Apixaban, carbamazepine, latanoprost, rituximab, and semaglutide linked to neovascular AMD reporting risk.

Neovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible vision loss, despite effective anti-VEGF therapies. These treatments often require frequent intraocular injections, posing logistical burdens and potential risks. A significant gap exists in understanding systemic drug-associated risks for nAMD, which could inform patient safety and drug prescribing. Recent pharmacovigilance signals, particularly concerning GLP-1 receptor agonists like semaglutide and other ocular adverse events, underscore the need for comprehensive drug-risk assessments in retinal diseases.

Researchers conducted an integrative pharmacovigilance and proteogenomic study. They first analyzed the US FDA Adverse Event Reporting System (FAERS) to identify drugs with disproportionately high reporting rates of nAMD. Subsequently, drug targets were mapped, and causality was assessed using summary-based Mendelian randomization (SMR) and colocalisation analyses, leveraging cis-pQTL data. Single-cell RNA sequencing from nAMD patients was employed to evaluate cell type-specific gene expression, followed by protein-protein interaction and pathway enrichment analyses to elucidate underlying biological mechanisms.

FAERS analysis identified five drugs significantly associated with higher reporting risks of nAMD: apixaban, carbamazepine, latanoprost, rituximab, and semaglutide. These drugs showed disproportionate reporting compared to other medications.

Summary-based Mendelian randomization (SMR) implicated six genes—IGFBP6, MAPKAPK2, NFKB1, RGMA, RNASE1, and WARS1—in nAMD risk, with strong evidence supporting colocalisation for WARS1. Most candidate genes were predominantly expressed in vascular remodelling endothelial cells, while WARS1 showed high specificity in monocytes. Enrichment analysis further highlighted the critical involvement of these genes in immune and inflammatory responses, particularly within the Toll-like receptor, TNF, and NF-kappa B signalling pathways. These findings suggest potential molecular mechanisms linking these drugs to nAMD pathogenesis.