Joint association of estimated glucose disposal rate and aggregate index of systemic inflammation with mortality in general population: a nationwide prospective cohort study

BACKGROUND: The COLCOT trial showed that patients with diabetes may benefit from low-dose colchicine, suggesting a potential interplay between insulin resistance (IR) and inflammation. Whether their combined assessment improves mortality risk stratification in the general population remains unclear. METHODS: We analyzed 50,654 adults from NHANES 1999-2018 linked to the National Death Index. IR and inflammation were assessed using estimated glucose disposal rate (eGDR) and the log₂-transformed aggregate index of systemic inflammation (AISI), respectively. Survey-weighted Cox proportional hazards models were used for all-cause mortality. For cardiovascular (CVD) mortality, cumulative incidence functions (CIFs) were estimated with Gray's test for between-group comparisons, and Fine-Gray subdistribution hazard models were fitted treating non-CVD death as a competing event. Discrimination was assessed using time-dependent ROC curves at 5 and 10 years. Robustness was evaluated through sensitivity analyses excluding immune-modifying conditions/treatments, applying a 24-month lag, and excluding extreme absolute lymphocyte counts. RESULTS: Over a median follow-up of 120 months, 6,936 all-cause deaths and 2,170 CVD deaths occurred. Higher eGDR was inversely associated with mortality (all-cause HR per 1-unit increase 0.90, 95% CI 0.88-0.92; CVD sHR 0.88, 95% CI 0.85-0.91), whereas higher log₂(AISI) was positively associated (all-cause HR per doubling 1.10, 95% CI 1.06-1.15; CVD sHR 1.13, 95% CI 1.06-1.20). In joint analyses, participants with low eGDR (≤ 8.40) and high log₂(AISI) (> 7.98) had the highest risks of all-cause mortality (HR 1.58, 95% CI 1.38-1.81) and CVD mortality (cause-specific HR 2.09, 95% CI 1.58-2.77; Fine-Gray sHR 2.13, 95% CI 1.66-2.74), with graded separation of CIFs (Gray's test P < 0.001). The combined model showed improved discrimination (AUCs at 5/10 years: all-cause 0.705/0.723; CVD 0.754/0.769). Results were consistent across sensitivity analyses. CONCLUSION: In a nationally representative U.S. cohort, eGDR and log₂(AISI) were independently and jointly associated with all-cause and CVD mortality. Their combined assessment improves risk stratification and may help identify individuals most likely to benefit from targeted preventive and anti-inflammatory strategies.