Ocular complications from glucagon-like peptide-1 receptor agonists: Clinical evidence, potential mechanisms, and clinical recommendations

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—central to type 2 diabetes mellitus (T2DM) management owing to their comprehensive benefits (glycemic control, weight reduction, cardiovascular benefits, and renal protection)—exhibit a concerning ocular safety profile. Clinical trial data, notably from SUSTAIN-6, revealed a higher incidence of diabetic retinopathy (DR) complications with semaglutide, particularly in patients with preexisting DR and rapid HbA1c reduction, reflecting early worsening. Conversely, the REWIND and LEADER trials reported no significant increase in DR risk, suggesting variability among agents and the potential influence of glycemic trajectory. Observational studies and meta-analyses provide mixed findings: some suggest increased DR progression risk in vulnerable populations, while others indicate a lower risk than insulin therapy. Beyond DR, recent pharmacoepidemiologic studies and pharmacovigilance reports have implicated GLP-1 RAs—especially semaglutide—in nonarteritic anterior ischemic optic neuropathy (NAION), leading the European Medicines Agency to classify NAION as a very rare adverse effect and prompting regulatory scrutiny. Conversely, real-world data suggest possible protective associations with other retinal disorders, including reduced incidence of neovascular age-related macular degeneration and diabetic macular edema, although findings remain inconsistent. The mechanistic pathways involve rapid metabolic shifts, vascular dysregulation, and potentially direct effects on retinal or optic nerve tissue. While GLP-1 RAs confer substantial systemic benefits, their ocular risks appear concentrated in high-risk subgroups. Individualized prescribing, baseline ophthalmic assessment, and interdisciplinary monitoring are essential until ongoing prospective trials clarify their long-term ocular impact.

Lay Summary: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are medicines widely used for type 2 diabetes because they lower blood sugar, help with weight loss, and protect the heart and kidneys. However, recent research has raised questions about their effects on the eyes. Clinical trials showed that semaglutide may increase the risk of diabetic retinopathy complications, particularly in people with existing eye disease and when blood sugar drops too quickly. Other studies have linked GLP-1 RAs, especially semaglutide, to a rare eye condition called NAION, which can cause sudden vision loss. On the other hand, some evidence suggests these drugs might lower the risk of other eye problems, such as age-related macular degeneration or diabetic macular edema. Overall, while GLP-1 RAs provide major health benefits, eye risks appear limited to certain high-risk groups. Careful monitoring and collaboration between diabetes and eye specialists are recommended.

1. INTRODUCTION

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are integral in type 2 diabetes mellitus (T2DM) care, owing to their broad benefits in terms of glycemic, cardiovascular, renal, and weight outcomes. GLP-1 RAs enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety, achieving hemoglobin A1c (HbA1c) reductions of ~1% to 1.5% alongside weight loss and minimal hypoglycemia risk.¹ The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was a large randomized, double-blind, placebo-controlled cardiovascular outcome trial that enrolled over 9000 patients with type 2 diabetes at high cardiovascular risk.² It demonstrated that liraglutide reduced major adverse cardiovascular events by 13% without a significant increase in diabetic retinopathy (DR) progression. The SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes) enrolled 3297 high-risk patients and showed a 26% reduction in cardiovascular events but an unexpected rise in DR complications, particularly among patients with preexisting DR and rapid HbA1c reduction.³ The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial, evaluating dulaglutide in a broader diabetes population over 5.4 years, showed cardiovascular benefit without a significant DR signal, likely owing to slower glycemic improvement. These concise introductions help readers unfamiliar with these pivotal trials understand the differing study designs, populations, and ocular outcomes that inform current interpretations of GLP-1 RAs–related retinal risk.⁴ These agents also improve renal endpoints. Consequently, the 2022 American Diabetes Association (ADA)/European Association for The Study of Diabetes (EASD) guidelines recommend liraglutide, semaglutide, or dulaglutide for patients with Atherosclerotic Cardiovascular Disease (ASCVD) or obesity, independent of HbA1c.⁵

