Furong Han

The expanding clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and obesity has raised concerns about underrecognized ocular adverse events (AEs). Despite their metabolic benefits, fragmented evidence and methodological limitations in pharmacovigilance systems hinder comprehensive risk characterization. This study aimed to systematically evaluate ocular toxicity signals associated with GLP-1 RAs using advanced signal mining across the FDA Adverse Event Reporting System (FAERS) and VigiBase. Data from FAERS (2005-2025 Q1) and VigiBase (1987-2025 Q1) were analyzed for ocular AEs linked to five GLP-1 RAs (exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide). Disproportionality analyses using Bayesian (Information Component, IC₀₂₅ > 0) and frequentist (Reporting Odds Ratio, ROR 95% CI > 1) methods identified significant signals. Duplicate reports and incomplete data were excluded, with statistical processing performed in R packages and Excel software. Across both databases, ocular AEs predominantly occurred in individuals aged 45-64 and females. Semaglutide exhibited the strongest signals, notably for NAION (ROR = 40.18, IC₀₂₅ = 2.06 in VigiBase and ROR = 31.46, IC₀₂₅ = 4.84 in FAERS), with 2,878 cases in VigiBase and 2,047 in FAERS. Dulaglutide showed high rates of visual impairment and diabetic retinopathy. Early-onset AEs (≤ 30 days) were common with dulaglutide and semaglutide, while exenatide-related events peaked after > 360 days. Discrepancies between databases emerged, such as absent liraglutide/lixisenatide signals in VigiBase but moderate activity in FAERS. Furthermore, review of the prescribing information for these GLP-1RAs indicates that ocular adverse events are incompletely characterized. Diabetic retinopathy is reported solely for semaglutide and dulaglutide, while blurred vision is the only ocular event listed for lixisenatide. Other potential ocular risks are not mentioned in any of the respective drug labels. This large-scale pharmacovigilance analysis suggests underrecognized ocular safety signals associated with GLP-1 RAs, most prominently NAION with semaglutide and visual impairment/diabetic retinopathy with dulaglutide. The distinct AE profiles, temporal patterns (early vs. late onset), and database discrepancies highlight the complexity of GLP-1 RA ocular toxicity. These findings underscore the need for enhanced clinical vigilance, targeted post-marketing surveillance, and consideration of label updates to reflect these emerging ocular safety concerns.

Background: Protocatechualdehyde (PCA), a phenolic compound derived from Salvia miltiorrhiza, exhibits anti-proliferative and antioxidant properties. However, its molecular mechanisms in reducing oxidative stress in diabetic cataract (DC) remain unclear. This study systematically investigated the role of PCA in modulating glyoxalase-1 (GLO1)-dependent suppression of advanced glycation end product (AGE)-receptor for AGE (RAGE) axis activation and oxidative stress in DC models.Methods: A galactose-induced DC rat model and high glucose-stimulated human lens epithelial cells (HLECs) were employed. Lens opacity was assessed using slit-lamp microscopy. GLO1, AGE, and RAGE expressions were analyzed through immunohistochemistry (IHC), immunofluorescence (IF), ELISA, and Western blotting. Molecular docking was performed to validate PCA–GLO1 interactions.Results: PCA administration (25 mg/kg) significantly alleviated lens opacity and epithelial cell disorganization in DC rats (p < 0.01). In vitro, PCA (10 μM) restored HLEC viability under hyperglycemic conditions (p < 0.05). Mechanistically, PCA upregulated GLO1 expression while suppressing AGE accumulation and RAGE activation in both models. Molecular docking revealed strong binding affinities between PCA and GLO1 (-CDOCKER energy: 26.41 kcal/mol).Conclusion: PCA ameliorates DC progression by enhancing the GLO1-mediated detoxification of AGE precursors, thereby inhibiting AGE/RAGE-driven oxidative stress. These findings provide a foundation for PCA as a therapeutic candidate for DC.