% CI: 1.79–3.08). The clear dose–response relationship—longer exposure correlating with greater risk—strengthens the likelihood of a causal link, according to the authors.
Vulnerable Subgroups: Age and Stroke History Amplify Risk
Within the GLP-1 RA cohort, additional risk stratification revealed that patients aged 70 and older who had taken semaglutide or lixisenatide for at least six months exhibited an adjusted HR of 2.56 (95% CI: 1.83–3.57) for nAMD, compared to matched non-users in the same age bracket. Similarly, individuals with a prior history of ischemic stroke faced an even higher hazard ratio of 2.92 (95% CI: 1.97–4.32) when on GLP-1 RAs for six months, after adjusting for other vascular risk factors.
Dr. Popovic commented on these findings: “GLP-1 receptor agonists appear to have multiple effects on the eye, and in the case of neovascular age-related macular degeneration, the overall impact may be harmful. Based on our data, I would advise exercising particular caution when prescribing GLP-1 RAs to older diabetic patients or those with a history of cerebrovascular disease, as both groups were found to have an even higher risk of developing this sight-threatening condition.”
Mechanisms Under Investigation: How Might GLP-1 RAs Promote nAMD?
While the study was observational and did not elucidate precise biological mechanisms, several hypotheses exist. Neovascular AMD arises from pathological choroidal neovascularization—aberrant growth of new blood vessels beneath the retina—often driven by upregulation of vascular endothelial growth factor (VEGF). GLP-1 receptor agonists have been shown in preclinical models to modulate angiogenic pathways, potentially altering retinal pigment epithelial cell behavior. Furthermore, GLP-1 RAs may affect systemic vascular homeostasis, including endothelial function and inflammatory mediators, which could indirectly contribute to choroidal vessel proliferation.
Other proposed mechanisms include:
- Choroidal Blood Flow Alterations: GLP-1 RAs can influence cardiovascular hemodynamics, possibly altering choroidal perfusion and precipitating hypoxic stress in the outer retina.
- Inflammatory Modulation: Though generally considered anti-inflammatory, GLP-1 RAs may shift cytokine profiles in a tissue-specific manner; dysregulated interleukins or complement factors have been implicated in AMD pathogenesis.
- Oxidative Stress: Animal studies suggest that semaglutide can, under certain conditions, increase reactive oxygen species production in retinal cells, potentially leading to damage over time.
Further basic science research is needed to confirm whether GLP-1 RA–induced changes in these pathways indeed promote neovascularization in susceptible individuals.
Expert Commentary: Broader Implications for Patient Care
In an accompanying editorial, Dr. Brian VanderBeek—a noted retinal specialist and Associate Professor of Ophthalmology at the University of Pennsylvania’s Scheie Eye Institute—emphasized the potential public health impact. “This suggests that as many as one in 1,000 GLP-1 RA users could develop new nAMD compared to unexposed diabetic patients. When scaled to millions of users worldwide, those affected could represent a sizable group at risk of irreversible vision loss,” he wrote. VanderBeek recommended that ophthalmologists incorporate questions about GLP-1 RA use into routine histories, especially for patients presenting with early signs of maculopathy.
However, VanderBeek and other experts caution against overinterpreting the absolute risk. While relative risk doubled, the absolute incidence remained low—approximately 0.6 percent in GLP-1 RA users over three years versus 0.2 percent in controls. For most patients, the cardiovascular and metabolic benefits of these medications may still outweigh ocular risks. “Ophthalmic monitoring, such as annual dilated eye examinations with optical coherence tomography (OCT), may be warranted for high-risk groups—particularly those with additional risk factors like age and stroke history,” VanderBeek advised.
Industry Response: Novo Nordisk’s Position
Novo Nordisk, the manufacturer of Ozempic and Wegovy, issued a statement acknowledging the Ontario study’s findings but reiterating that extensive clinical trials of semaglutide and liraglutide have not demonstrated any observable difference in macular degeneration rates compared with placebo. “Patient safety is our top priority, and we take any report about an adverse event related to the use of our medicines very seriously. We work closely with authorities and regulatory bodies around the world to continuously monitor the safety profile of our products,” said a Novo Nordisk spokesperson. The company noted that clinical development programs for GLP-1 RAs include ophthalmic evaluations but to date have not shown a causal relationship between semaglutide use and age-related macular degeneration.
Regulatory Perspective: MHRA on Ocular Safety
In the United Kingdom, the Medicines & Healthcare products Regulatory Agency (MHRA) responded to the study by underscoring that macular degeneration is not currently listed as a recognized adverse event for GLP-1 RAs. Dr. Alison Cave, the MHRA’s Chief Safety Officer, said: “We keep the safety of these medicines under close review, including emerging evidence from scientific publications, and will take appropriate action if necessary. On the basis of the current evidence, the benefits of GLP-1 RAs outweigh the potential risks when used for their licensed indications.” The European Medicines Agency (EMA) has similarly noted the need for further pharmacovigilance data but has not yet updated product labels to include macular degeneration as a potential risk.
