2nd Edition of Diabetes and Endocrinology World Conference 2026

Abstract

Introduction: Insulin resistance (IR) contributes to CVD pathogenesis, but whether IR-related indices exhibit differential associations with early- vs. late-onset CVD, and how genetic susceptibility modifies these associations, remains unclear.

Methods: Data were obtained from the UK Biobank. Six IR-related indices were assessed, including the estimated glucose disposal rate (eGDR), metabolic score for IR (METS-IR), triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), and triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio. Genetic susceptibility to CVD was quantified using a Polygenic Risk Score (PRS). Analyses were conducted separately for early-onset (male <55 years and female <65 years) and late-onset CVD using Cox proportional hazards regression.

Results: Among 235,115 participants eligible for early-onset analysis, 5,416 early-onset CVD events occurred over 3,187,261.7 person-years. Among 316,141 participants eligible for late-onset analysis, 32,865 late-onset CVD events occurred over 4,117,658.7 person-years. Comparing the highest vs. lowest quartile (Q4 vs. Q1), hazard ratios (HRs) for early-onset CVD were 2.56 for eGDR, 2.11 for METS-IR, 1.95 for TyG, 1.92 for TyG-BMI, 2.15 for TyG-WC, and 2.03 for TG/HDL-C; corresponding HRs for late-onset CVD were 1.85, 1.71, 1.39, 1.67, 1.75, and 1.48, respectively. Ratios of HRs (early vs. late) for Q4 vs. Q1 were >1 across all indices (all P-difference <0.05). We observed significant multiplicative and additive interactions between these indices and PRS, and the associations between these indices and CVD were amplified in those with high genetic predisposition. Notably, these interactions were more pronounced in early-onset CVD. Among all indices, eGDR provided the greatest incremental improvement in risk prediction and ranked highest in relative importance for risk stratification.

Conclusion: IR-related indices showed stronger associations with early-onset CVD and stronger interactions with PRS in early-onset CVD than in late-onset CVD. These findings support the use of IR-related indices for early risk stratification and emphasize the value of early metabolic intervention in individuals with high genetic susceptibility.