Phenotypic Heterogeneity in Glaucoma: The Systemic and Vascular Landscape Behind Functional Loss

Objective To analyze the direct and indirect associations between structural, functional, and systemic variables in patients with primary open‐angle glaucoma (POAG), normal‐tension glaucoma (NTG), and controls using structural equation modeling (SEM). Methods A cross‐sectional observational study was conducted including 156 participants: 55 with POAG, 49 with NTG, and 52 age‐ and sex‐matched controls. Clinical variables included intraocular pressure (IOP), central corneal thickness (CCT), vertical cup‐to‐disc ratio (VCDR), and visual‐field mean deviation (MD). Systemic variables comprised age and cardiovascular risk factors (hypertension, diabetes, and dyslipidemia). SEM was applied to assess direct and indirect effects on the diagnosis of glaucoma. Results The model showed a good overall fit ( χ 2 (9) = 15.968; p = 0.068; χ 2 /df = 1.774; CFI = 0.972; RMSEA = 0.071) and explained 46.0% of the variance in glaucoma diagnosis ( R 2 = 0.460). The most influential predictors were VCDR ( β = 0.40), age ( β = 0.14), and cardiovascular risk factors ( β = 0.19). A significant negative correlation was observed between CCT and MD ( r = –0.29), indicating greater functional damage in eyes with thinner corneas. An inverse association between cardiovascular risk burden and IOP was also identified ( r = –0.18). Conclusions Our findings support the hypothesis of distinct glaucomatous phenotypes, including a vascular subtype with lower IOP and altered perfusion, potentially influenced by systemic comorbidities and chronic treatments. Reduced CCT was also confirmed as an independent marker of advanced functional loss. SEM helps disentangle complex mechanisms and may inform personalized therapeutic strategies, particularly in NTG.