Abstract P019: Compensatory Hyperinsulinemia Is An Independent Risk Factor For Atherosclerotic Cardiovascular Disease: CARDIA 30-year Follow Up

Abstract

Introduction: Compensatory hyperinsulinemia (CH) is the heightened response of thepancreas and liver to early insulin resistance. Elevated blood insulin compensates for insulin resistance in tissues, maintainingfasting glucose, triglycerides and HDL-cholesterol within normal limits. Individuals with CH, as defined here, do notmeet the harmonized criteria for metabolic syndrome and elude screening for cardiovascularrisk. Previously, we reported that CH isprevalent in the U.S., especially in teenagers, young adults, Hispanic andBlack populations. However, it wasunclear whether CH increases the risk of future atherosclerotic cardiovasculardisease (ASCVD) or simply is a benign adaptation to energy imbalance. Hypothesis: Compensatory hyperinsulinemia is an independentrisk factor for ASCVD. Methods: We conducted a retrospectivecohort study of CARDIA: Coronary ArteryRisk Development in Young Adults. Theparent study enrolled 5,113 participants, ages 18-30 at baseline, with studyvisits every five years for a mean follow up of 30 years. In our study, the baseline exclusion criteriawere hyperglycemia, hypertriglyceridemia and low HDL-C (all using metabolicsyndrome cutpoints), as well as pregnancy, fasting <8 hours, baseline diabetesor cardiovascular disease. The resulting 3,292 participants wereanalyzed using Cox models that included CH, as well as the 2019 ACC/AHA riskfactors for ASCVD: hypertension, LDL ≥160mg/dL, family history of premature ASCVD, elevated waist circumference or BMI, fitness,race, nicotine use (serum cotinine) and estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m 2 . Theprimary outcome was time to incident ASCVD. The effect size was hazard ratio (HR) with 95% confidence intervals (CI). Results: In an adjusted Cox model that included CH, waistcircumference and the other ACC/AHA risk factors mentioned above, CH atbaseline was an independent risk factor for ASCVD: HR 1.86, 95% CI: 1.32, 2.61, p=0.0004. The other risk factors were significantexcept for race, eGFR, fitness and waist circumference. In an adjusted Cox model that substituted BMIcategory (≥25 vs. <25 kg/m 2 ) for elevated waist circumference, CHremained significant: HR 1.74, 95% CI:1.23, 2.46, p=0.0017. In that model, overweight/obesewas statistically significant as well (p=0.0289). To assess possible effect modificationbetween CH and BMI, a Cox model incorporating an interacting categorical variablerevealed that CH is a significant risk factor in overweight/obese participants (HR3.52, 95% CI: 1.76, 7.03, p=0.0004), but not those with BMI<25 (HR 1.23, 95%CI: 0.79, 1.94, p=0.3476). Thisobservation was confirmed using Cox models stratified by BMI category. Conclusion: After adjusting for canonical risk factors, compensatoryhyperinsulinemia is an independent risk factor for future ASCVD among CARDIA participantswho were overweight or obese at baseline.