Role of Estimated Glucose Disposal Rate in Staging and Death Risk of Cardiovascular-Kidney-Metabolic Syndrome: Insights from NHANES 1999-2018

<b>Background:</b> The concept of cardiovascular-kidney-metabolic syndrome (CKM) was recently proposed by the American Heart Association. Insulin resistance (IR) is closely linked to metabolic disorders, chronic kidney disease, and cardiovascular disease, which are the key components of CKM. As a surrogate IR marker, estimated glucose disposal rate (eGDR) may help identify high-risk patients. However, the specific role of eGDR in CKM progression and outcomes remains undefined. We aimed to evaluate the associations between eGDR and CKM progression, as well as its association with death in patients with CKM. <b>Methods:</b> Data was obtained from the National Health and Nutrition Examination Survey 1999-2018. Adults aged ≥ 20 years with complete data on CKM components and eGDR were included. Study outcomes were CKM progression and death outcomes. Multinomial logistic regression was used to evaluate the association between eGDR and CKM staging. Kaplan-Meier curves and Cox proportional hazard models assessed death outcomes, with restricted cubic splines exploring non-linear relationships. Stratified and sensitivity analyses tested the robustness of results. The predictive performance of eGDR was compared with the Homeostasis Model Assessment of Insulin Resistance and triglyceride-glucose index for death outcomes. <b>Results:</b> 29,290 participants were included (median age: 53.00 years, 51.96% males), with 27,769 classified as having CKM. Higher eGDR was also associated with lower odds of progression to advanced CKM stages. In CKM patients, over a median follow-up of 8.92 years, 4,926 deaths occurred (17.7%), with 1,330 (4.8%) cardiovascular deaths and 3,596 (12.9%) non-cardiovascular deaths. Compared with the lowest eGDR quartile, CKM patients in the highest quartile had lower risk of all-cause death (HR=0.59, 95%CI: 0.52-0.66), cardiovascular death (HR=0.52, 95%CI: 0.41-0.66), and non-cardiovascular death (HR=0.60, 95%CI: 0.53-0.69) (all <i>P</i><0.001). Non-linear relationships between eGDR and death outcomes were observed (all <i>P for nonlinear</i><0.001). Subgroup and sensitivity analyses confirmed the robustness of these associations. Additionally, eGDR predicted death in CKM patients better than other IR markers. <b>Conclusions:</b> Our findings support the utility of eGDR as a risk stratification tool in CKM populations. Lower eGDR levels were associated with more advanced CKM stages and higher long-term mortality, suggesting its potential role in identifying high-risk individuals.