Despite offering systemic benefits, GLP-1 RAs have raised concerns for ocular complications. In SUSTAIN-6, semaglutide was linked to higher rates of DR-related events, including vitreous hemorrhage and the need for intravitreal therapy, particularly among patients with preexisting DR; this was attributed partly to rapid glucose lowering.^3,6 Pharmacovigilance reports have since associated semaglutide and tirzepatide with NAION, papillitis, and paracentral acute middle maculopathy, with stronger signals from injectable forms.⁷ Conversely, emerging real-world data suggest protective associations in other ocular diseases. A large U.S. cohort of nearly 10 000 users demonstrated reduced incidence of neovascular age-related macular degeneration (nAMD) compared with patients on insulin, metformin, or statins.⁸ Thus, while GLP-1 RAs may trigger early worsening in DR or NAION, they might confer long-term ocular benefits, highlighting the need for individualized risk assessment and prospective studies.

This review critically evaluates the association between GLP-1 RAs and ocular complications, including worsening DR, nAMD, and NAION (Fig. 1). First, we examine the available evidence from the randomized controlled trials (RCTs), observational, and pharmacovigilance studies. RCTs provide the highest level of evidence and thus carry greater interpretive weight in our conclusions. Findings from SUSTAIN-6, REWIND, and LEADER form the primary evidence base for assessing DR risk, given their rigorous design and adjudicated outcomes. Observational and pharmacovigilance studies, while valuable for hypothesis generation and detecting rare events such as NAION, are interpreted cautiously due to potential confounding and reporting bias. Further, we discuss biological plausibility and provide clinical recommendations.

Fig. 1.

NPDR (A) and PDR (B) represent progressive stages of microvascular damage caused by chronic hyperglycemia. NPDR is characterized by microaneurysms, intraretinal hemorrhages, and cotton-wool spots, while PDR exhibits neovascularization and vitreous hemorrhage, posing a high risk of vision loss. C, nAMD is a degenerative maculopathy associated with abnormal choroidal neovascular growth and leakage beneath the retinal pigment epithelium, leading to central vision distortion and scarring. D, NAION results from sudden hypoperfusion of the short posterior ciliary arteries in anatomically crowded optic discs, producing optic-nerve swelling and altitudinal visual field defects. NAION = nonarteritic anterior ischemic optic neuropathy; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy.

2. GLP-1 RAs AND WORSENING DR

GLP-1 RAs have transformed the management of type 2 diabetes, offering potent glycemic, weight, and cardiorenal benefits.^9,10 However, concerns have emerged regarding their potential to exacerbate DR—a leading cause of vision impairment—particularly among participants with preexisting DR at baseline.^2–4 Consequently, labels for semaglutide caution that patients with a history of DR should be monitored; further, they note a higher absolute risk in patients with baseline DR and remind clinicians that rapid glucose improvement can transiently worsen DR.¹¹

2.1. Evidence from RCTs

The semaglutide SUSTAIN-6 cardiovascular outcome trial was the first to spotlight a potential DR risk: the rate of DR complications (vitreous hemorrhage, need for photocoagulation or intravitreal therapy, or blindness) was higher for semaglutide than for placebo, especially among those with preexisting DR.² This suggested that the rapid glucose-lowering effect of semaglutide might trigger early worsening, a known risk from prior trials. In contrast, the REWIND trial of dulaglutide did not report a significant increase in DR events.⁴ The longer study duration (median 5.4 years) and more gradual HbA1c reduction may have mitigated the acute worsening effect. The discrepancy between REWIND and SUSTAIN-6 raises questions about whether the DR risk is molecule-specific or related to the speed and magnitude of glycemic improvement. The LEADER trial also failed to show significant associations between liraglutide and DR progression, further supporting the hypothesis that semaglutide’s potent glucose-lowering capability (especially with subcutaneous weekly dosing), rather than a class effect, may drive the risk.³

2.2. Observational studies linking GLP-1 RAs to worsening DR

A 2024 single-center retrospective cohort study from the Cleveland Clinic compared the effects of GLP-1 RAs and sodium–glucose cotransporter-2 inhibitors (SGLT-2is) based on propensity score matching.¹² In the 981 patients followed for a mean of 1.5 years, no significant difference in DR worsening (defined using International Classification of Diseases codes and confirmed via manual review) was observed between the groups (odds ratio [OR]: 0.33, 95% CI, 0.11-1.03). Similarly, no difference in DR-related procedural interventions was detected, suggesting that in routine practice, GLP-1 RA use was not linked to increased DR progression risk.

This association was further examined using large-scale population-level data from Taiwan’s National Health Insurance Research Database.¹³ Among the 97 413 patients initiating GLP-1 RAs or SGLT-2i therapy between 2016 and 2017, those with preexisting DR experienced a higher risk of DR progression with GLP-1 RAs (subdistribution hazard ratio: 1.50, 95% CI, 1.01-2.23), driven mainly by tractional retinal detachment events. No increased risk was observed in patients without baseline DR, highlighting that preexisting retinal disease remains a key vulnerability factor.

Tirzepatide, a dual GLP-1 and GIP receptor agonist, is also associated with an increased risk of new-onset proliferative DR (PDR), despite its overall favorable metabolic profile.¹⁴ In a large matched cohort, tirzepatide exposure doubled the odds of incident PDR, particularly among individuals with preexisting mild or moderate non-PDR with maculopathy, whereas it paradoxically reduced the risk of DR in those without baseline retinal disease.¹⁴ These findings highlight the importance of individualized retinal monitoring when initiating tirzepatide in high-risk patients to mitigate potential early worsening of DR.

2.3. Meta-analyses and systematic reviews

The meta-analytic evidence reinforces the complexity of these findings. Yoshida et al¹⁵ conducted a systematic review and meta-analysis of 13 RCTs evaluating GLP-1 RAs and DR progression in T2DM. In four major cardiovascular-outcome trials, GLP-1 RAs (liraglutide, semaglutide, and dulaglutide) were significantly associated with an increased risk of DR progression (OR: 1.23). The risk of DR progression was greater in placebo-controlled studies and in those longer than 52 weeks. The elevated risk is likely due to the rapid reduction in HbA1c rather than direct toxicity. The authors emphasized that further data are needed, particularly from dedicated retinal safety studies.¹⁵

Recently, a systematic review pooling >240 000 patients found that GLP-1 RA use was associated with a significantly lower risk of incident DR than insulin (relative risk [RR]: 0.66, 95% CI, 0.48-0.91), while it posed a higher risk of DR complications than oral antidiabetic drugs (RR: 1.39, 95% CI, 1.07-1.80).¹⁰ However, in systematic reviews, pooled analysis is hampered by the heterogeneity in DR definitions, grading criteria, and follow-up durations across studies. Consequently, the authors advocate for harmonized retinal endpoints in future trials to enable more robust comparisons and to clarify potential agent-specific risks in vulnerable patient groups.¹⁰ Table 1 reveals the association between GLP-1 RAs and worsening DR in patients with diabetes.

Table 1.

The association between GLP-1 receptor agonists and worsening retinopathy (DR)

Study/year	GLP-1 RA(s) studied	Design	Population	Key findings
SUSTAIN-6 (Marso 2016)3	Semaglutide	Randomized controlled trial (CVOT)	T2DM, high CV risk	↑ DR complications (esp. preexisting DR, rapid HbA1c fall)
REWIND (Gerstein 2019)10	Dulaglutide	Randomized controlled trial (CVOT)	T2DM, wide risk spectrum	No significant increase in DR events; longer duration, gradual HbA1c reduction may explain
LEADER (Marso 2016)2	Liraglutide	Randomized controlled trial (CVOT)	T2DM, high CV risk	No significant association with DR progression
Cleveland Clinic Cohort (Joo 2024)12	Mixed GLP-1 RAs	Single-center retrospective cohort	981 patients, mean FU 1.5 yr	No significant difference in DR worsening vs SGLT-2i (OR: 0.33, 95% CI, 0.11-1.03)
Taiwan NHIRD (Lin 2024)13	Mixed GLP-1 RAs	Population-based cohort (NHIRD)	97 413 patients (2016-2017)	↑ DR progression in pts with baseline DR (SHR: 1.50, 95% CI, 1.01-2.23); no risk in DR-free pts
Meta-analysis (Yoshida 2022)15	Liraglutide, Semaglutide, Dulaglutide	Systematic review and meta-analysis of 13 RCTs	13 RCTs in T2DM	GLP-1 RAs ↑ DR progression risk in CVOTs (OR: 1.23), esp. ≥52 wk and placebo-controlled; rapid HbA1c drop implicated
Meta-analysis (Kapoor 2023)8	Mixed GLP-1 RAs	Meta-analysis of RCTs	RCTs of T2DM with DR outcomes	GLP-1 RAs ↑ DR risk in pooled RCTs, semaglutide strongest signal
Meta-analysis (Kapoor 2025)9	Mixed GLP-1 RAs	Meta-analysis of clinical studies (~240 000 pts)	~240 000 patients across studies	GLP-1 RAs ↓ incident DR vs insulin (RR: 0.66), ↑ DR complications vs oral drugs (RR: 1.39)
Tirzepatide real-world cohort (Buckley 2025)14	Tirzepatide	Real-world cohort study	Real-world tirzepatide users	Early worsening of DR observed with tirzepatide initiation

