BACKGROUND: The value of metabolomic biomarkers for cardiovascular risk prediction is unclear. This study aimed to evaluate the potential of improved prediction of the 10-year risk of major adverse cardiovascular events (MACE) in large population-based cohorts by adding metabolomic biomarkers to the novel SCORE2 model, which was introduced in 2021 for the European population without previous cardiovascular disease or diabetes. METHODS: Data from 187,039 and 5,578 participants from the UK Biobank (UKB) and the German ESTHER cohort, respectively, were used for model derivation, internal and external validation. A total of 249 metabolites were measured with nuclear magnetic resonance (NMR) spectroscopy. LASSO regression with bootstrapping was used to identify metabolites in sex-specific analyses and the predictive performance of metabolites added to the SCORE2 model was primarily evaluated with Harrell's C-index. RESULTS: Thirteen metabolomic biomarkers were selected by LASSO regression for enhanced MACE risk prediction (three for both sexes, six male- and four female-specific metabolites) in the UKB derivation set. In internal validation with the UKB, adding the selected metabolites to the SCORE2 model increased the C-index statistically significantly (P<0.001) from 0.691 to 0.710. In external validation with ESTHER, the C-index increase was similar (from 0.673 to 0.688, P=0.042). The inflammation biomarker, glycoprotein acetyls, contributed the most to the increased C-index in both men and women. CONCLUSIONS: The integration of metabolomic biomarkers into the SCORE2 model markedly improves the prediction of 10-year cardiovascular risk. With recent advancements in reducing costs and standardizing processes, NMR metabolomics holds considerable promise for implementation in clinical practice.

The authors have declared no competing interest.

Not applicable.

The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland state ministry for Social Affairs, Health, Women and Family Affairs (Saarbrücken, Germany). UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish government, and Northwest Regional Development Agency. It has also had funding from the Welsh assembly government and the British Heart Foundation. The sponsors had no role in data acquisition or the decision to publish the data.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The UKB received ethical approval from the North-West Multicentre Research Ethics Committee (REC reference: 11/NW/03820). The ESTHER study was approved by the Ethics Committee of the Medical Faculty of the University of Heidelberg (Application number: S-58/2000). Both UKB and ESTHER study are conducted in accordance with the 1964 Helsinki declaration and its later amendments. All study participants of UKB and ESTHER study gave written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data from ESTHER is available upon reasonable request that is compatible with participants informed consent. Data from the UK Biobank (https://www.ukbiobank.ac.uk/) is available to bona fide researchers on application.