Association Between Cardiovascular-Kidney-Metabolic Syndrome and Cancer Development: Insights From a Nationwide Database Study in Japan

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome is a recently proposed framework emphasizing the interconnected nature of cardiovascular, kidney, and metabolic disorders. These conditions share risk factors with cancer, but the relationship between CKM stage and cancer risk remains unclear. We aimed to investigate a longitudinal association in a large-scale, nationwide population. METHODS: We conducted a retrospective cohort study using the DeSC administrative claims database in Japan, including individuals who had available health checkup data and insurance claims between April 2014 and August 2023. After excluding those with prior cancer or missing covariates, 1 390 901 participants were analyzed. Baseline CKM stage (0–4) was defined according to the 2023 American Heart Association statement, incorporating cardiometabolic risk, chronic kidney disease, and atherosclerotic cardiovascular disease. The primary outcome was incident cancer ( International Classification of Diseases, Tenth Revision codes C00–C97). Cox proportional hazards models were used to estimate hazard ratios and 95% CIs, adjusting for demographic, clinical, and lifestyle factors. Subgroup and sensitivity analyses were also performed. RESULTS: Over a median follow-up of 3.4 years, higher baseline CKM stages were associated with increased cancer risk. Adjusted hazard ratios (95% CIs) for cancer were 1.03 (0.99–1.08), 1.02 (0.99–1.05), 1.25 (1.21–1.29), and 1.30 (1.25–1.35) for CKM Stages 1–4, respectively, compared with Stage 0. The stage-specific association was consistent across cancer types and in analyses stratified by age and sex, with similar patterns observed across subgroups. Sensitivity analyses using alternative CKM definitions supported the robustness of the findings. CONCLUSIONS: Advancing baseline CKM stage, particularly Stages 3 and 4, was associated with increased cancer risk. These findings extend the clinical relevance of the CKM framework beyond cardiovascular and kidney outcomes, underscoring the need for integrated risk assessment and prevention in multimorbid individuals.