CVOT = cardiovascular outcome trial; DR = diabetic retinopathy; OR= odds ratio; RR = relative risk.

2.4. Pathophysiology and mechanistic insights

The Diabetes Control and Complications Trial (DCCT) in type 1 diabetes¹⁶ and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes¹⁷ demonstrated that intensive insulin therapy produced substantial long-term microvascular benefits but was associated with transient DR worsening within the first 6 to 12 months among patients with preexisting DR and rapid HbA1c reduction. Similarly, studies by Henricsson et al¹⁸ and Bain et al¹⁹ confirmed that abrupt glycemic improvement can transiently destabilize retinal microvasculature through osmotic and vascular growth factor–mediated mechanisms.

GLP-1 RAs can trigger early worsening of DR, a transient phenomenon linked not to direct retinal toxicity (since the GLP-1 receptor is minimally expressed in the human retina) but to rapid, substantial HbA1c reductions.²⁰ As seen with insulin intensification and post-bariatric surgery, large and abrupt glycemic improvements—especially in patients with long-standing diabetes, high baseline HbA1c, and preexisting DR—may accelerate microvascular changes.^21,22 The potential mechanisms of this include insulin-like growth factor-1 elevation, promoting neovascularization; osmotic shifts from sudden glucose drops, leading to retinal edema; and vascular endothelial growth factor upregulation in hypoxic retinal tissue. Although data from clinical trials such as SUSTAIN-6 indicate this early worsening often stabilizes or regresses, careful ophthalmic monitoring is advised during the first months of GLP-1 RAs therapy in high-risk patients, to ensure that cardiovascular and metabolic benefits are achieved without compromising vision.

2.5. Clinical implications and recommendations for worsening DR

Although GLP-1 RAs—especially potent agents like semaglutide and tirzepatide—may confer a small, transient risk of DR worsening in patients with preexisting DR and rapid glycemic improvement, these drugs offer immense cardiorenal and metabolic benefits. Baseline assessment, glycemic planning, and ophthalmologic follow-up is therefore recommended.¹¹ Before initiating GLP-1 RA therapy, patients with baseline HbA1c ≥8.5% should undergo a comprehensive ophthalmologic evaluation by an eye specialist before starting GLP-1 receptor agonist therapy, to exclude active or unstable DR. For those with HbA1c between 7.0% and 8.5%, a retinal examination within the past three months is recommended before initiation. This approach ensures early detection of preexisting retinal pathology and minimizes the risk of transient worsening of DR associated with rapid glycemic improvement during GLP-1 RA treatment initiation. In patients without or with only mild nonproliferative diabetic retinopathy (NPDR), a reduction in HbA1c of up to 1% to 1.5% over approximately three months is generally considered safe, provided that routine ophthalmologic follow-up continues. For those with moderate-to-severe NPDR or previously treated proliferative diabetic retinopathy (PDR) or center-involved diabetic macular edema, a more gradual reduction—ideally no more than about 1% per 3 months—is recommended, avoiding abrupt normalization of glycemia. In such cases, close coordination with an ophthalmologist is essential to monitor for potential disease progression. When active, untreated PDR or center-involved diabetic macular edema is present, retinal stabilization or treatment should precede any major intensification of glucose-lowering therapy. Intensive glycemic reduction should be deferred until the ocular condition is controlled, minimizing the risk of sight-threatening exacerbation.

