Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia

E. Leitersdorf*, S. Eisenberg, O. Eliav, Y. Friedlander, N. Berkman, E. J. Dann, D. Landsberger, E. Sehayek, V. Meiner, M. Wurm, J. M. Bard, J. C. Fruchart -, Y. Stein

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

94 Scopus citations

Abstract

Background. In familial hypercholesterolemia, plasma lipoproteins can be modulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, although the underlying response mechanisms are still unknown. Methods and Results. A single-blind study with fluvastatin, an HMG-CoA reductase inhibitor, was conducted in 64 familial hypercholesterolemia patients who had defined apolipoprotein E (apo E) and apolipoprotein(a) [apo(a)] isoforms. Plasma lipids and lipoproteins were analyzed throughout the study. The patients were grouped according to low density lipoprotein (LDL) receptor genotype. After 4 weeks of treatment with 40 mg of fluvastatin, the mean decrease in plasma LDL cholesterol (LDL-C) in patients with the genetically characterized 'Sephardic' and 'Lithuanian' mutations was 16-18%, whereas in the other three groups, it was 25-30% (p<0.005). High density lipoprotein cholesterol (HDL-C) levels increased in all groups. Multivariate analyses suggested that 41% of the LDL-C response can be explained by the LDL receptor mutation, body mass index, apo E3/E4 phenotype, apo(a) isoform LpS2, and baseline LDL-C levels, and 46% of the change in HDL- C is associated with age, sex, body mass index, baseline HDL-C, and the Sephardic mutation. Conclusions. Fluvastatin exhibits diverse and independent effects on plasma lipoproteins related to several constitutional, genetic, and familial factors. Information regarding these factors may provide better prediction of patients' clinical responses to fluvastatin.

Original languageAmerican English
Pages (from-to)III35-III44
JournalCirculation
Volume87
Issue number4 SUPPL.
StatePublished - 1993
Externally publishedYes

Keywords

  • HMG-CoA reductase inhibitor
  • cholesterol
  • fluvastatin
  • genetics

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