Inhibition of the ANGPTL3/8 Complex for the Prevention and Treatment of Atherosclerotic Cardiovascular Disease.

Purpose of review

Dyslipidemia is a casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with dyslipidemias. Angiopoietin-like protein 3 (ANGPTL3) and ANGPTL8 play key roles in triglyceride trafficking and energy balance in humans. We review the functional role of these ANGPTL proteins in the regulation of lipoprotein metabolism, and recent clinical trials targeting ANGPTL3 and ANGPTL3/8 with monoclonal antibody and/or nucleic acid therapies, including antisense oligonucleotides and small interfering RNA.

Recent findings

Cumulative evidence supports the roles of ANGPTL3 and ANGPTL8 in lipid metabolism through inhibition of lipoprotein lipase and endothelial lipase activity. ANGPTL3 and ANGPTL3/8 inhibitors are effective in lowering plasma triglycerides and low-density lipoprotein (LDL)-cholesterol, with the possible advantage of raising high-density lipoprotein (HDL)-cholesterol with the inhibition of ANGPTL3/8. Therapeutic inhibition of ANGPTL3 and ANGPTL3/8 can lower plasma triglyceride and LDL-cholesterol levels possibly by lowering production and upregulating catabolism of triglyceride-rich lipoprotein and LDL particles. However, the effect of these novel agents on HDL metabolism remains unclear. The cardiovascular benefits of ANGPTL3 and ABGPTL3/8 inhibitors may also include improvement in vascular inflammation, but this requires further investigation.

COI Statement

Declarations. Ethical Disclosure: None to disclose Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Information Pertaining to Writing Assistance: No writing assistance was utilized in the production of this manuscript. Competing Interests: The authors declare no competing interests. Conflict of Interest: GFW has received honoraria for lectures, advisory boards or research grants from Amgen Inc., Arrowhead, AstraZeneca, Esperion, Kowa, Novartis, Regeneron, and Sanofi. DCC does not declare any conflict of interest.

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