ANGPTL3 inhibitors reduce triglycerides and LDL-C, offering a novel strategy to address residual atherosclerotic risk in patients with homozygous familial hypercholesterolemia and mixed dyslipidemia.
Do ANGPTL-directed therapies improve lipid profiles and reduce cardiovascular risk in patients with dyslipidemia?
ANGPTL-directed therapies represent a novel, LDL receptor-independent strategy for lipid lowering and cardiovascular risk reduction in patients with HoFH and mixed dyslipidemia.
Purpose of Review The angiopoietin-like protein (ANGPTL) 3–4–8 axis has emerged as a central regulator of lipoprotein lipase and lipid metabolism. This review examines the mechanistic basis of ANGPTL pathway modulation and therapeutic implications for cardiovascular risk reduction across diverse phenotypes of dyslipidemia. Recent Findings Genetic studies demonstrate that loss-of-function variants in ANGPTL3 and ANGPTL4 are associated with lower triglycerides and decreased coronary artery disease risk. Pharmacologic inhibition of ANGPTL3 with monoclonal antibodies and RNA-based therapies reduces triglycerides, remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) through mechanisms predominantly independent of the LDL receptor. Clinical trials with ANGPTL3 inhibitors have demonstrated marked LDL-C reductions in patients with homozygous familial hypercholesterolemia (HoFH), as well as broad lipid-lowering effects in patients with mixed dyslipidemia. Emerging strategies targeting the ANGPTL3/8 complex and ANGPTL4 further refine lipid-lowering effects, while early genome-editing data suggest the potential for durable ANGPTL3 suppression. Summary Modulation of the ANGPTL–lipoprotein lipase axis is a novel strategy to address residual atherosclerotic risk beyond traditional LDL receptor–dependent therapies. ANGPTL3 inhibitors have been practice-changing in HoFH, and more broadly, ANGPTL-directed therapies hold promise for patients with mixed dyslipidemia to mitigate cardiovascular risk.
Bitencourt et al. (Sat,) conducted a review in Dyslipidemia. ANGPTL3 inhibitors was evaluated. ANGPTL3 inhibitors reduce triglycerides and LDL-C, offering a novel strategy to address residual atherosclerotic risk in patients with homozygous familial hypercholesterolemia and mixed dyslipidemia.