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statin myopathy

Etiology: - most common adverse effect of statins - dose-dependent, statin specific dependency - hydrophilic statins (fluvastatin, pravastatin, & rosuvastatin) less likely than lipophilic statins (atorvastatin, simvastatin, lovastatin) [7] - a statin-associated autoimmune-necrotizing myopathy with autoantibody directed against HMG-CoA reductase, the pharmacologic target of statins [6,17] - occurs in a minority of patients with statin-induced myopathy - continues to progress even after discontinuing statin [7] - diet may be a trigger in the absence of statin prescription [19] - risk factors [8] - older age - female gender - renal insufficiency - coadministration of fibrates, niacin, & CYP3A4 inhibitors (macrolides, cyclosporine, itraconazole) - hypothyroidism - alcoholism - genetic predisposition Epidemiology: - adverse effects occur in 17% of patients, mostly myopathy [11] - myopathy in 31% of persons initiating statin, resulting in discontinuation of statin in 13% [24] - 2-3 cases of statin-associated autoimmune-necrotizing myopathy per 100,000 - may be more common 3/1000 in some Native American populations [22] Pathology: - statin use attenuates substrate use during maximal exercise, induces muscle fatigue during repeated muscle contractions, & decreases muscle mitochondrial oxidative capacity [21] - evidence presented that statin-associated autoimmune-necrotizing myopathy may be associated with a specific HLA subtype [23] Genetics: - genetic variants in SLCO1B1 gene may predispose to statin myopathy [16] - LILRB5 variant rs12975366: T > C Asp247Gly may predispose to statin myopathy [18] Clinical manifestations: - myalgias, muscle tenderness, muscle cramping, proximal muscle weakness - hyporeflexia may be noted - low back pain has been reported [7] - no rach Laboratory: - increase in serum creatine kinase (mild to rhabdomyolysis) - may occur with normal serum creatine kinase [1] - serum C-reactive protein generally normal - SLCO1B1 genotyping (simvastatin) [16] - LILRB5 genotyping (no corresponding Loinc) Special laboratory: - normal electromyography, generally not indicated Complications: - acute renal failure to due rhabdomyolysis - increased risk of hospitalization for acute renal failure with high-dose or potent statin [5] Differential diagnosis: - muscle tenderness distinguishes from inflammatory myopathy - polymyositis, dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy - inclusion body myositis with slow onset typically preexisting weakness for 5 years at presentation - polymyositis: - muscle pain & tenderness, if present, are mild - serum creatine kinase elevated - diabetic amyotrophy with no involvement of upper extremities - myasthenia gravis presents with fluctuating weakness of extraocular, bulbar, & proximal limb muscles & is painless. Management: - stop statin if - serum creatine kinase > 10-fold upper reference value, or severe myalgias [2] - elevated serum creatine kinase (mild-moderate), known CVD, on atorvastatin, stop atorvastatin & start rosuvastatin 20-40 mg when myalgias have resolved [25] - adverse effects occur in 13% of patients after rechallange with a different statin [11] - symptoms usually subside within a month or two after stopping the statin, but they sometimes persist longer [4] - fluvastatin, pravastatin, & rosuvastatin associated with less risk of myopathy than other statins [7] - simvastatin & pravastatin score best in overall safety profile [13] - CoQ10 may or may not help myalgias [2,3,7,9,20] - CoQ10 of no benefit [15] - no benefit of vitamin D [24] - immunosuppression may be required in patients with autoimmune- necrotizing statin myopathy [7]

Related

HMG CoA reductase inhibitor (statin)

Specific

immune-mediated necrotizing myopathy (IMNM)

