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ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis

Farzahna Mohamed1, Brett S Mansfield1, Frederick J Raal2

  • 1Department of Internal Medicine, Faculty of Health Sciences, Division of Endocrinology and Metabolism, University of the Witwatersrand, Johannesburg, South Africa.

Current Atherosclerosis Reports
|November 11, 2022
PubMed

Insights

Angiopoietin-like 3 (ANGPTL3) inhibitors offer a new way to lower low-density lipoprotein cholesterol (LDL-C) and reduce atherosclerotic cardiovascular disease (ASCVD) risk. These novel therapies target ANGPTL3, a key protein in lipid metabolism.

Area of Science:

  • Cardiovascular Medicine
  • Lipid Metabolism
  • Pharmacology

Background:

  • Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) are key risk factors for atherosclerotic cardiovascular disease (ASCVD).
  • Achieving target LDL-C levels remains challenging with current maximally tolerated lipid-lowering therapies (LLT).

Purpose of the Study:

  • To review novel therapeutic agents, specifically angiopoietin-like 3 (ANGPTL3) inhibitors, for managing dyslipidemia and reducing ASCVD risk.
  • To highlight the role of ANGPTL3 in lipoprotein metabolism and its potential as a therapeutic target.

Main Methods:

  • Review of genetic and clinical studies on ANGPTL3.
  • Evaluation of pharmacological inactivation of ANGPTL3 using monoclonal antibodies like evinacumab.
  • Discussion of nucleic acid-based therapies targeting ANGPTL3.

Main Results:

  • Lower ANGPTL3 levels correlate with reduced plasma LDL-C, triglycerides (TG), and other lipoproteins.
  • Pharmacological inhibition of ANGPTL3, e.g., with evinacumab, significantly reduces LDL-C (up to 50%), even in severe cases like homozygous familial hypercholesterolemia (HoFH).
  • ANGPTL3 inhibition offers an LDL-receptor (LDLR)-independent mechanism for LDL-C reduction and impacts TRLs.

Conclusions:

  • ANGPTL3 is a promising novel target for managing lipid disorders and reducing ASCVD risk.
  • Targeted therapies like ANGPTL3 inhibitors represent a significant advancement in lipid management.
  • Future lipid management will likely involve safe and effective targeted nucleic acid-based therapies.
Abstract

Keywords:
ANGPTL3AtherosclerosisEndothelial lipaseLDL-CLipoprotein lipaseResidual cardiovascular riskTriglycerides

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