title: Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia.
abstract: Fasting plasma mevalonic acid (MVA), an indicator of in vivo cholesterol synthesis, was measured in 35 patients with familial hypercholesterolaemia (FH) of whom 7 were treated with pravastatin 10-40 mg/day, 7 with simvastatin 10-40 mg/day and 21 with atorvastatin 80 mg/day. Reductions in low density lipoprotein (LDL) cholesterol and MVA on maximal dose therapy differed significantly between the three drugs: 34.7%, 42.9% and 54.0% (P = 0.0001), and 31.6%, 48.9% and 58.8% (P = 0.004), respectively. Patients on atorvastatin were subdivided according to whether their reduction in LDL cholesterol on treatment was above or below the mean percentage change for the whole group. Basal values of LDL cholesterol did not differ significantly, but above average responders had a significantly higher mean pre-treatment level of MVA (6.2 +/- 0.60 vs. 4.3 +/- 0.61 ng/ml, P < 0.05) than below average responders. When all three drug groups were pooled above average responders showed a significantly greater absolute decrease in MVA on treatment than below average responders (3.85 +/- 0.48 vs. 2.33 +/- 0.40 ng/ml, P < 0.05). However, there was no significant correlation between the magnitude of the decreases in LDL cholesterol and MVA. These findings suggest that FH patients who responded well to statins had a higher basal level of plasma MVA, i.e. a higher rate of cholesterol synthesis, which was more susceptible to pharmacological inhibition. The more marked cholesterol lowering effect of atorvastatin 80 mg/day presumably reflects, at least in part, its ability to inhibit HMG-CoA reductase to a greater extent than maximal recommended doses of pravastatin and simvastatin of 40 mg/day.
authors.affiliation: MRC Lipoprotein Team and Department of Clinical Pharmacology, Hammersmith Hospital, London, UK.
authors.forename: R P
authors.initials: RP
authors.lastname: Naoumova
authors.forename: A D
authors.initials: AD
authors.lastname: Marais
authors.forename: J
authors.initials: J
authors.lastname: Mountney
authors.forename: J C
authors.initials: JC
authors.lastname: Firth
authors.forename: N B
authors.initials: NB
authors.lastname: Rendell
authors.forename: G W
authors.initials: GW
authors.lastname: Taylor
authors.forename: G R
authors.initials: GR
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069059:Atorvastatin; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000209:etiology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008798:Mevalonic Acid / Q000097:blood*; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D019821:Simvastatin
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D008077:Lipoproteins, LDL; D011758:Pyrroles; D002784:Cholesterol; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid