A comprehensive review and meta-analysis of risk factors for statin-induced myopathy
To aid prescribers in assessing a patient’s risk for statin-induced myopathy (SIM), we performed a comprehensive review of currently known risk factors and calculated aggregated odds ratios for each risk factor through a meta-analysis.
This meta-analysis was done through four phases: (1) Identification of the relevant primary literature; (2) abstract screening using inclusion and exclusion criteria; (3) detailed review and data extraction; and (4) synthesis and statistical analysis.
Out of 44 papers analyzed from 836 papers searched from MEDLINE, 18 different potential risk factors were collected, divided into three categories: three demographics (11 papers), ten clinical factors (31 papers), and five pharmacogenetics/biomarkers (12 papers). Risk factors significant for myopathy and/or rhabdomyolysis included age, gender, diabetes, renal impairment, cardiovascular disease, certain interacting drugs, and mutations of the SLCO1B1 gene, which encodes a transporter protein in the liver. Several factors, such as gender, race, cardiovascular disease, and the GATM gene, which encodes a protein for creatine synthesis, appeared to be protective in terms of the outcomes of interest.
This comprehensive assessment of risk factors can help support clinicians in reducing the incidence of SIM in their patient population on statins.
KeywordsStatins Risks Risk factors Comprehensive review Myotoxicity Statin-induced myopathy
This work was made possible by the support of Clem MacDonald chair account and by Lilly Endowment Inc. Physician Scientist Initiative. We gratefully acknowledge Lane Coffee’s help with manuscript preparation, and Sandy Poremba’s and Lisa Gill’s in preparing the bibliography.
This work was further supported by VA HSR&D grant CIN 13-416 at the Richard L. Roudebush Veterans Affairs Medical Center in Indianapolis, Indiana.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- 1.Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes the MIRACL study: a randomized controlled trial. JAMA 285:1711–1718CrossRefPubMedGoogle Scholar
- 4.Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, de Backer G, de Bacquer D, Ducimetière P, Jousilahti P, Keil U, Njølstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM, SCORE project group (2003) Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 24:987–1003. https://doi.org/10.1016/S0195-668X(03)00114-3 CrossRefPubMedGoogle Scholar
- 5.Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D (2008) Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 52:1769–1781. https://doi.org/10.1016/j.jacc.2008.08.039 CrossRefPubMedGoogle Scholar
- 7.Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD (2010) Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf 33:171–187. https://doi.org/10.2165/11319380-000000000-00000 CrossRefPubMedGoogle Scholar
- 8.Gu Q, Paulose-Ram R, Burt VL, Kit BK (2014) Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003–2012. NCHS data brief, no 177. National Center for Health Statistics, HyattsvilleGoogle Scholar
- 9.Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF, American College of Cardiology/American Heart Association Task Force on Practice Guidelines (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the american college of cardiology/american heart association task force on practice guidelines. Circulation 129:85–S45. https://doi.org/10.1161/01.cir.0000437738.63853.7a CrossRefGoogle Scholar
- 11.Alfirevic A, Neely D, Armitage J, Chinoy H, Cooper RG, Laaksonen R, Carr DF, Bloch KM, Fahy J, Hanson A, Yue QY, Wadelius M, Maitland-van der Zee AH, Voora D, Psaty BM, Palmer CNA, Pirmohamed M (2014) Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther 96:470–476. https://doi.org/10.1038/clpt.2014.121 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol 8:S58–71. https://doi.org/10.1016/jjacl201403.004
- 15.Thompson PD, Clarkson P, Karas RH (2003) Statin-associated myopathy. JAMA 289:1681.1690Google Scholar
- 17.Patel J, Superko HR, Martin SS, Blumenthal RS, Christopher-Stine L (2015) Genetic and immunologic susceptibility to statin-related myopathy. Atherosclerosis 240:260–271. https://doi.org/10.1016/j.atherosclerosis.2015.03.025 CrossRefPubMedGoogle Scholar
- 21.Gamboa CM, Safford MM, Levitan EB, Mann DM, Yun H, Glasser SP, Woolley JM, Robert R, Farkouh M, Muntner P (2014) Statin underuse and low prevalence of LDL-C control among U.S. adults at high risk of coronary heart disease. Am J Med Sci 348:108–114. https://doi.org/10.1097/MAJ.0000000000000292 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Gupta A, Thompson PD (2011) The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis 215:23–29. https://doi.org/10.1016/j.atherosclerosis.2010.11.039 CrossRefPubMedGoogle Scholar
- 26.Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod H, Voora D, Krauss RM, Roden DM, Feng Q, Cooper-Dehoff RM, Gong L, Klein TE, Wadelius M, Niemi M, Clinical Pharmacogenomics Implementation Consortium (CPIC) (2012) The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 92:112–117. https://doi.org/10.1038/clpt.2012.57 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Luzum JA, Kitzmiller JP, Isackson PJ, Ma C, Medina MW, Dauki AM, Mikulik EB, Ochs-Balcom HM, Vladutiu GD (2015) GATM polymorphism associated with the risk for statin-induced myopathy does not replicate in case-control analysis of 715 dyslipidemic individuals. Cell Metab 21:622–627. https://doi.org/10.1016/j.cmet.2015.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Mangravite LM, Engelhardt BE, Medina MW, Smith JD, Brown CD, Chasman DI, Mecham BH, Howie B, Shim H, Naidoo D, Feng QP, Rieder MJ, Chen YDI, Rotter JI, Ridker PM, Hopewell JC, Parish S, Armitage J, Collins R, Wilke RA, Nickerson DA, Stephens M, Krauss RM (2013) A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 502:377–380. https://doi.org/10.1038/nature12508 CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Su J, Xu H, Yang J, Yu Q, Yang S, Zhang J, Yao Q, Zhu Y, Luo Y, Ji L, Zheng Y, Yu J (2015) ABCB1 C3435T polymorphism and the lipid-lowering response in hypercholesterolemic patients on statins: a meta-analysis. Lipids Health Dis 14:122. https://doi.org/10.1186/s12944-015-0114-2 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Ghatak A, Faheem O, Thompson PD (2010) The genetics of statin-induced myopathy. Atherosclerosis 210:337–343. https://doi.org/10.1016/j.atherosclerosis.2009.11.033 CrossRefPubMedGoogle Scholar
- 43.Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M (2014) The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update suppl material. Clin Pharmacol Ther 96:1–6. https://doi.org/10.1038/clpt.2014.125 CrossRefGoogle Scholar