Cardiovascular-kidney-metabolic syndrome modifies smoking-related risk for cardiovascular diseases: findings from an observational cohort study in UK Biobank

Background The present study aims to investigate the association of smoking behaviors and cardiovascular-kidney-metabolic (CKM) syndrome with incident cardiovascular disease (CVD), and to evaluate whether the cardiovascular benefits of smoking cessation vary across different CKM conditions. Methods This study included 242,636 white European participants from the UK Biobank who were classified as CKM syndrome Stages 0 to 3 and free of CVD at baseline. Covariates adjusted Cox proportional hazards models were employed to evaluate the associations of CKM syndrome with the risks of total CVD, stroke, coronary heart disease (CHD), major adverse cardiovascular events (MACE), and 13 CVD subtypes. The impact of smoking behavior across different CKM stages and the joint effect of smoking and CKM syndrome on CVD risk were also evaluated. To investigate the potential effect modification by CKM syndrome, we examined the multiplicative scale by interaction terms in Cox models, and quantified the additive scale using statistics such as the relative excess risk due to interaction (RERI). Results The risk of total CVD, stroke, and CHD increased progressively with advancing CKM stages, with Stage 3 associated with hazard ratios (HRs) of 3.38 (95% CI: 3.05-3.74), 3.01 (2.49-3.64), and 3.65 (3.25-4.10), respectively (P for trend < 0.001). The time required to reduce CVD risk to a level not significantly different from that of never smokers tends to be longer for individuals with advancing CKM stage: smokers at Stages 0-1 achieved this after approximately 10 years of cessation, whereas those at Stages 2-3 required more than 25 years. Compared with never smokers at CKM Stage 0, current smokers at CKM Stage 3 had substantially higher risk of total CVD (HR = 4.14, 95% CI: 3.54-4.83) and several subtypes, particularly abdominal aortic aneurysm (HR = 17.68, 95% CI: 6.33-49.43) and peripheral vascular disease (HR = 10.53, 95% CI: 6.79-16.34). CKM syndrome appeared to act as a positive additive effect modifier in smoking-related risk of total CVD (RERI = 0.20, 95% CI: 0.05-0.32), as well as several CVD subtypes, suggesting that the combined effect of smoking and CKM progression exceeds the sum of their individual effects. Conclusions Our finding emphasizes the importance of smoking cessation among individuals with advanced CKM syndrome, as they face heightened CVD risk. However, compared to those at earlier CKM stages, the short-term benefits of smoking cessation may be less pronounced in this population. Interventions that combine smoking cessation promotion with CKM syndrome management may yield greater reductions in the risk of several CVD outcomes.