Electrophysiologic and clinico-pathologic characteristics of statin-induced muscle injury

Document Type: Original Article


1 Department of Physiology, College of Medicine, Al-Nahrain University, Baghdad, Iraq

2 Department of Medicine, College of Medicine, Al-Nahrain University, Baghdad, Iraq


Objective(s):In this study, we aimed at evaluation of electrophysiological and histopathalogical characteristics of statin-induced muscle injury as well as clinical features of patients who develop this condition in terms of frequency and pattern of evolution.
Materials and Methods: Forty patients (age 39-74 years) including 25 subjects with type 2 diabetes mellitus, 9 with cardiovascular diseases and 6 with hyperlipidemia,  who were receiving atrovastatin 40 mg/day for variable period, were studied. Thirty three healthy subjects (age 31-74 years) served as control group. Creatine phosphokinease level, thyroid function, motor unit potential parameters and muscle fiber conduction velocity of biceps brachii and tibialis anterior muscles were measured.
Results: Creatine phosphokinase level was elevated in statin users, particularly in those with diabetes mellitus. Less than 50% of statinusers experienced symptoms related to muscle injury. Muscle fiber conduction velocity of the biceps brachii muscle was significantly reduced. Statinusers with diabetes mellitus showed significant changes in electrophysiological parameters as compared to those with cardiovascular diseases and hyperlipidemia. Muscle biopsies showed muscle fiber variation in size, fibrosis and mild inflammatory cell infiltration. Immunohistochemical evaluation of muscle biopsies showed positive expression of Bcl-2 and one patient showed positive P53 immunohistochemical expression with elevated level of creatine phosphokinase.
Conclusion: Atorvastatin increased average creatine kinase, suggesting, statins produce mild muscle injury even in asymptomatic subjects. Diabetic statin users were more prone to develop muscle injury than others. Muscle fiber conduction velocity evaluation is recommended as a simple and reliable test to diagnose statin-induced myopathy instead of invasive muscle biopsy.


1. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf 2011; 10:373-387.

2. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, et al. Effect of statins on skeletal muscle function. Circulation 2013; 127:96-103.

3. Banach M, Serban C, Sahebkar A, Ursoniu S, Rysz J, Muntner P, et al. Effects of coenzyme Q10 on statin-induced myopathy: A Meta-analysis of randomized controlled trials. Mayo Clin Proc 2015; 90:24-34.

4. Al-Sulaiman AA, Al-Khamis FA. Statin-induced myopathy: a clinical perspective. Bahrain Med Bull 2009; 31.

5. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med 2009; 150:858-68.

6. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. National lipid association statin safety assessment task force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97:89C-94C.

7. Tomaszewski M, Stępień KM, Tomaszewska J, Czuczwar SJ. Statin-induced myopathies. Pharmacol Rep 2011; 63:859-66.

8. Paganoni S, Amato A. Electrodiagnostic Evaluation of myopathies. Phys Med Rehabil Clin N Am 2013; 24:193-207.

9. Baer AN, Wortmann RL. Myotoxicity associated with lipid-lowering drugs. Curr Opin Rheumatol 2007; 19:67-73.

10. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002; 137:581-585.

11. Findling O, Meier N, Sellner J, Nedeltchev K, Arnold M. Clinical reasoning: rhab- domyolysis after combined treatment with simvastatin and fluconazole. Neurology 2008; 71:e34-e37.

12. Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008; 8:66-72.

13. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002; 40:163-71.

14. Huynh T, Cordato D, Yang F, Choy T, Johnstone K, Bagnall F, et al. HMG CoA reductase-inhibitor-related myopathy and the influence of drug interactions. Intern Med J 2002; 32:486-490.

15. Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010; 41:185-190.

16. American Diabetes Association. Standards of medical care in diabetes -2014. Diab Care 2014; 37:S1.

17. Ahmad Z. Statin intolerance. Am J Cardiol 2014; 113:1765-1767.

18. Gloth FM III, Scheve AA, Stober CV, Chow S, Prosser J. The functional pain scale: reliability, validity, and responsiveness in an elderly population. J Am Med Dir Assoc 2001; 2:110-114.

19. Troni W, Cantello R, Rainero I. Conduction velocity along human muscle fibers in situ. Neurology 1983; 33:1453-1459.

20. Wald JJ. The effects of toxins on muscle. Neurol Clin 2000; 18:695-717.

21. Sieb JP, Gillessen T. Iatrogenic and toxic myopathies. Muscle Nerve 2003; 27:142-156.

22. Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiat 2009; 80:832-838.

