Additive interaction of insulin sensitivity and age on new-onset cardiovascular disease: a national population-based cohort study

Abstract Background Insulin resistance (IR), a core mechanism of cardiovascular-kidney-metabolic (CKM) syndrome, drives diabetes progression and cardiovascular disease (CVD). Estimated glucose disposal rate (eGDR), a practical IR biomarker, remains understudied for CVD risk prediction in early-stage CKM (stages 0-3), particularly in aging populations. Purpose To evaluate the association between eGDR and incident CVD risk and quantify the additive interaction between insulin sensitivity and age on the risk of new-onset CVD in middle-aged and elderly individuals with CKM syndrome. Methods Based on China Health and Retirement Longitudinal Study (CHARLS) data (2011–2020), participants with CKM syndrome stage 0-3 and aged ≥45 years were recruited. The primary outcome was defined as newly diagnosed CVD during follow-up. Cox regressions were used to analyze the association between eGDR and CVD risk. The interaction analyses explored potential additive interaction between eGDR and age. Results This study included 6741 participants with a mean age of 58.04 ± 8.61 years and 45.41% of them were male. The average eGDR was 9.47 mg/kg/min. In fully adjusted models, individuals in the highest eGDR tertile had a 36% lower risk of developing CVD compared to those in the lowest tertile (HR 0.64, 95%CI:0.57–0.73, P 0.0001). Restricted cubic spline confirmed the inverse association. Age modified the association between eGDR and risk of CVD (P for interaction=0.002). The relative excess risk of interaction (RERI) of higher level of eGDR and advancing age was significantly negative (RERI= - 0.33, 95% CI: - 0.62 – - 0.07), which implied the antagonistic effect. Conclusion In the CKM population, eGDR serves as a novel biomarker for guiding the management of incident cardiovascular disease risk, with younger patients likely to derive greater benefits from early eGDR-targeted interventions.