Longitudinal estimated glucose disposal rate trajectories and cumulative exposure predict cardiovascular disease in population with Cardiovascular- Kidney-Metabolic syndrome stages 0-3: A nationwide prospective cohort study

<title>Abstract</title> <p>Background The baseline estimated glucose disposal rate (eGDR), a surrogate for insulin resistance (IR), is linked to cardiovascular disease (CVD) in early-stage Cardiovascular-Kidney-Metabolic (CKM) syndrome. However, the impact of its longitudinal changes is unknown. We aimed to explore the dynamic changes in eGDR—cumulative exposure and control level trajectories—are associated with CVD incidence in individuals with CKM syndrome stages 0–3. Methods In this nationwide prospective cohort study, we analyzed data from 4,667 participants in the China Health and Retirement Longitudinal Study (CHARLS) without baseline CVD. We assessed dynamic changes in eGDR between 2012 and 2015 using two metrics: cumulative eGDR (cum eGDR), reflecting total burden over three years, and eGDR control levels (eGDR trajectories), derived from K-means clustering to identify the longitudinal trajectories (Persistent High, Rapidly Decreas- ing, and Persistent Low group). The primary outcome was incident CVD events during follow-up to 2018. Results A total of 4667 CKM syndrome stages 0–3 participants were included in the study, of whom 571 developed CVD during the 3-year follow-up period. Multivariate Logistic regression analysis showed that Class 2 (OR = 1.312, 95% CI: 1.042–1.652; P = 0.021) and Class3 (OR = 2.228, 95% CI: 1.728–2.872; P = 0.001) had significantly higher risk of CVD compared with Class 1 at the eGDR trajectories. In addition, the elevated cum eGDR (OR = 0.581, 95% CI: 0.515–0.656; P = 0.001) was associated with the decrease of the risk in CVD. Subsequent subgroup analyses revealed that eGDR trajectories were influenced by T2 diabetes mellitus (DM) status (P = 0.007), whereas cum eGDR remained unaffected (P &gt; 0.05). Further, mediation analyses in the non-DM population showed that the effect of eGDR trajectories on new-onset CVD was partially mediated by lipid factors. Conclusions Our study demonstrates that worsening longitudinal eGDR trajectories and greater cum eGDR are powerful predictors of CVD in population with CKM syndrome stages 0–3. The association between eGDR trajectories and CVD was particularly significant in the non-DM population and was partially mediated by lipid factors. These highlight the ability of dynamic eGDR surveillance to guide early targeted prevention strategies.</p>