Abstract/Summary

Current cardiometabolic disease prevention guidelines recommend increasing dietary unsaturated fat intake while reducing saturated fats. However, standard cardiometabolic risk markers may not fully capture the metabolic benefits. Here, we use deep lipidomics data from a randomized controlled dietary intervention trial to construct a multi-lipid score (MLS), summarizing the significant effects (FDR<.05) of replacing saturated fat with unsaturated fat on forty-five lipid metabolite concentrations. In the EPIC-Potsdam study, the intervention diet related difference in this MLS is associated with a significant reduction in the incidence of cardiovascular disease (-32%; 95%CI, -21% to -42%) and type 2 diabetes (-26%; 95%CI, -15% to -35%). We built a closely correlated simplified score (rMLS) and replicated diet and disease associations in the Nurses’ Health Study, observing that beneficial 10-year rMLS changes are associated with lower diabetes risk (OR per SD 0.76; 95%CI, 0.59 to 0.98). Furthermore, we detected significant effect modification in the PREDIMED primary prevention trial. An olive oil-rich Mediterranean diet intervention primarily reduced diabetes incidence among participants with unfavorable pre-intervention rMLS levels. Our findings contribute to a more precise understanding of the health outcomes of specific dietary fat quality modifications and highlight the potential of lipidomics-based scores for biomarker-guided precision nutrition