Targeting angiopoietin‐like 3 in atherosclerosis: From bench to bedside

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid‐lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low‐density lipoprotein cholesterol (LDL‐C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid‐lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin‐like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL‐C and high‐density lipoprotein cholesterol (HDL‐C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss‐of‐function mutations, which leads to low levels of LDL‐C, HDL‐C and TG, and has a 34% decreased risk of ASCVD compared with non‐carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3‐targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.

Correlation Between the Levels of ANGPTL3, ANGPTL4, ANGPTL8 and Postprandial Triglyceride-Rich Lipoprotein (TRL)

“…ANGPTL3 affects lipid deposition in tissues primarily by inhibiting LPL, liver lipase, and endothelial lipase (EL), ultimately influencing lipid levels. 17 Moreover, ANGPTL3’s inhibition of EL can affect the expression of HDL phospholipids, 18 , 19 resulting in reduced levels of HDL-C. Because ApoA1 is the main structural component of HDL, 20 its levels change accordingly. Our study also determined that ANGPTL3 levels are correlated with age and blood pressure, although the exact mechanism remains unclear and requires further investigation.…”

Hypertriglyceridemia may contribute to stroke and pancreatitis: A case report and review of the literature

“…In the latest study, the safety profile of fenofibrate in combination with a statin was acceptable, and this combination significantly reduced the risk of vascular events in patients with typical diabetic dyslipidemia ( 57 ). In recent years, researchers have made significant progress in developing targeted therapies, such as volanesorsen ( 58 , 59 ), evinacumab ( 60 , 61 ), lomitapide ( 62 ) and icosapent ethyl ( 63 ).…”

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

“…Frequent adverse events of evinacumab include mild local injection reaction, flu-like illness, headache, urinary tract infection and limb pain. 285 In addition, no clinically apparent liver injury or serious hepatic adverse events attributable to treatment were reported.…”