J Clin Lipidol. 2026 Aug 14:S1933-2874(26)00452-6. doi: 10.1016/j.jacl.2026.07.022. Online ahead of print.
ABSTRACT
BACKGROUND: Cardiovascular risk factors accelerate around the final menstrual period (FMP), yet no operational method separates expected physiology from risk-relevant divergence, and age-weighted calculators may under-recognise midlife women.
OBJECTIVE: To define the expected physiological envelope of menopausal lipid remodelling, distinguish it from risk-relevant divergence, and test whether sex-neutral guideline cutpoints correctly represent female absolute risk against incident major adverse cardiovascular events (MACE).
METHODS: We analysed 273,036 UK Biobank women (63,939 premenopausal; 165,276 postmenopausal; status self-reported) with nuclear magnetic resonance metabolomics (n=222,487), cardiac magnetic resonance imaging (n=42,033), an age-matched male reference (n=228,900) and incident MACE follow-up (224,256 women, 16,961 events; Cox subcohort 151,812, 11,237 events). Analyses integrated FMP-anchored trajectories, male-matched classification, treatment-adjusted change, oestradiol mediation, Mendelian randomisation (MR), low-density lipoprotein receptor (LDLR) stratification and cutpoint calibration.
RESULTS: Postmenopausal women had higher LDL-C (+15.3%), ApoB (+13.5%), non-HDL-C (+16.8%) and triglycerides (+29.9%); treatment adjustment raised LDL-C and ApoB to +19.8% and +17.5%. Male-matching classified ApoB, LDL-C and remnants as menopause-linked. LDL-C and ApoB accelerated around the FMP (breakpoints 4.32 and 4.48 years); oestradiol mediated 61.5% of the LDL-C difference. MR supported LDL-C causality (HR 1.196 [1.018-1.374]) with a null menopause interaction; LDLR carriers started higher but did not rise faster (+11.5% vs +15.3%). ApoB tracked ischaemic heart disease (HR 1.125 [1.104-1.146]) but not heart failure. At age 58, ApoB ≥1.2 g/L conferred 10.88% versus 4.34% 10-year MACE risk in men versus postmenopausal women; sex-neutral models over-predicted women.
CONCLUSION: Menopausal lipid remodeling comprises an expected physiological envelope and a risk-relevant, ApoB-rich divergence predicting ischaemic heart disease. Because static sex-neutral cutpoints misestimate female risk, transition-era prevention needs sex-specific absolute-risk interpretation; monitoring bands are hypothesis-generating, requiring prospective validation.
PMID:42859115 | DOI:10.1016/j.jacl.2026.07.022