EARLY METABOLIC IMBALANCE IS AN INDEPENDENT RISK FACTOR FOR INCIDENT METABOLIC SYNDROME: A RETROSPECTIVE COHORT STUDY

Abstract

Therapeutic Area: Metabolic Syndrome Background: Early metabolic imbalance (EMI) is a hidden condition that includes compensated insulin resistance, hyperinsulinemia, oxidative stress, hypoxia, and inflammation (Fig. 1). The high circulating insulin compensates for insulin resistance, such that fasting glucose, triglycerides, hemoglobin A1c, and high-density lipoprotein-cholesterol (HDL-C) all remain within normal limits. Thus, individuals with EMI do not meet the criteria for prediabetes or metabolic syndrome (MetS) and elude risk screening for diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). In prior work, we reported that EMI is an independent risk factor for T2D and CVD. Here, we tested the hypothesis that EMI in apparently healthy young adults increases the risk for incident MetS. Methods: We conducted a retrospective cohort study of CARDIA: Coronary Artery Risk Development in Young Adults. The parent study enrolled 5,113 adults, ages 18-30 at baseline, with study visits every five years for a mean follow-up of 30 years. For this retrospective analysis, the baseline exclusion criteria were hyperglycemia, hypertriglyceridemia, low HDL-C, pregnancy, diabetes, or cardiovascular disease; n=3,292. Metabolic syndrome was defined using the international harmonized criteria, requiring at least 3 of the following 5: hyperglycemia, hypertriglyceridemia, low HDL-C, increased blood pressure, and/or elevated waist circumference. Cox proportional hazards regression was performed using Stata 18.0. The primary exposure was EMI, a latent variable that combines homeostatic model of insulin resistance v2, waist circumference, white blood cell count, and gamma-glutamyl transferase. The primary outcome was time-to-incident MetS. Results were reported as a Cox hazard ratio (HR) with 95% confidence interval (CI) and p-value. Reported models met the proportional hazards assumption. Results: Across the 30-year follow-up period, there were 880 cases of incident MetS. Cox Model 1 included categorical EMI (above/below median) with no covariates: HR=2.3 (95% CI 2.0, 2.7; p2-fold increase in risk for incident MetS compared to those with healthy balanced metabolism.