Experts are urging screening and monitoring for eye disease for all patients on GLP-1 receptor agonists, after a large retrospective study suggested the risk of new-onset diabetic retinopathy (DR) increased slightly, but significantly, in patients taking GLP-1 receptor agonists for diabetes, despite a lower risk of vision-threatening complications.
A propensity-matched comparison showed a 7% higher incidence of new DR among users of GLP-1 agonists, they said, although the risk of ischaemic optic neuropathy did not differ significantly between users and non-users.
Moreover, in a subgroup of patients with existing DR, use of the drugs was not associated with an increased risk of progression to proliferative retinopathy or diabetic macular edema (DME), reports Medpage Today.
The findings suggest that patients with type 2 diabetes treated with GLP-1 agonists require regular screening and monitoring for ophthalmic complications, regardless of baseline DR status, reported Sarju Ganatra, MD, of Beth Israel Lahey Health in Burlington, Massachusetts, and co-authors in JAMA Network Open.
“In our study, although the use of GLP-1 RAs (receptor agonists) was associated with a modest increase in the rate of incident DR (0.2% increase) over two years, the absolute number of new DR diagnoses was low at 2.7%, likely below the expected annual incidence in U.S. patients with T2D [type 2 diabetes],” the authors wrote. “Furthermore, GLP-1 RA use was associated with a 24.2% reduction in the risk of vision loss progressing to blindness, with 30.2% reduction in patients with pre-existing DR.”
A separate study published simultaneously also showed a slightly higher risk of non-arteritic ischaemic optic neuropathy (NAION) in patients treated with semaglutide (Ozempic) or tirzepatide (Mounjaro) for diabetes.
Although overall rates of optic nerve disorders were low, the findings emphasise the need for close monitoring of the conditions, reported Rong Xu, PhD, of Case Western Reserve University School of Medicine in Cleveland, and co-authors.
Support for monitoring
Collectively, the two studies support an association between incretin receptor agonists (IRAs) and eye outcomes in patients with diabetes, specifically DR and NAION, noted the authors of an accompanying editorial.
The association with NAION is consistent with a recent European Medicines Agency decision to classify NAION as a rare adverse reaction in patients using semaglutide.
“IRAs remain transformative for obesity and diabetes care, with unequivocal cardiovascular, kidney, and hepatic benefits,” wrote Sally Ong, MD, of the Wake Forest School of Medicine in Winston-Salem, North Carolina, and Francisco Pasquel, MD, MPH, of Emory University School of Medicine in Atlanta.
“Yet the accumulating, although still rare, reports of NAION mandate vigilance. Patients initiating semaglutide or tirzepatide should be counselled on the rare but serious NAION risk, especially if they have pre-existing optic-disc crowding.
“Patients with DR require close ophthalmic monitoring when IRAs are initiated or intensified,” they noted. “Slower titration to avoid abrupt glycaemic swings or lower maintenance doses in individuals at highest risk merit formal evaluation. Mechanistic studies that measure retinal and optic-nerve perfusion during rapid HbA1c declines induced by IRAs or insulin could clarify underlying pathways.”
Neither of the studies included patients treated with SGLT2 inhibitors, such as empagliflozin (Jardiance) and dapagliflozin (Farxiga).
One recent analysis showed a lower incidence of sight-threatening DR compared with other anti-diabetes agents, including GLP-1 receptor agonists. Notably, the analysis did not show an increased risk of DR among patients treated with GLP-1 drugs, as had been suggested in pivotal trials of semaglutide.
A large retrospective cohort study showed an increased risk of DR in patients who received GLP-1 agonists in addition to SGLT2 drugs for obesity and heart failure.
Data reported to date also include a large meta-analysis of 61 randomised trials showing no substantive differences among anti-diabetic drugs with respect to the risk of DR. Another large retrospective cohort study showed no association between semaglutide and NAION.
Diabetic Retinopathy Study
Previous studies did not specifically assess the risk of sight-threatening complications related to DR, Ganatra and co-authors noted. They sought to address that limitation in a retrospective cohort analysis of data from the TriNetX database, a global network of real-world data in life sciences and healthcare.
The authors queried the database for the time period of January 2015 to September 2022 to identify adults with type 2 diabetes and an HbA1c ≥6.5%. They separated the patients into a cohort who had at least two prescriptions for a GLP-1 agonist at least six months apart and all others to a control group.
Follow-up continued for two years, and the primary endpoints were associations between GLP-1 drugs and the risk of new DR, NAION, or sight-threatening complications.
A propensity-matched analysis included 185 066 patients, equally distributed between the GLP-1 and control groups. Use of GLP-1 drugs was associated with a hazard ratio of 1.07 for the risk of DR (95% CI 1.03-1.11). A hazard ratio of 1.26 for NAION did not achieve statistical significance (95% CI 0.94-1.70).
