Phenotype Standardization for Statin-Induced Myotoxicity

Re iew na u e publishing g oup S a ins, 3-hyd oxy-3-me hylglu a yl coenzyme A educ ase inhibi o s, a e e ec i e in lowe ing blood choles e ol as well as in p ima y and seconda y p e en ion o ca dio ascula e en s. App oxima ely 25 million people wo ldwide a e ak- ing s a ins.1–3 S a ins a e sa e and e ec i e in he majo i y o pa ien s, bu hey a e associa ed wi h muscle oxici y, which, al hough a e, can be se ious and po en ially li e h ea ening.4,5 The clinical spec um o s a in-induced myo oxici y a ies g ea ly om asymp oma ic ele a ions o c ea ine kinase (CK) wi hou muscle pain, o muscle pain o weakness wi h aised CK le els, myosi is wi h biopsy-p o en muscle in lamma ion, and, inally, habdomyolysis wi h muscle symp oms, high CK, and po en ial o acu e kidney inju y (Table 1). 6,7 Whe he s a ins cause muscle pain in he absence o CK changes emains con- o e sial. Al hough milde o ms o myo oxici y end o be sel - limi ing and disappea a e cessa ion o he apy, hey can lead o poo quali y o li e, poo d ug compliance, and, consequen ly, he ailu e o p e en ca dio ascula e en s. Because s a in-induced myo oxici y is uncommon, i is neces- sa y o pool and analyze da a om a ious sou ces, including mul icen e clinical ials and obse a ional s udies, o s udy gene ic e iology. In addi ion, elec onic medical eco ds linked o biological eposi o ies o o indi idual pa ien s ha e been use ul in iden i ying and ec ui ing pa ien s wi h d ug-induced oxici ies.6,8–12 The Pheno ype S anda diza ion P ojec was s a ed a ew yea s ago o acili a e such mul icen e esea ch collabo a ions on a ious ypes o se ious ad e se d ug eac- ions (ADRs). Pheno ype consensus pape s on d ug-induced li e inju y, skin inju y, and o sade de poin es ha e been pub- lished by mul idisciplina y g oups o in e na ional expe s. 13–15 The aim o his a icle is o p o ide consensus de ini ions o s a in-induced myo oxici y pheno ypes, o acili a e c oss-s udy compa isons om he exis ing coho s, o aid in he ec ui - men o e ospec i e and newly diagnosed pa ien s wi h s a in-induced muscle damage, and o de ine he pheno ype o genomic da a analyses. We con ened an in e na ional expe wo kshop on s a in- induced myo oxici y in Decembe 2013 in Li e pool, UK, o ag ee on de ini ions and a minimum se o c i e ia o help in iden i ica ion and ec ui men . We epo on he delibe a ions o his wo kshop: i s , we summa ize e idence o he clinical and biochemical pheno ypes ha ha e been epo ed, and second, we epo on ou sugges ed s anda diza ion o he e minology and pheno ypes o s a in-induced muscle oxici y. Recei ed 25 Ma ch 2014; accep ed 27 May 2014; ad ance online publica ion 2 July 2014. doi:10.1038/clp .2014.121 Clinical Pha macology & The apeu ics 10.1038/clp .2014.121 Re iew 2July2014 96 4 25Ma ch2014 27May2014 S a ins a e widely used lipid-lowe ing d ugs ha a e e ec i e in educing ca dio ascula disease isk. Al hough hey a e gene ally well ole a ed, hey can cause muscle oxici y, which can lead o se e e habdomyolysis. Resea ch in his a ea has been hampe ed o some ex en by he lack o s anda dized nomencla u e and pheno ypic de ini ions. We ha e used nume ical and desc ip i e classi ica ions and de eloped an algo i hm o de ine s a in- ela ed myo oxici y pheno ypes, including myalgia, myopa hy, habdomyolysis, and nec o izing au oimmune myopa hy. 1Depa men o Molecula and Clinical Pha macology, TheWol son Cen e o Pe sonalised Medicine, Ins i u e o T ansla ional Medicine, Uni e si y o Li e pool, Li e pool, UK; 2Depa men o Clinical Biochemis