Oxidative balance-related metabolite signature and incident cardiovascular disease and type 2 diabetes within the PREDIMED trial

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AIM: Despite growing evidence linking better oxidative balance to improved cardiometabolic health, metabolite signatures reflecting oxidative status remain still poorly characterized. We aimed to identify a plasma metabolite signature of the oxidative balance score (OBS) and to examine its association with incident cardiovascular disease (CVD) and type 2 diabetes (T2D). METHODS: The discovery population included 1732 participants at high cardiovascular risk from the PREDIMED study with available plasma metabolomics using LC-MS and OBS data at baseline. The OBS was calculated at baseline and after 1-year of follow-up based on 12 a priori selected pro- and antioxidant dietary and non-dietary lifestyle factors, with higher scores indicating a more favorable antioxidant balance. A set of metabolites predicting OBS was selected from 388 candidate metabolites using elastic net regression. Multivariable Cox models were used to examine the associations between the OBS metabolite signature and incident CVD and T2D. RESULTS: A subset of 21 metabolites was consistently selected (amino acids, vitamins, nucleotides, lipid species, xenobiotics, and others). The metabolite signature was inversely associated with incident CVD in the baseline sample (HR per SD 0.70; 95% CI 0.61-0.81), but not in the 1-year sample (HR 0.94; 95% CI 0.81-1.09). In addition, baseline (HR 0.70; 95% CI 0.60-0.80) and 1-year (HR 0.84; 95% CI 0.72-0.97) OBS metabolite signatures were inversely associated with T2D risk. CONCLUSIONS: A plasma metabolite signature reflecting oxidative balance-related exposures was inversely associated with CVD and T2D risk at baseline. The association with T2D was also observed when the signature was applied to 1-year measurements and in an independent external cohort, whereas the association with CVD was not replicated at 1 year. Most metabolites showed biologically plausible patterns, correlating with specific pro- and antioxidant exposures and including metabolites previously implicated in oxidative stress-related processes. CLINICAL TRIAL REGISTRATION: This trial was registered at controlled-trials.com as ISRCTN35739639.

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