Abstract
BACKGROUND: We aim to discover whether HbA1c affects incident cardiovascular disease (CVD) through regulating endogenous metabolites. METHODS AND RESULTS: Totally, 2019 plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Logistic regression and linear regression were used to screen metabolites which were associated with both CVD and HbA1c. The VanderWeele's mediation approach was performed to assess the direct effect and indirect effect (IE) in the counterfactual model. Forty-eight metabolites showed an association with both HbA1c and CVD risk. Forty-four of the 48 metabolites worked as mediators mediated in HbA1c's effect on CVD (odds ratio [OR](IE) from 0.997 to 6.098, false discovery rate q < 0.05, mediated proportion from 0.4% to 85.4%). Pathway enrichment analysis indicated that different metabolic pathway showed significant IE (butanoate metabolism OR(IE) = 1.058, mediated proportion = 16.0%; alanine, aspartate and glutamate metabolism OR(IE) = 1.082, mediated proportion = 21.8%; TCA (citric acid) cycle metabolism OR(IE) = 1.048, mediated proportion = 13.8%; phenylalanine metabolism OR(IE) = 1.067, mediated proportion = 18.4%; glycerophospholipid metabolism OR(IE) = 3.007, mediated proportion = 82.2%; all the P < .01). CONCLUSIONS: Our findings suggest that metabolites mediate the effect of HbA1c on incident CVD and provide a new study sight into pathogenesis of CVD.