Abstract
Cardiometabolic multimorbidity (CMM), defined as the co-occurrence of two or more of the following: diabetes, ischemic heart disease, stroke, and other cardiovascular diseases, is a leading cause of global mortality. Although vitamins and fatty acid are known to influence cardiometabolic diseases through lipid metabolism, the mediating role of lipid metabolites in linking dietary vitamins and fatty acid intake to CMM remains unclear. We conducted a case-control study based on the Ningxia cohort, including 200 patients with CMM and 200 age- and sex-matched controls. Dietary intake was assessed using a semi-quantitative food frequency questionnaire, and plasma lipid profiles were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. We assessed associations between dietary nutrients and CMM using logistic regression and their relationships with lipid metabolites via Pearson correlation. Mediation analysis identified lipid metabolites that link vitamin and fatty acid intake to CMM, and these mediators were incorporated into a predictive model. We found that higher intake of vitamin E (VE), total fatty acids (FA), polyunsaturated fatty acids (PUFA), and monounsaturated fatty acids (MUFA) was significantly associated with lower CMM risk (OR < 1, FDR ≤ 0.05). Lipid profiling identified 349 differentially abundant metabolites, primarily triglycerides and diglycerides, elevated in CMM patients. Mediation analysis revealed 292 significant pathways: dietary intake VE and PUFA was linked to lower CMM risk via modulation of glycerolipid metabolites, while dietary intake FA and MUFA was linked to lower risk through regulation of glycerophospholipids. A predictive model incorporating age, sex, dietary factors, and key mediating lipids achieved good discrimination (AUC: 0.765-0.812). These findings suggest that dietary intake of VE, FA, PUFA, and MUFA is associated with reduced CMM risk through modulation of plasma lipid metabolism, with specific lipid metabolites potentially acting as key mediators.