Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia
Introduction
The low-density lipoprotein receptor (LDLR) is responsible for the cellular binding and subsequent uptake and degradation of low-density lipoprotein (LDL) and remnant lipoproteins from the blood and plays a key role in regulating the plasma concentrations of LDL [1]. Familial hypercholesterolaemia (FH) is an inherited disorder caused by mutations in the LDLR gene which results in either the failure to synthesize receptors from the mutant gene or in the production of receptors which fail to bind or internalize LDL normally [2]. The LDL receptor deficiency results in an impaired clearance of LDL from plasma and the resultant hypercholesterolaemia predisposes these patients, if untreated, to premature atherosclerosis, particularly coronary artery disease. The HMG CoA reductase inhibitors, or statins, act primarily in the liver to inhibit the rate limiting enzyme in cholesterol synthesis, which in turn leads to a decrease in the intracellular pool of cholesterol and results in an increased expression of LDL receptors and a concurrent increase in the catabolism of LDL and other apolipoprotein-B containing lipoproteins [3]. Patients with heterozygous FH respond remarkably well to statin therapy due to their ability to upregulate the remaining normal LDLR allele and thus, the number of functional LDL receptors. In contrast, patients with homozygous FH (HFH), in whom both LDLR alleles are abnormal, respond poorly, if at all, to conventional doses of statin therapy, because they produce only a small quantity of functional receptors (receptor defective) or no receptors at all (receptor negative) [2]. HFH remains a very difficult condition to treat and the majority of patients with this disorder die from accelerated atherosclerosis before 30 years of age. Recent advances in therapy have, however, improved the prognosis for patients with HFH. Regular plasma exchange or LDL-apheresis has been shown to reduce the integrated mean LDL-cholesterol levels by 40–50% and can delay the progression of coronary artery disease and improve survival [4]. Apheresis is expensive, concentrated in a few highly specialized centres and requires 4–5 h every week or 2 weeks to be effective. Liver transplantation is the most definitive treatment currently available for HFH but carries a significant risk of morbidity and mortality, including that associated with the long term use of immunosuppressants [5]. More recently, gene therapy has been attempted, with little success, to restore function of the defective LDLR gene [6]. In view of the lack of convenient and safe treatment modalities to lower LDL-cholesterol in patients with HFH, we have evaluated the LDL-cholesterol lowering efficacy and short term safety of expanded doses of simvastatin (80 and 160 mg/day) which are beyond the current recommended dosage range in patients with HFH. The rationale for the study was that higher doses of simvastatin would result in more profound inhibition of cholesterol synthesis leading to decreased hepatic production of apo-B containing lipoproteins.
Section snippets
Patients
Patients with HFH attending the Lipid Clinic at the Johannesburg Hospital were asked to participate in the study. The diagnosis of HFH was based on the presence of (i) serum LDL-cholesterol levels consistently greater than 12 mmol/l; (ii) the appearance of xanthomas in the first decade of life; (iii) documentation in both parents of hypercholesterolaemia or clinical signs indicative of the heterozygous state; and (iv) confirmation by DNA analysis of the LDL receptor gene. Familial defective
Results
A total of 12 patients, seven males and five females, were recruited for the study. Nine patients were homozygotes or compound heterozygotes for FH Afrikaner-1, -2 or -3. These three founder-type LDLR mutations together account for more than 80% of FH in Afrikaners [18]. The FH Afrikaner-1 and -3 mutations are functional class 2B mutations which have 10–20% of residual LDLR activity (receptor defective) 19, 20. The FH Afrikaner-2 mutation is a functional class two and five mutation with <2% of
Discussion
This study shows that doses of simvastatin beyond the recommended maximum dose of 40 mg/day are effective in lowering LDL-cholesterol in subjects with HFH. At a dose of 160 mg/day there was a 31% decrease in LDL-cholesterol. The LDL-cholesterol lowering effect appears to be dose dependent and is not determined by the frequency of administration of simvastatin. Reduction of LDL-cholesterol can induce regression of coronary atherosclerosis in patients with familial hypercholesterolaemia [25]. In
Acknowledgements
This study was supported by a grant from Merck. Dr Maritha Kotze, University of Stellenbosch, is kindly acknowledged for performing the DNA analysis. J. Pieters is thanked for preparing the manuscript.
References (41)
- et al.
The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day
Am J Cardiol
(1997) - et al.
Cholesterol lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia
Atherosclerosis
(1993) - et al.
Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study
Atherosclerosis
(1995) - et al.
Role of cholesterol in regulating apolipoprotein B secretion by the liver
J Lipid Res
(1996) - et al.
Lovastatin therapy reduces low-density-lipoprotein apo-B levels in subjects with combined hyperlipidaemia by reducing the production of apo-B containing lipoproteins: Implications for the pathophysiology of apo-B production
J Lipid Res
(1990) - et al.
Comparative hypolipidaemic effects of lovastatin and simvastatin in patients with heterozygous familial hypercholesterolaemia
Atherosclerosis
(1992) - et al.
A receptor mediated pathway for cholesterol homeostasis
Science
(1986) - Goldstein JL, Brown MS. Familial hypercholesterolaemia. In: Stanburg JB, Wyngaarden JB, Fredrickson DS, editors. The...
HMG-CoA reductase inhibitors for the treatment of hypercholesterolaemia
New Engl J Med
(1988)- et al.
Advances in LDL-apheresis for the treatment of severe hypercholesterolaemia
Curr Opin Lipidol
(1994)
Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolaemia
New Engl J Med
A pilot study of ex-vivo gene therapy for homozygous familial hypercholesterolaemia
Nature Med
Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia
Drugs
Standardization of micromethods for plasma cholesterol, triglyceride and HDL-cholesterol with the Lipid Clinics methodology
J Clin Chem
The Centers for Disease Control-National Heart, Lung and Blood Institiute Lipid Standardization Program: An approach to accurate and precise lipid measurements
Clinics Lab Med
A comprehensive evaluation of the heparin manganese precipitation procedure for estimating high-density lipoprotein cholesterol
J Lipid Res
Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge
Clin Chem
International Federation of Clinical Chemistry Standardization Project for Measurements of Apolipoproteins A-1 and B-II: Evaluation and selection of candidate reference materials
Clin Chem
Development of a competitive binding enzyme-linked immunoabsorbent assay (ELISA) for plasma apoprotein E using a monoclonal antibody (Mab)
Clin Chem
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2017, The Lancet Diabetes and EndocrinologyCitation Excerpt :Conventional therapy consists of statins and ezetimibe, which are modestly effective; statins reduce LDL cholesterol by 25% and ezetimibe reduces LDL cholesterol by 20%. When available, LDL apheresis can be used in addition to these treatments.5–8 The very high baseline concentrations of LDL cholesterol in these patients translates into large absolute reductions and apparent improvements in morbidity and mortality from cardiovascular disease with both statins and apheresis.8,9