When the Pendulum Swings

Finding balance in the retinal effects of GLP-1 drugs

Rapid metabolic change can tip the retina off balance before it finds its rhythm.

In medicine, every breakthrough comes with a backswing. The harder we push the pendulum toward progress, the more forcefully it can swing back. Nowhere is that motion more literal than in the story of glucagon-like peptide-1 (GLP-1) receptor agonists: the drugs that reshaped diabetes care and weight management in one sweeping arc.

For the rest of the body, the benefits are easy to see with steadier glucose, lower cardiovascular risk and smaller waistlines. But in the eye, that rapid correction can feel like whiplash. Reports of retinopathy “worsening,” rare optic-nerve events and even new experiments in neuroprotection have turned the retina into a reflection of the wider metabolic swing.

To separate rhythm from recoil, Prof. Rafael Simó (Spain) has spent years charting how systemic change reverberates through the retina. His message is one of balance. The danger isn’t the drug, it’s actually the speed of control.

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When speed becomes strain

As Prof. Simó explained in his EURETINA 2025 lecture, the eye sometimes protests when the body’s chemistry changes too fast.¹ His work (and a growing body of research) suggests it isn’t the molecule that harms, but the velocity of change.

Early worsening of diabetic retinopathy (DR) reminds clinicians that even improvement can have consequences. It occurs when a rapid fall in glycated hemoglobin (HbA₁c) produces transient vascular stress in the retina, particularly when fragile neovessels already exist. Risk appears when HbA₁c drops by more than 1.5% in three months or 2% in six months.²

Yet real-world evidence tempers this fear. In a large Spanish population study, rapid HbA₁c reduction did not correlate with progression of mild or moderate non-proliferative diabetic retinopathy (NPDR), confirming that glucose optimization should not be delayed in early disease.² The risk emerges mainly in advanced stages, where fragile vasculature cannot adapt to sudden metabolic change.

Across major cardiovascular-outcome trials, the pattern is consistent. A meta-analysis of five GLP-1RA studies found that each percentage-point decrease in HbA₁c increased short-term retinopathy risk, with no specific drug effect.³ At the Cleveland Clinic’s Cole Eye Institute, GLP-1RA users showed no higher odds of DR progression than matched sodium-glucose cotransporter 2 (SGLT-2) inhibitor users.⁴

Even the latest dual agonist, tirzepatide, follows the same rhythm. In a matched cohort, investigators observed higher odds of incident proliferative DR in those with pre-existing disease, but lower odds of new-onset DR in those without baseline retinopathy.⁵ The signal, once again, reflects velocity rather than toxicity.

READ MORE: Perfuse Therapeutics Shares Promising Phase IIa Results in Glaucoma and Diabetic Retinopathy

Prof. Simó’s practical advice is to document baseline retinopathy and titrate gradually in advanced cases, but not to hold back therapy in early disease. “Clinicians should not be afraid to optimize blood glucose in a relatively short period in subjects with mild or moderate non-proliferative diabetic retinopathy,” he emphasized.

The picture we’re seeing now is one of careful adjustment rather than caution. The retina may flinch when the pendulum of control swings too fast, but in most eyes, it quickly regains its balance.

The counter-swing toward protection

Every pendulum that swings too far eventually reverses course. For GLP-1 receptor agonists, that reversal has taken an unexpected direction: from suspected harm to potential protection.

In Prof. Simó’s laboratory, the very molecules once blamed for worsening retinopathy are showing signs of safeguarding the retina when given by a different route. In preclinical studies, GLP-1 analogues delivered as eyedrops reached the posterior segment within minutes, bypassing systemic metabolism entirely.

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In diabetic animal models, topical GLP-1 receptor agonists prevented retinal neurodegeneration, curbing glial activation and preserving neuronal architecture.⁶ When semaglutide was administered topically, it went further by blocking NF-κB, which mediated inflammation, reducing interleukin-1 beta (IL-1β), IL-6 and IL-18, and the adhesion molecule ICAM-1, and preventing vascular leakage without altering blood glucose.⁷

Prof. Simó reported trans-scleral absorption with retinal drug levels detectable by 15 minutes. Complementary preclinical studies confirmed elevated retinal GLP-1 levels at one to two hours post-dose and improved ganglion-cell function through enhanced gamma-aminobutyric acid (GABA) release—effects abolished when GLP-1 or GABA-A receptors were blocked.⁸

“GLP-1 receptor agonists administered by the topical route exert beneficial effects,” Prof. Simó told the EURETINA audience. Taken together, the data suggest the pendulum has swung toward equilibrium. What once unsettled the retina through rapid systemic change may, in time, become a direct shield against neurodegeneration.

At the outer edge of risk

Every pendulum has its outer edge, and for GLP-1–based drugs, that edge is defined by the optic nerve. Recent reports have linked semaglutide and tirzepatide to non-arteritic anterior ischemic optic neuropathy (NAION), a sudden, usually unilateral ischemic event affecting the optic nerve head.

