Divergent ocular safety profiles of glucagon-like peptide-1 receptor agonists: a pharmacological heterogeneity framework.

Review article synthesizing clinical, pharmacological, and mechanistic data to propose an integrative model of GLP-1RA ocular effects.

“This review explores the pharmacological underpinnings of this difference by combining three lines of evidence: biased agonism and trafficking at the receptor level, cell-type-specific signaling microenvironments, and a recently proposed hemodynamic mechanism based on GLP-1RA-mediated changes in intracranial pressure.”

Patients with type 2 diabetes, obesity, or non-diabetic individuals using GLP-1RAs, along with preclinical models involving ocular cell types and animal studies.

“Key areas for future research include head-to-head comparisons of different GLP-1RAs' signaling in specific ocular cell types and the risk-benefit equation in non-diabetic individuals using these drugs for weight loss.”

Not applicable as this is a review article summarizing data from multiple studies with varying sample sizes, including registry studies with over 61,000 and 424,000 participants.

“A Danish-Norwegian registry study of more than 61,000 semaglutide initiators reported a pooled adjusted hazard ratio of 2.81 (95% CI 1.67–4.75) compared to SGLT-2 inhibitor initiators...”

Not applicable as this is a review article; referenced studies include follow-up periods ranging from weeks to years, with some NAION risks emerging within the first year.

“Cumulative incidence curves started to separate about nine months after the treatment started- a time trend hard to explain by rapid glycemic correction, as HbA1c decreases are mostly observed within the first 12–16 weeks.”

Semaglutide shows a stronger signal for non-arteritic anterior ischemic optic neuropathy (NAION) and early diabetic retinopathy worsening compared to other GLP-1RAs like liraglutide and dulaglutide.

“The data point to a consistent pattern that is the key question in GLP-1RA ocular safety: semaglutide produces stronger signals than liraglutide, dulaglutide or exenatide for both NAION and early diabetic retinopathy progression.”

GLP-1RAs may modulate intracranial pressure (ICP), potentially leading to optic nerve head hypoperfusion and NAION risk, particularly with long-acting agents.

“The decrease in CSF production caused by GLP-1RA decreases ICP, which decreases the size of the optic nerve subarachnoid space. The resulting sheath narrowing may compromise perfusion of the anterior optic nerve head...”

GLP-1RA use is associated with a lower risk of age-related macular degeneration (AMD) in some studies, contrasting with the NAION risk.

“Several large cohort studies have shown that GLP-1RA use is associated with lower risk of dry AMD.”

Causality for NAION is not definitively established; evidence relies on observational data and pharmacovigilance signals with potential confounding; mechanisms like ICP modulation remain unproven in humans.

“An agreement statement by the North American Neuro-Ophthalmology Society and the American Academy of Ophthalmology recognized the observational evidence but stressed that causality is not established and the absolute risk, should it exist, is extremely low.”