High-dose statins and skeletal muscle metabolism in humans: A randomized, controlled trial

• Published in: Clinical pharmacology and therapeutics 2005-07, Vol.78 (1), p.60-68
• Main Authors: Päivä, Hannu, Thelen, Karin M., Van Coster, Rudy, Smet, Joél, De Paepe, Boel, Mattila, Kari M., Laakso, Juha, Lehtimäki, Terho, Bergmann, Klaus, Lütjohann, Dieter, Laaksonen, Reijo
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Atorvastatin Calcium; Biological and medical sciences; 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; Medical sciences; Middle Aged; Muscles - drug effects; Muscles - metabolism; Muscles - pathology; Patient Selection; Pharmacology. Drug treatments; 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
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2005.03.006

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. Clinical Pharmacology & Therapeutics (2005) 78, 60–68; doi: 10.1016/j.clpt.2005.03.006