y, Newcas le upon Tyne Hospi als NHS Founda ion T us , Royal Vic o ia In i ma y, Newcas le upon Tyne, UK; 3Clinical T ial Se ice Uni , Ox o d, UK; 4Cen e o Musculoskele al Resea ch/NIHR Manches e Musculoskele al Biomedical Resea ch Uni , Uni e si y o Manches e , Manches e , UK; 5MRC/ARUK Ins i u e o Ageing and Ch onic Disease, Facul y o Heal h & Li e Sciences, Uni e si y o Li e pool, Li e pool, UK; 6Zo a Biosciences L d, Tieo ie 2, Espoo, Finland; 7The Medical P oduc s Agency, Uppsala, Sweden; 8Depa men o Medical Sciences, Clinical Pha macology and Science o Li e Labo a o y, Uppsala Uni e si y, Uppsala, Sweden; 9Di ision o Pha macoepidemiology and Clinical Pha macology, U ech Uni e si y, Facul y o Science, U ech Ins i u e o Pha maceu ical Sciences, U ech , The Ne he lands; 10Duke Ins i u e o Genome Sciences and Policy, Du ham, No h Ca olina,USA; 11Ca dio ascula Heal h Resea ch Uni , Depa men s o Medicine, Epidemiology and Heal h Se ices, Uni e si y o Washing on, Sea le, Washing on, USA; 12G oup Heal h Resea ch Ins i u e, G oup Heal h Coope a i e, Sea le, Washing on, USA; 13Medical Resea ch Ins i u e, Ninewells Hospi al and Medical School, Dundee, UK. Co espondence: A Al i e ic (Ana.Al i [email p o ec ed].uk) Pheno ype S anda diza ion o S a in-Induced Myo oxici y AAl i e ic1, DNeely2, JA mi age3, HChinoy4, RGCoope 5, RLaaksonen6, DFCa 1, KMBloch1, JFahy1, AHanson1, Q-YYue7, MWadelius8, AHMai land- an De Zee9, DVoo a10, BMPsa y11,12, CNAPalme 13 and MPi mohamed1 Open see REVIEW page 477 470 VOLUME 96 NUMBER 4 | OCTOBER 2014 | www.na u e.com/cp Re iew CONSENSUS PROCESS The PREDICTION-ADR conso ium, unded by he EU Se en h F amewo k P og amme, o ganized a join mee ing on 10 Decembe 2013 in Li e pool wi h a mul idisciplina y eam o expe s on s a in- ela ed myopa hy and angio ensin con e - ing enzyme-inhibi o angioedema. An in e na ional eam wi h known expe ise in he a ea was assembled by in i a ion. The g oup comp ised clinical and basic pha macologis s, in e nis s, heuma ology and myopa hy expe s, immunology and clinical chemis y scien is s, alle gis s, egula o y agency ep esen a- i es, and manage s o elec onic medical eco d da abases. A d a manusc ip ci cula ed be o e he mee ing con ained a b ie li e a u e e iew on s a in- ela ed myopa hy and a desc ip- ion o main pheno ypes. The expe g oup was asked o con- side he minimum se o c i e ia o pa ien ec ui men . An in oduc o y alk was gi en o s a he discussions. In addi ion, an algo i hm was designed o aid s anda diza ion o nomencla- u e and pheno ypes, and ecommenda ions we e made abou he ypes o da a o be collec ed om each pa ien (Figu e 1). A e he mee ing, he e ised manusc ip comp ising he c i- e ia (Table 1) and algo i hm was app o ed by all con ibu o s. We did no discuss causali y assessmen o mally, as he chal- lenges o his ask a e common o many ADRs.16 They equi e es ablishing a empo al ela ionship, along wi h dechallenge and echallenge in o ma ion, and, pa icula ly impo an o s a in- ela ed myo oxici y, igilan in o ma ion on muscle inju y om alls, auma, o igo ous exe cise. We also ecommend inde- penden assessmen o causali y by an adjudica ion panel, using me hodology ha has been success ully applied o e ospec i e and p ospec i e ec ui men o pa ien s wi h a e ADRs, includ- ing se e e d ug-induced skin inju y.15 INCIDENCE The a e o s a in-induced myo oxici y has been es ima ed om ad e se e en da a in case se ies and andomized con olled ials.17–24 Howe e , es ima ing ad e se e en s om andomized con olled ials may be challenging because (i) hey a e no usually