High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.
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.
Päivä
Hannu
H
Department of Internal Medicine, University Hospital of Tampere, Finland.
Thelen
Karin M
KM
Van Coster
Rudy
R
Smet
Joél
J
De Paepe
Boel
B
Mattila
Kari M
KM
Laakso
Juha
J
Lehtimäki
Terho
T
von Bergmann
Klaus
K
Lütjohann
Dieter
D
Laaksonen
Reijo
R
D000328:Adult; D000367:Age Factors; D000368:Aged; D000069059:Atorvastatin; D001706:Biopsy; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D002950:Citrate (si)-Synthase / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D006538:Heptanoic Acids / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018579:Patient Selection; D010840:Phytosterols / Q000096:biosynthesis / Q000097:blood; D011758:Pyrroles / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D012737:Sex Factors; D019821:Simvastatin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D012855:Sitosterols / Q000097:blood; D013384:Succinate Cytochrome c Oxidoreductase / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014451:Ubiquinone / Q000097:blood / Q000737:chemistry
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010840:Phytosterols; D011758:Pyrroles; D012855:Sitosterols; D014451:Ubiquinone; C021273:campesterol; C001521:lathosterol; D002784:Cholesterol; D000069059:Atorvastatin; D019821:Simvastatin; D013384:Succinate Cytochrome c Oxidoreductase; D002950:Citrate (si)-Synthase