3. GLP-1 RAs AND nAMD

nAMD, a leading cause of irreversible central vision loss in older adults, is characterized by choroidal neovascularization (CNV) that leads to retinal fluid accumulation, hemorrhage, and fibrotic scarring if untreated.²¹ In addition to their increasing use in metabolic and cardiovascular disease management, GLP-1 RAs (including exenatide, liraglutide, dulaglutide, and semaglutide) provide systemic anti-inflammatory and vasculoprotective effects.²² While no clinical trials have produced direct evidence linking GLP-1 RAs to changes in the risk of nAMD, preclinical and epidemiologic data suggest possible interactions.

3.1. Overview of nAMD pathophysiology

The late-stage, exudative form of age-related macular degeneration (AMD), nAMD, is characterized by CNV, in which abnormal vessels breach Bruch’s membrane and leak beneath or into the retina,^23,24 leading to hemorrhage, exudation, and fibrovascular scar formation and resulting in central vision loss. Oxidative stress plays a central role, as the macula is highly metabolically active and particularly vulnerable to reactive oxygen species. Defective antioxidant defense, resulting from impaired Nrf2 signaling and accumulation of oxidation-specific epitopes, contributes to apoptosis and immune dysregulation in the retinal pigment epithelium (RPE).²⁵ Chronic inflammation, complement activation, and lipid deposition further exacerbate RPE damage and drusen accumulation. Vascular endothelial growth factor (VEGF) is the key driver of CNV, making anti-VEGF therapies the standard of care.²¹ Based on epidemiologic studies, advanced AMD is estimated to affect millions worldwide and will increase with population aging.^26,27 In some patients, despite effective VEGF inhibition, AMD remains refractory or advances to atrophy, underscoring the need to explore systemic modulators such as GLP-1 RAs that may influence oxidative, inflammatory, or angiogenic pathways in the macula.

3.2. Observational studies linking GLP-1 RAs and nAMD

A large population-based retrospective cohort study in Ontario, Canada, investigated the risk of nAMD among GLP-1 RAs users with diabetes.²⁸ Using linked administrative health data from 2020 to 2023, the study compared 46 334 GLP-1 RA–exposed patients to 92 668 unexposed matched controls. The hazard of incident nAMD was more than doubled in GLP-1 RAs users (adjusted hazard ratio: 2.21, 95% CI 1.65-2.96), highlighting a potential safety signal that warrants further mechanistic clarification.²⁸

This finding is particularly relevant given the increasing global burden of AMD. According to the Global Burden of Disease 2021 analysis, over 8 million individuals were visually impaired by AMD in 2021, with projections estimating more than 21 million cases by 2050.²⁷ Although its age-standardized prevalence is declining, the absolute case numbers continue to rise, owing to population aging. The influence of modifiable risk factors such as tobacco use on the AMD burden was confirmed, reinforcing the multifactorial pathogenesis of the disease.²⁷

Observational data for other macular diseases provide contradictory results. A multicenter real-world analysis of systemic medications in T2DM found that GLP-1 RA therapy was associated with a reduced risk of diabetic macular edema (hazard ratio: 0.77, 95% CI, 0.70-0.85), suggesting potentially divergent retinal effects across disease entities.²⁹ Therefore, while GLP-1 RAs appear to reduce microvascular risk in some contexts, their association with nAMD requires cautious interpretation. These findings underscore the need for additional longitudinal studies to confirm causality and inform clinical decision-making in balancing cardiometabolic benefits against emerging ocular risks. Table 2 shows the association between GLP-1 RA and nAMD in the different studies.

Table 2.

The association between glucagon-like peptide-1 receptor agonists and neovascular age-related macular degeneration (nAMD)

Study/ Year	GLP-1RA(s) Studied	Design	Population	Key Findings
Ontario cohort (Shor 2025)28	Mixed GLP-1RAs (population-level exposure)	Population-based retrospective cohort study (Ontario, Canada)	46,334 GLP-1RA users vs 92,668 matched controls (2020–2023)	↑ Risk of incident nAMD with GLP-1RAs (HR 2.21, 95% CI 1.65–2.96)
Multicenter diabetic macular edema study (Muayad 2025)29	GLP-1RAs (systemic medications in T2DM)	Multicenter real-world analysis in T2DM patients	T2DM patients, real-world multicenter data	GLP-1RAs ↓ risk of diabetic macular edema, suggesting divergent retinal effects
Preclinical/ Experimental (Hernández 2016)30	GLP-1 RAs (topical administration, experimental diabetes)	Animal and retinal tissue experimental study	Experimental diabetic animals; human retinal tissue expression studies	Topical GLP-1RAs prevented retinal neurodegeneration; potential protective mechanism via reduced oxidative stress & inflammation

