Comparative evaluation of insulin resistance indices for predicting adverse cardiovascular events in hyperuricemia: insights from UK biobank and Shanghai Pudong cohort

Abstract

Background Hyperuricemia (HUA) frequently coexists with glucolipid metabolic disturbances characterized by insulin resistance, dyslipidemia, and adipose tissue dysfunction. However, the association between insulin resistance (IR)-related indices and cardiovascular disease (CVD) incidence/mortality in HUA patients remains not yet fully established. Methods Data from the UK Biobank (UKBB) and Shanghai Pudong cohort were analyzed, enrolling 35,853 and 12,680 HUA patients, respectively. Associations between seven IR-related indices and adverse cardiovascular events were assessed using multivariate Cox proportional hazards models, restricted cubic spline analyses, time-dependent receiver operating characteristic, random forest modeling, and Mendelian randomization. Mediation analyses evaluated the role of phenotypic aging biomarkers and inflammatory markers in these relationships. Results All seven IR indices exhibited significant associations with CVD events and mortality in HUA patients from two cohorts. TyG-WHTR showed comparable 10-year CVD mortality predictive performance to SCORE2 in UKBB (AUC, 0.733). Elevated TyG-WHTR correlated with increased CVD mortality [T3 vs. T1: HR, 1.76 (95%CI: 1.48–2.11)], while higher CMI predicted myocardial infarction [HR, 1.52 (1.31–1.76)]. C-reactive protein (mediation ratio: 1.3–13.3%) and accelerated aging (4.5–34.4%) partially mediated these associations. Genetically predicted TyG index elevation was linked to myocardial infarction risk [OR, 1.79 (1.48–2.16)]. Conclusion IR-related indices serve as clinically valuable tools for CVD risk stratification in HUA, with inflammatory activation and accelerated aging constituting key mechanistic pathways. These findings provide novel insights for early identification and targeted prevention of cardiovascular complications in HUA patients.