Brief Communications1 October 2002
    Author, Article, and Disclosure Information



    Muscle symptoms in patients who are treated with statins and have normal creatine kinase levels are not well understood.


    To report biopsy-confirmed myopathy and normal creatine kinase levels associated with statin use.


    Case reports from preliminary analysis of an ongoing clinical trial.


    Clinical research center in a community hospital.


    Four patients with muscle symptoms that developed during statin therapy and reversed during placebo use.


    1] Patients' ability to identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength.


    All four patients repeatedly distinguished blinded statin therapy from placebo. Strength testing confirmed weakness during statin therapy that reversed during placebo use. Muscle biopsies showed evidence of mitochondrial dysfunction, including abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy.


    Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum creatine kinase levels.

    *For members of the Scripps Mercy Clinical Research Center, see the Appendix.


    • 1. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med1998;339:1349-57. [PMID: 9841303] CrossrefMedlineGoogle Scholar
    • 2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet1994;344:1383-9. [PMID: 7968073] MedlineGoogle Scholar
    • 3. Sacks FMPfeffer MAMoye LARouleau JLRutherford JDCole TGet al The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med1996;335:1001-9. [PMID: 8801446] CrossrefMedlineGoogle Scholar
    • 4. Farmer JALearning from the cerivastatin experience. Lancet2001;358:1383-5. [PMID: 11705478] CrossrefMedlineGoogle Scholar
    • 5. England JDWalsh JCStewart PBoyd IRohan AHalmagyi GMMitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors—simvastatin and pravastatin [Letter]. Aust N Z J Med1995;25:374-5. [PMID: 8540887] CrossrefMedlineGoogle Scholar
    • 6. Sinzinger HSchmid PO'Grady JTwo different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Co-enzyme-A-reductase inhibitor treatment [Letter]. Atherosclerosis1999;143:459-60. [PMID: 10217378] MedlineGoogle Scholar
    • 7. Ucar MMjörndal TDahlqvist RHMG-CoA reductase inhibitors and myotoxicity. Drug Saf2000;22:441-57. [PMID: 10877038] CrossrefMedlineGoogle Scholar
    • 8. Masters BAPalmoski MJFlint OPGregg REWang-Iverson DDurham SKIn vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol1995;131:163-74. [PMID: 7878672] CrossrefMedlineGoogle Scholar
    • 9. Nakahara KKuriyama MSonoda YYoshidome HNakagawa HFujiyama Jet al Myopathy induced by HMG-CoA reductase inhibitors in rabbits: a pathological, electrophysiological, and biochemical study. Toxicol Appl Pharmacol1998;152:99-106. [PMID: 9772205] CrossrefMedlineGoogle Scholar
    • 10. Marino MNicholas JAGleim GWRosenthal PNicholas SJThe efficacy of manual assessment of muscle strength using a new device. Am J Sports Med1982;10:360-4. [PMID: 7180955] CrossrefMedlineGoogle Scholar
    • 11. Dubowitz VMuscle Biopsy—A Practical Approach. London: Bailliere Tindall; 1985. Google Scholar
    • 12. Stubbs RJSchwartz MSGerson RJThornton TJBayne WFComparison of plasma profiles of lovastatin (mevinolin), simvastatin (epistatin) and pravastatin (epstatin) in the dog. Drug Invest1990;2 Suppl 2 18-28. CrossrefGoogle Scholar
    • 13. Gruer PJVega JMMercuri MFDobrinska MRTobert JAConcomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol1999;84:811-5. [PMID: 10513779] CrossrefMedlineGoogle Scholar
    • 14. Gaist DRodríguez LAHuerta CHallas JSindrup SHLipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology2001;12:565-9. [PMID: 11505177] CrossrefMedlineGoogle Scholar
    • 15. Lanctôt KLNaranjo CAComparison of the Bayesian approach and a simple algorithm for assessment of adverse drug events. Clin Pharmacol Ther1995;58:692-8. [PMID: 8529335] CrossrefMedlineGoogle Scholar
    • 16. Raskind JYEl-Chaar GMThe role of carnitine supplementation during valproic acid therapy. Ann Pharmacother2000;34:630-8. [PMID: 10852092] CrossrefMedlineGoogle Scholar
    • 17. Ogasahara SEngel AGFrens DMack DMuscle coenzyme Q deficiency in familial mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A1989;86:2379-82. [PMID: 2928337] CrossrefMedlineGoogle Scholar
    • 18. Phillips PHaas RBarshop BBannykh SAmjadi DUtility of abnormal 3-methylglutaconic aciduria (3MGA) in diagnosing statin associated myopathy. Atheroscler Thromb Vasc Biol Online Journal2002;22:878. Google Scholar
    • 19. Scaglia FSutton VRBodamer OAVogel HShapira SKNaviaux RKet al Mitochondrial DNA depletion associated with partial complex II and IV deficiencies and 3-methylglutaconic aciduria. J Child Neurol2001;16:136-8. [PMID: 11292221] CrossrefMedlineGoogle Scholar