In a JAMA Network Open study of 159,398 matched patients, GLP-1RA use was associated with a small but significant uptick in optic-nerve disorders, including NAION (35 versus 19 cases) over two years.⁹ Despite the relative increase, the absolute risk remains extremely low.

A separate 2025 analysis reported a 24.2% reduction in progression to blindness and fewer sight-threatening complications overall, even among patients with pre-existing DR.¹⁰ Together, these findings point toward balance and awareness, not alarm.

A meta-analysis of ten studies found a pooled hazard ratio (HR) of 2.62 for NAION, largely driven by semaglutide, which accounted for ~86% of reported cases. The signal became significant only after two years of continuous exposure, suggesting a time-dependent rather than immediate risk.¹¹

Baseline risk matters too. Diabetes alone increases NAION incidence by roughly 50%, and common comorbidities like hypertension, obesity, sleep apnea and “disc-at-risk” anatomy add to that vulnerability.²

READ MORE: From Rare to Repair: Inherited Retinal Disease Therapies Advance at Speed

Prof. Simó recommends proportion over panic. “To avoid semaglutide based only on concerns regarding the risk of NAION might not be justified,” he said.¹ For patients over 60 with vascular disease, neuropathy or sleep apnea, a cup-to-disc ratio under 0.3 can help flag higher risk. For most, though, GLP-1 drugs are still both safe and systemically beneficial.

The broader message for ophthalmologists is one of calibration. Rapid HbA₁c reduction does not appear to accelerate mild or moderate NPDR,² and any small rise in early retinopathy risk is outweighed by fewer blindness cases overall.¹⁰ In advanced disease, the approach is simply slower: document baseline DR, titrate doses gradually and monitor more closely when vasculature is fragile.

At the same time, the pendulum’s counter-swing is hopeful. GLP-1 eyedrops and dipeptidyl peptidase-4 (DPP-4) inhibitors have shown neuroprotective effects in preclinical models, preserving ganglion cells and curbing glial activation.^8,12 What began as a metabolic therapy may yet become a tool for protecting the eye itself: a balance between systemic success and retinal resilience.

The rhythm of adaptation

Medicine is a study in motion. GLP-1 receptor agonists may shift the rhythm at first, but with care, their motion tends toward protection. The eye, like the body, adapts best when change happens at a manageable pace.

With steady treatment, consistent screening and growing insight into ocular effects, clinicians can keep both systems in sync. Balance isn’t about freezing the pendulum, it’s about keeping time with its swing.

Editor’s Note: Prof. Rafael Simo’s insights in this article are based on his Day 4 presentation at EURETINA 2025 Paris, titled “Diabetes and Weight Loss Drugs: Retinal Effects and Their Clinical Relevance”. This content is intended exclusively for healthcare professionals. It is not intended for the general public. Products or therapies discussed may not be registered or approved in all jurisdictions, including Singapore. A version of this article was first published in PIE Issue 37.

References

1. Simó R. Diabetes and weight loss drugs: Retinal effects and their clinical relevance. Lecture at EURETINA 2025. Paris, France. September 7, 2025.
2. Simó R, Franch-Nadal J, Vlacho B, et al. Rapid reduction of HbA1c and early worsening of diabetic retinopathy: A real-world population-based study in subjects with type 2 diabetes. Diabetes Care. 2023;46(9):1633-1639.
3. Bethel MA, Diaz R, Castellana N, et al. HbA1c change and diabetic retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: A meta-analysis and meta-regression. Diabetes Care. 2021;44(1):290-296.
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5. Buckley AJ, Tan GD, Gruszka-Goh M, et al. Early worsening of diabetic retinopathy in individuals with type 2 diabetes treated with tirzepatide: A real-world cohort study. Diabetologia. 2025;68(9):2069-2076.
6. Hernández C, Bogdanov P, Corraliza L, et al. Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes. 2016;65(1):172-187.
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8. Shao YQ, Wang YC, Wang L, et al. Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes. Neural Regen Res. 2026;21(2):800-810.
9. Wang L, Volkow ND, Kaelber DC, Xu R. Semaglutide or tirzepatide and optic nerve and visual pathway disorders in type 2 diabetes. JAMA Netw Open. 2025;8(8):e2526327.
10. Ramsey DJ, Makwana B, Dani SS, et al. GLP-1 receptor agonists and sight-threatening ophthalmic complications in patients with type 2 diabetes. JAMA Netw Open. 2025;8(8):e2526321.
11. Chen KY, Chan HC, Chan CM. Does semaglutide increase the risk of non-arteritic anterior ischemic optic neuropathy? A systematic review and meta-analysis of emerging evidence. Asia Pac J Ophthalmol (Phila). 2025 Sep 15:100245.
12. Simó R, Ramos H, García-Ramírez M, Hernández C. Effect of sitagliptin on diabetes-induced hyperpermeability of blood-retinal barrier components. Eye (Lond). 2025 Aug;39(12):2485-2486.