Integrating menopause duration and plasma metabolomics enhances cardiovascular risk stratification in aging women

Menopause-related metabolic remodeling may contribute to the excess cardiovascular disease (CVD) burden in aging women, yet the longitudinal metabolic correlates of time since menopause (TSM) and their prognostic value are unclear. In this prospective analysis of 67,582 postmenopausal women without baseline CVD from the UK Biobank, we profiled 251 plasma metabolites by nuclear magnetic resonance and followed participants for a median 13.7 years (8313 incident CVD events). Elastic net regression identified a 95‑metabolite TSM-associated metabolomic signature (Spearman r with TSM = 0.29). In multivariable Cox models, each 5-year increment in TSM (HR 1.14, 95% CI 1.11-1.16) and each 1-standard deviation increases in the metabolomic signature (HR 1.18, 95% CI 1.15-1.21) were independently associated with higher composite CVD risk, with consistent associations across myocardial infarction, ischemic heart disease, atrial fibrillation, heart failure and stroke. Mendelian randomization supported potential causal roles for 29 of the signature metabolites in CVD. Adding TSM or the metabolomic signature to SCORE2 improved 10‑year risk discrimination (area under the curve 0.584 to 0.657 and 0.660, respectively) and reclassification (net reclassification improvement +0.027 and +1.043). These findings implicate cumulative postmenopausal metabolic alterations in vascular risk and support metabolomic enhancement of risk stratification in postmenopausal women.