GLP-1RAs: A Cause for Concern?

First introduced in 2017 and 2022, respectively, semaglutide and tirzepatide are considered two revolutionary first-line treatments for people living with type 2 diabetes and obesity. Overall, use of both glucagon-like peptide-1 receptor agonists (GLP-1RAs) suggests a very positive risk–benefit profile, providing clear cardiometabolic benefits and showing an association with lower rates of stroke and dementia. Ophthalmologists, however, have recently raised concerns regarding the effect of GLP-1RAs on the retina that, despite their many beneficial effects, need serious consideration.

“Initially, these drugs were associated with an acute worsening of diabetic retinopathy in treated patients,” Francesco Bandello MD said. “This was considered a primary adverse effect of GLP-1RAs, but further investigations pointed out a negative association between this effect and a rapid glucometabolic improvement. This is a phenomenon that was already observed in patients undergoing more intense insulin-based treatments.”

Investigations such as the Diabetes Control and Complications Trial (DCCT) and the Steno 1 study showed a rapid metabolic improvement could have a long-term beneficial effect on a patient with an active retinopathy, Professor Bandello underlined.^1,2 “Paradoxically, in the short run, a sharp glucometabolic improvement was strongly associated with an increase in retinal complications, and this is something we all experience in our clinical practice as retina specialists.”

“As glycaemia rapidly improves in diabetic patients, so does the risk of onset of diabetic retinopathy, mostly in the first six months from the start of treatment,” added Enrico Borrelli MD, PhD. “Moreover, the same drugs have recently been associated with an increased risk of ischaemic optic neuropathy, especially in patients more than 60 years of age.”

Such an increase might well be associated with the vascular response provoked by the rapid decline in blood glucose levels induced by the GLP-1RAs, suggested Lonny Stokholm MScPH, PhD: “This leads to a transient ischaemia, potentially contributing to a higher incidence of non-arteritic anterior ischaemic optic neuropathy (NAION).”

A national registry-based prospective cohort investigated the association between semaglutide and NAION.^3,4 As part of the research team, Dr Stokholm pointed out that while there is still no confirmed mechanism explaining this association, several plausible hypotheses exist. One leading explanation involves rapid glycaemic control and the same early worsening phenomenon that can affect retinopathy in diabetic patients. Semaglutide can cause a rapid reduction in haemoglobin 1Ac, Dr Stokholm said, while emphasising that type 2 diabetes, hypertension, dyslipidaemia, and obesity can all be strong predisposition factors to NAION rather than a direct drug effect. On the other hand, as tirzepatide was only approved in Denmark in October 2024, the current follow-up time and patient numbers are still insufficient to evaluate any potential association with this drug, she observed.

Despite the concerns, there is no scenario where a specialist could suggest an abrupt interruption of the treatment. Semaglutide and tirzepatide are revolutionary drugs, particularly for their ability to reduce the risk of hypoglycaemia—a well-known, potentially life-threatening complication for patients treated with insulin. Thanks to their ability to stimulate the secretion of insulin only when blood glucose levels are high, there is no risk of putting the patient at risk, Prof Borrelli said.

Certainly, both semaglutide and tirzepatide represent one of the most important resources not only for a diabetic patient, but also for patients suffering from obesity and related cardiovascular comorbidities. According to Prof Bandello, many obese patients struggle throughout their lives to achieve a normal body weight, seldom obtaining consistent results despite diets and exercise. This frustrating lack of results can be incredibly discouraging, he said. It is no surprise that the introduction of these drugs brought hope, offering patients not only a chance to lose weight but also improvement in their mental health.

Despite the groundbreaking efficacy, patients taking GLP-1RAs require careful monitoring throughout treatment from their endocrinologist and diabetologist. These drugs can be harmful if self-administered, Prof Bandello said. The risk, especially for diabetic patients, is never zero. Although NAION remains a very rare event—occurring in less than one in ten thousand patients under semaglutide treatment—it is a severe side effect that needs to be taken seriously, Dr Stokholm said.

Both NAION and diabetic retinopathy have a fundamental and grave impact on the visual function, Prof Borrelli added, suggesting the need for a strict collaboration between specialists when managing a patient under GLP-1RA treatment.

“A tight communication between the diabetologist and the ophthalmologist has always been essential, and it is even more essential now,” he said.

“It is necessary to assess the patient’s condition, check if the retina presents major lesions, and recommend frequent check-ups,” Prof Bandello said. “As ophthalmologists, we need to protect the patient and their visual acuity, especially through the first critical phase of glucometabolic improvement.”

The risk–benefit ratio is undoubtedly favourable but can be further improved with a little care from the clinicians and further research.

“It is important to remember that, even if the rare side effects need to be carefully considered, GLP-1RAs are amongst the most effective modern treatments for patients with type 2 diabetes, offering patients substantial improvement in diabetic control,” Dr Stokholm concluded. “Our findings highlight the need for continued observations and further studies to clarify whether these associations represent a drug-related effect or reflect [the patients’] underlying risk factors.”

Francesco Bandello MD, FEBO is Professor and Chairman of the Department of Ophthalmology, University Vita-Salute, Ospedale San Raffaele, Milan, Italy.

Enrico Borrelli MD, PhD, FEBO is Associate Professor of Ophthalmology and Senior Consultant at the University of Turin, Italy.

Lonny Stokholm MScPH, PhD is Associate Professor and Head of the Research Unit of Ophthalmology at the University of Southern Denmark, Denmark.

1. DCCT Research Group. Diabetes Care, 1987 Jan–Feb; 10(1):1–19, doi: 10.2337/diacare.10.1.1.

2. Stougaard EB, et al. Diabetes Obes Metab, 2025 Oct; 27(10):5432–5443, doi:10.1111/dom.16606.

3. Grauslund, et al. Int J Retina Vitreous, 2024 Dec 18; 10(1): 97.

4. Wang L, et al. JAMA Netw Open, 2025 Aug 1; 8(8): e2526327.