DrugSaf2010;33(3):171-1870114-5916/10/0003-0171/$49.95/0
ª2010AdisDataInformationBV.Allrightsreserved.
RiskFactorsandDrugInteractions
PredisposingtoStatin-InducedMyopathy
ImplicationsforRiskAssessment,PreventionandTreatment
YiannisS.Chatzizisis,1,2KonstantinosC.Koskinas,2GesthimaniMisirli,1ChristosVaklavas,3ApostolosHatzitolios4andGeorgeD.Giannoglou111stCardiologyDepartment,AHEPAUniversityHospital,AristotleUniversityMedicalSchool,Thessaloniki,Greece
2CardiovascularDivision,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,MA,USA3DepartmentofInternalMedicine,UniversityofTexasMedicalSchoolatHouston,Houston,TX,USA41stPropedeuticDepartmentofInternalMedicine,AHEPAUniversityHospital,AristotleUniversityMedicalSchool,Thessaloniki,Greece
Contents
Abstract.................................................................................1.DefinitionandEpidemiologyofStatin-InducedMyopathy...................................2.ComparisonbetweenStatins............................................................3.MechanismsofStatin-InducedMyopathy.................................................4.PhysicochemicalandPharmacokineticPropertiesofStatins.................................5.RiskFactorsthatPrecipitateStatin-InducedMyopathy......................................
5.1PatientCharacteristics..............................................................
5.1.1DemographicCharacteristics..................................................5.1.2GeneticFactors..............................................................5.1.3Co-Morbidities...............................................................5.2StatinProperties...................................................................
5.2.1Dose-DependentEffects......................................................5.2.2PhysicochemicalPropertiesofStatins:LipophilicityversusHydrophilicity...............5.3Statin-DrugInteractions.............................................................
5.3.1InteractionswithNon-HypolipidaemicAgents....................................5.3.2InteractionswithOtherHypolipidaemicAgents...................................
6.RecommendationsforthePreventionandManagementofStatin-InducedMyopathy..........
6.1PreventionofStatin-InducedMyopathy...............................................6.2ManagementofStatin-InducedMyopathy............................................7.Conclusions...........................................................................
171173173174174175175175176177177177178178179180181181181182
Abstract
HMG-CoAreductaseinhibitors(‘statins’)representthemosteffectiveandwidelyprescribeddrugscurrentlyavailableforthereductionoflow-densitylipoproteincholesterol,acriticaltherapeutictargetforprimaryandsecond-arypreventionofcardiovascularatheroscleroticdisease.Inthefaceoftheestablishedlipidloweringandtheemergingpleiotropicpropertiesofstatins,thepatientpopulationsuitableforlong-termstatintreatmentisexpectedtofurtherexpand.Anoverallpositivesafetyandtolerabilityprofileofstatins
172Chatzizisisetal.
hasbeenestablished,althoughadverseeventshavebeenreported.Skeletalmuscle-relatedeventsarethemostcommonadverseeventsofstatintreat-ment.Statin-inducedmyopathycan(rarely)manifestwithsevereandpo-tentiallyfatalcasesofrhabdomyolysis,thusrenderingtheidentificationoftheunderlyingpredisposingfactorscritical.
Thepurposeofthisreviewistosummarizethefactorsthatincreasetheriskofstatin-relatedmyopathy.Datafrompublishedclinicaltrials,meta-analyses,postmarketingstudies,spontaneousreportsystemsandcasereportsforrareeffectswerereviewed.Briefly,theepidemiology,clinicalspectrumandmolecularmechanismsofstatin-associatedmyopathyarediscussed.Wefurtheranalyseindetailtheriskfactorsthatprecipitateorincreasethelike-lihoodofstatin-relatedmyopathy.Individualdemographicfeatures,geneticfactorsandco-morbiditiesthatmayaccountforthesignificantinter-individualvariabilityinthemyopathicriskarepresented.Physicochemicalpropertiesofstatinshavebeenimplicatedinthedifferentialriskofcurrentlymarketedstatins.Pharmacokineticinteractionswithconcomitantmedica-tionsthatinterferewithstatinmetabolismandaltertheirsystemicbioavail-abilityarereviewed.Ofparticularclinicalinterestincasesofresistantdyslipidaemiaistheinteractionofstatinswithotherclassesoflipid-loweringagents;currentdataontherelativesafetyofavailablecombinationsaresummarized.Finally,weprovideanupdateofcurrentguidelinesforthepreventionandmanagementofstatinmyopathy.
Theidentificationofpatientswithanincreasedproclivitytostatin-inducedmyopathycouldallowmorecost-effectiveapproachesofmonitoringandscreening,facilitatetargetedpreventionofpotentialcomplications,andfurtherimprovethealreadyoverwhelminglypositivebenefit-riskratioofstatins.
