Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia

Frederick J. Raal, Gillian J. Pilcher, D. Roger Illingworth, Anuradha Pappu, Evan A. Stein, Peter Laskarzewski, Yale B. Mitchel, Michael R. Melino

Research output: Contribution to journalArticle

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Abstract

Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolemia 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 them 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.

Original languageEnglish (US)
Pages (from-to)249-256
Number of pages8
JournalAtherosclerosis
Volume135
Issue number2
DOIs
StatePublished - Dec 1997
Externally publishedYes

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Hyperlipoproteinemia Type II
Simvastatin
LDL Receptors
LDL Cholesterol
Blood Component Removal
Therapeutics
Mevalonic Acid
Hypercholesterolemia
LDL Lipoproteins
Pharmaceutical Preparations
Coronary Disease
Alleles
Cholesterol
Placebos
Diet
Safety
Drug Therapy
Mutation

Keywords

  • HMG CoA reductase inhibitors
  • Homozygous familial hypercholesterolaemia
  • Low density lipoprotein- cholesterol
  • Simvastatin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Raal, F. J., Pilcher, G. J., Illingworth, D. R., Pappu, A., Stein, E. A., Laskarzewski, P., ... Melino, M. R. (1997). Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis, 135(2), 249-256. https://doi.org/10.1016/S0021-9150(97)00168-8

Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. / Raal, Frederick J.; Pilcher, Gillian J.; Illingworth, D. Roger; Pappu, Anuradha; Stein, Evan A.; Laskarzewski, Peter; Mitchel, Yale B.; Melino, Michael R.

In: Atherosclerosis, Vol. 135, No. 2, 12.1997, p. 249-256.

Research output: Contribution to journalArticle

Raal, FJ, Pilcher, GJ, Illingworth, DR, Pappu, A, Stein, EA, Laskarzewski, P, Mitchel, YB & Melino, MR 1997, 'Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia', Atherosclerosis, vol. 135, no. 2, pp. 249-256. https://doi.org/10.1016/S0021-9150(97)00168-8
Raal, Frederick J. ; Pilcher, Gillian J. ; Illingworth, D. Roger ; Pappu, Anuradha ; Stein, Evan A. ; Laskarzewski, Peter ; Mitchel, Yale B. ; Melino, Michael R. / Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. In: Atherosclerosis. 1997 ; Vol. 135, No. 2. pp. 249-256.
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abstract = "Patients with homozygous familial hypercholesterolaemia (HFH) have abnormalities in both low-density lipoprotein (LDL) receptor alleles, resulting in severe hypercholesterolemia 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 them 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.",
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