title: Avasimibe, an ACAT inhibitor, enhances the lipid lowering effect of atorvastatin in subjects with homozygous familial hypercholesterolemia.
abstract: This study assessed the efficacy and safety of avasimibe (CI-1011), an inhibitor of acyl coenzyme A-cholesterol acyltransferase (ACAT) in subjects with homozygous familial hypercholesterolemia (HoFH). Twenty seven subjects were enrolled in a double-blind, randomized, 3-sequence crossover trial of atorvastatin 80 mg QD, avasimibe 750 mg QD, and the combined treatment of atorvastatin 80 mg QD and avasimibe 750 mg QD after a washout period of 4 weeks. Each treatment period was administered over 6 weeks for a total of 18 weeks. There were no significant lipid changes resulting from the administration of avasimibe monotherapy. Avasimibe in combination with atorvastatin resulted in a significantly better reduction of total cholesterol (TC) as compared to atorvastatin alone (-22% versus -18%) (P < 0.05). All other lipid changes were not statistically significant for combination therapy compared to atorvastatin monotherapy, however there were greater reductions in triglycerides (TG) (-24% versus -13%), low-density lipoprotein cholesterol (LDL-C) (-23% versus -19%), very low-density lipoprotein cholesterol (VLDL-C) (-24% versus -13%) and high-density lipoprotein cholesterol (HDL-C) (-11% versus -6%). Avasimibe may modestly enhance the lipid-reducing effect of atorvastatin by further inhibiting the production of intracellular cholesterol through mechanisms that appear to be compatible in this population.
authors.affiliation: Carbohydrate and Lipid Metabolism Research Unit, University of the Witwatersrand, Johannesburg Hospital, Johannesburg, South Africa.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Raal
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Ellen
authors.initials: E
authors.lastname: Klepack
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lovalvo
authors.forename: Richard
authors.initials: R
authors.lastname: McLain
authors.forename: Therese
authors.initials: T
authors.lastname: Heinonen
mesh_terms: D000081:Acetamides; D000085:Acetates / Q000008:administration & dosage*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000069059:Atorvastatin; D002648:Child; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000188:drug therapy*; D008075:Lipoproteins, HDL / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011336:Probability; D011758:Pyrroles / Q000008:administration & dosage*; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D012737:Sex Factors; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000008:administration & dosage*; D016896:Treatment Outcome; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000081:Acetamides; D000085:Acetates; D000069059:Atorvastatin; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011758:Pyrroles; D002785:Sterol O-Acyltransferase; D013449:Sulfonamides; D013451:Sulfonic Acids; D000097587:Sterol O-Acyltransferase 2; C423185:avasimibe