title: Effect of evolocumab on cholesterol synthesis and absorption.
abstract: The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-cholesterol (LDL-C), but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial. At 2 weeks, changes in β-sitosterol/total cholesterol (TC) from baseline were 4% for placebo, 10% for evolocumab 140 mg (nonsignificant vs. placebo), and 26% for evolocumab 420 mg (P < 0.001 vs. placebo). Changes in campesterol/TC at week 2, relative to baseline between placebo and evolocumab, were all nonsignificant. Evolocumab had a modest effect on markers of cholesterol synthesis. At 2 weeks, changes in desmosterol/TC were 1% for placebo, 7% for evolocumab 140 mg (nonsignificant vs. placebo), and 15% for evolocumab 420 mg (P < 0.01 vs. placebo). Changes from baseline in lathosterol/TC at week 2 between placebo and evolocumab were nonsignificant. These results suggest that evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-C lowering.
authors.affiliation: Amgen Inc., Thousand Oaks, CA. Electronic address: matt.peach@gilead.com.
authors.forename: Matthew
authors.initials: M
authors.lastname: Peach
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: Ren
authors.initials: R
authors.lastname: Xu
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: Dan
authors.initials: D
authors.lastname: Fitzpatrick
authors.affiliation: Amgen Ltd., Uxbridge, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hamilton
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: Ransi
authors.initials: R
authors.lastname: Somaratne
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Scott
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Amgen Inc., Thousand Oaks, CA.
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Djedjos
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000096:biosynthesis / Q000097:blood*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D012855:Sitosterols / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D012855:Sitosterols; C577155:evolocumab
keywords: cholesterol/absorption; cholesterol/biosynthesis; drug therapy; lipid-lowering; lipids; low density lipoprotein; proprotein convertase subtilisin/kexin type 9; statin