MetaboHealth and Metabolic Vulnerability Index as Risk Factors for Cardio–Renal–Metabolic Multimorbidity: A Large‐Scale Prospective Cohort Study

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BACKGROUND: Cardio-renal-metabolic (CRM) multimorbidity is an increasing public health challenge in aging populations. Metabolomics-based composite scores may capture dimensions of systemic metabolic burden that are not fully reflected by conventional risk factors. METHODS: This population-based cohort study included UK Biobank participants with available metabolomics data. Cross-sectional analyses among 269 530 participants examined associations of the Metabolic Vulnerability Index (MVX) and the MetaboHealth score with baseline CRM disease status. Among 240 576 participants free of any CRM component disease at baseline, Cox and Fine-Grey models were used to assess incident CRM multimorbidity. Mutual adjustment, joint stratification and apparent 10-year prediction performance analyses were further performed. Multistate models were used to evaluate sequential CRM transition pathways. RESULTS: In cross-sectional analyses, the MetaboHealth score, but not MVX, was associated with prevalent CRM multimorbidity after full adjustment. During follow-up, 8876 participants developed CRM multimorbidity. In fully adjusted Cox models, each 1-SD increment in MVX and the MetaboHealth score was associated with a higher risk of incident CRM multimorbidity, with HRs of 1.213 (95% CI 1.186-1.241, p < 0.001) and 1.503 (95% CI 1.469-1.538, p < 0.001), respectively. Fine-Grey competing risk models and multiple sensitivity analyses yielded broadly consistent findings. The association for MVX was attenuated after mutual adjustment, whereas the MetaboHealth score remained associated with incident CRM multimorbidity and showed greater incremental improvement in apparent 10-year prediction performance. In multistate models, both scores were associated with transitions from a disease-free state to a first CRM component disease, direct transition to CRM multimorbidity and subsequent progression from a first CRM component disease to CRM multimorbidity. CONCLUSIONS: MVX and the MetaboHealth score were associated with incident CRM multimorbidity and CRM disease progression, with more consistent findings observed for the MetaboHealth score.

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