powe ed o cap u e low- equency ADRs; (ii) pa ien s a e exposed o d ugs and moni o ed only o a sho pe iod o ime when myo oxici y may no ye ha e de eloped; (iii) he diag- nos ic c i e ia o eac ion e en s may a y ac oss di e en ials; and (i ) hey may ha e s ic inclusion and exclusion c i e ia ha may exclude some popula ions who a e a highe isk o ADRs. The isk o habdomyolysis among hospi alized pa ien s ecei - ing lipid-lowe ing d ugs has ecen ly been es ima ed in a eal- wo ld clinical se ing. Claims da a om 9 million membe s o i e US heal h plans we e used o con i m 42 cases in >470,000 pa ien s exposed o lipid-lowe ing d ugs. The isk o habdomy- olysis o indi iduals on di e en s a in p epa a ions, including combina ion he apy, and he isk o como bidi ies we e es ima ed o be be ween 0.3 and 8.4 in 10,000 pa ien -yea s.25 The au ho s es ima ed ha he isk in compa ison wi h a o as a in as a e e - ence was signi ican ly highe when s a ins we e used in combina- ion wi h cy och ome P450 (CYP)3A4 inhibi o s (odds a io: 7.1, 95% con idence in e al: 1.6–31.6) and o ce i as a in mono- he apy (odds a io: 4.7, 95% con idence in e al: 1.1–21.1).25 DIAGNOSTIC CRITERIA The diagnosis o s a in-induced myo oxici y is based on medi- cal his o y, clinical examina ion, and labo a o y es s and can be con i med by muscle biopsy (Supplemen a y Table S1 online). Muscle biopsies can e eal muscle ibe nec osis, ype II ibe a ophy, and inc eased lipid s o es in muscle ibe s o in lamma ion. 26–29 In clinical p ac ice, a p agma ic app oach is adop ed: discon inua ion o he culp i d ug and a oidance o i s u u e use.30 Moni o ing o s a in he apy o muscle oxici y includes CK measu emen s, al hough ou ine labo a o y es ing is ecommended only o symp oma ic pa ien s.31 The po en ial ha m o in oducing ou ine CK moni o ing in all pa ien s who ake s a ins may ou weigh he bene i s om se e al pe spec- i es, including alse-posi i e esul s wi h po en ially ensuing in asi e in es iga ions, a psychological e ec on pa ien s ha may esul in educ ion o s a in use, and an inc eased cos o he heal h-ca e sys em. A ecen s udy on pa ien s’ pe cep ions Table 1 S a in- ela ed myo oxici y pheno ype classi ica ion SRM classi ica ion Pheno ype Incidence De ini ion Re e ence SRM 0 CK ele a ion <4× ULN 1.5–26% No muscle symp oms Re s. 1,20,34,35,67 SRM 1 Myalgia, ole able 190/100,000 Pa ien -yea s; 0.3–33% Muscle symp oms wi hou CK ele a ion Re s. 1,19,21,50,68 SRM 2 Myalgia, in ole able 0.2–2/1,000 Muscle symp oms, CK <4× ULN, comple e esolu ion on dechallenge Re . 20 SRM 3 Myopa hy 5/100,000 Pa ien -yea s CK ele a ion >4× ULN <10× ULN ± muscle symp oms, comple e esolu ion on dechallenge Re . 1 SRM 4 Se e e myopa hy 0.11% CK ele a ion >10× ULN <50× ULN, muscle symp oms, comple e esolu ion on dechallenge Re s. 20,69 SRM 5 Rhabdomyolysis 0.1–8.4/100,000 Pa ien -yea s CK ele a ion >10× ULN wi h e idence o enal impai men + muscle symp oms o CK >50× ULN Re s. 4,6,25,44,45 SRM 6 Au oimmune-media ed nec o izing myosi is ~2/million pe yea HMGCR an ibodies, HMGCR exp ession in muscle biopsy, incomple e esolu ion on dechallenge Re s. 51,70 Nume ic classi ica ion was de eloped by an expe g oup; desc ip i e nomencla u e was adap ed om he ecommenda ion o he Ame ican College o Ca diology/Ame ican Hea Associa ion/Na ional Hea , Lung, and Blood Ins i u e Clinical Ad iso y Boa d.3,7 CK, c ea ine kinase; HMGCR, 3-hyd oxy-3-me hylglu a yl-coenzyme A educ ase; SRM, s a in- ela ed myo oxici y; ULN, uppe limi o no mal. ClInICAl PhARMACology & TheRAPeuTICS | VOLUME 96 NUMBER 4 | OCTOBER 2014 