Atheroscleroticcardiovasculardiseaseisthemostfrequentcauseofmorbidityandmortalityindevelopedcountries.Low-densitylipoproteincholesterol(LDL-C)reductionattenuatesthepro-gressionofatherosclerosisandreducestheriskofcardiovascularevents.Amonghypolipidae-micmedications,HMG-CoAreductaseinhibitors(‘statins’)haveunequivocallyrevolutionizedbothprimaryandsecondarypreventionofcardiovas-culardisease,duetotheirlipid-loweringpotentialandpleiotropiceffectsthatbeneficiallyaffectatheroscleroticplaquestability.[1]Statinsarecom-petitiveinhibitorsofHMG-CoAreductase,therate-limitingenzymeincholesterolbiosynthesisthatconvertsHMG-CoAintomevalonate.TheylowerplasmaLDL-Cthroughintracellularcho-lesteroldepletionandupregulationoftheexpres-sionofLDLreceptorsinhepatocytes.[2]Thenumberofpatientsreceivingstatins,oftenincombinationwithotherclassesoflipid-lowering
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agents,hasexpandedwiththeimplementationofmoreaggressivegoalsforLDL-Clowering,[3]whiletheadditionalbenefitattributedtointensivestatintherapyhasresultedinhigherdosestatinregimens.[4]Accumulatingevidencefromcontrolledtrialsandclinicalexperiencedemonstratesthatstatinsarewelltoleratedmedicineswithagoodsafetyprofile.[5-8]Themajorandmostcommoncom-plicationtotheiruseisavarietyofskeletalmuscle-relatedevents,whichrepresentaclinicallyimportantcauseofstatinintoleranceanddis-continuation.Statinsconferasmallbutdefiniteriskofmyopathy,adose-dependentadverseef-fectassociatedwithallstatins(classeffect).[9]Muscularadverseeffectsareusuallymildandreversible;however,theseadverseeffectsmaybeapreludetorhabdomyolysis,averyrarebutpo-tentiallyseriousandevenlife-threateningclinicalcondition.Theassociationofstatinswithcasesof
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severemyopathiceventsmayhaveresultedinexcessivesafetyconcernsforthisrevolutionaryclassofmedications.[10]Notwithstandingtheoverallgoodsafetyprofile,knowledgeoftheun-derlyingmechanismsandriskfactorsisrequiredforpromptidentificationandpropermanage-mentofadversemuscleevents.Thepurposeofthisreviewistoinvestigatetheriskfactorsthatprecipitatestatin-inducedmuscleadverseevents,andalsotosummarizecurrentguidelinesontheadministrationofstatinswithregardtotheirpotentialmyotoxicity.
1.DefinitionandEpidemiologyofStatin-InducedMyopathy
Inthepresentreviewtheterm‘myopathy’willbeusedasageneraltermtodescribeallskeletalmuscle-relatedproblems.[11]Several,oftencon-troversial,termshavebeenusedtodescribetheclinicalmanifestationsandlaboratoryfindingsofstatin-inducedmyopathy.Thespectrumofmyo-pathyincludesasymptomaticincreaseofcreatinekinase(CK),myalgia,myositisandrhabdomyo-lysis,assummarizedintableI.Rhabdomyolysisrepresentstheleastfrequent,thoughpotentiallyfatal,complicationcausedbyskeletalmusclebreakdown,whichleadstothereleaseoftoxicintracellularconstituentsintothebloodcircula-tionandeventuallycausesacuterenalfailure.Thelackofconsensusinthedefinitionofstatin-inducedmuscleeventshinderstheprecise
TableI.Theclinicalspectrumofstatin-inducedmyopathy[11]ConditionDefinition
Myopathy
Generaltermtodescribeallskeletalmuscle-relatedadverseeffectsAsymptomaticCKelevationCKelevationwithoutmusclesymptoms
MyalgiaMusclepainorweaknesswithoutCKelevation
MyositisMusclesymptomswithCKelevationtypically<10·ULNRhabdomyolysis
MusclesymptomswithCK
elevationtypically>10·ULN,andwithcreatinineelevation(usuallywithbrownurineandurinarymyoglobin)
CK=creatinekinase;ULN=upperlimitofnormal.
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estimationoftheirtrueincidence.Becausepatientswithaconsideredhighsusceptibilitytostatintoxicityaregenerallyexcludedfromclinicaltrialsofstatins,reportedadverseeventratesfromcon-trolledtrialsmayunderestimatethetruerateoftheseadverseeffectsinanunselectedpatientpo-pulation.Complaintsofmusclesymptomsoccurin1.5–3.0%ofclinicaltrialparticipants,whilerateswidelyrangebetween0.3%and33%inroutinepractice.[12]Noconclusiveevidencesupportsin-creasedmyalgiaassociatedwithstandardstatindoses,[13]althoughthishasbeenreportedinpa-tientsreceivinghigherdoses.[14]Theoverallexcessriskofmyopathyattributedtostandardstatindo-sesistypically<0.01%.[13]Accordingtodatafromrandomizedclinicaltrialsandcohortstudies,theincidenceofmyopathyisestimatedat5patientsper100000person-yearsandrhabdomyolysisat1.6patientsper100000person-years,[15]whereasreportingratesintheUSFDAAdverseEventReportingSystemdatabase(AERS)are0.3–2.2casesofmyopathyand0.3–13.5casesofrhabdo-myolysisper1000000statinprescriptions.[16]Arecent,large-scaletrialevaluatingrosuvastatatin20mgdailyreportedcomparableratesofmyo-pathybetweenrecipientsofdrugandplacebo(0.1%).[17]Regardinghigherdosestatinregimens,increasedriskofmyopathyhasbeenreportedforsimvastatin80mgdaily[18]butnotforhigherdosesofatorvastatin(80mg).[4,19,20]2.ComparisonbetweenStatins
Reportsassociatingtheuseofallmarketedstatinswiththeentirespectrumofmyopathysuggestthatthisisaclasseffect.[21]Thesafetyprofilesofdifferentstatinsatstandarddosesseemcomparablebutnotidentical,asindicatedbythesignificantlygreaterriskandsubsequentwithdrawalofcerivastatin,[22,23]whileexcessriskseemstobeclearlyrelatedtoincreaseddoses.Onthebasisofcurrentevidence,andintheabsenceofrandomizedtrialsdirectlycomparingtheriskofeachavailablestatinincomparabledosesandwithstandarddefinitionsofmyopathicevents,nodefiniteconclusionsontherelativemyopathicpotentialconferredbyeachofthecurrentlymarketedstatinscanbedrawn.[21]Anoverall
