Risk of cardiovascular disease and all-cause mortality based on cardiovascular-kidney-metabolic syndrome in the community

Abstract Introduction Cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes mellitus frequently coexist and exert synergistic effects on morbidity and mortality. To capture this interconnection, the American Heart Association recently introduced the cardiovascular-kidney-metabolic (CKM) syndrome. Purpose To investigate the longitudinal association between CKM stages and the risk of incident CVD, atherosclerotic CVD (ASCVD), and all-cause mortality (ACM) in the general population, and to assess whether these associations differ by sex. Methods We analyzed data from 5,752 adults enrolled in a population-based cohort study and classified participants into CKM stages 0–4 at baseline. Stage 0, no CKM risk factors; Stage 1, excess/dysfunctional adiposity; Stage 2, metabolic risk factors and/or moderate- to high-risk CKD; Stage 3, very high-predicted CVD risk per SCORE2 or very high-risk CKD; and Stage 4, clinical CVD. We applied Cox regression to incident outcomes, and evaluated model performance using discrimination (AUC) and calibration. Results Among 5,752 participants (53.2% women; mean age: women 53.1 ± 10.7, men 52.3 ± 10.7 years), 580 CVD events, 381 ASCVD events, and 723 deaths occurred over 14.3 years of follow-up. CKM stage distribution differed substantially between sexes. In men, CKM stages 0, 1, 2, 3, and 4 were observed in 9.9%, 13.3%, 62.6%, 9.4%, and 4.8%, respectively. In women the corresponding proportions were 26.1%, 13.7%, 56.8%, 1.7%, and 1.7%. Compared with stage 0, stages 2 and 3 were incrementally associated with higher odds of CVD (HR 1.69 95% CI, 1.20–2.37 and 3.21 2.16–4.23, respectively) and ASCVD (1.57 1.04–2.33 and 2.81 1.72–4.38, respectively). Compared with stage 0, stages 2, 3 and 4 were also associated with a high risk of ACM with HR of 1.51 (1.09–2.09), 1.78 (1.21–2.61), and 2.11 (1.40–3.17), respectively. Sex-specific analyses showed stronger associations in men, particularly at stage 3 (CVD, HR 5.16 95% CI, 2.61–10.19; ASCVD, HR 3.82 95% CI, 1.76–8.27). In women, stage 3 was associated with ACM (HR 3.43 95% CI, 1.92–6.10). CKM stages demonstrated good discrimination for all outcomes, with AUCs ranging from 0.71 to 0.82. Conclusion In this population-based cohort, higher CKM stages (2 to 4) were strongly associated with CVD, ASCVD, and ACM, with increased risks of CVD and ASCVD in men and of ACM in women, particularly at stage 3. Implementation of CKM in clinical practice has the potential to improve early identification of high-risk individuals in the general population.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.