Triglyceride-Rich Lipoprotein Metabolism and Cardiovascular Risk in Diabetes: Bedside to Bench to Bedside

Type 1 diabetes and type 2 diabetes are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), manifested as myocardial infarction, ischemic stroke, and peripheral artery disease. The increased ASCVD risk in diabetes cannot be fully explained by traditional risk factors. This review highlights the dysregulation of TRLs (triglyceride-rich lipoproteins; VLDL [very low-density lipoprotein] and chylomicrons), and their remnants, as contributors to ASCVD risk in diabetes by examining 6 typical clinical cases integrated with mechanistic data obtained in preclinical models. Type 2 diabetes is often associated with insulin resistance and increased hepatic secretion of VLDL particles, which are enlarged by an increased lipid load, increased intestinal secretion of chylomicrons, and reduced hepatic clearance of both VLDL and chylomicron remnants. The increased levels of TRLs in turn contribute to the predominance of smaller, denser LDL (low-density lipoprotein) particles and smaller cholesterol-depleted HDL (high-density lipoprotein) particles compared with people without diabetes. When type 2 diabetes occurs in individuals with genetic variants causing altered function of proteins stimulating TRL clearance (LPL, APOC2, APOA5, GPIHBP1, LMF1, or LDLR) or suppressing TRL clearance (APOC3, ANGPTL3, ANGPTL4, ANGPTL8), the result is a compounded accumulation of TRLs and their remnants in plasma and an associated increased ASCVD risk. VLDL secretion is usually unaltered in individuals with well-controlled type 1 diabetes, but ASCVD risk is increased when insulin resistance and defects in TRL clearance are also present. Mechanistically, TRLs enhance ASCVD risk at least in part by exacerbating local vascular inflammation caused by the accumulation of free cholesterol and triglyceride lipolysis products. Because cardiovascular outcome trials targeting triglyceride levels to date have been mostly futile, the field is now focused on trials targeting proteins involved in TRL clearance. Carefully determining inclusion and exclusion criteria for such trials will be critical for advancing our understanding of how to better prevent ASCVD in individuals living with diabetes.