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174higherriskofrhabdomyolysishasbeenasso-ciatedwithsimvastatin80mg,whereasthelowestincidenceapparentlyoccurswithfluvastatinandpravastatin,presumablyassociatedwiththeirweakerHMG-CoAreductaseinhibitorcapa-city.[12,15,24,25]Accordingtoameta-analysisoftrialscomparingstandarddosesofallcur-rentlymarketedstatinsexceptrosuvastatin,atorvastatinwasassociatedwiththerelativelyhighestriskandfluvastatinwiththelowestriskofadverseeventsingeneral,andmusculareventsinparticular.[26]Arecentlypublishedmeta-analysisofrandomizedcontrolledtrialscomparingdiffer-entdosesofatorvastatin(10–80mg)androsu-vastatin(5–40mg)revealednosignificantdifferenceinadversemusculareventsbetweenthesetwostatinsatanydoseratio.[27]3.MechanismsofStatin-InducedMyopathy
Thepathogeneticmechanismsofstatin-inducedmyopathyhavebeenthoroughlyreviewedbyVaklavasetal.[28]andarepresentedbrieflyinthisreview.TheinterruptionoftheHMG-CoAre-ductasebiosyntheticpathwayandtheconsequentintracellulardepletionofdownstreamintermediatemetabolites(i.e.isopentenylatedproteinsgeranylpyrophosphataseandfarnesylpyrophosphatase)andendproducts(i.e.cholesterol,dolichols,ubi-quinone)areconsideredthecornerstoneofthemyotoxiceffectsofstatins.Reductionofpre-nylatedproteinscanresultindysprenylationofproteins,includinglaminsandsmallguanosinetriphosphatases,therebycausinganimbalanceintheintracellularsignallingcascadesandenhancingapoptosis.Sarcolemmalcholesteroldeficiency,asaresultofthedynamicequilibriumbetweenmem-braneandplasmalipids,mayadverselymodifymembranephysicalproperties,integrityandfluid-ity,thusresultinginmembranedestabilization.[29]Inhibitionofdolicholsynthesishasbeenimpli-catedindefectiveN-linkedglycosylationofplasmamembraneproteinsandimpairedresponsetogrowthfactors.[28]UbiquinoneorcoenzymeQ10(CoQ10)isare-cognizedconstituentofoxidativephosphorylationandadenosinetriphosphateproductioninmito-ª2010AdisDataInformationBV.Allrightsreserved.
Chatzizisisetal.
chondriarequiredtomaintaincellintegrity.[30]Consistently,thedecreasedCoQ10biosynthesisandthusenergydepletionmediatedbystatinshasbeenpostulatedtoaccountforthepotentialmyo-toxicityofstatins.Statin-mediatedreductionofcirculating,butnotintramuscular,[31]CoQ10levelshasbeenreported,whilenodirectassociationbetweendecreasedintramuscularCoQ10levelsandmitochondrialmyopathyhasbeenestablished.Accordingly,CoQ10deficiencymayrepresentapredisposingratherthanetiopathogenicfactorofstatinmediatedmyopathy,possiblyinasyner-gisticmannerwithcoexistingCoQ10-depletingconditions.[32]Theequilibriumbetweenintramuscularstatintransportandeffluxmaybeacriticalregulatorofintramusculardrugconcentrationandconse-quentlytheriskofmyopathy.Organicaniontransportingpolypeptide(OATP)2B1,are-cognizedhepaticuptaketransporterforstatins,hasalsobeenidentifiedinskeletalmyofibres,[33]andtheOATPinhibitorestronesulphatepro-tectedtheskeletalmyofibresagainstpravastatin-andfluvastatin-inducedtoxicity.Furthermore,isoforms-1,-4and-5ofthemultidrugresistance-associatedprotein(MRP),awellcharacterizedstatineffluxtransporter,arehighlyexpressedinskeletalmuscle,andtheinhibitionofMRPwithprobenecidprecipitatesskeletalmuscletoxicityinratstreatedwithrosuvastatin,[34]implyingthatMRP-1maybeinvolvedinstatineffluxatthemyocytelevel.
4.Physicochemicaland
PharmacokineticPropertiesofStatinsThephysicochemicalpropertiesofstatins,whichdeterminetheirbioavailabilityandtherebyaffecttheriskofmyopathy,aresummarizedintableII.Watersolubilityaffectsstatinperme-abilitythroughcellularmembranesofnon-hepa-tic(includingmuscular)cellsandtheirabilitytocrosstheblood-brainbarrier.Pravastatin,rosu-vastatinandtosomeextentfluvastatinexhibithydrophilicproperties,asopposedtothelipo-philicityoftheotherstatinmolecules(i.e.ator-vastatin,simvastatinandlovastatin).[35]DrugSaf2010;33(3)
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TableII.PhysicochemicalandpharmacokineticpropertiesofstatinsCharacteristicDailydosage(mg)OriginProdrugSolubilityCNSpermeationEffectoffoodintakeonabsorption
First-passmetabolismProteinbinding(%)Half-life(hours)Hepaticexcretion(%)Renalexcretion(%)
Lovastastin20–80FungiYesLipophilicYesIncreasedabsorptionCYP3A4952–36930
Simvastatin10–80SemisyntheticYesLipophilicYesNoneCYP3A4952–37913
Pravastatin20–80FungiNoHydrophilicNoDecreasedabsorptionMultipleways501–24660
Fluvastatin40–80SyntheticNo
IntermediateNoNoneCYP2C9980.5–2>68<6
Atorvastatin10–80SyntheticNoLipophilicNoNoneCYP3A49013–16Notavailable<2
Rosuvastatin10–40SyntheticNoHydrophilicNoNone
LimitedCYP2C990196310
CYP=cytochromeP450enzyme.
ThehepaticcytochromeP450enzyme(CYP)systemisresponsibleforthemetabolismofmanydrugs,includingstatinstosomeextentwiththeexceptionofpravastatin.[36]Lovastatin,simvas-tatinand,toalesserextent,atorvastatinaremetabolizedbytheCYP3A4isozyme.Coadminis-trationofthepreviouslymentionedstatinswithmedicationsorfoodthateitherinhibitoraresubstratesofCYP3A4decreasesthestatins’first-passmetabolism,therebyresultinginincreasedbioavailability.[37]Fluvastatinismainlymeta-bolizedbyCYP2C9,andtoamuchlesserextentbyCYP3A4andCYP2C8,andconse-quentlydoesnotinteractwithCYP3A4inhibi-tors.Pravastatinismetabolizedthroughseveralpathways,includingisomerization,sulfation,glutathioneconjugationandoxidation,andonlytoasmallextent(1%)bytheCYPenzymesystem;itistheonlystatinwithasignificantrenalexcre-tion(approximately60%oftheabsorbedquan-tity),inkeepingwithitshydrophilicnature.[38]Thistheoreticallyrendersitsaferasfarasitspotentialdruginteractionsareconcerned.[9]Ro-suvastatinundergoesminimalmetabolismviatheCYP2C9isoenzyme,[39]while90%iseliminatedastheparentcompoundinthefaeces.