A subgroup analysis involving 32 695 patients with existing DR showed no association between use of GLP-1 agonists and DR progression to proliferative DR or DME (HR 1.06, 95% CI 0.97-1.15 and HR 0.98, 95% CI 0.95-1.01). Use was associated with a significantly lower risk of vitreous haemorrhage (HR 0.74, 95% CI 0.68-0.80), neovascular glaucoma (HR 0.78, 95% CI 0.68-0.88), and blindness (HR 0.77, 95% CI 0.73-0.82).
Optic nerve disorders
Xu and co-authors looked specifically at use of semaglutide or tirzepatide, the two most widely prescribed GLP-1 agonists, and risk of new diagnoses of optic nerve or visual pathway disorders in patients with type 2 diabetes. Based on a national multicentre database of electronic health records, a propensity-matched analysis included 159 398 patients, half treated with one of the two GLP-1 drugs and half with prescriptions for other anti-diabetes drugs, including other GLP-1 agents.
The analysis had a two-year follow-up period, and the primary endpoint was first-time diagnosis of NAION or other optic nerve disorders.
Overall, 35 new cases of NAION were documented among patients treated with semaglutide or tirzepatide versus 19 in the matched cohort. Though the numbers were small, the difference translated into a NAION hazard ratio of 1.76 for patients in the GLP-1 group (95% CI 1.01-3.07).
“The slope for the semaglutide or tirzepatide group was consistently higher than that for the comparison group during the two-year follow-up, indicating a sustained association of semaglutide or tirzepatide with the risk of developing optic nerve disorders,” the authors noted.
For all other optic nerve disorders, 93 cases were documented in the GLP-1 group versus 54 in the control arm, a hazard ratio representing a 65% increase (95% CI 1.18-2.31).
The investigators also analysed NAION and other optic nerve disorders in the semaglutide/tirzepatide group and a matched group of patients who received other GLP-1 drugs (71 459 patients in each group). Semaglutide and tirzepatide were not associated with an increased risk of NAION (HR 1.75, 95% CI 0.98-3.10), but the duo was associated with an increased risk of other optic nerve disorders (HR 1.94, 95% CI 1.32-2.85) and optical disc disorders (HR 1.39, 95% CI 1.00-1.93).
Semaglutide and tirzepatide were compared directly with each other, but the numbers were too small to draw conclusions, the authors reported.
Study details
GLP-1 Receptor Agonists and Sight-Threatening Ophthalmic Complications in Patients With Type 2 Diabetes
David Ramsey, Bhargav Makwana, Sourbha Dani, et al.
Published in JAMA Network on 11 August 2025
Abstract
Importance
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with increased risk of diabetic retinopathy (DR) and nonarteritic anterior ischaemic optic neuropathy (NAION). The risk of sight-threatening complications associated with GLP-1 RAs is under-examined.
Objective
To investigate whether the use of GLP-1 RAs in patients with T2D is associated with the development of DR, NAION, or DR complications.
Design, Setting, and Participants
This retrospective cohort study of adults (aged ≥18 years) with T2D and a recent heamoglobin A1c level of 6.5% or higher was conducted between January 1, 2015, and September 30, 2022, using the TriNetX database. The cohort was divided into 2 groups, adjusted for baseline characteristics through propensity score matching (PSM), based on whether the individuals received prescriptions for a GLP-1 RA. The statistical analysis was conducted on October 10, 2024.
Exposures
At least 2 prescriptions of a GLP-1 RA given 6 months apart.
Main Outcomes and Measures
Cox proportional hazard regression models were used to evaluate the primary outcome: association between GLP-1 RAs and the risk of incident DR, NAION, or sight-threatening complications over a 2-year follow-up period.
Results
After PSM, 185 066 individuals (mean [SD] age, 59.0 [12.5] years; 93 389 females [50.5%]) were prescribed GLP-1 receptor agonists. Use of GLP-1 RAs was associated with an increased incidence of DR (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11), while no statistically significant difference was observed in the risk of NAION (HR, 1.26; 95% CI, 0.94-1.70). In a subgroup analysis of 32 695 patients with pre-existing DR, GLP-1 RAs were not associated with progression to proliferative DR (HR, 1.06; 95% CI, 0.97-1.15) or diabetic macular oedema (HR, 0.98; 95% CI, 0.95-1.01) but were associated with a lower occurrence of vitreous haemorrhages (HR, 0.74; 95% CI, 0.68-0.80), neovascular glaucoma (HR, 0.78; 95% CI, 0.68-0.88), or blindness (HR, 0.77; 95% CI, 0.73-0.82).
Conclusions and Relevance
In this cohort study of individuals with T2D, GLP-1 RA use was associated with a modestly increased risk of incident DR; however, fewer patients experienced sight-threatening DR complications, including blindness, even among those with pre-existing DR.
These findings suggest that all patients with T2D treated with GLP-1 RAs, regardless of pre-existing DR, should be regularly screened and monitored for potential complications of T2D.
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