Background: Recently, the American Heart Association introduced the concept of the cardiovascular-kidney-metabolic (CKM) syndrome. Although previous studies have established its value in stratifying overall mortality risk, its association with cancer risk, and the impact of healthy lifestyle remain unclear.
Objective: This study aimed to explore the associations of CKM stages with cancer incidence and mortality, assess the associations of healthy lifestyle with cancer risk across different CKM stages, and further evaluate their combined effects.
Methods: The study included 227,330 cancer-free participants from UK Biobank. CKM stages were defined using the American Heart Association criteria. Lifestyle factors included smoking, alcohol consumption, physical activity, and diet. A healthy lifestyle score was categorized as unfavorable (0-1), intermediate (2), and favorable (3-4). The hazard ratios (HRs) and lifetime risks of cancer were estimated by Cox model and Fine and Gray’s model, respectively.
Results: During a median follow-up of 11.46 years for cancer incidence and 13.65 years for mortality, 24,916 cancer cases and 7791 deaths were identified. Risks of cancer incidence and mortality increased progressively with advancing CKM stages (Ptrend <0.001). Compared with participants at CKM stage 0, the multivariate-adjusted HRs (95 % CIs) of incident cancer were 1.08 (1.02-1.15), 1.05 (1.00-1.10), 1.21 (1.14-1.28), and 1.23 (1.15-1.30) for stages 1 to 4. For cancer mortality, the corresponding HRs (95% CIs) were 1.12 (0.98-1.27), 1.21 (1.09-1.33), 1.47 (1.32-1.64), and 1.58 (1.41-1.78) for stages 1 to 4, respectively. The cumulative risks of cancer incidence by age 80 years for CKM stages 0-4 were 26.95%, 28.93%, 27.86%, 33.26%, and 32.48%, respectively, while the corresponding risks for cancer mortality were 5.94%, 6.77%, 7.23%, 9.07%, and 10.02% across stages 0-4. Favorable lifestyle was associated with decreased risks across stages 0-4. For cancer incidence, the HRs (95% CIs) of favorable vs. unfavorable lifestyle were 0.83 (0.74-0.93), 0.86 (0.76-0.96), 0.83 (0.79-0.88), 0.80 (0.75-0.85), and 0.76 (0.69-0.83) for CKM stages 0 to 4. For cancer mortality, the corresponding HRs (95% CIs) were 0.62 (0.49-0.79), 0.60 (0.46-0.77), 0.78 (0.70-0.86), 0.64 (0.58-0.72), and 0.63 (0.54-0.74) for stages 0 to 4, respectively. 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 group had the highest risks of cancer incidence and mortality, with HRs (95% CIs) of 1.54 (1.39-1.70) and 2.43 (1.97-2.99). The cumulative risks of cancer by age 80 years were also notably higher in the stage 4/unfavorable lifestyle group (incidence: 34.77%; mortality: 11.65%). 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.
Conclusions: Higher CKM stages were associated with increased risks of cancer incidence and mortality in a graded manner. Adherence to favorable lifestyle was associated with decreased cancer risks across all CKM stages and attenuated the detrimental effects of CKM syndrome. These findings support the potential utility of CKM stages for cancer risk stratification and highlight the importance of lifestyle intervention.
 

Joint associations of CKM syndrome stages and healthy lifestyle score on the cancer incidence and mortality.