HR= hazard ratio; CI= confidence interval

3.3. Possible mechanism linking GLP-1 RAs and nAMD

GLP-1 receptors are expressed in human retinal tissue, including the RPE and neural retina, providing a plausible pathway for the direct ocular effects of GLP-1 RAs.³⁰ Experimental studies have shown that GLP-1 RAs exert neuroprotective actions by reducing glutamate excitotoxicity, attenuating oxidative stress, and suppressing inflammatory cascades. These effects could theoretically protect against nAMD pathogenesis, which involves oxidative injury and chronic inflammation.^23,25 Conversely, abrupt glucose lowering, as observed in clinical trials of semaglutide, has been linked to transient worsening of microvascular disease, raising concerns of paradoxical harm to eyes with fragile vasculature. In nAMD specifically, GLP-1 activation may reduce oxidative RPE stress, although its influence on angiogenesis remains uncertain. In animal models of diabetes, GLP-1 RAs prevent retinal neurodegeneration without affecting glucose levels, supporting a receptor-mediated protective mechanism.³⁰ Whether these findings also apply to nAMD remains to be validated. Nonetheless, the convergence of oxidative stress, inflammation, and angiogenesis in nAMD pathogenesis provides a mechanistic rationale for further study.

3.4. Clinical recommendations on GLP-1 RAs and nAMD

Given the limited but emerging evidence, clinicians should adopt a balanced approach when prescribing GLP-1 RAs in patients at risk for or living with nAMD. The current data do not justify withholding GLP-1 RAs solely due to nAMD risk, as their proven cardiovascular and metabolic benefits outweigh the unconfirmed ocular concerns.^21,24 However, vigilance is warranted. Baseline ophthalmic evaluation should be considered in elderly diabetic patients initiating GLP-1 RAs, particularly those with established nAMD lesions or strong risk factors such as family history, smoking, or complement gene polymorphisms.^23,25 Patients should be counseled to promptly report new visual symptoms such as distortion or central scotoma. Collaboration between endocrinologists and ophthalmologists is essential to monitor for potential drug-related effects on the macula.

4. GLP-1 RAs AND NAION

NAION, a relatively common acute optic neuropathy in individuals over 50 years of age,³¹ is characterized by sudden, painless vision loss due to infarction of the anterior optic nerve. While GLP-1 RAs have transformed T2DM management via their ability to improve glycemic control, reduce cardiovascular risk, and promote weight loss,³² emerging case reports and pharmacovigilance signals suggest a potential association between GLP-1 RAs and NAION.

4.1. NAION pathophysiology

A “disc at risk”—a small optic disc with a crowded cup-to-disc ratio—predisposes a person to NAION by limiting the capacity to accommodate axonal swelling, resulting in compartment syndrome when ischemia-induced edema occurs.³¹ This swelling further compromises capillary perfusion, exacerbating ischemia and triggering a vicious cycle leading to retinal ganglion cell apoptosis.³³ The ischemic insult is believed to occur primarily in the laminar and retrolaminar optic nerve head (ONH), often without significant choroidal circulatory involvement, implicating the paraoptic branches of the short posterior ciliary arteries (SPCAs) as the vascular source.³⁴ Factors such as nocturnal systemic hypotension, arteriosclerosis, diabetes, hyperlipidemia, and sleep apnea have been identified as significant systemic risk contributors.³³ Vasospasm, venous congestion, and microembolic phenomena have also been proposed as potential precipitants.^35,36

Autoregulation of ONH blood flow is normally robust; however, in NAION, it may be impaired by vascular endothelial dysfunction, atherosclerosis, or neurohumoral mediators such as endothelin-1, allowing systemic or local perfusion drops to precipitate ischemia.^34,37 Once ischemia occurs, secondary neuronal degeneration and glial changes can cause progressive axonal loss beyond the initial insult.³⁴

4.2. Pharmacovigilance and case reports

The U.S. Food and Drug Administration’s Adverse Event Reporting System [US FDA (FAERS)] (Q4 2024) lists GLP-1 RAs—including semaglutide products—as associated with NAION, stating: “FDA is evaluating the need for regulatory action”.³⁸

