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

Abstract 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. Graphical abstract