Thesystematicbioavailabilityofstatinsisquitelow.Allstatinspresentahighaffinitywithbloodproteins(95%),exceptpravastatin(approximately50%).Atorvastatinandrosuvas-tatinarethetwostatinswithlongerhalf-lives
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(13–16hours)andthispropertyismostprobablylinkedtotheirhigherlipid-loweringefficacy.5.RiskFactorsthatPrecipitateStatin-InducedMyopathy
Whenadministeringstatins,physiciansshouldtakeintoconsiderationaseriesoffactorsthatpotentiallyincreasetheriskofmyopathicevents.Assummarizedinfigure1,aconstellationoffactorsareassociatedwiththeriskofstatin-associatedmyopathydevelopment,including(i)patientcharacteristics(demographiccharacter-istics,co-morbidities,geneticfactors);(ii)drugproperties(specificstatinmolecule,dose,phar-macokineticproperties);and(iii)concomitantinteractingmedications.Systemicexposureisconsideredtoplayapivotalroleinstatin-associatedmyopathy,andriskfactorsthatenhancetherespectiveriskmaydoso,atleastpartly,byincreasingeitherstatinsystemicbioavailabilityorthesensitivitytoincreasedstatinbloodlevels.
5.1PatientCharacteristics
5.1.1DemographicCharacteristics
Certaindemographiccharacteristicshavebeenassociatedwithanincreasedriskofstatin-inducedmyopathy.Ithasbeenobservedepidemiologicallythatadvancedage(particularly>80years),femalesex,smallbodyframeandfrailtyincreasethemyopathiceffectof
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176Chatzizisisetal.
Drug propertiesDosePharmacokinetic properties water solubility first-pass metabolism protein bindingPatient characteristicsDemographic characteristics age race sexGenetic predisposition transporting polypeptides CYP isoenzymesCo-enzyme Q10 depletionCo-morbidites systemic diseases infectious diseases alcoholism/drug addiction major surgical operations myopathy hereditary acquiredConcomitant medicationsPharmacokinetic interactions CYP metabolism CYP3A4 CYP2C9 glucuronidationPharmacodynamic interactions synergic myotoxicityIncreased systemic bioavailabilityEnhanced susceptibility to elevated blood levels of statinsMyopathyFig.1.Riskfactorsforstatin-inducedmyopathy.CYP=cytochromeP450enzyme.
statins.[11,13,40]Myopathicsymptomsmaybehardtodifferentiatefrommuscularcomplaintscommonlyexperiencedinelderlypatients.Poly-pharmacyandage-relatedimpairmentofrenalfunctionmayinpartaccountfortheincreasedriskofmyopathyamongelderlyindividuals.AgreaterriskhasbeenattributedtoChineseorJapanesedescent,althoughthisconceptisinadequatelysupportedbycurrentevidence.Typi-cally,AsiansachievesimilarbenefitstoCauca-siansatlowerstatindoses.Plasmalevelsofrosuvastatininparticularhavebeenshowntobe2-foldhigherinAsianthaninCaucasianin-dividualsreceivingsimilarrosuvastatindoses.[41]ThesmallerbodymassindexinAsianshasbeenpostulatedastheunderlyingcauseofthediffer-encesindrugresponseinsome[42,43]butnotallcomparablestudies.[44,45]GeneticdifferencesinstatinmetabolisminvolvingtheCYP450enzymesandtheOATPsaremorelikelytoaccountfortheheightenedresponsetostatinsinAsians.[46-48]Althoughtheincreasedsystemicbioavailabilityachievedwithsimilarstatindoses[41]hasnotbeenclearlyrelatedtoahighermyopathicriskinAsians,rosuvastatinislabelledforlowerdosesinAsians[49]andnoneofthestatinsareapprovedinJapanatthehighestdosesapprovedintheUS.[50]ª2010AdisDataInformationBV.Allrightsreserved.
5.1.2GeneticFactors
Geneticpredispositionandinterindividualvariabilityinsusceptibilitytostatin-inducedad-versemusculareventshavebeenreported.Anumberofcandidategenevariantsthatencodestatinmetabolizingenzymesandreceptors,[51,52]OATPs[53]andCoQ10[54]havebeenimplicated.GeneticpolymorphismsmayresultinvariantexpressionoftheCYPisoenzymesbothintheli-verandsmallintestine.LowhepaticorintestinalexpressionoftheCYP3A4isoenzyme(‘poormetabolizers’)resultsindecreasedfirst-passme-tabolismforlovastatin,simvastatinandatorv-astatin,whichincreasestheirbioavailability.Inarecentlypublishedstudythatperformedagenome-widescaninpatientswithdefiniteorin-cipientmyopathyreceivingsimvastatin80mgdaily,commonvariantsinsolutecarrierorganicaniontransporter(SLCO)1B1onchromosome12,whichencodestheOATPandtherebythehepaticuptakeofmoststatins,werelinkedtoasubstantialexcessriskofstatinmyopathy,with60%ofallmyopathycasesattributabletoonespecificcommonvariant(rs4149056C).Hetero-zygotesforthisvariantdisplayeda4-foldin-creaseintheincidenceofmyopathy,whereasthehomozygoteshada17-foldincrease.[55]Notably,
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theseassociationsweredemonstratedamongpatientsreceivinghighdosesofsimvastatin(80mgdaily),indicatingthatgenotypiccontrolcouldoptimizetailoredtherapeuticadjustmentsinpatientsunderhigh-doseregimensandwithcoexistingriskfactors.
