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| {{CMG}}; {{AE}} [[User:Rim Halaby|Rim Halaby]] | | {{CMG}}; {{AE}} [[User:Rim Halaby|Rim Halaby]] |
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| ==Overview==
| | {{Statin induced myopathy}} |
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| ==Definition== | | ==[[Statin induced myopathy overview|Overview]]== |
| [[Statin induced myopathy]] is a spectrum of muscular problems caused by the intake of [[statins]]. [[Myopathy]] by definition is any pathology of the [[muscle]]. | |
| The spectrum of [[statin induced myopathy]] includes:
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| ====Myalgia==== | |
| * [[Myalgia]] is defined as one or combination of symptoms of muscle weakness, tenderness or pain in the context of normal or minimally elevated [[creatinine kinase]].
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| * Patients usually complain of cramping feeling in the muscles.
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| ====Asymptomatic Increase in Creatine Kinase==== | | ==[[Statin induced myopathy classification|Classification]]== |
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| ====Myositis==== | | ==[[Statin induced myopathy pathophysiology|Pathophysiology]]== |
| * [[Myositis]] is the inflammation of the muscle.
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| * [[Myositis]] is defined as the presence of symptoms of muscle weakness, tenderness or pain in the setting of an [[elevated creatine kinase]] up to ten folds the normal level.
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| ====Rhabdomyolysis==== | | ==[[Statin induced myopathy epidemiology and demographics|Epidemiology & Demographics]]== |
| * [[Rhabdomyolysis]] is the acute degeneration of the [[skeletal muscle]].
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| * It is a potentially lethal condition due to its associated nephrotoxicity caused by myoglobinuria and myoglobinemia.
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| * [[Creatine kinase]] is elevated in [[rhabdomyolysis]] more than ten folds the upper normal limits.
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| * The complications of [[rhabdomyolysis]] are [[acute tubular necrosis]], [[hypocalcemia]], [[hyperkalemia]], [[metabolic acidosis]], [[hyperuricemia]], [[DIC]] and [[cardiomyopathy]].<ref name="baker">Baker, S.K. & Tarnopolsky, M.A. (2001). Statin myopathies: pathophysiologic and clinical perspectives. Clin. Invest. Med., 24(5): 258-272.</ref>
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| ====Other Statin Induced Myopathies==== | | ==[[Statin induced myopathy epidemiology and demographics|Risk Factors]]== |
| * Elevated [[creatine kinase]] after [[statin]] withdrawal<ref name="pmid12672737">{{cite journal| author=Thompson PD, Clarkson P, Karas RH| title=Statin-associated myopathy. | journal=JAMA | year= 2003 | volume= 289 | issue= 13 | pages= 1681-90 | pmid=12672737 | doi=10.1001/jama.289.13.1681 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12672737 }} </ref>
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| * Autoimmune myopathy requiring immunosuppressive therapy<ref name="pmid18367041">{{cite journal| author=Radcliffe KA, Campbell WW| title=Statin myopathy. | journal=Curr Neurol Neurosci Rep | year= 2008 | volume= 8 | issue= 1 | pages= 66-72 | pmid=18367041 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18367041 }} </ref>
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| ==Pathophysiology== | | ==[[Statin induced myopathy screening|Screening]]== |
| [[Statin induced myopathy]] has a complex poorly understood multifactorial pathophysiology. It is postulated that [[statin induced myopathy]] is caused by [[apoptosis]] of the skeletal muscle cells because of disrupted intracellular calcium signaling and mitochondrial dysfunction due to depletion of mevalonate metabolism products, notably isoprenoids.<ref name="pmid16885396">{{cite journal| author=Dirks AJ, Jones KM| title=Statin-induced apoptosis and skeletal myopathy. | journal=Am J Physiol Cell Physiol | year= 2006 | volume= 291 | issue= 6 | pages= C1208-12 | pmid=16885396 | doi=10.1152/ajpcell.00226.2006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16885396 }} </ref> | |
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| The following changes are caused by [[statin]]:
| | ==[[Statin induced myopathy differential diagnosis|Differentiating Statin induced myopathy from other Diseases]]== |
| * Changes in [[cholesterol]] content and alteration of the membrane fluidity of [[skeletal muscle]] cells which disrupts their normal function
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| * Changes in [[skeletal muscle]] cells membrane electrical properties
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| * Changes in Na+/K+ pump density resulting in decreased production of ATP
