A novel metabolic imbalance index combining insulin resistance and inflammation for cardiovascular prognosis: evidence from three international cohorts in middle-aged and older adults

Background Chronic inflammation and insulin resistance are key pathophysiological mechanisms underlying cardiovascular disease (CVD). Persistent low-grade inflammation promotes endothelial dysfunction and accelerates atherosclerotic plaque formation. Insulin resistance contributes to metabolic disturbances, including hyperglycemia and dyslipidemia, which further increase vascular damage. Although both processes are independently associated with CVD, their combined impact on cardiovascular risk remains insufficiently understood. Methods We analyzed data from three international cohorts: CHARLS (China, n=6,414), HRS (USA, n=3,705), and ELSA (UK, n=3,569). We developed a metabolic–inflammatory index (eMII) based on the estimated glucose disposal rate (eGDR) to capture the combined contribution of these pathways to long-term CVD risk. We assessed the combined effect of insulin resistance and inflammation on CVD risk. Results A total of 13,688 middle-aged and older adults were included (mean age 61.2 ± 9.3 years). In fully adjusted Cox models, low eGDR, elevated hs-CRP, and their combined status were all associated with increased CVD risk, with the highest risk observed in participants with both poor metabolic function and high inflammation. Mediation analysis indicated that eGDR accounted for 44.6%, 24.9%, and 17.2% of the inflammation–CVD association in CHARLS, HRS, and ELSA, respectively (Figure 1). In terms of the new index-eMII, higher eMII levels were consistently linked to elevated CVD risk across all cohorts; compared with the lowest quartile, the highest quartile showed hazard ratios of 2.22 (CHARLS), 1.74 (HRS), and 1.68 (ELSA) (P all <0.001)(Table 1). Lastly, incorporating eMII into traditional risk models significantly improved cardiovascular risk prediction, as reflected by consistent improvements in discrimination, risk reclassification, and long-term predictive performance across cohorts. Conclusions eMII is a robust, cross-population predictor of CVD, highlighting metabolic impairment as a key factor through which inflammation drives cardiovascular risk. It provides a practical tool for long-term risk stratification in middle-aged and older adults and supports targeted metabolic and anti-inflammatory prevention strategies.