EARLY METABOLIC IMBALANCE IN YOUNG ADULTS HAS VARIABLE IMPACT ON 35-YEAR MORTALITY RISK

Abstract

Therapeutic Area: ASCVD/CVD Risk Factors Background: Early metabolic imbalance (EMI) is a hidden condition characterized by compensated insulin resistance, often accompanied by oxidative stress, subclinical inflammation, and hypoxia. Individuals with EMI have fasting glucose, triglycerides, hemoglobin A1c, and high-density lipoprotein cholesterol (HDL-C) values all within normal limits. Thus, EMI is undetected in routine screening for diabetes and cardiovascular risk. Previously, we reported that EMI is an independent risk factor for type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD). Hypothesis: EMI in young adults increases the 35-year mortality risk compared with healthy, balanced metabolism. Methods: We conducted a retrospective cohort study using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. The parent study began in 1985, enrolling 5,113 young adults ages 18-30, with study visits every five years for 35 years. For this retrospective analysis, the baseline exclusion criteria were fasting hyperglycemia, hypertriglyceridemia, low HDL-C, pregnancy, diabetes, or CVD; n=3,292. Cox proportional hazards regression analysis was performed using Stata 18.0 (StataCorp). The primary exposure variable was EMI, measured as the upper and lower halves of baseline homeostatic model assessment of insulin resistance v.2 (HOMA2-IR). The baseline covariates included other known causes of death. The primary outcome was time-to-incident mortality or censor. Mortality risk was measured as a Cox hazard ratio (HR) with 95% confidence interval (CI) and p-value. Each model met the assumption of proportional hazards. Results: Over the 35-year follow-up period, 280 individuals died for a cumulative incidence of 8.5%. Cox Model 1 incorporated categorical HOMA2-IR (high/low) at baseline. Model 2 included the interaction between HOMA2-IR, sex, and race as a categorical variable (Table 1). Model 3 included the interaction variable from Model 2, along with other causes of death as covariates. As seen in Table 1, the Cox hazard ratios for EMI were modified by sex and race. Conclusions: For young adults in CARDIA, EMI had a variable impact on 35-year mortality. The risk was modified by sex and race, even after adjusting for known risk factors. Further analysis is warranted.