Introduction Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol150.Issue2.Jun2000:

Atherosclerosis 150 2000 421 – 428 Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia Frederick J. Raal a, , Anuradha S. Pappu b , D. Roger Illingworth b , Gillian J. Pilcher a , A. David Marais c , Jean C. Firth c , Maritha J. Kotze d , Therese M. Heinonen e , Donald M. Black e a The Carbohydrate and Lipid Metabolism Research Group, Department of Medicine, Uni6ersity of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South Africa b The Di6ision of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health Sciences Uni6ersity, Portland, OR, USA c The Department of Internal Medicine and MRC Cape Heart Group, Uni6ersity of Capetown Medical School, Capetown, South Africa d The Di6ision of Human Genetics, Faculty of Medicine, Uni6ersity of Stellenbosch, Tygerberg, South Africa e Parke-Da6is Pharmaceutical Research, Ann Arbor, MI, USA Received 13 July 1999; received in revised form 28 September 1999; accepted 15 October 1999 Abstract 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 atorvastatinday. The dose of atorvastatin was increased further to 120 mgday in 20 subjects and to 160 mgday in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mgkg body wt per day. LDL cholesterol levels were reduced by 17 at the 40 mgday and by 28 at the 80 mgday dosage P B 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 mgday dose and by 63 at the 80 mgday dosage P B 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 mgday 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 mgday. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords : Atorvastatin; Cholesterol synthesis; Mevalonic acid; Homozygous familial hypercholesterolaemia www.elsevier.comlocateatherosclerosis

1. Introduction

Homozygous familial hypercholesterolaemia HoFH is an autosomal dominantly inherited disorder charac- terized by markedly elevated levels of plasma low density lipoprotein LDL cholesterol, tendon xanthomas, and severe premature coronary artery disease [1]. If un- treated, the majority of patients with this disorder die from accelerated atherosclerosis before the age of 30 years [2]. HoFH has hitherto been regarded as refractory to lipid-lowering drugs necessitating the use of radical forms of therapy such as apheresis, portacaval shunting and liver transplantation. High dose HMG CoA reduc- tase inhibitor or statin therapy has recently been shown to be partially effective in lowering LDL cholesterol levels in this patient group [3,4]. However, the mecha- nisms by which high dose statins reduce LDL choles- terol levels in HoFH requires further elucidation. Corresponding author. Tel.: + 27-11-488-3538; fax: + 27-11-643- 8777. E-mail address : 014fredchiron.wits.ac.za F.J. Raal 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 3 5 - 9 Mevalonic acid MVA, an intermediate in choles- terol synthesis and the immediate product of HMG CoA reductase is present in plasma and urine [5]. Previous studies have shown that the concentrations of mevalonate in plasma and urine parallel the rates of hepatic and whole body cholesterol synthesis in both animals and man [6,7]. There is also a very good correlation between plasma MVA and the rate of incor- poration of deuterium into plasma free cholesterol in humans [8]. Plasma MVA concentrations exhibit diur- nal variations, whereas the 24-h urinary MVA excretion reflects the integrated plasma concentrations and thus provides a more practical way of measuring the influ- ence of dietary or pharmaceutical manipulations on cholesterol synthesis than conventional sterol balance techniques [9]. In the present study, we evaluated the effects of high doses of atorvastatin 40 – 160 mgday on steady state concentrations of plasma lipids and lipoproteins, plasma MVA and the 24-h urinary excretion of MVA in patients with well characterized HoFH.

2. Methods