High-dose Statins and Skeletal Muscle Metabolism in Humans: A Randomized, Controlled Trial

Clin Pharmacol Ther. 2005 Jul;78(1):60-8. doi: 10.1016/j.clpt.2005.03.006.

Abstract

Background: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle.

Methods: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up.

Results: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin.

Conclusions: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Atorvastatin
  • Biopsy
  • Cholesterol / analogs & derivatives*
  • Cholesterol / biosynthesis
  • Cholesterol / blood
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / drug effects
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / drug effects
  • Citrate (si)-Synthase / drug effects
  • Citrate (si)-Synthase / metabolism
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Electron Transport / drug effects
  • Female
  • Heptanoic Acids / blood
  • Heptanoic Acids / pharmacology
  • Heptanoic Acids / therapeutic use
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Hypercholesterolemia / drug therapy
  • Male
  • Middle Aged
  • Muscles / drug effects*
  • Muscles / metabolism*
  • Muscles / pathology
  • Patient Selection
  • Phytosterols / biosynthesis
  • Phytosterols / blood
  • Pyrroles / blood
  • Pyrroles / pharmacology
  • Pyrroles / therapeutic use
  • Sex Factors
  • Simvastatin / blood
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use
  • Sitosterols / blood
  • Succinate Cytochrome c Oxidoreductase / drug effects
  • Succinate Cytochrome c Oxidoreductase / metabolism
  • Time Factors
  • Ubiquinone / blood
  • Ubiquinone / chemistry

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Phytosterols
  • Pyrroles
  • Sitosterols
  • Ubiquinone
  • campesterol
  • lathosterol
  • Cholesterol
  • Atorvastatin
  • Simvastatin
  • Succinate Cytochrome c Oxidoreductase
  • Citrate (si)-Synthase