5.1.3Co-Morbidities
Theincidenceofstatin-inducedrhabdomyo-lysismaybehigherinpatientswithexistingmyopathies,eitherhereditary(e.g.carnitinepal-mityltransferaseIIdeficiency,McArdle’sdiseaseandmyoadenylatedeaminasedeficiency)orac-quired(e,g.postpolyomyelitissyndrome).[56,57]Statinshavealsobeenimplicatedinthepotentialaggravationofmyastheniagravis.[58]Further-more,anunderlyingmetabolicpredispositionconsistingofbiochemicalabnormalitiesinmito-chondrialorfattyacidmetabolisminmyocytesmayrendersomeapparentlyhealthyindividualsmoresusceptibletothedevelopmentofstatin-inducedmyopathicoutcomesthanothers.[59]Underlyingchronicsystemicdiseasesmayserveasnon-modifiableriskfactorsthatdecreasestatinmetabolismandexcretion,andtherebyin-creasetheirsystemicbioavailability.Thesefac-torsrendersomepatientsmoresusceptibletomyopathyandincreasetheprobabilityofadversemuscleevents,whichmayensueatanytimeduringtheadministrationofastatin.Althoughlimiteddatasuggestabeneficialcardiovasculareffectofstatinsinpatientswithmoderaterenalimpairment,[60]coexistingrenalfailureincreasestheriskofstatin-inducedmyopathicevents.[13]Diabetesmellitusconstitutesafurthermyopathicriskfactorinpatientsreceivingstatins,particu-larlycombinedwithadvancedageandchronicrenalfailure,[11]althoughthereisnoconsensusofopinion.[61]Enhancedriskofstatin-inducedmyopathywithexcessivealcoholconsumptioncannotbeconclusivelysupportedbydatafromrandomizedtrialsasalcoholismisanexclusioncriterioninmosttrials.However,increasedal-coholintakeperseconfersamyotoxicpoten-tial[62]andalcoholabusecouldraisethebloodlevelsofstatins.[12]Untreatedhypothyroidismisconsideredtoincreasetheriskofstatinmyo-pathy,[11,25,63]andstatinsmayaggravatethe
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musclesymptomsandCKelevationcausedbyocculthypothyroidism.Liverdysfunctionhasbeenconsideredariskfactorforstatinmyo-pathy,[11,64-66]mainlyduetotheinvolvementofthehepatobiliarysysteminthemetabolismandexcretionofmoststatins.Althoughhepaticdys-functionhasbeenassociatedwithstatin-inducedrhabdomyolysisinreportsbyregulatoryautho-rities,[67]theexclusionofpatientswithhepaticfailurefromrandomizedcontrolledtrialspre-ventstheestablishmentofadirectlinkbetweenimpairedliverfunctionandheightenedriskofmyopathy.[4,6,17]Furthermore,acutelyactingfactorspredis-posetomyopathyindependently,andmaytrig-gerthedevelopmentofseveremyopathy,evenrhabdomyolysis,instatin-receivingindividuals.Suchprecipitatingconditionsincludetheuseofaddictivedrugs(e.g.amfetamines,cocaine,heroin,LSD,ecstasy),[62]seriousviral[68]orbac-terialinfection,[69,70]majortraumaandintensemuscleactivity.Statinscanexacerbateexercise-inducedskeletalmuscleinjury,asreportedinanobservationalstudyinpatientsreceivinghigh-dosestatins[25]andassuggestedbythegreaterCKresponsetoexerciseinstatin-comparedwithplacebo-treatedpatients.[71]Statin-relatedmyo-pathyhasbeenreportedinthesettingofextensivesurgicaloperations;[72,73]therefore,ashort-termwithdrawalofstatinsduringhospitalizationformajorsurgeryisrecommended.[11]Inthecaseofvascularsurgeryinparticular,includingcor-onarybypassprocedures,statinsshouldnotbediscontinued[74]inlightoftheirbeneficialplaque-stabilizingeffect,withtheexceptionofpreopera-tivemuscularsymptoms,markedperioperativetissuecompressionorprolongedpostoperativeenergydeprivation.[75]5.2StatinProperties
5.2.1Dose-DependentEffects
WhilethetherapeuticbenefitfromstatintherapyisrelatedtotheachievedLDL-Creduc-tion,[76]theriskofadversemusculareventsap-pearstobeadose-dependentadverseeffect[21]regardlessofthedegreeofLDL-Cdecrease.[15]However,theredoesnotappeartobealinear
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178relationshipbetweenplasmalevelsachievedbyacertaindrugdoseandtheriskofadversemuscularevents.Increasedmyopathicriskhasbeende-monstratedwithhigherthancurrentlymarketeddosesofsimvastatin(160mg)[76]andpravastatin(160mg).[77]Anincreasedincidenceofmyopathyhasalsobeenshowninpatientswithacutecor-onarysyndromesreceivingsimvastatin80mgdailycomparedwithplaceboorsimvastatin20mg.[18]Ahigherincidenceofstatin-relatedmyalgiawasat-tributedtoatorvastatin80mgcomparedwithsimvastatin20mg[14]butnotablythisdidnotoccurwhenatorvastatin80mgwascomparedwitheitheratorvastatin10mg[19]orplacebo.[20]5.2.2PhysicochemicalPropertiesofStatins:LipophilicityversusHydrophilicity
Invitroresearchdataindicatethatpravastatin,whichiswatersoluble,islessmyotoxicinrelationtolovastatinandsimvastatin.[78]Althoughthein-hibitionofhepatocellularcholesterolsynthesiswascomparablebetweenthesethreestatins,theeffectofpravastatinwas85timesweakerinratmyo-cytes.Moreover,pravastatinwas100-200times(inaninverselydose-dependentmode)lessmyo-toxic.[78]Overall,differentstatinsseemtoexertdi-versedose-dependenteffectsontheHMGCoAreductaseactivityofnon-hepaticcellsinvitro.Thedecreasedmyotoxicityofpravastatinappearstoberelatedtoitsdecreasedpenetrationofthecellmembraneandthusuptakebyextra-hepatictis-sues,presumablyassociatedwiththehydro-philicityofthemolecule.Pravastatinistakenupbythehepaticcellsviaasodium-independentbileacidtransporter,theOATP,[79]which,alongwithsodium-dependenttaurocholatecotransportingpolypeptide,alsomediatestheactivehepaticup-takeofthehydrophilicrosuvastatinmolecule.Thelipid-richmembranesofnon-hepaticcells,suchasmusclecells,lackOATPsothattheyfunctionasabarriertohydrophilicstatinswhileallowingpas-sivediffusiontolipophilicstatins.However,thehydrophilicityofsomestatinspersehasnotbeenproventoofferclinicallysignificantmuscularpro-tection[12]andnoclinicalevidencesupportsadirectassociationbetweenthedegreeoflipophilicityandthemyotoxicpotential[9]sincecasesof
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Chatzizisisetal.