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| * Changes in the excitation-contraction coupling
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| * Changes in the cell surface receptor transduction cascades
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| * Decreased synthesis of ubiquinone (Q10), a component of the mitochondrial electron transport chain, leading to decreased ATP production and decreased free radical scavenging
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| * Increased intracellular calcium causing apoptosis of the skeletal muscle cells<ref name="baker">Baker, S.K. & Tarnopolsky, M.A. (2001). Statin myopathies: pathophysiologic and clinical perspectives. Clin. Invest. Med., 24(5): 258-272.</ref>
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| * Decreased mevalonate metabolism products, particularly isoprenoids, leading to a chain of events that culminate in the [[apoptosis]] of skeletal muscle cells<ref name="pmid16885396">{{cite journal| author=Dirks AJ, Jones KM| title=Statin-induced apoptosis and skeletal myopathy. | journal=Am J Physiol Cell Physiol | year= 2006 | volume= 291 | issue= 6 | pages= C1208-12 | pmid=16885396 | doi=10.1152/ajpcell.00226.2006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16885396 }} </ref>
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| In addition, muscle biopsies of patients suffering from statin induced rhabdomyolysis show a ragged red fibers appearance.<ref>Mohaupt MG, Karas RH, Babiychuk EB, et al.: Association between statin-associated myopathy and skeletal muscle damage. CMAJ Can Med Assoc J 2009, 181:E11–E18</ref>
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| ;Shown below is an image depicting the mechanism of statin induced myopathy through increasing the intracellular calcium concentration.
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| [[Image:Statin_induced_myopathy.png|center|Statin induced myopathy through increased intracellular calcium]]
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| ==Prevalence==
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| The prevalence of [[statin induced myopathy]], described as a spectrum of clinical conditions ranging from [[myalgia]] to [[myositis]] and [[rhabdomyolysis]], is almost 10-15%<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| ==Risk Factors==
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| ===Intrinsic Risk Factors===
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| *Advanced age (> 80 years)<ref name="pmid19217515">{{cite journal| author=Venero CV, Thompson PD| title=Managing statin myopathy. | journal=Endocrinol Metab Clin North Am | year= 2009 | volume= 38 | issue= 1 | pages= 121-36 | pmid=19217515 | doi=10.1016/j.ecl.2008.11.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19217515 }} </ref>
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| *Carnitine palmityl transferase II deficiency
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| *[[Diabetes mellitus]]
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| *Genetic polymorphisms of [[CYP450]] isoenzymes (single nucleotide polymorphism of the gene SLCO1B1)<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| *Hepatic disease
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| *[[Hypertension]]
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| *[[Hypothyroidism]]
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| *[[McArdle disease]]
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| *[[Metabolic muscle disease]]
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| *Myadenylate deaminase deficiency<ref name="toth">Toth PP, Harper CR, Jacobson TA: Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev Cardiovasc Ther 2008, 6:955–969</ref>
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| *Renal disease
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| *Small body mass index<ref name="pmid19217515">{{cite journal| author=Venero CV, Thompson PD| title=Managing statin myopathy. | journal=Endocrinol Metab Clin North Am | year= 2009 | volume= 38 | issue= 1 | pages= 121-36 | pmid=19217515 | doi=10.1016/j.ecl.2008.11.002 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19217515 }} </ref>
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| ===Extrinsic Risk Factors===
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| *[[Alcohol]] consumption
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| *[[Amiodarone]]
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| *[[Antigunfals|Azole antifungals]]
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| *[[Cyclosporins]]
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| *[[Fibrates]] particularly [[gemfibrozil]] (Cerivastatin in combination with [[gemfibrosil]])<ref name="pmid11758079">{{cite journal| author=Hamilton-Craig I| title=Statin-associated myopathy. | journal=Med J Aust | year= 2001 | volume= 175 | issue= 9| pages= 486-9 | pmid=11758079 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11758079 }} </ref>