General

toxic myopathy; drug-induced myopathy

References

  1. Journal Watch 22(23):171, 2002 Phillips PS et al Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 137:581, 2002 PMID: 12353945
  2. Statin-Associated Myopathy Detail-Document#: 220310 (subscription needed) http://www.prescribersletter.com
  3. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007 May 15;99(10):1409-12. Epub 2007 Apr 3. PMID: 17493470
  4. Prescriber's Letter 16(10): 2009 COMMENTARY: Statin Myopathy CHART: Clinically Significant Statin Drug Interactions GUIDELINES: Use and Safety of Statins (ACC/AHA/NHLBI, 2002) etail-Document#: 251008 (subscription needed) http://www.prescribersletter.com
  5. Dormuth CR et al Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ 2013;346:f880 PMID: 23511950 http://www.bmj.com/content/346/bmj.f880
  6. Mohassel P and Mammen AL The Spectrum of Statin Myopathy. Curr Opin Rheumatol. 2013;25(6):747-752. PMID: 24061077 http://www.medscape.com/viewarticle/814502
  7. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2021.
  8. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
  9. Lipid Lowering with Statins: How low should LDL go? Prescriber's Letter 11(4):19 2004 Detail-Document#: 200401 (subscription needed) http://www.prescribersletter.com
  10. Mansi I et al. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med 2013 PMID: 23877079 http://archinte.jamanetwork.com/article.aspx?articleid=1691918
  11. Zhang H et al Discontinuation of Statins in Routine Care Settings: A Cohort Study. Ann Intern Med. 2 April 2013;158(7):526-534 PMID: 23546564 http://annals.org/article.aspx?articleid=1671715 - Grundy SM Statin Discontinuation and Intolerance: The Challenge of Lifelong Therapy. Ann Intern Med. 2 April 2013;158(7):562-563 PMID: 23546569 http://annals.org/article.aspx?articleid=1671720
  12. Naci H et al Comparative Tolerability and Harms of Individual Statins: A Study-Level Network Meta-Analysis of 246,955 Participants from 135 Randomized Controlled Trials. Circulation. July 9, 2013 PMID: 23838105 http://circoutcomes.ahajournals.org/content/early/2013/07/09/CIRCOUTCOMES.111.000071.full.pdf+html
  13. Harper CR, Jacobson TA. Evidence-based management of statin myopathy. Curr Atheroscler Rep. 2010 Sep;12(5):322-30. PMID: 20628837
  14. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009 Jun 16;150(12):858-68. PMID: 19528564
  15. Banach M et al. Effects of coenzyme Q10 on statin-induced myopathy: A meta- analysis of randomized controlled trials. Mayo Clin Proc 2015 Jan; 90:24 PMID: 25440725 - Taylor BA et al. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015 Feb; 238:329. PMID: 25545331
  16. Ramsey LB, Johnson SG, Caudle KE et al The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014 Oct;96(4):423-8 PMID: 24918167
  17. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve. 2013 Oct;48(4):477-83 PMID: 23519993
  18. Siddiqui MK, Maroteau C, Veluchamy A et al A Common Missense Variant of LILRB5 Is Associated With Statin Intolerance and Myalgia. Eur Heart J. 2017;38(48):3569-3575 Medscape. March 2018 PMID: 29020356 Free PMC Article https://www.medscape.com/viewarticle/891063
  19. Brooks M Diet May Be a Source of 'Statin' Exposure. Medscape - Mar 21, 2018. https://www.medscape.com/viewarticle/894299 - Barbacki A, Fallavollita SA, Karamchandani J, Hudson M. Immune-Mediated Necrotizing Myopathy and Dietary Sources of Statins. Ann Intern Med. 2018. Feb 20 PMID: 29459987 http://annals.org/aim/article-abstract/2673071/immune-mediated-necrotizing-myopathy-dietary-sources-statins
  20. Taylor BA. Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms? Pharmacological and Methodological Considerations. Am J Cardiovasc Drugs. 2018 Apr;18(2):75-82. Review. PMID: 29027135
  21. Allard NAE, Schirris TJJ, Verheggen RJ et al Statins Affect Skeletal Muscle Performance. Evidence for Disturbances in Energy Metabolism. J Clin Endocrinol Metab. 2018;103(1):75-84 PMID: 29040646 https://www.medscape.com/viewarticle/892235
  22. Wei J et al. Increased risk of statin-associated autoimmune myopathy among American Indians. Arthritis Rheumatol 2022 Sep; 74:1602. PMID: 35333459 https://onlinelibrary.wiley.com/doi/10.1002/art.42126
  23. Mammen AL Statin-Associated Autoimmune Myopathy. N Engl J Med 2016; 374:664-669 PMID: 26886523 https://www.nejm.org/doi/10.1056/NEJMra1515161
  24. Hlatky MA, Gonzalez PE, Manson JE et al Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo. JAMA Cardiol. Published online November 23, 2022. PMID: 36416841 https://jamanetwork.com/journals/jamacardiology/fullarticle/2798958
  25. NEJM Knowledge+ Endocrinology