Post-marketing pharmacovigilance analyses provide an additional perspective. A study of disproportionality in FAERS retrieved 96 NAION cases associated with GLP-1 RAs, 83 involving semaglutide (reporting OR [ROR]: 17.57, 95% CI, 13.93-21.90).³⁹ This signal remained significant after adjusting for therapeutic indication and comparator drug class, with a notable clustering of cases in Denmark. While these findings cannot confirm causality, their magnitude and temporal trend prompted the European Medicines Agency (EMA) to initiate a formal review in January 2025. Another FAERS-based analysis revealed notably higher reporting of vision impairment for semaglutide than for other antidiabetic or weight-loss medications (ROR: ca. 1.95-3.89).⁴⁰ Collectively, these converging signals raise concerns regarding a real safety issue, underscoring the need for heightened post-marketing surveillance and mechanistic studies to clarify the causal relationship.

In June 2025, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) concluded that NAION is a very rare side effect of semaglutide (Ozempic, Rybelsus, Wegovy), potentially affecting up to 1 in 10 000 users, equating to one extra case per 10 000 person-years of treatment. Several large epidemiological studies have suggested an approximately two-fold increased risk of NAION among semaglutide users. Consequently, PRAC recommended updating the product information to reflect this risk and advising patients to stop treatment if NAION is diagnosed.⁴¹

4.3. Meta-analyses and systematic reviews

Several recent large-scale pharmacoepidemiologic studies have investigated the association between GLP-1 RAs and NAION. A retrospective analysis of Observational Health Data Sciences and Informatics (OHDSI) network data for over 37 million adults with T2DM was conducted to compare the risks of NAION among GLP-1 RAs and non-GLP-1 RAs users.³² When applying a more specific definition of NAION, semaglutide users exhibited a moderately higher risk of NAION than users of certain non-GLP-1 RAs, particularly empagliflozin (hazard ratio: 2.27, 95% CI, 1.16-4.46), although no significant increase was observed when applying the primary (sensitive) NAION definition.³² A self-controlled case-series meta-analysis within the same study suggested an incidence rate ratio (IRR) of 1.32 (95% CI, 1.14-1.54) for semaglutide exposure, indicating a small but measurable increase in RR for semaglutide.³²

Conversely, a TriNetX-based multicenter retrospective cohort study of patients with T2DM involving >120 000 semaglutide-treated patients and 220 000 patients on any GLP-1 RAs revealed no significant elevation in the risk of NAION or ischemic optic neuropathy relative to matched non-GLP-1 RAs users.⁴² The cumulative five-year NAION risk for semaglutide users with T2DM was 0.065%, suggesting an overall low absolute risk. Table 3 shows the association between GLP-1 RAs and NAION in the available data.

Table 3.

The association between glucagon-like peptide-1 receptor agonists and nonarteritic anterior ischemic optic neuropathy (NAION)

Study/ year	GLP-1RA(s) Studied	Design	Population	Key Findings
FDA FAERS (2024–2025)38	Semaglutide (Ozempic, Rybelsus, Wegovy)	Pharmacovigilance safety signal (FAERS)	FAERS spontaneous reports, 96 NAION cases (83 semaglutide)	Signal of NAION with semaglutide; FDA evaluating regulatory action
EMA PRAC (2025)41	Semaglutide	Regulatory review (EMA PRAC)	EMA safety review of semaglutide users	NAION classified as very rare (≈1/10,000 person-years); label update recommended
FAERS disproportionality (Azab 2025)39	Semaglutide	FAERS disproportionality study	FAERS dataset	Significant ROR 17.57, higher-than-expected NAION reporting
FAERS analysis (Massy 2025)40	Semaglutide vs other antidiabetic drugs	FAERS analysis (vision impairment reporting)	FAERS dataset, ROR ~1.95–3.89	Semaglutide had higher vision-impairment reporting vs comparators
Retrospective analysis (Cai 2025)32	Semaglutide	OHDSI retrospective & self-controlled case series	37 million adults with T2D across OHDSI network	Modest ↑ NAION risk with semaglutide (HR 2.27 in specific definition); IRR 1.32 during exposure
TriNetX cohort (Abbass 2025)42	Semaglutide and other GLP-1RAs	TriNetX-based multicenter retrospective cohort	120,000 semaglutide-treated & 220,000 GLP-1RA-treated patients	No significant increased risk; 5-year absolute NAION risk 0.065%

