Midlife Metabolic Syndrome as Mediator Between Early-Life Insulin Resistance and Later-Life Cardiovascular Diseases

BACKGROUND: The cardiovascular-kidney-metabolic syndrome framework describes progression from early metabolic dysfunction to clinical cardiovascular disease. Insulin resistance (IR) in young adulthood may contribute to later atherosclerotic cardiovascular disease (ASCVD), but the extent to which this association is mediated through midlife metabolic syndrome (MetS) remains unclear. OBJECTIVES: We aimed to evaluate the association between young-adulthood IR and later-life ASCVD and quantify mediation through midlife MetS. METHODS: We analyzed 3,622 Black and White participants in the Coronary Artery Risk Development in Young Adults study who were aged 18 to 30 years at baseline and free of ASCVD through year 20. IR was defined as a Homeostatic Model Assessment of Insulin Resistance value at or above the 75th percentile (≥2.67). MetS was assessed at year 20, and ASCVD events were ascertained through year 35. Parametric g-computation with pooled logistic regression estimated total and mediated effects on cumulative ASCVD risk at the end of follow-up, accounting for midlife lifestyle factors as exposure-induced mediator-outcome confounders. RESULTS: At baseline, 907 of 3,622 participants (25%) had IR. During a median follow-up of 14 years (Q1-Q3: 14-14 years) after year 20, 143 of 3,622 (3.9%) participants experienced an ASCVD event. Young-adulthood IR was associated with a 1.50-fold higher ASCVD risk at the end of follow-up (95% CI: 1.13-2.01), with 63.4% of the association mediated through midlife MetS (indirect risk ratio: 1.29; 95% CI: 1.13-1.48). CONCLUSIONS: Young-adulthood IR was associated with higher later-life ASCVD risk, with a substantial proportion mediated through midlife MetS. These findings suggest early identification of IR and prevention of progression to MetS may help reduce long-term cardiovascular risk.