Insulin-resistance indices and cardiovascular mortality in cardiovascular–kidney–metabolic syndrome stage 2: a comparative analysis of eGDR, TyG and METS-IR

Cardiovascular–kidney–metabolic syndrome stage 2 (CKM–S2) markedly elevates cardiovascular mortality. Insulin-resistance (IR) surrogates—including the triglyceride-glucose (TyG) index, metabolic score for insulin resistance (METS-IR) and estimated glucose-disposal rate (eGDR)—may improve risk stratification, yet their comparative performance in CKM–S2 is unknown. We analysed 13,098 adults with CKM–S2 from NHANES 2001–2018. TyG, METS-IR and eGDR were calculated at baseline. Cardiovascular mortality through 31 December 2019 was ascertained via National Death Index linkage. Associations were tested with survey-weighted Cox models, Kaplan–Meier curves and restricted cubic splines; predictive gain over a clinical base model was quantified with C-statistics, net re-classification improvement (NRI), integrated discrimination improvement (IDI) and likelihood ratio (LR) test. During a median follow-up of 103 months, 732 cardiovascular deaths occurred. eGDR showed a linear, inverse relation with cardiovascular mortality (adjusted HR per unit = 0.91, 95% CI 0.87–0.95). TyG and METS-IR exhibited U-shaped curves: risk rose sharply above TyG = 8.78 and METS-IR ≈ 46.8. Adding eGDR to the base model improved the C-statistic from 0.736 to 0.752, NRI by 0.241 and IDI by 0.0176 (all P < 0.001), outperforming TyG and METS-IR. eGDR is a robust, linear predictor of cardiovascular death in CKM–S2, whereas TyG and METS-IR convey threshold-dependent risk. Incorporating eGDR routinely and applying cut-off-guided interpretation for TyG and METS-IR could refine clinical risk assessment in CKM–S2.