Atherosclerotic Cardiovascular Risk Before and After Type 2 Diabetes Onset and the Roles of Ectopic Fat and Ethnic Variation: The 2025 Edwin Bierman Award Lecture

Atherosclerotic cardiovascular disease (ASCVD) risk begins increasing years before the clinical onset of type 2 diabetes, driven in part by ectopic lipid accumulation. Many individuals predisposed to diabetes often gain weight rapidly and have limited capacity to expand subcutaneous fat, leading to central fat storage and ectopic lipid deposition-especially in the liver. Hepatic fat contributes to metabolic dysfunction and elevated triglyceride-rich lipoproteins (TRLs), which are atherogenic. Alongside higher blood pressure, these factors accelerate atherosclerosis even before hyperglycemia is evident. Although traditional cardiovascular risk factors like LDL cholesterol (LDL-C) and smoking have declined, rising obesity-particularly among younger individuals-is shifting ASCVD risk more toward pathways linked to ectopic lipid accumulation and prolonged exposure to diabetes-related metabolic disturbances. Ethnic variation plays a significant role in modifying this risk. South Asians, for example, develop type 2 diabetes at lower BMIs and tend to have higher hepatic fat and TRL levels than White individuals, contributing to their increased ASCVD burden. Conversely, people of African ancestry often have lower hepatic fat and TRL levels at similar BMIs, correlating with lower ASCVD risk despite elevated diabetes risk. Risk profiles in other ethnic groups remain understudied. These findings highlight the need for early obesity prevention and ethnically tailored strategies for ASCVD risk assessment and management. Without targeted interventions, rising global rates of obesity and type 2 diabetes, especially in low- and middle-income countries, will increase ectopic lipid accumulation, TRLs, and blood pressure, ultimately accelerating ASCVD progression and reversing prior gains made in cardiovascular prevention.