23. Mammen AL, Amato AA. Statin myopathy: a review of recent progress. Curr Opin Rheumatol 2010; 22: 644-650.

24. Karas RH , Mohaupt MG, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L, et al. Association between statin-associated myopathy and skeletal muscle damage. CMAJ 2009; 181:E11-E18.

25. Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep 2010; 12:213-220.

26. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther 2005; 19:403-414.

27. Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006; 114:2788-2797.

28. Chatzizisis Y, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy. Drug Saf 2010; 33:171-187.

29. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin associated myopathy. Arch Intern Med 2005; 165:2671-2676.

30. Mantel-Teeuwisse AK, Klungel OH, Herings RM, van Puijenbroek EP, Porsius AJ, de Boer A. Myopathy due to statin/fibrate use in the Netherlands. Ann Pharmacother 2002; 36:1957-1960.

31. Wright RS, Murphy JG, Bybee KA, Kopecky SL, LaBlanche JM. Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: efficacy and mechanism of benefit. Mayo Clin Proc 2002; 77:1085-1092.

32. Rubin DI, Daube JR. Application of clinical neurophysiology: assessing peripheral neuromuscular symptom complexes. In: Daube JR, Rubin DI. Linical Neurophysiology.3rd ed. Chapter 47. Oxford University Press; 2009. p.827.

33. Strommen JA,  Johns  JS,  Kim  CT,  Williams FH, Weiss  LD,  Weiss  JM,  et al. Neuromuscular rehabilitation and electrodiagnosis. 3. Diseases of muscles and neuromuscular junction. Arch Phys Med Rehabil 2005; 86:S18-27.

34. Hanaoka BY, Peterson CA, Horbinski C, Crofford LJ. Implications of glucocorticoid therapy in idiopathic inflammatory myopathies. Nat Rev Rheumatol 2012; 8:448-457.

35. Gutiérrez GG, Lopez CB, Navacerrada F, Martínez AM. Use of electromyography in the diagnosis of inflammatory myopathies. Reumatol Clin 2012; 8:195-200.

36. Andreassen S, Arendt-Nielsen L. Muscle fiber conduction velocity in motor units of the human anterior tibial muscle: a new size principle parameter. J Physiol 1987; 391:561-571.

37. Blijham PJ, Ter Laak HJ, Schelhaas HJ, van Engelen BG, Stegeman DF, Zwarts MJ. Relation between muscle fiber conduction velocity and fiber size in neuromuscular disorders. J Appl Physiol 2006; 100:1837-1841.

38. Minetto MA, Botter A, Lanfranco F, Baldi M, Ghigo E, Arvat E. Muscle fiber conduction slowing and decreased levels of circulating muscle proteins after short-term dexamethasone administration in healthy subjects. J Clin Endocrinol Metab 2010; 95:1663-1671.

39. Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M. Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells. J Pharmacol Exp Ther 2005; 314:1032-1041.

40. Matzno S, Yasuda S, Juman S, Yamamoto Y, Nagareya-Ishida N, Tazuya-Murayama K, et al. Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. J Pharm Pharmacol 2005; 57:1475-1484.

41. Achanta G, Huang P. Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species generating agents. Cancer Res 2004; 64:6233-6239.

42. Cafforio P, Dammacco F, Gernone A, Silvestris F. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 2005; 26:883-891.

43. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy an observational clinical cohort study. J Am Coll Cardiol 2012; 60:2384-2390.

44. Alzira A, Carvalho S, Poti Lima ÜW, Valiente RA. Statin and fibrate associated myopathy: Study of eight patients. Arq Neuropsiquiatr 2004; 62:257-261.

45. Law M, Rudnicka AR. Statin safety: A systematic review. Am J Cardiol 2006; 97: 52c-60c.

46. Josan K, Majumdar SR, McAlister FA. The Efficacy and safety of intensive statin therapy: A Meta-analysis of randomized trials. CMAJ 2008; 178:576-84.

47. Dostalek M, Sam WJ, Paryani KR, Macwan JS, Gohh RY, Akhlaghi F. Diabetes mellitus reduces the clearance of atorvastatin lactone: results of a population pharmacokinetic analysis in renal transplant recipients and in vitro studies using human liver microsomes. Clin Pharmacokinet 2012; 51:591-606.

48. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy. J Am Coll Cardiol 2007; 49:2231-2237.