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| *Grapefruit juice (> 1quart/day)
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| *Heavy [[exercise]]
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| *High dose of [[statin]]<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| *[[Macrolide]] [[antibiotics]]
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| *Major trauma<ref name="pmid11758079">{{cite journal| author=Hamilton-Craig I| title=Statin-associated myopathy. | journal=Med J Aust | year= 2001 | volume= 175 | issue= 9 | pages= 486-9 | pmid=11758079 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11758079 }} </ref>
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| *Polypharmacy<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| *[[Protease inhibitors]]<ref name="toth">Toth PP, Harper CR, Jacobson TA: Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev Cardiovasc Ther 2008, 6:955–969</ref>
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| *[[Surgery]]<ref name="pmid11758079">{{cite journal| author=Hamilton-Craig I| title=Statin-associated myopathy. | journal=Med J Aust | year= 2001 | volume= 175 | issue= 9 | pages= 486-9 | pmid=11758079 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11758079 }} </ref>
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| *[[Warfarin]]
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| ==Screening==
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| *The American Heart Association and the National Heart, Lung, and. Blood Institute (AHA/NHLBI) statin clinical advisory panel recommends the measurement of the [[creatine kinase]] level before the initiation of statin therapy.
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| * The national lipid association does not recommend the measurement of the [[creatine kinase]] level before the initiation of [[statin]] therapy for all patients. It is useful to check the creatine level in patients with high risk factors for [[statin induced myopathy]] as for example patient with kidney diseases.
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| * Otherwise, the level of [[creatine kinase]] should be measured only in the presence of symptoms of muscle pain, tenderness or pain<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| ==Symptoms==
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| The symptoms of [[statin induced myopathy]] belong to a spectrum ranging from being mild and asymptomatic to severe and lethal. The time of onset of symptoms varies among people, but the median of onset of symptoms is four weeks since the beginning of the treatment. Similarly, the time for the resolution of symptoms after appropriate management also varies among individuals.<ref>Bruckert E, Hayem G, Dejager S, et al.: Mild to moderate muscular symptoms with high-dosage statin therapy in hyper- lipidemic patients–the PRIMO study [see comment]. Cardiovasc Drugs Ther 2005, 19:403–414.</ref>
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| The list of symptoms is the following:
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| *[[Fatigue]]
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| *Generalized aching
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| *Low back or proximal muscle pain
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| *[[Myalgia]]
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| *[[Cramp|Nocturnal muscle cramps]]
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| *Tendon pain
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| *[[Weakness]]<ref>Toth PP, Harper CR, Jacobson TA: Clinical characterization and molecular mechanisms of statin myopathy. Expert Rev Cardiovasc
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| Ther 2008, 6:955–969.</ref>
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| ==Diagnosis== | | ==Diagnosis== |
| ====Initial Evaluation====
| | [[Statin induced myopathy history and symptoms|History & Symptoms]] | [[Statin induced myopathy laboratory tests|Lab Tests]] |
| A proper evaluation should be done by checking the following:
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| * The level of [[creatine kinase]] compared to the upper limit of normal (ULN)
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| * The list of medications the patient is taking
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| **[[CYP450[[ inhibitors: examples of CYP450 inhibitors are azole [[antifungals]] ([[itraconazole]], [[ketoconazole]], [[fluconazole]]), [[macrolide]] antibiotics ([[erythromycin]], [[clarithromycin]]), [[protease inhibitors]] ( ritonavir, nelfinavir, indinavir).
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| ** [[Fibrates]]: the combination of statin with fibrates is beneficial in the case of [[metabolic syndrome]] or [[diabetic dyslipidemia]]; however, [[fibrates]] increases the risk of statin induced myopathy.