471 Re iew o s a in he apy has demons a ed educed adhe ence o s a in he apy in hose conce ned abou ADRs.32,33 CLINICAL PRESENTATIONS OF STATIN-INDUCED MUSCLE TOXICITY S a in-induced muscle oxici y can p esen in many di e en ways, bu he ecognized pheno ypes and deg ees o se e i y a e classi ied in o se en di e en ca ego ies, as ep esen ed in Table1 (s a in- ela ed myo oxici y (SRM) 0–SRM 6). Muscle symp oms S a in-induced muscle oxici y may p esen wi h a wide a ie y o symp oms, including a igue, muscle pain, muscle weakness, muscle ende ness, and c amps. These symp oms a e usually p oximal and symme ical bu may be gene alized. They can be agg a a ed by igo ous exe cise and some imes by addi ion o a new medica ion.2 Pain ole ance a ies g ea ly in di e en indi- iduals, and many s udies ha e elied on sel - epo ing o muscle symp oms. I pa ien s can ole a e mild muscle pain, s a ins a e no usually discon inued (SRM 1, Table 1). Plasma CK ele a ion Asymp oma ic se um CK ele a ions (SRM 0) and muscle pain wi hou an inc ease in CK (SRM 1) ha e been he wo mos commonly (occu ing in up o 33% o pa ien s) desc ibed ea u es o s a in-induced oxici y.20,34,35 Wi h he inc easing use o elec onic medical eco ds, i may be possible o use CK ele a ions o iden i y pa ien s wi h s a in myo oxici y. Howe e , because he use o CK as a sc eening es o muscle inju y is no ecommended, he iden i ica ion o an isola ed CK ele a ion in an elec onic (o pape -based) eco d may indica e suspicion o he clinician o muscle oxici y, e en i symp oms a e a i- ably eco ded. CK le els a e o en used as a c ude es ima e o se e i y, bu he co ela ion be ween muscle symp oms and CK le els is impe ec , and he clinical in e p e a ion o CK le els is complex.36 The e is conside able a iabili y in he inclusion c i e ia and CK le els in he li e a u e, pa icula ly in gene ic suscep ibili y s udies. Some au ho s in es iga e pa ien s wi h sel - epo ed myalgia and CK le els om 1 o 3× he uppe limi o no mal (ULN) (SRM 2), whe eas o he s apply mo e s ingen c i e ia wi h CK ele a ions >4× ( e . 1) (SRM 3) o >10× he ULN (SRM 4) o myopa hy and ≥50× he ULN o habdo- myolysis (SRM5),9,35,37–42 which a e he c i e ia used in some ecen indus y- unded s udies. To p e en inclusion o pa ien s wi h CK ele a ions om causes o he han s a in myo oxici y, we ha e adop ed he >4× he ULN o myopa hy (SRM 3) and >10× he ULN o se e e myopa hy (SRM 4). Al hough hese cu o poin s ha e been commonly used in clinical ials and in se e al guidelines, hey a e somewha a bi a y. Howe e , u u e analyses based on hese cu o poin s (<4× he ULN, 4–10× he ULN, and >10× he ULN) will help in de ining he sensi i i y and speci ici y o di e en gene ic ma ke s, and p o ide a i s s ep in u u e e inemen o cu o le els. Some in es iga o s ha e also used alanine amino ans e ase ele a ion o iden i y mus- cle inju y;35 his may be o use when measu ed in combina ion wi h CK. Isola ed ele a ion o alanine amino ans e ase, in he Figu e 1 Algo i hm o de ining he ype o s a in- ela ed myo oxici y. New nomencla u e was in oduced o e lec he pheno ype classi ica ion and se e i y (SRM 0 o SRM 6) o s a in- ela ed oxici y. CK, c ea ine kinase; HMGCR, 3-hyd oxy-3-me hylglu a yl-coenzyme A educ ase; LLD, lipid-lowe ing d ug; SRM, s a in- ela ed myo oxici y; ULN, uppe limi o no mal. Check enal unc ion u ine myoglobin Rhabdomyolysis No neg pos Symp oms esol e a e s a in - wi hd awal? No S a in discon inua ion? Yes Nec o izing au oimmune myopa hy SRM6 Yes Nons a in myopa hy Pa ien ea ed wi h s a ins (>2 weeks) CK >4X ULN <10X ULN ± symp