Abstract

BACKGROUND: Diabetes confers a greater risk of coronary heart disease (CHD) in women than in men, potentially due to women's antecedent of metabolic risk factors. We examined circulating metabolites and their associations with CHD risk in men and women across glycemic statuses. METHODS: We analyzed data from 97,271 CHD-free UK Biobank participants. Metabolomic profiling was performed by nuclear magnetic resonance (NMR) spectroscopy of baseline plasma samples. We used linear regression models to examine the association between sex and log-transformed metabolites in newly diagnosed type 2 diabetes (T2D), prediabetes, and euglycemia, adjusting for age, race/ethnicity, Townsend deprivation index, income, smoking, alcohol consumption, physical activity, body mass index, and medication use (for diabetes, lipid-lowering, and hypertension). Cox regression models were used to evaluate associations between metabolites and CHD risk (fatal or nonfatal myocardial infarction) stratified by sex and adjusted for the same covariates. We further considered menopausal status, and all analyses were adjusted for false discovery rate. The analyses were replicated in 6199 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with NMR data. RESULTS: With worsening glycemic status, women exhibited significantly higher atherogenic lipid/lipoprotein markers, fatty acids, and glycoprotein acetyls (GlycA) than men, as well as lower albumin and lactate (all P-values <.0001). Sex differences persisted regardless of menopausal status. In adjusted Cox regressions, 1 SD increase in triglyceride (TG), saturated fatty acids (SFA), and GlycA was associated with a greater risk of CHD in women with T2D than men over a 10-year follow-up (hazard ratios 1.2-1.5 in women and 0.9-1.04 in men, P-interaction <.05). CONCLUSIONS: With worsening glycemic status, women exhibit higher levels of atherogenic lipid and inflammatory markers. TG, GlycA, and SFA are more strongly associated with CHD risk in women with T2D than in men.