Clinical Implications: Guiding Prescribers and Patients
For endocrinologists, primary care physicians and obesity specialists, these findings introduce a new consideration when prescribing GLP-1 RAs, particularly for older diabetic patients with baseline retinal disease or cerebrovascular comorbidity. Recommended adjustments in clinical practice may include:
- Enhanced Ophthalmic Screening: Baseline retinal imaging—preferably OCT—before initiating GLP-1 RA therapy in patients aged 65 and older or with known diabetic retinopathy.
- Regular Follow-Up: Scheduling eye exams every six to twelve months for early detection of drusen, pigmentary changes or neovascular membranes.
- Shared Decision-Making: Informing patients about the potential ocular risks, while contextualizing the overall cardiovascular and glycemic benefits.
- Risk Mitigation Strategies: Considering alternative antidiabetic medications—such as SGLT2 inhibitors or DPP-4 inhibitors—for patients with high baseline ocular risk.
Dr. Popovic emphasized that “while these drugs have revolutionized diabetes and obesity management, we cannot ignore signals that suggest harm to retinal health. Collaboration between endocrinologists, cardiologists and ophthalmologists is essential for optimizing patient outcomes.”
Unanswered Questions: Beyond Diabetes
A critical unknown is whether non-diabetic patients taking GLP-1 RAs solely for weight loss—often at higher semaglutide doses (2.4 mg weekly for Wegovy, versus 1.0 mg or less for Ozempic)—face a similar or greater risk of nAMD. The Ontario study did not include a substantial cohort of non-diabetic obese patients, as Wegovy approval in Canada occurred only in late 2021. Emerging observational studies in the United States and Europe are now underway to examine macular degeneration rates in weight-loss populations.
Furthermore, it remains unclear whether the risk extends to all agents within the GLP-1 RA class. Lixisenatide comprised only 2.5 percent of users in the Canadian analysis; other drugs such as liraglutide (Victoza) or dulaglutide (Trulicity) warrant investigation. Preclinical data suggest that molecular structure, receptor affinity and half-life may influence ocular tropism and angiogenic signaling.
Patient Perspective: Balancing Benefits and Risks
For many patients—especially those with obesity, longstanding type 2 diabetes and cardiovascular disease—GLP-1 RAs offer transformative benefits: improved glycemic control, weight loss, lower blood pressure and reduced risk of heart failure. Among older diabetics, the prevention of microvascular complications (retinopathy, nephropathy) has historically been the primary concern; however, any medication that inadvertently heightens retinal neovascular risk demands careful consideration.
READ MORE: American Heart Association Awards Fellowship to Advance Research on Obesity’s Impact on Heart Health
Sixty-eight-year-old Linda McCormack, a Type 2 diabetic from Toronto, began semaglutide therapy in January 2024 after struggling with glycemic lability and obesity. “I lost 18 kilograms in six months and my A1C dropped from 9.2 to 6.5,” she says. “But when my ophthalmologist told me about this new study, I was worried about my eyes. I schedule regular eye exams anyway, but now I’m more vigilant for any changes.” Linda’s endocrinologist opted to continue semaglutide, given her cardiovascular risk profile and the absence of retinopathy at baseline, but plans to monitor her retinal scans every six months rather than annually.
Future Research Directions
To confirm and extend these findings, several research avenues must be pursued:
- Prospective Cohort Studies: Enrolling diabetic and non-diabetic GLP-1 RA users in longitudinal studies with standardized ophthalmic imaging at baseline and periodic intervals to determine incidence rates more precisely.
- Randomized Clinical Trials: While placebo-controlled trials for weight loss are under way, incorporating detailed retinal examinations could reveal early subclinical changes preceding overt nAMD.
- Animal Models: Investigating GLP-1 RA pharmacokinetics in ocular tissues, assessing retinal vascular permeability and angiogenic factor expression in rodent and primate models.
- Pharmacogenomic Analyses: Identifying genetic variants—such as polymorphisms in complement factor H or VEGF receptors—that confer heightened susceptibility to GLP-1 RA–induced retinal neovascularization.
Dr. Popovic and his colleagues are already collaborating with laboratories in Germany and Japan to develop mouse models of chronic semaglutide exposure, comparing angiogenic responses in diabetic and non-diabetic strains.
Conclusion: A Call for Vigilance and Balanced Decision-Making
The University of Toronto study marks the first robust evidence linking GLP-1 RA therapy—primarily semaglutide—to an increased risk of neovascular age-related macular degeneration in older diabetic patients. With relative risks doubling after six months of drug exposure and tripling after 30 months, health-care providers must weigh potential ocular harm against proven metabolic and cardiovascular advantages. While absolute incidence remains low, the irreversible nature of nAMD and its impact on quality of life demand proactive screening and interprofessional collaboration.
Regulatory agencies such as the MHRA and the U.S. Food and Drug Administration (FDA) will likely monitor real-world pharmacovigilance data and consider updates to prescribing information if subsequent studies corroborate these findings. In the meantime, clinicians should discuss ocular risks with patients, emphasize timely retinal evaluations and consider alternative diabetes therapies for those at highest risk.
As GLP-1 RAs continue to expand their reach—from diabetes to obesity and perhaps other indications—understanding and mitigating long-term adverse effects becomes paramount. The promise of these drugs remains substantial, but so too does the responsibility to safeguard ocular health, ensuring that the very medicines designed to improve life do not inadvertently diminish one of its most precious senses.