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| * [[TSH]] level as [[hypothyroidism]] is a risk factor for statin induced myopathy.
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| * History of excessive exercise or trauma.<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| ==Treatment== | | ==Treatment== |
| When symptoms of [[myopathy]] or elevation of creatine kinase occur in the setting of a patient taking [[statin]], the majority of patients safely continue the treatment with [[statin]]. The decision on whether the patient can discontinue or continue statin depends on two factors:
| | [[Statin induced myopathy medical therapy|Medical Therapy]] |
| # Severity of the symptoms
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| # Increase in the creatine kinase level
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| ====Tolerable Symptoms with Absent or Mild Elevation of Creatine Kinase<5ULN====
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| * Continue [[statin]]<ref name="pmid21414023">{{cite journal| author=Blaier O, Lishner M, Elis A| title=Managing statin-induced muscle toxicity in a lipid clinic. | journal=J Clin Pharm Ther | year= 2011 | volume= 36 | issue= 3 | pages= 336-41 | pmid=21414023 | doi=10.1111/j.1365-2710.2011.01254.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21414023 }} </ref>
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| * Consider lowering the dose of [[statin]], adjust the optimal dose of [[statin]] depending on the symptoms of the patient
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| ====Tolerable Symptoms with Absent or Mild Elevation of Creatine Kinase>5ULN or with Rhabdomyolysis====
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| * Discontinue [[statin]]
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| * Ensure an appropriate management for [[rhabdomyolysis]] if present by good hydration and follow up<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| * Resume the treatment with [[statin]] once the symptoms are resolved. Modify the treatment regimen as follows:
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| **Administration of a lower dose [[statin]]
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| **Alternation in the dosing
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| **Twice weekly dosing with longer half lives statins
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| **Different type of [[statin]].<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| *Monitor [[creatinine kinase]] levels.
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| ====Intolerable Symptoms====
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| * Discontinue statin regardless of the level of the creatine kinase.<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| * Resume the treatment with statin once the symptoms are resolved. Modify the treatment regimen as follows:
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| **Administration of a lower dose statin
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| **Alternation in the dosing
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| **Twice weekly dosing with longer half lives statins
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| **Different type of statin.<ref name="pmid20628837">{{cite journal| author=Harper CR, Jacobson TA| title=Evidence-based management of statin myopathy. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 5 | pages= 322-30 | pmid=20628837 | doi=10.1007/s11883-010-0120-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20628837 }} </ref>
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| * Monitor [[creatinine kinase]] levels.
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| ====Recurrence of Symptoms====
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| If the symptoms recur despite appropriate management consider:
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| =====Multiple statin therapy at multiple doses=====
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| *[[Rosuvastatin]]: daily, low dose (2.5-5 mg/day) or alternate-day dose or weekly<ref>Athyros VG, Tziomalos K, Kakafika AI, et al.: Effectiveness of ezetimibe alone or in combination with twice a week Atorvastatin (10 mg) for statin intolerant high-risk patients. Am J Cardiol 2008, 101:483–485.</ref>
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| *[[Atorvastatin]]: either alternate-day dose (5-10 mg) or 10 mg twice weekly<ref>Rivers SM, Kane MP, Busch RS, et al.: Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract 2007, 13:11–16.</ref>
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| *[[Fluvastatin]] XL: 80 mg/day<ref>Backes JM, Venero CV, Gibson CA, et al.: Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother 2008, 42:34–346.</ref>
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| =====Other lipid lowering drugs<ref>Lu Z, Kou W, Du B, et al.: Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol 2008, 101:1689–1693.</ref>=====
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| =====Lifestyle changes including diet and exercise=====
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| ;Shown below is an image summarizing the management plan for statin induced myopathy.<ref>Jacobson TA: Toward “pain-free” statin prescribing: clinical
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| algorithm for diagnosis and management of myalgia [see comment]. Mayo Clin Proc 2008, 83:687–700.</ref>
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| [[Image:Management_of_statin_induced_myopathy.png|center|550px|Management of statin induced myopathy]]
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| ==References== | | ==References== |