title: Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia.
abstract: Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy and mechanism of action of a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin, was therefore investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. Changes in plasma lipids and mevalonic acid, an index of cholesterol synthesis, were measured and the kinetics of the rebound of low density lipoprotein cholesterol and apolipoprotein B after apheresis were analyzed. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo, accompanied by a 63% decrease in mevalonic acid. Percentage changes in low density lipoprotein cholesterol and mevalonic acid were closely correlated (r = 0.89, P = 0.007). The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo (P < 0.005 and <0.02) but changes in mean fractional clearance rates were not statistically significant. We conclude that atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein.
authors.affiliation: Department of Internal Medicine, University of Cape Town Medical School, Cape Town, South Africa.
authors.forename: A D
authors.initials: AD
authors.lastname: Marais
authors.forename: R P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: J C
authors.initials: JC
authors.lastname: Firth
authors.forename: C
authors.initials: C
authors.lastname: Penny
authors.forename: C K
authors.initials: CK
authors.lastname: Neuwirth
authors.forename: G R
authors.initials: GR
authors.lastname: Thompson
mesh_terms: D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001055:Apolipoproteins B / Q000097:blood; D000069059:Atorvastatin; D001781:Blood Component Removal; D008078:Cholesterol, LDL / Q000096:biosynthesis / Q000097:blood*; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008798:Mevalonic Acid / Q000097:blood; D011758:Pyrroles / Q000627:therapeutic use*
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D008055:Lipids; D008077:Lipoproteins, LDL; D011758:Pyrroles; D000069059:Atorvastatin; D008798:Mevalonic Acid