Cardiovascular
Racial Heterogeneity in the Mediated Effect of Young-Adulthood Insulin Resistance (IR) on Later-Life Atherosclerotic Cardiovascular Disease (ASCVD) Through Midlife Metabolic Syndrome (Mets) in CARDIA Cohort Chuyue Wu* Chuyue Wu Wu Wu Wu Wu Wu Wu Department of Epidemiology, UCLA Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095
Insulin resistance (IR) often emerges in young adulthood and contributes to the development of atherosclerotic cardiovascular disease (ASCVD), yet the life-course mechanisms and racial heterogeneity of this association remain unclear. The objective was to quantify the proportion of the association between young-adulthood IR and later-life ASCVD mediated by midlife metabolic syndrome (MetS) and to assess racial differences in these mediation pathways. We analyzed 3,622 Black and White participants from the CARDIA cohort (baseline ages 18–30 years) who had fasting insulin and glucose measured at baseline. Young-adulthood IR was defined based on body mass index (BMI) and the homeostatic model assessment of insulin resistance (HOMA-IR): BMI >28.9 kg/m², HOMA-IR >4.65, or BMI >27.5 kg/m² combined with HOMA-IR >3.60. Midlife MetS was assessed at Year 20 (ages 38-50 years) using harmonized criteria, defined by the presence of at least three of five components: central obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure or use of antihypertensive medication, and elevated fasting glucose or use of hypoglycemic medication. Incident fatal and nonfatal ASCVD events were ascertained from Year 20 to 35 (through 2021). Causal mediation analysis for time-to-event outcomes was conducted using parametric G-computation with pooled logistic regression, adjusting for baseline confounders and accounting for midlife lifestyle (diet quality and physical activity) as an exposure-induced mediator-outcome confounder. During a median of 14 years of follow-up, 143 events occurred. At the end of follow-up, young-adulthood IR was associated with 1.7-fold increased ASCVD risk (95% CI, 1.2-2.4). Midlife MetS mediated 52% of this effect. Among Black participants, 55% of the IR–ASCVD association was mediated by midlife MetS, compared with 25% among White participants (Figure). IR in young adulthood substantially increases later-life ASCVD risk primarily through progression to midlife metabolic syndrome, with stronger mediation among Black adults. Early IR identification and intervention may reduce ASCVD burden and racial disparities.
