Beyond Glycemic Control: Metformin's Multi-Target Role in Preventing and Treating Major Ocular Pathologies.

Metformin, a first-line therapy for type 2 diabetes, is increasingly recognized as a pleiotropic agent with potential relevance to ocular disease beyond glycemic control. Accumulating epidemiological evidence suggests that metformin exposure may be associated with reduced risk or slower progression of diabetic retinopathy, primary open-angle glaucoma, and age-related macular degeneration, while emerging data also implicate possible benefits in dry eye disease, uveitis, retinal vascular disorders, inherited retinal degeneration, and cataract. Mechanistically, metformin may modulate multiple disease-relevant pathways, including AMPK-mTOR signaling, autophagy, mitochondrial homeostasis, NRF2-mediated antioxidant defense, NF-κB/PARP-related inflammation, VEGF-driven angiogenesis, TXNIP-associated neurodegeneration, and TGF-β-dependent fibrosis. However, current evidence remains insufficient to support metformin as an established ophthalmic therapy. Most clinical data are observational and susceptible to confounding by diabetes severity, comorbidities, treatment indication, and survival bias; randomized evidence is limited, and the METforMIN trial did not significantly slow geographic atrophy progression. In addition, many preclinical studies use concentrations exceeding clinically achievable systemic exposure, whereas ocular pharmacokinetics, tissue bioavailability, transporter dependence, and dose-toxicity relationships remain poorly defined. Signals of dose-dependent risk, including high-intensity exposure in diabetic retinopathy and stress responses in meibomian gland epithelial cells, further underscore the need for caution. Future studies should prioritize prospective ocular endpoints, measured intraocular drug concentrations, target-engagement biomarkers, transporter-informed delivery strategies, and rigorous dose-ranging safety assessments.