Transition‐Specific Associations of Cardiometabolic Biomarker Burden With Cardio‐Renal‐Metabolic Multimorbidity Progression: A Multistate Cohort Study

AIMS: To identify representative cardiometabolic biomarkers and examine how individual biomarkers and combined biomarker burden are associated with transition-specific progression of cardio-renal-metabolic multimorbidity (CRMM). METHODS: This prospective cohort study included 262 464 UK Biobank participants free of cardiovascular disease (CVD), type 2 diabetes (T2D) and chronic kidney disease (CKD) at baseline. Forty-nine candidate biomarkers across five domains, including inflammation, insulin resistance, dyslipidemia, adiposity and blood pressure, were evaluated using time-dependent area under the curve and concordance index to select representative markers. Multistate models estimated associations of individual biomarkers, elevated-marker count and a weighted 5-Item Cardiometabolic Risk Score (5-CMRS) with sequential transitions from baseline to first cardio-renal-metabolic disease (FCRMD), FCRMD to Double CRMD and Double to Triple CRMD. RESULTS: During a median follow-up of 15.62 years, 44 339 participants developed FCRMD, 7218 progressed to Double CRMD and 721 progressed to Triple CRMD. Five representative biomarkers were selected: C-reactive protein-to-albumin ratio, metabolic score for insulin resistance (METS-IR), triglyceride-to-HDL cholesterol ratio, waist-to-height ratio and systolic blood pressure. Higher elevated-marker count showed graded associations across all transitions. Compared with the lowest 5-CMRS category, the highest category was associated with hazard ratios of 2.80, 1.84 and 1.71 for the three sequential transitions. Disease-specific analyses showed the strongest associations with incident T2D. METS-IR showed the largest relative contributions across all transitions, whereas additive interactions were mainly observed during early CRMM progression. CONCLUSION: Combined cardiometabolic biomarker burden was associated with graded, transition-specific risks across CRMM progression, supporting integrated cardiometabolic risk assessment across inflammatory, metabolic, adiposity, lipid and blood-pressure domains.