Estimated glucose disposal rate stratifies mortality risk, especially in younger adults with cardiovascular-liver-metabolic overlap

The cardiovascular-liver-metabolic (CLM) overlap population faces an elevated risk of mortality, yet prognostic tools integrating dynamic insulin resistance (IR) remain limited. This study aimed to evaluate the prognostic impact of estimated glucose disposal rate (eGDR) on mortality within the CLM overlap population. An analysis of a prospectively linked national dataset was conducted on 1,126 eligible NHANES participants (1999–2018) with concomitant cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD). eGDR was calculated using clinical parameters. Multivariable Cox regression, restricted cubic splines, Kaplan-Meier survival analysis, and causal mediation models were employed to assess mortality associations and the mediating role of inflammation. Over a median follow-up of 85 months, 453 deaths occurred, including 155 cardiovascular deaths. Lower eGDR showed a borderline inverse association with cardiovascular mortality (HR = 0.84, 95% CI: 0.70–1.01, P = 0.065). eGDR exhibited a threshold-dependent non-linear association with all-cause mortality ( P for non-linearity = 0.001), with lower mortality below the inflection point of 5.5901 mg/kg/min (HR = 0.78, 95% CI: 0.66–0.91) and higher mortality above it (HR = 1.16, 95% CI: 0.99–1.36). The pathway from eGDR through systemic inflammation response index (SIRI) to mortality was statistically detectable for all-cause mortality (indirect effect = 6.530, 95% CI: 2.146–11.878), and SIRI mediated 11.3% of the total effect for cardiovascular mortality. Notably, the reduction in mortality risk per 1-unit increase in eGDR was significantly stronger in patients aged < 60 years (all-cause mortality HR = 0.71, 95% CI: 0.60–0.85, P = 0.003; P for interaction = 0.001). In the CLM overlap population, eGDR demonstrates a linear association with cardiovascular mortality and a non-linear association with all-cause mortality, partially mediated by systemic inflammation. Its enhanced prognostic value in younger adults highlights its potential for early risk stratification and could inform targeted interventions focusing on IR-driven pathways.