title: Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.
abstract: Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.
authors.affiliation: The Carbohydrate and Lipid Metabolism Research Group, Department of Medicine, University of the Witwatersrand, 7 York Road, Parktown, 2193, Johannesburg, South Africa. O14fred@chiron.wits.ac.za
authors.forename: F J
authors.initials: FJ
authors.lastname: Raal
authors.forename: A S
authors.initials: AS
authors.lastname: Pappu
authors.forename: D R
authors.initials: DR
authors.lastname: Illingworth
authors.forename: G J
authors.initials: GJ
authors.lastname: Pilcher
authors.forename: A D
authors.initials: AD
authors.lastname: Marais
authors.forename: J C
authors.initials: JC
authors.lastname: Firth
authors.forename: M J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: T M
authors.initials: TM
authors.lastname: Heinonen
authors.forename: D M
authors.initials: DM
authors.lastname: Black
mesh_terms: D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000097:blood / Q000652:urine; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000097:blood / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011973:Receptors, LDL; D004247:DNA; D002784:Cholesterol; D000069059:Atorvastatin; D008798:Mevalonic Acid