rhabdomyolysishavealsobeenattributedtohy-drophilicstatins.
5.3Statin-DrugInteractions
Theinteractionofstatinswithothercategoriesofmedicationscanenhancetheirmyotoxicpo-tential(tableIII).Indeed,approximately60%ofcasesofstatin-relatedrhabdomyolysisarerelatedtodruginteractions.[24]Theunderlyingmechan-ismusuallyhasapharmacokineticbasisinvol-vingintestinalabsorption,distribution,metabo-lism,proteinbindingorexcretionofstatins.Themajorityofreportedcasespertaintocompetitionatthelevelofhepaticmetabolism,[80]consideringthatoverhalfofcurrentlyavailabledrugsaremetabolizedbytheCYP3A4isoenzyme;inhibi-tionoftheCYPactivitybycoadministereddrugsincreasestheriskofmyopathicevents.Simvas-tatinandlovastatinappeartobemoresusceptibletotheinhibitingeffectofotherCYP3A4sub-stratesthanatorvastatin.Similarly,theinter-actionbetweenfluvastatinandCYP2C9inhibitorsorcompetitivesubstratesmaybeofclinicalim-portance,whereasCYP450isoenzymesaremini-mallyinvolvedinrosuvastatinclearance.
TableIII.Substancesthatmayprecipitatestatin-inducedmyopathyNon-hypolipidaemicmedicinesCiclosporin
Macrolideantibacterials(erythromycin,clarithromycin)Azoleantifungals(itraconazole,ketoconazole,fluconazole)Calciumchannelantagonists(diltiazem,verapamil)Nefazodone
HIVproteaseinhibitors(ritonavir,nelfinavir,indinavir)Warfarin
HistamineH2receptorantagonists(cimetidine,ranitidine)OmeprazoleAmiodarone
Hypolipidaemicmedicines
Fibrates(gemfibrozil>bezafibrate,clofibrate,fenofibrate)Niacin
OthersubstancesGrapefruitjuice
Over-the-countermedications(Chineseredricefungus)
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OthersitesofpotentialpharmacokineticinteractionsincludeinhibitionofmetabolismbyintestinalwallisoenzymesoftheCYPsystem,preventionoftheOATP-mediatedhepatocel-lularuptake,blockingofbiliaryexcretionandinhibitionoftherenaleliminationofhydrophilicmetabolites.[80]Pharmacodynamicinteractionsinvolvingsta-tinsarelesscommonbecauseofthehighselectivityofstatinsasHMG-CoAreductaseinhibitors.Theconcomitantadministrationofagentswithanindependentmyotoxiceffect,suchasfibrates,cansynergisticallyincreasetheriskofstatin-associatedmyopathy.Inthatcase,apharmacokineticcom-ponentmayalsocomeintoplay.
5.3.1InteractionswithNon-HypolipidaemicAgentsPharmacokineticInteractionswithCytochromeP450Enzyme(CYP)3A4InhibitorsandCompetingSubstrates
InhibitorsofCYP3A4isoenzymedecreasestatinmetabolismandthusincreasetheirserumlevelsandthelikelihoodofmyopathy.Suchen-zymaticinhibitorsincludeazoleantifungals(itraconazole,ketoconazole,fluconazole),[37,81,82]macrolideantibacterials(erythromycin,clari-thromycin),[83,84]calciumchannelantagonistsdiltiazem[85,86]andverapamil,theantidepressantnefazodoneandtheconsumptionofgrapefruitjuiceexceedingapproximately1Ldaily.Grape-fruitjuicecontains60,70-dihydroxybergamottin,whichactsasaninhibitoroftheintestinalCYP3A4isoenzymeresultingindecreasedmeta-bolismandtherebyenhancedbioavailabilityofstatins.[80]HIVproteaseinhibitors(ritonavir,nelfinavir,indinavir)arerecognizedCYP3A4inhibitorsandthispropertyrendersthemyotoxicpotentialoftheircombinationwithstatinshighrisk,[87]inparticularthosestatinsthatrelytoalargeextentontheCYP3A4isoformfortheirmetabolism.OfclinicalinterestistheadverseeffectofHIVpro-teaseinhibitorsonthelipidprofile,[88]whichmayincreasetheriskofcardiovasculardiseaseandpancreatitisandoftenrequirestheadministrationoflipid-loweringagents.[89]ª2010AdisDataInformationBV.Allrightsreserved.
