Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia

Atherosclerosis. 2000 Jun;150(2):421-8. doi: 10.1016/s0021-9150(99)00435-9.


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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / therapeutic use*
  • Atorvastatin
  • Biomarkers / blood
  • Biomarkers / urine
  • Child
  • Child, Preschool
  • Cholesterol / biosynthesis*
  • Cholesterol / blood
  • Cholesterol, LDL / blood
  • DNA / genetics
  • DNA Mutational Analysis
  • Female
  • Heptanoic Acids / administration & dosage
  • Heptanoic Acids / therapeutic use*
  • Homozygote*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hyperlipoproteinemia Type II / drug therapy*
  • Hyperlipoproteinemia Type II / genetics
  • Hyperlipoproteinemia Type II / metabolism
  • Male
  • Mevalonic Acid / blood
  • Mevalonic Acid / urine
  • Mutation
  • Polymorphism, Single-Stranded Conformational
  • Prognosis
  • Pyrroles / administration & dosage
  • Pyrroles / therapeutic use*
  • Receptors, LDL / blood
  • Receptors, LDL / genetics


  • Anticholesteremic Agents
  • Biomarkers
  • Cholesterol, LDL
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Receptors, LDL
  • DNA
  • Cholesterol
  • Atorvastatin
  • Mevalonic Acid