Cardiovascular‐Kidney‐Metabolic Syndrome, Healthy Lifestyles, and Risk of Cancer Incidence and Mortality: A Prospective Cohort Study

ABSTRACT Cardiovascular‐kidney‐metabolic (CKM) syndrome has been proposed, yet its utility for cancer risk stratification and behavior modification remains unclear. The study included 227,330 cancer‐free participants from UK Biobank. CKM stages were defined using the American Heart Association (AHA) criteria, and lifestyle factors included smoking, alcohol consumption, physical activity, and diet. The hazard ratios (HRs) and lifetime risks of cancer were estimated using the Cox model and Fine and Gray's model, respectively. During a median follow‐up of 11.46–13.65 years, 24,916 cancer cases and 7791 deaths were identified. Risks of cancer incidence and mortality increased progressively with advancing CKM stages ( P trend < 0.001), with HRs (95% CIs) of 1.23 (1.15–1.30), and 1.58 (1.41–1.78) for stage 4. Compared with participants with unfavorable lifestyle, those with favorable lifestyle were associated with decreased risks across stages 0–4, with risk reductions of 14%–24% for cancer incidence, and 22%–40% for cancer mortality. Joint analyses showed that the increased cancer risks associated with CKM stages were eliminated or attenuated by adopting favorable lifestyle, particularly in stages 1–2. Participants in stage 4/unfavorable lifestyle had the highest risks of cancer incidence and mortality, with HRs (95% CI) of 1.54 (1.39–1.70) and 2.43 (1.97–2.99), and cumulative risks by age 80 of 34.77% and 11.65%, respectively. Furthermore, CKM stage 4/unfavorable lifestyle was associated with higher incidence of breast, colorectal, lung, kidney, pancreas, bladder, head and neck, esophagus, and liver cancers. These findings support the potential utility of CKM stages for cancer risk stratification and highlight the importance of lifestyle intervention.