ANGPTL3 and residual atherosclerotic risk: from lipid metabolism to therapeutic targeting

Despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, many patients remain at high risk of cardiovascular events due to elevated triglyceride-rich lipoproteins and remnants. Angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for addressing this residual risk. As a liver-secreted regulator of lipoprotein metabolism, ANGPTL3 influences triglycerides, LDL-C, and high-density lipoprotein cholesterol through inhibition of lipoprotein lipase and endothelial lipase. Human genetic studies and pharmacologic interventions consistently show that ANGPTL3 inhibition improves lipid profiles and lowers apolipoprotein B-containing lipoproteins, independent of LDL receptor function. This review integrates biological, genetic, and clinical evidence, and provides an overview of novel ANGPTL3-targeted therapies, offering new perspectives for cardiovascular prevention and lipid management.