title: Treatment of low HDL-C subjects with the CETP modulator dalcetrapib increases plasma campesterol only in those without ABCA1 and/or ApoA1 mutations.
abstract: We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9%) and FCH (+18.4, +12.1%), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (-31.5, +120.9%) and FCH (-26.6, +111.9%), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0%), but only campesterol was markedly increased in FCH (+25.0%, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.
authors.affiliation: Metabolic and Vascular Diseases, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland, eric_j.niesor@roche.com.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Niesor
authors.forename: David
authors.initials: D
authors.lastname: Kallend
authors.forename: Darren
authors.initials: D
authors.lastname: Bentley
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: G
authors.initials: G
authors.lastname: Kees Hovingh
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D000577:Amides; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004952:Esters; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010840:Phytosterols / Q000097:blood*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000577:Amides; D016632:Apolipoprotein A-I; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D010840:Phytosterols; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C021273:campesterol; C001521:lathosterol; D002784:Cholesterol