Elsevier

Atherosclerosis

Volume 135, Issue 2, December 1997, Pages 249-256
Atherosclerosis

Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia

https://doi.org/10.1016/S0021-9150(97)00168-8Get rights and content

Abstract

Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolaemia and premature coronary heart disease. Limited treatment options are available and the response to drug therapy has been poor. In the present paper, we have evaluated the efficacy and safety of simvastatin at doses beyond the current maximal dose of 40 mg/day in patients with HFH. After a 4 week placebo diet run-in period, 12 patients with well-characterized HFH were randomized to simvastatin 80 mg/day administered in three divided doses (n=8; group 1) or 40 mg once daily (n=4; group 2). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day, but with the drug given in three divided doses and treatment continued for an additional 9 weeks. All 12 patients completed the study and there were no serious or unexpected adverse effects. LDL-cholesterol concentrations fell by 14% at the 40 mg/day dose, but were reduced further at the higher doses (25% at the 80 mg/day and by 31% at the 160 mg/day dosage, P<0.0001). Excretion of urinary mevalonic acid, as an index of in vivo cholesterol biosynthesis, was reduced but did not correlate with reduction in LDL-cholesterol in the individual patients. The magnitude of response to therapy was not predicted by the LDL-receptor gene defect as patients with the same LDL-receptor mutations responded differently to the same dose of simvastatin therapy. The ability of expanded doses of simvastatin (80 or 160 mg/day) to reduce LDL-cholesterol levels in patients with HFH, even if receptor negative, suggests that at these doses, the drug reduces LDL production. Simvastatin therapy, at doses of 80 or 160 mg/day, should therefore be considered in all patients with HFH, either as an adjunct to apheresis, or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.

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.

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