Beyond intraocular pressure: vascular and metabolic modifiers of optic nerve vulnerability in glaucoma.

purposeTo critically integrate epidemiological, mechanistic, and clinical evidence linking systemic blood pressure dysregulation and diabetes mellitus with glaucomatous optic nerve injury, while distinguishing biological plausibility and association from demonstrated causality.

methodsPubMed/MEDLINE was searched from database inception through 30 June 2026 using three prespecified blocks covering blood pressure exposures, diabetes and candidate antidiabetic therapies, and glaucoma subtypes. Backward citation tracking and targeted journal and publisher searches identified additional and recently published studies. Owing to clinical and methodological heterogeneity, evidence was synthesised as a structured narrative review.

resultsChronic hypertension may be associated with higher intraocular pressure, vascular remodelling, and impaired autoregulation, whereas systemic hypotension, nocturnal over-dipping, and blood pressure variability may reduce or destabilize ocular perfusion. Diabetes has plausible microvascular, metabolic, and neurodegenerative effects, but epidemiological findings are inconsistent and glycated haemoglobin does not consistently predict glaucoma progression. Evidence is strongest for primary open-angle and normal-tension glaucoma. Findings concerning metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors remain predominantly observational, genetic, translational, or preclinical.

conclusionSystemic vascular and metabolic factors may modify optic nerve susceptibility but are not established independent causes or treatment targets. Intraocular pressure lowering remains the therapeutic cornerstone, and prospective glaucoma-specific intervention studies are needed before systemic treatment recommendations can be made.