ROR= reporting odd ratio; HR= hazard ratio; IRR= incidence rate ratio

4.4. Possible mechanism linking GLP-1 RAs and NAION

Although the mechanisms linking GLP-1 RAs and NAION remain incompletely understood, several pathophysiological hypotheses have been proposed. NAION results from ischemic injury to the ONH, typically due to compromised perfusion of the SPCAs in individuals with a structurally crowded optic disc.³¹ GLP-1 RAs may influence this process via systemic, metabolic, and vascular pathways.

One proposed mechanism involves rapid glycemic improvement, which has been associated with transient microvascular dysregulation and ocular ischemic events. In the context of DR, abrupt reductions in HbA1c can precipitate microvascular changes; a similar mechanism could theoretically compromise ONH perfusion in susceptible individuals.³² This effect may be potentiated in patients with preexisting small cup-to-disc ratios or other vascular risk factors. GLP-1 RAs also reduce systemic blood pressure, particularly nocturnal pressure, through natriuretic and vasodilatory effects.⁴² In patients with impaired optic nerve autoregulation, excessive nocturnal hypotension could reduce perfusion pressure below the threshold needed to sustain the ONH, triggering ischemia.³⁷

Another hypothesis involves direct vascular effects. GLP-1 receptors are expressed in retinal and optic nerve tissues, and GLP-1 RAs may modulate endothelial function, nitric oxide pathways, and vascular tone.³⁹ While these changes may be protective in some contexts, dysregulated vasomotor responses could lead to localized hypoperfusion in predisposed optic nerves.

4.5. Clinical recommendations for GLP-1 RAs administration in NAION

Emerging pharmacoepidemiologic and pharmacovigilance evidence suggests a possible association between the use of GLP-1 RAs, particularly semaglutide, and NAION, although the absolute risk remains low.^32,39 Clinical decision-making should therefore be individualized, with careful assessment of NAION risk factors such as a small cup-to-disc ratio, prior NAION in the fellow eye, systemic vascular disease, nocturnal hypotension, and sleep apnea.^31,37 In high-risk patients, clinicians should balance the established cardiometabolic benefits of GLP-1 RAs with their potential ocular risks, engaging in shared decision-making.⁴² Targeted baseline ophthalmic evaluation may be appropriate in patients with ONH crowding or prior ischemic optic neuropathy. Patients should be counseled to promptly report acute, painless vision loss or visual field defects, particularly early in therapy.³² Close collaboration across specialties and prompt reporting of suspected cases are essential for refining risk–benefit evaluation.³⁹

5. CONCLUSIONS AND SUGGESTIONS

GLP-1 RAs represent a cornerstone of modern T2DM therapy, owing to their robust glycemic, cardiovascular, renal, and weight-reducing benefits. However, their ocular safety profile remains complex. Evidence from RCTs, particularly SUSTAIN-6, has raised concerns about early worsening of DR in patients with preexisting DR, attributed largely to the rapid reduction in HbA1c. Real-world studies and meta-analyses suggest that this risk is most pronounced in individuals with advanced DR at baseline, while those without prior DR appear less vulnerable. Conversely, some epidemiologic evidence indicates potential protective associations between GLP-1 RA use and other retinal conditions, including reduced risk of diabetic macular edema or even nAMD, although findings are inconsistent. Pharmacovigilance and case reports have linked semaglutide use to NAION, prompting regulatory updates by the EMA and ongoing FDA review.

Collectively, the current evidence underscores a nuanced balance: while GLP-1 RAs offer undeniable systemic benefits, they may impose ocular risks in susceptible subgroups. Future research priorities include utilizing harmonized retinal endpoints in clinical trials, performing mechanistic studies on angiogenesis and optic nerve perfusion, and using large-scale prospective cohorts to clarify causality. Until then, vigilant monitoring with shared decision-making remains the most prudent strategy.

ACKNOWLEDGMENTS

This study was supported by grants from the Taipei Veterans General Hospital (V112C-189 and V113C-076).

We thank Uni-edit (www.uni-edit.net) for editing and proofreading this manuscript.