oms = SRM3 CK >10X ULN <50X ULN ± symp oms = SRM4 CK >10X ULN symp oms o CK <50 ULN SRM5 Myalgia Myopa hy A e he muscle- ela ed symp oms ole able? S a in he apy wi h clinical and CK moni o ing S a in challenge o al e na i e LLD Muscle biopsy i a ailable Se um an i-HMGCR an ibody es Yes No Muscle pain and weakness un ela ed o auma No muscle symp oms, CK ele a ed Ele a ed CK <4X ULN No symp oms = SRM0 Ele a ed CK <4X ULN + symp oms = SRM2 No mal CK + symp oms = SRM1 472 VOLUME 96 NUMBER 4 | OCTOBER 2014 | www.na u e.com/cp Re iew absence o an inc ease in CK le els, should aise he suspicion o li e inju y, which can also a ely occu wi h s a ins.43 Rhabdomyolysis Rhabdomyolysis (SRM 5), he mos se ious ADR associa ed wi h s a ins,4,6,25,44,45 is cha ac e ized by muscle nec osis, elease o myoglobin in o he bloods eam, and some imes acu e enal ailu e.4,6,26,45,46 Muscle symp oms a e accom- panied by ma ked CK ele a ion, ypically g ea e han 50× he ULN. Pigmen neph opa hy wi h b own u ine is ypically e iden due o myoglobinu ia and is consis en wi h se um c ea inine ele a ion.7 HMGCR au oan ibodies A numbe o s udies (e.g., e .46) ha e epo ed he occu - ence o an au oimmune-media ed nec o izing myopa- hy (SRM 6) a e s a in exposu e, wi h symp oms ha con inued a e d ug wi hd awal. Se um au oan ibodies agains 3-hyd oxy-3-me hylglu a yl-coenzyme A educ ase (HMGCR), he pha macological a ge o s a ins, ha e been epo ed in pa ien s wi h s a in-induced au oimmune myo- pa hy. 47 Muscle biopsies can also be diagnos ically use ul o he de ec ion o HMGCR exp ession on he cell su ace o egene a ing muscle ibe s.47 In 51 pa ien s wi h sel -lim- i ed s a in in ole ance, an i-HMGCR an ibodies we e no obse ed in a single indi idual.48 This sugges s ha sel - limi ed s a in myopa hy has a dis inc biological mechanism om s a in-induced au oimmune myopa hy. In addi ion, a o as a in and sim as a in p omo e a p oin lamma o y o Th1 esponse in ac i a ed pe iphe al blood mononuclea cells by inc easing he numbe o in e e on-γ-sec e ing T cells.49 I should be no ed, howe e , ha many au oimmune myopa hy cases a e likely o be excluded om s udies because wi hd awal o he s a ins does no alle ia e symp oms and Table 2 Repo ed isk ac o s o de eloping s a in-induced myopa hy Risk ac o Desc ip ion Re e ence Pa ien ac o s Ad anced age >80 yea s) Re . 7 Female gende Re . 42 Low body mass index Como bidi ies Un ea ed hypo hy oidism Re . 50, Supplemen a y e s. 71 and 72 Low i amin D le el Supplemen a y e . 73 online Ch onic enal insu iciency (GFR 60 ml/min), especially when associa ed wi h diabe es Re . 7,25 In ec ion, li e impai men , hype ension Re . 25 Alcohol abuse Re . 7 Physical exe cise Supplemen a y e s. 74–76 Su ge y The Ame ican Hea Associa ion ecommends empo a y cessa ion o s a ins be o e majo su ge y Re . 7 His o y o s a in myopa hy Pe sonal o amily his o y o s a in myopa hy Re . 50 D ug ac o s Highe s a in dose Inc eased equency o myopa hy Supplemen a y e s. 77 and 78 In e ac ing d ugsaCYP3A4 enzyme inhibi o s (pa icula ly impo an o CYP3A4 subs a es sim as a in, lo as a in, and a o as a in): dil iazem, e apamil, cla i h omycin, eli h omycin, e y h omycin, i aconazole, cyclospo ine, p o ease inhibi o s ( i ona i , indina i , and saquina i ), amioda one, and usidic acid Re s. 59–62, Supplemen a y e s. 79–81 CYP2C9 enzyme inhibi o s (wi h e ec s on lu as a in, a CYP2C9 subs a e): omep azole and luconazole Supplemen a y e s. 82–84 OATP1B1 inhibi ion (wi h e ec s on sim as a in, p a as a in, lo as a in, and osu as a in): gem ib ozilb Re s. 53–57 Supplemen a y e s. 85 and 86 Die - ela ed in e ac ions G ape ui juice (>200 ml daily) inc eases le els o sim as a in, a o as a in, and lo as a in Supplemen a y e s. 71–87 a e p o ided wi h Supplemen a y Table S1 online. CYP, cy och ome P450; GFR, glome ula il a ion a e; OATP, o ganic anion- anspo ing polypep ide. aOnly a selec ion o d ug in e ac ions wi h s a ins has been p esen ed. Reade s should e e o mo e ex ensi e e iews o a ulle lis o in e ac ing d ugs (Kellick e al., 2014 (Supplemen a y e . 