Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.
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.
Raal
F J
FJ
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
Pappu
A S
AS
Illingworth
D R
DR
Pilcher
G J
GJ
Marais
A D
AD
Firth
J C
JC
Kotze
M J
MJ
Heinonen
T M
TM
Black
D M
DM
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
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