Abstract Multidimensional metabolic dysregulation is implicated in hypertension development, but the utility of comprehensive metabolic vulnerability indices for assessing hypertension risk associations remains unclear. This prospective cohort study analyzed 150,591 participants from the UK Biobank. The Metabolic Vulnerability Index and its components—IVX and MMX—were calculated from six metabolites (GlycA, small HDL particles, leucine, valine, isoleucine, and citrate) measured by NMR spectroscopy. Cox proportional hazards models assessed associations with incident hypertension, adjusting for demographic, lifestyle, and clinical factors. Restricted cubic spline analyses examined dose-response relationships, and subgroup analyses explored effect modifications by polygenic risk score (PRS), BMI, and C-reactive protein levels. During follow-up, 32,198 participants developed hypertension. After comprehensive adjustment, IVX and MVX showed significant positive associations with hypertension risk (highest vs lowest quartile: HR=1.25 95%CI: 1.20-1.31 and HR=1.19 95%CI: 1.15-1.24, respectively P <0.001). Each standard deviation increase in IVX and MVX was associated with 9% and 7% higher hypertension risk, respectively. Conversely, MMX demonstrated a slight protective effect (HR=0.96 95%CI: 0.92-0.99, P =0.016) and exhibited a U-shaped relationship with hypertension risk. Notably, associations between IVX/MVX and hypertension were significantly stronger in non-obese individuals (BMI<30) compared to obese participants (BMI≥30) (p-interaction<0.001 and P =0.007, respectively). Results remained robust in sensitivity analyses excluding extreme values and early hypertension cases. Metabolic vulnerability, particularly its inflammatory component, is independently associated with hypertension risk beyond traditional risk factors. These findings highlight the potential utility of comprehensive metabolomic profiling for early identification of individuals at elevated hypertension risk.
Ding et al. (2026) studied this question.