87), h p://www.mh a.go .uk/Sa e yin o ma ion/D ugSa e yUpda e/D ugSa e yUpda esea ch esul s/index.h m, and h p://pha macis sle e . he apeu ic esea ch.com/pl/A icleDD.aspx?nidchk=1&cs=&s=PL&p =2& p =31&dd=280606&pb=PL&ca =4803&segmen =4421&AspxAu oDe ec CookieSuppo =1).bThe main mechanism o he in e ac ion is men ioned in he able, bu i is impo an o no e ha in some cases he e may be mul iple mechanisms. Fo example, wi h gem ib ozil, in addi ion o OATP1B1 inhibi ion, CYP2C8 and UGT1 inhibi ion may also con ibu e. UGT, u idine diphospha e glucu onyl ans e ase. ClInICAl PhARMACology & TheRAPeuTICS | VOLUME 96 NUMBER 4 | OCTOBER 2014 473 Re iew hus s a ins may be discoun ed as he causal agen s o myo- pa hy pa hogenesis. TIME TO ONSET In he PRIMO (P edic ion o Muscula Risk in Obse a ional Condi ions) s udy, he median ime o onse in he 832 o 7,924 pa ien s who de eloped muscula symp oms was one mon h a e s a in ini ia ion.50 A s udy o 45 pa ien s epo ed a mean du a ion o s a in he apy be o e myopa hic symp oms o 6.3 mon hs, wi h a maximum o 9.8 mon hs.19 A la ge s udy, using a case-c osso e design o de e mine s a in myo oxici y in wo p ima y-ca e da abases comp ising 93,831 pa ien s, sugges ed ha mos cases occu wi hin he i s 12 weeks o s a in exposu e. 21 The au ho s ecommended a 26-week cu o o enable ewe misclassi ica ions o exposed cases.21 A 26-week cu o seems sensible o hose pa ien s who ha e been on a s able dose o s a in mono he apy; how- e e , his may need o be ex ended. I is impo an o no e ha some pa ien s can de elop s a in myo oxici y ei he a e a s a in dose inc ease o a e he concomi an adminis a ion o an in e ac ing d ug, which may occu any ime du ing he li e cycle o s a in use. Fu he mo e, au oimmune myopa hy may ake longe o de elop, wi h a ime o onse as long as 3yea s.51 RISK FACTORS Concomi an medica ions Fib a es. A signi ican body o e idence sugges s an inc eased isk o s a in myopa hy, pa icula ly habdomyolysis, in pa ien s aking s a ins in combina ion wi h ib a es.4 Analysis o he US Food and D ug Adminis a ion Ad e se E en Repo ing Sys em be ween 1998 and 2002 was used o de e mine epo - ing a es o habdomyolysis in pa ien s aking eno ib a e and gem ib ozil in combina ion wi h s a ins.52 Gem ib ozil, a ib ic acid de i a i e, inc eases sys emic exposu e o ac i e sim as a- in acid by inhibi ing bo h glucu onida ion and o ganic anion- anspo ing polypep ide (OATP)1B1 anspo e –media ed up ake in o he li e .53,54 O e all a es o habdomyolysis o any s a in medica ion use s cop esc ibed eno ib a e o gem ib ozil we e 4.5 and 8.7 pe million p esc ip ions, espec i ely. When s a i ied o hose pa ien s ecei ing ce i as a in only, he a es inc eased o 140 and 4,600 pe million p esc ip ions wi h eno ib a e/ce i as a in and gem ib ozil/ce i as a in combina ion he apy, espec i ely.52 Al hough he e ec o ib a e coadminis a ion on s a in bio- a ailabili y exis s o he majo i y o s a ins,53,55–57 he inc ease in myopa hy isk is especially p onounced wi h ce i as a in.5,58 Al hough ce i as a in was wi hd awn in 2001, he iden i ica ion