期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 41, 期 5, 页码 1753-1759出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.315204
关键词
angiopoietin-like protein; cholesterol; LDL; familial hypercholesterolemia; isotope; leucine; lipoprotein
资金
- Regeneron Pharmaceuticals
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001878]
The study found that treatment with evinacumab is associated with an increase in the fractional catabolic rate of apoB-containing lipoproteins, suggesting that it lowers LDL-cholesterol mainly through increased clearance of these lipoproteins.
OBJECTIVE: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. APPROACH AND RESULTS: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5-H-2(3))-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59 +/- 2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616 +/- 504% and 113 +/- 14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. CONCLUSIONS: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway.
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