Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia

• Published in: Atherosclerosis Vol. 150; no. 2; pp. 421 - 428
• Main Authors: Raal, Frederick J., Pappu, Anuradha S., Illingworth, D.Roger, Pilcher, Gillian J., Marais, A.David, Firth, Jean C., Kotze, Maritha J., Heinonen, Therese M., Black, Donald M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.06.2000
• Subjects: Adolescent; Adult; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - therapeutic use; Atorvastatin; Biomarkers - blood; Biomarkers - urine; Child; Child, Preschool; Cholesterol - biosynthesis; Cholesterol - blood; Cholesterol synthesis; Cholesterol, LDL - blood; DNA - genetics; DNA Mutational Analysis; Female; Heptanoic Acids - administration & dosage; Heptanoic Acids - therapeutic use; Homozygote; Homozygous familial hypercholesterolaemia; 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; Mevalonic Acid - blood; Mevalonic Acid - urine; Mutation; Polymorphism, Single-Stranded Conformational; Prognosis; Pyrroles - administration & dosage; Pyrroles - therapeutic use; Receptors, LDL - blood; Receptors, LDL - genetics; Atorvastatin; Mevalonic acid; Cholesterol synthesis; Homozygous familial hypercholesterolaemia
• ISSN: 0021-9150; 1879-1484
• 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.