Statinsarethemosteffectivemedicinesforthetreatmentofhypercholesterolaemiainpatientswhohaveundergonetransplantation,[90]andtheirimmunomodulatorypropertiesappeartoprovidegeneralprotectionforthegraft.How-ever,ciclosporin(cyclosporine)inhibitsbothin-testinalandhepaticCYP3A4activityandcanthereforeleadtoincreasedbioavailabilityofsta-tinsmetabolizedbythiscytochrome.[91]Themorelipophilicthestatinandthegreaterthesystemicexposuretounboundactivestatincompound,thegreaterthepotentialformyopathy.[73,92]Pravas-tatinandfluvastatinarelesslikelytointeractwithciclosporinonapharmacokineticbasis.However,ciclosporinhasbeenreportedtoin-creaseserumlevelsofpravastatin.[93]Competi-tionatthelevelofbiliaryclearanceresultinginreducedpravastatinremovalthroughthebileductandpreventionoftheP-glycoproteintrans-ferareconsideredthemainpathomechanisms,indicatingthatCYP3A4isnottheonlysitein-volvedinclinicallyrelevantciclosporin-statininteractions.
Thecombinationofstatinswithwarfarinislikelytoincreasetheserumlevelsofwarfarin,therebypotentiatingitsanticoagulanteffect.[94]Regularanticoagulationcontrolandpossiblywarfarindoseadjustmentmaythusberequired.However,thepotentiatingeffectofwarfarinonstatinlevelshasnotbeenstudiedsufficiently.[95]Ahypothesishasbeenarticulatedthataswar-farinconstitutesthesubstrateofCYP2C9,andpartlyofCYP3A4,itcouldcompetewithstatinsintheirenzymaticconversion.
PharmacokineticInteractionswithCYP2C9InhibitorsandCompetingSubstrates
Azoleantifungalagentsarerecognizedin-hibitorsofCYP2C9,aswellasthepreviouslymentionedCYP3A4.Thisnecessitatesahigherindexofsuspicionwhentheyareadministeredinpatientsreceivingfluvastatin.Forexample,flu-conazolehasbeenreportedtoincreasefluvastatinbioavailability,[96]althoughnocasesofrhab-domyolysisattributabletosuchacombinationareknown.Furthermore,histamineHandranitidine,2receptorantagonistscimetidineandtheprotonpumpinhibitoromeprazole,whichare
DrugSaf2010;33(3)
180alsosubstratesofCYP2C9,enhancefluvastatin’ssystemicexposure,butwithoutparticularclinicalsignificance.Ofnote,omeprazolealsoappearstopossessaCYP3A4inductioncapacity,poten-tiallyincreasingthebiotransformationandthusdecreasinglevelsofstatinsthataresubstratesoftheCYP3A4isoenzyme.[37]5.3.2InteractionswithOtherHypolipidaemicAgentsFibrates
Inmanycasesofmixeddyslipidaemia,india-beticpatientsorinpatientswithhightriglycer-idesdespitetheachievementofthedesirableLDL-Cgoal,thecoadministrationofstatinswithfibratesisanattractivetherapeuticoption.Ac-cordingtodatafromepidemiologicalstudiesandclinicaltrials,thecombinationofanystatinwithfibratesincreasestheriskofmyopathy,whichisusuallyobservedwithinthefirst12weeksbytheinitiationoftreatment.Theincidenceofmyo-toxicitywiththiscombinationis0.12%.[97]Evenifmostreportsinvolvegemfibrozil,[98,99]otherfibrates(bezafibrate,clofibrate,fenofibrate)havealsobeenimplicatedincasesofrhabdomyolysiswhenusedaloneandhaveanadditivemyotoxicpotentialwhencombinedwithstatins.[99]Thepresenceofgemfibrozilinmostcasesofrhabdo-myolysisispartlyexplainedbyitswiderclinicalusethanotherfibrates;however,thedifferentialsafetyprofileoffibratesseemstoremainevenaftercorrectionforthewiderprescriptionofgemfibrozil.[100]SincefibratesdonotinterferewithCYP-mediatedstatinelimination,theadditiveadverseeffectwhencombinedwithstatinsappearstohaveapredominantlypharmacodynamicbasis(synergy).Theincidenceofhospitalizedpatientswithrhabdomyolysisprescribedfibratemono-therapyhasbeenreportedtobemorethan5timeshigherthanwithatorvastatin,pravastatinorsimvastatinmonotherapy.[101]Pharmacoki-neticparametersarealsobelievedtoaccounttosomedegreefortheobservedinteractions.Statinglucoronidationisanintermediatestepintheconversionofactiveacidformstolactones,whichinturnaremetabolizedbythehepaticP450sys-tem.[102]Theinhibitionofstatinhydroxyacid
ª2010AdisDataInformationBV.Allrightsreserved.
Chatzizisisetal.
