Sex Differences in Metabolomics and Risk of Coronary Heart Disease in Type 2 Diabetes

BackgroundWomen with type 2 diabetes (T2D) have a 50% excess risk of coronary heart disease (CHD) than men with T2D. We compared circulating metabolites and their associations with CHD in men and women across glycemic status. MethodsWe used metabolomic data (lipoproteins, fatty acids, amino acids, glycolysis, ketones, inflammation, and fluid balance) for 87,326 CHD-free UK Biobank participants. We used linear regressions to examine the association of sex and metabolites (log) in newly diagnosed T2D (diagnosis<2 yrs from baseline), prediabetes (A1c 5.7-6.5%), and euglycemia, accounting for age, race, Deprivation Index, income, smoking, alcohol drinking, obesity, physical activity, medications for hypertension, hyperlipidemia, and diabetes. We used Cox models to evaluate the association of metabolites and CHD risk by sex, adjusting the same covariates and menopausal status (women). All analyses were FDR-adjusted. FindingsWe included 1250 individuals with new T2D, 12,706 with prediabetes, and 83,315 with euglycemia. In adjusted linear regressions, women showed a progressive increase in atherogenic lipid and lipoprotein markers and inflammatory marker, glycoprotein acetyls, compared to men as their glycemic status advanced. However, women had lower levels of albumin during this transition. Menopausal status did not alter these sex differences. In a 10-year follow-up, an SD higher total TG, TG in VLDL, LDL, and HDL, saturated fatty acids (SFA) were positively associated with a higher risk of CHD in women with T2D but not in men (p-interactions 0.03-0.15). InterpretationWith advancing glycemic status, women exhibited higher levels of atherogenic lipids and lipoproteins, as well as inflammatory markers, but lower circulating albumin. Women with T2D appear to be at a higher risk of CHD associated with TG, VLDL-TG, LDL-TG, and HDL-TG, and SFA than men with T2D.