Long-term MCMI exposure patterns, CVD risk, and mediating pathways in CKM stage 0–3 patients: a nationwide prospective cohort study

The modified cardiometabolic index (MCMI) is a novel surrogate marker of insulin resistance, but the association between long-term MCMI exposure patterns and cardiovascular disease (CVD) risk in patients with early-stage cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. Moreover, the mediating pathways underlying this association have not been quantified. This nationwide prospective cohort study included 3,363 participants aged ≥ 45 years with CKM stages 0–3 from the China Health and Retirement Longitudinal Study (CHARLS). MCMI was calculated using measurements from 2011 to 2015. Unsupervised K-means clustering was performed to identify long-term MCMI exposure patterns. The primary outcome was incident CVD (including heart disease and stroke) through 2020. Logistic regression and Cox proportional hazards regression models were used to evaluate the association between MCMI exposure patterns and CVD risk. Mediation analysis with 1,000 Bootstrap resamples was conducted to quantify the mediating effects of obesity-related indicators, lipid profiles, and inflammatory markers. Three distinct long-term MCMI exposure patterns were identified: persistent low-exposure (37.3%), persistent moderate-exposure (42.8%), and persistent high-exposure (19.9%). After full adjustment for sociodemographic, lifestyle, and clinical confounders, the persistent moderate-exposure group retained a significant direct association with increased CVD risk (OR = 1.26, 95% CI: 1.03–1.56, P = 0.028; HR = 1.23, 95% CI: 1.03–1.47, P = 0.024) even after accounting for downstream mediators. Kaplan-Meier survival analysis demonstrated significantly lower CVD-free survival with higher MCMI exposure levels (log-rank P < 0.001). Mediation analysis revealed that obesity (BMI: 41.26%) accounted for the largest mediating proportion, followed by atherogenic dyslipidemia (LDL-C: 9.97%) and an inflammatory marker (white blood cell count: 4.72%). Long-term MCMI exposure patterns are significant predictors of CVD risk in middle-aged and older adults with CKM stages 0–3, with obesity-related indicators serving as the predominant mediators driving this overall association. These findings support the use of repeated MCMI assessments for early risk stratification and highlight weight management as a key intervention target in this population. Not applicable (observational cohort study).