Inhibition of cholesterol synthesis by atorvastatin in homozygous familialhypercholesterolaemia

Patients with homozygous familial hypercholesterolaemia (HoFH) have markedl y elevated low density lipoprotein (LDL) cholesterol levels that are refrac tory 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 excretio n of MVA in patients with well characterized HoFH. Thirty-five HoFH patient s (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. Th e dose of atorvastatin was increased further to 120 mg/day in 20 subjects a nd 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 fi ve receptor negative patients was similar to that achieved in the 30 patien ts with residual LDL receptor activity. Plasma MVA and 24-h urinary excreti on of MVA, as markers of in vivo cholesterol synthesis, were elevated at ba seline and decreased markedly with treatment. Urinary MVA excretion decreas ed by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P < 0.0 1). There was a correlation between reduction in LDL cholesterol and reduct ion 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 furth er reduction in LDL cholesterol or urinary MVA excretion suggesting a plate au effect with no further inhibition of cholesterol synthesis at doses of a torvastatin greater than 80 mg/day. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.