o p edisposing pha macogenomics ac o s may s ill be o use o elucida ing p edisposing ac o s o muscle oxici y wi h he s a ins mo e commonly used nowadays. CYP3A4 inhibi ion. CYP3A4 inhibi o s such as azole an i un- gals, p o ease inhibi o s, amioda one, cyclospo ine, calcium channel blocke s, and mac olide an ibio ics, o name a ew, inc ease isk o myopa hy o s a ins ha unde go CYP3A4 me abolism (sim as a in, a o as a in, and lo as a in).59–62 In addi ion, some oods such as g ape ui juice, which con ains u anocouma ins, i e e sibly inhibi CYP3A4 in he gu . The e ec is educed gu wall me abolism o s a ins (pa icula ly sim as a in) and inc eased sys emic exposu e, which can lead o ad e se e ec s.60,63 Como bidi ies A lis o como bidi ies ha a e associa ed wi h an inc eased isk o de eloping s a in- ela ed myo oxici y is shown in Table 2. They include hypo hy oidism, ch onic enal insu iciency, in ec- ion, impai ed li e unc ion, hype ension, physical exe ion, and diabe es. Exe cise I is commonly belie ed ha igo ous exe cise inc eases he isk o s a in-induced myopa hy. Indeed, i is hough ha myopa hic symp oms may occu in 25% o s a in use s who exe cise, as compa ed wi h a popula ion incidence es ima ed a 1–5% o hose who exe cise bu do no ake s a ins.64 In p o essional a hle es, i is es ima ed ha as many as 75% o hose aking s a ins may de elop muscula symp oms;65 howe e , his may be o e es ima ed. CONCLUSIONS Gi en he high p e alence o s a in use wo ldwide and hei sig- ni icance in he p e en ion o ca dio ascula and ce eb o ascu- la disease, ex ensi e esea ch on he p edic ion and p e en ion o se ious ad e se e ec s such as s a in- ela ed myo oxici y is jus i ied. Imp o ed pa ien ole abili y and adhe ence o s a ins is c ucial because i educes he incidence and he cos o any heal h-ca e sys em o ea ing ca dio ascula disease. La ge p ospec i e s udies o pa ien coho s ea ed wi h s a ins a e equi ed o iden i y new gene ic suscep ibili y bioma ke s o s a in- ela ed myo oxici y ha could be implemen ed in o clinical p ac ice. To da e, one o he p oblems in compa ing he esul s o obse a ional s udies on s a in myo oxici y has been he lack o pheno ype classi ica ion and s anda diza ion o nomencla u e. In addi ion, gi en he a i y o he mos se e e pheno ypes, a small sample size o se e al s udies has hampe ed gene ic bioma ke disco e y. We ha e adap ed a p e iously desc ibed consensus app oach15 o de ine pheno ypic c i e ia ha can be used in an e o o s anda dize s a in- ela ed myo oxici y pheno ypes using he nume ical and desc ip i e nomencla u e gi en in Table 1. Ou s anda diza ion was based on expe opinion om a mul idis- ciplina y g oup and he li e a u e. The ollowing a e key c i e ia o be used in he deep pheno yping o pa ien s wi h suspec ed s a in-induced muscle inju y: • A CK le el ha is >4× he ULN in he p esence o absence o clinical symp oms o he de ini ion o myopa hy. We ha e adop ed he >4× he ULN le el p agma ically, as we eel, based on he li e a u e, ha his cu o p o ides he igh balance in p e en ing inclusion o pa ien s wi h CK ele a ion due o no mal a ia ion o o he causes, while 474 VOLUME 96 NUMBER 4 | OCTOBER 2014 | www.na u e.com/cp Re iew simul aneously ensu ing ha we do no unnecessa ily exclude aluable pa ien s in s udies in es iga ing gene ic ac o s p edisposing o s a in myo oxici y. A CK >10× he ULN should be ca ego ized as habdomyolysis i accompa- nied by enal impai men . The adop ion o he classi ica- ion shown in Table 1 may help in mo e clea ly de ining he a ious pheno ypes ha a e ec ui ed in di e en s udies. Pape