Inhibition of angiopoietin-like 3 for the management of severe hypercholesterolemia

Curr Opin Lipidol. 2021 Aug 1;32(4):213-218. doi: 10.1097/MOL.0000000000000755.

Abstract

Purpose for review: Despite the therapeutic advances for patients with severe hypercholesterolemia, particularly those with homozygous familial hypercholesterolemia (HoFH), most patients are unable to achieve target low-density lipoprotein cholesterol (LDL-C) levels with the current available standard lipid-lowering therapy (LLT). We review the role of angiopoietin-like 3 (ANGPTL3) inhibition as an additional therapeutic option for severe hypercholesterolemia, particularly HoFH.

Recent findings: Evinacumab is a monoclonal antibody against ANGPTL3, and reduces LDL-C independent of LDL-receptor activity. ANGPTL3 inhibitors are effective in lowering LDL-C in patients with FH, with a 50% reduction in LDL-C in those with HoFH. Longer-term efficacy and safety have been demonstrated with reductions in LDL-C maintained following 48 weeks of therapy. Gene silencing strategies directed against ANGPTL3 include antisense oligonucleotide and small-interfering ribonucleic acid (siRNA). ARO-ANG3 is a siRNA directed against ANGPTL3 messenger ribonucleic acid and is associated with up to a 42% reduction in LDL-C.

Summary: With the promise of these emerging novel therapeutics directed against ANGPTL3 on the horizon, achieving acceptable target LDL-C levels in HoFH without the need for lipoprotein apheresis may finally be a realistic goal and we can anticipate a decrease in cardiovascular morbidity and mortality in these difficult to treat patients.

Publication types

  • Review

MeSH terms

  • Angiopoietin-Like Protein 3* / antagonists & inhibitors
  • Angiopoietin-like Proteins* / antagonists & inhibitors
  • Homozygous Familial Hypercholesterolemia* / therapy
  • Humans
  • Hypercholesterolemia* / therapy
  • RNA, Small Interfering / therapeutic use

Substances

  • ANGPTL3 protein, human
  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins
  • RNA, Small Interfering