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

• Published in: Current opinion in lipidology Vol. 32; no. 4; p. 213
• Main Authors: Mohamed, Farzahna, Botha, Theunis C, Raal, Frederick J
• Format: Journal Article
• Language: English
• Published: England 01.08.2021
• Subjects: Angiopoietin-Like Protein 3 - antagonists & inhibitors; Angiopoietin-like Proteins - antagonists & inhibitors; Homozygous Familial Hypercholesterolemia - therapy; Humans; Hypercholesterolemia - therapy; RNA, Small Interfering - therapeutic use
• ISSN: 1473-6535
• DOI: 10.1097/MOL.0000000000000755

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. 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. 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.