s epo ing gene ic ac o s p edisposing o s a in-induced muscle inju y should show he e ec size o he gene ic polymo phism based on he deg ee o CK ele a ion, as has been done in ecen s udies.9,66 • Clinical symp oms need o be ca e ully eco ded in he pa ien s; hese should include no only he muscle symp- oms bu also whe he he e is any in ol emen o he kidneys, which migh indica e habdomyolysis. Causali y assessmen as o whe he he s a in was esponsible should include de ails o he empo al ela ionship be ween onse o s a in use and he occu ence o myo oxici y, he e ec o dechallenge, and he e ec o any echallenge. Dechallenge may no always be success ul, o example, in pa ien s wi h au oimmune myopa hy, and should no necessa ily be used o exclude s a ins as e iological agen s. • Apa om CK, measu emen o alanine amino ans e ase, u ine myoglobin le els (when clinically indica ed), and enal unc ion may be use ul. In pa ien s wi h a suspec ed au oimmune myopa hy, he measu emen o an i-HMGCR an ibodies and muscle biopsy should be conside ed. • P edisposing ac o s, including in e ac ing d ugs, como - bidi ies, and exe cise, should be e alua ed in all pa ien s. Fac o s such as auma ha lead o muscle inju y i espec- i e o s a in use need o be excluded. • The ime o onse can be a iable and can be delayed as long as 3 yea s in pa ien s wi h au oimmune myopa hy. Howe e , in gene al, mos cases o s a in-induced myo- oxici y occu wi hin 6 mon hs o 1 yea o s a in onse , an inc ease in he dose o he s a in, o he concomi an adminis a ion o an in e ac ing d ug. We ha e also de eloped an algo i hm ha will help assign pheno ypes o indi idual pa ien s based on clinical and bio- chemical pa ame e s (Figu e 1). We hope he c i e ia desc ibed in his a icle will help clini- cians and esea che s o ca ego ize pheno ypes in pa ien s wi h s a in- ela ed myo oxici y in o de o acili a e esea ch in his a ea. SUPPLEMENTARY MATERIAL is linked o he online e sion o he pape a h p://www.na u e.com/cp ACKNOWLEDGMENTS This p ojec has ecei ed unding om he Eu opean Union’s Se en h F amewo k P og amme o esea ch, echnological de elopmen , and demons a ion unde g an ag eemen 602108. This wo k was p esen ed a he Pheno ype S anda diza ion Wo kshop, Li e pool, UK, 10 Decembe 2013. CONFLICT OF INTEREST The au ho s decla ed no con lic o in e es . © 2014 Ame ican Socie y o Clinical Pha macology and The apeu ics 1. Law,M. & Rudnicka,A.R. S a in sa e y: a sys ema ic e iew. Am. J. Ca diol. 97, 52C–60C (2006). 2. Sa hasi am,S. S a in induced myo oxici y. Eu . J. In e n. Med. 23, 317–324 (2012). 3. S one,N.J. e al. 2013 ACC/AHA Guideline on he T ea men o Blood Choles e ol o Reduce A he oscle o ic Ca dio ascula Risk in Adul s: A Repo o he Ame ican College o Ca diology/Ame ican Hea Associa ion Task Fo ce on P ac ice Guidelines. Ci cula ion 2013; e-pub ahead o p in 12 No embe 2013. 4. G aham,D.J. e al. 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Mohassel,P. & Mammen,A.L. S a in-associa ed au oimmune myopa hy and an i-HMGCR au oan ibodies. Muscle Ne e 48, 477–483 (2013). This wo k is licensed unde a C ea i e Commons A ibu ion-nonComme cial-noDe i s 3.0 unpo ed license. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle’s C ea i e Commons license, unless indica ed o he wise in he c edi line; i he ma e ial is no included unde he C ea i e Commons license, use s will need o ob ain pe mission om he license holde o ep oduce he ma e ial. To iew a copy o his license, isi h p://c ea i ecommons.o g/licenses/ by-nc-nd/3.0/ 476 VOLUME 96 NUMBER 4 | OCTOBER 2014 | www.na u e.com/cp