Joint association of estimated glucose disposal rate and physical activity with cardiovascular disease incidence in patients with cardiovascular-kidney-metabolic syndrome stages 0–3: a nationwide prospective cohort study based on the CHARLS database

Cardiovascular-kidney-metabolic (CKM) syndrome is a new concept proposed by the American Heart Association (AHA) that emphasizes the complex relationship between kidney disease, heart disease and metabolic factors. Many studies have shown that insulin resistance (IR) in CKM syndrome stages 0–3 is associated with the occurrence of cardiovascular disease (CVD); however, the impact of physical exercise on this process remains unclear. We included 3,050 participants with CKM syndrome stages 0–3 from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative prospective cohort, using data from the 2011 baseline survey and follow-up through 2020. The primary outcome was the incidence of CVD. Estimated glucose disposal rate (eGDR) was used as an evaluation index for IR, and metabolic equivalents (MET) score was used as an evaluation index for physical activity (PA). Cox regression analysis, restricted cubic spline (RCS) curve, Kaplan-Meier (K-M) survival curve, interaction and subgroup analyses were used to comprehensively evaluate the association between IR and PA with the incidence of CVD. Exploratory mediation analysis was performed to evaluate whether insulin resistance mediated the association between physical activity and CVD. During 2011–2020, 718 (23.54%) individuals developed CVD. Low eGDR and low MET scores were independently associated with higher incidence of CVD. In model 3, the hazard ratio (HR) of the high eGDR group was 0.61 (95% confidence interval [CI] 0.52–0.72), and the HR of the high PA group was 0.81 (95% CI 0.69–0.95). Compared with individuals with low eGDR and low PA levels, individuals with high eGDR and high PA levels showed a significantly lower incidence of CVD, with a HR of 0.52 (95% CI 0.42–0.65). The RCS curves showed a negative linear correlation with CVD, and no statistically significant additive or multiplicative interaction was observed between eGDR and PA. The mediation analysis revealed that eGDR significantly mediated the association between PA and CVD, accounting for 12.72% of the total effect ( P = 0.008). In participants with CKM syndrome stages 0–3, eGDR and PA demonstrated independent and additive protective associations with the occurrence of CVD. Insulin resistance may mediate the association between physical activity and CVD, highlighting the potential importance of physical activity in reducing CVD risk.