Metabolic Score for Insulin Resistance and Progression to Stage 4 of Cardiovascular–Kidney–Metabolic Syndrome: A Retrospective Cohort Study

Background and Objectives: Insulin resistance is central to cardiovascular–kidney–metabolic dysfunction, but longitudinal evidence linking a scalable insulin-resistance surrogate to stage 4 progression is limited. We evaluated the association between baseline Metabolic Score for Insulin Resistance (METS-IR) and progression to stage 4 and explored nonlinear, subgroup, mediation, and machine-learning patterns. Materials and Methods: We retrospectively analyzed 31,286 adults with baseline cardiovascular–kidney–metabolic syndrome stages 0–3 from six community health service centers in Tianjin, China, during 2014–2023. During a median 7-year follow-up, 810 participants progressed to stage 4. Cox models were adjusted for age, sex, smoking, high-salt diet, daily exercise, arrhythmia, family history of diabetes, and socioeconomic and household-environment factors. We also conducted restricted cubic spline analyses, subgroup analyses across 16 variables (with formal interaction tests for age and daily exercise), six sensitivity analyses, and an exploratory mediation analysis. We further evaluated 13 machine-learning algorithms. Results: In the fully adjusted model, each 1-standard-deviation increase in METS-IR was associated with a hazard ratio of 1.11 (95% confidence interval, 1.07–1.14), and the hazard ratio comparing the fourth with the first quartile was 2.03 (1.64–2.52; p for trend <0.001). Restricted cubic spline analysis suggested a nonlinear association (p for nonlinearity <0.001). Exploratory interaction analyses yielded p = 0.014 for age and p = 0.040 for daily exercise. Sensitivity analyses supported the primary findings. XGBoost achieved the highest test-set area under the curve among 13 models (AUC = 0.925). Exploratory mediation analysis suggested that baseline METS-IR accounted for an estimated 0.87% of the association between daily exercise and stage 4 progression; this estimate was not interpreted causally. Conclusions: Higher METS-IR was associated with progression to stage 4 cardiovascular–kidney–metabolic syndrome in this retrospective cohort. The findings are hypothesis-generating and may inform risk-stratification research, but they do not establish causality; external validation and formal evaluation of calibration, incremental predictive value, and clinical utility are required.