Introduction: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the 'ANGPT L3-4-8 triad'), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.Areas covered: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.Expert opinion: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans.
Keywords: ANGPTL; ANGPTL3-4-8 triad; Angiopoietin; LPL; PCSK9; REGN3776; cardiovascular disease; cholesterol; diabetes mellitus; evinacumab; metabolic syndrome obesity; triglycerides.