glucoronidationmediatedbygemfibrozil[103]butnotfenofibrateandsubsequentincreasedbio-availabilityofstatinsisbelievedtopartlyaccountfortheincreasedmyopathicriskassociatedwiththecombinationofstatinswithfibrates.Further-more,statin-fibrateinteractionsmayinpartbemediatedthroughtheactivationoftheperoxi-someproliferator-activatedfamilyofnuclearre-ceptors,[104]whichhavebeenshowntoaffectCYPregulation.Moreover,gemfibrozilhasbeenreportedtoreducetherenalclearanceofpravas-tatinbycompetitivelyactingatthetransportproteins[105]anditincreasespravastatinandro-suvastatinconcentrationsbyimpedingtheirbili-aryexcretion.[37]Niacin
Theadditionofniacininastatin-receivingpatientcanyieldcomplementarybenefitsinachievingacomprehensivelipidcontrol.Theconcomitantadministrationofstatinswithhighdosesofniacinhasbeenassociatedwithrhabdo-myolysisinalimitednumberofanecdotalreportedcases[106]throughamechanismthatre-mainsunknownbutappearstobeunrelatedtostatinserumlevels.Niacinisnotimplicatedasastrongprecipitatingfactorforstatin-inducedmyopathy,andthecombinationofstatinandniacinisconsideredtocarryalowerriskthanstatin-fibratecoadministration.[21]Basedoncur-rentevidence,noexcessiveriskofmyopoathyasaresultofastatin-niacincombination,comparedwiththatexpectedbyaddingoneagenttotheother,canbesupported.[107]Ezetimibe
Combinedinhibitionofintestinalcholesterolabsorptionmediatedbyezetimibeandhepaticcholesterolsynthesisviastatinshasemergedasachallengingtherapeuticoption.Anecdotalreportsofmyopathyattributedtothecombinationofsta-tinplusezetimibe[108,109]havenotbeenconfirmedinthesettingofrandomizedcontrolledtrials.Anenhancedlipid-loweringeffectandcomparablesafetyprofilewasshownwhenezetimibewasad-dedtostatinsinpatientswithhypercholester-olaemia.[110]Theincidenceofmuscle-relatedeventswasnothigherinpatientstakingsimvastatinalonethanthecombinationofsimvastatinplus
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Statin-InducedMyopathy:RiskFactorsandDrugInteractions181
ezetimibeaccordingtopooleddatafrom17re-lativerandomizedclinicaltrials.[111]Inrecentstud-ies,theadditionofezetimibe10mgresultedingreaterlipid-loweringefficacythan,andequalsafetyandtolerabilityto,uptitrationofatorvasta-tin20–40mginpatientsatmoderatelyhighrisk[112]andtothedoublingofatorvastatin40–80mginpatientsathighriskforcoronaryheartdisease.[113]Overall,currentevidencecannotsupportenhancedriskforstatin-relatedmyopathybythecoadmi-nistrationofezetimibe.[21]6.RecommendationsforthePreventionandManagementofStatin-InducedMyopathy
6.1PreventionofStatin-InducedMyopathy
Preventionandearlyrecognitionarethebestapproachestomanagingstatin-relatedmyopathyandavertingserioussequelae.Statintreatmentshouldbeginwithlowdosesthatcanbepro-gressivelyincreased;ifnecessary,theanticipatedclinicalbenefitshouldbeweighedagainsttheincreasedmyopathicrisk.Coadministrationofinteractingmedicationsshouldbeavoidedwheneverpossible.Whenahigh-riskcombina-tionisnecessary,smalldosesofthepresumablysafeststatinforanygivencombinationshouldbeprescribed.
Patientsshouldbecounselledontheriskandwarningsignsofmyopathy,andonthepossibilityofdruginteractions.Anyunexplainedmusclesymptomsshouldbereportedimmediatelytotheattendingphysician.Patientsathighriskshouldbefollowedupclinically,especiallyduringthefirstmonthsoftreatment.Whenacuteclinicalconditionsthatcanprecipitaterhabdomyoly-siscoexist,itisadvisabletointerruptstatinstemporarily.
RoutinemeasurementofpretreatmentCKlevelsisnotrecommendedbecauseoftherarityofmyopathywhenstatinsareprescribedatusualdosesinthegeneralpopulation.However,CKshouldbemeasuredinpatientsathighriskformyopathy,atbaselineandregularlyduringthecourseofstatintherapy.[21]ª2010AdisDataInformationBV.Allrightsreserved.
Ifastatin-fibratecombinationisrequired,fenofibrateisthepreferredoptionovergemfi-brozil.[80,100,114]Thestatindosesshouldremainbelowthemaximallevels.Fluvastatinmaybeap-propriateforcombinationwithgemfibrozil.[115]ParticularattentionisrequiredforpatientswithincreasedCKlevels,andrenalandhepaticdysfunction.
Onthebasisofcurrentevidence,routineCoQ10supplementationcannotberecommendedtopre-ventstatin-relatedmyopathicevents.[21]CoQ10supplementationmightbeconsideredinthesettingofCoQ10-depletingconditions,suchasadvancedageormultisystemdiseases.[30]6.2ManagementofStatin-InducedMyopathy
Statin-inducedmyopathyisusuallymildandreversibleuponstatindiscontinuation;however,inveryrarecasesitmayevolvetowardsseveremuscledamage,evenrhabdomyolysis.Ifstatin-relatedmyopathyissuspected,morecommoncausesofsymptomsand/orCKelevationshouldberuledoutbythoroughhistorytaking,physicalexaminationandlaboratorytests.Otheretiolo-giesofmusclesymptomsincludeunusualphysi-calactivity,trauma,falls,accidents,seizures,alcohol,drugs(corticosteroids,antipsychotics,cocaine,amfetamines),occulthypothyroidism,infectionsandautoimmunedisorders(polymyo-sitis,dermatomyositis,rheumaticpolymyal-gia).[116]InitialtestsincludeCKlevels,serumthyroid-stimulatinghormonelevels,andrenalfunctionwithurinalysisifrhabdomyolysisissuspected.Inrarecasesofpersistentsymptoma-tologydespitestatindiscontinuation,furtherin-vestigationsincludingelectromyographyandmusclebiopsymayberequired,inconsultationwithexpertsinmusclediseases.[116]TheintensityofclinicalsymptomsalongwiththemagnitudeofCKelevationshouldguideclinicalmanagement,assummarizedinfigure2.InthecaseofCKlevels<10·theupperlimitofnormal,withoutorwithtolerablemusclesymp-toms,thestatinmaybecontinuedatthesameorasmallerdose.[116]InthepresenceoftolerablesymptomswithCKserumelevation>10·the
DrugSaf2010;33(3)
182Chatzizisisetal.
Suspected statin-induced myopathyAsymptomatic CK elevationMuscle-related symptoms ± CK elevationExclude other causesMeasure CK levelsCK <10 × ULNContinue statin(same/reduced dose)Treatment adjustmentbased on CK monitoringCK >10 × ULNDiscontinuestatinNormalElevatedCK >10 × ULN and renal function impairmentNoYesRhabdomyolysisMyalgiaAssess symptom severityMyositisIntolerableRestart statin oncesymptoms resolve(same/different statin,same/reduced dose)NoSymptoms recurrence?YesDiscontinue statinTolerableAssess CK levelsCK >10 × ULNDiscontinue statinCK <10 × ULNContinue statin(same/reduced dose)Treatment adjustmentbased on symptomsFig.2.Assessmentandmanagementofstatin-inducedmyopathy.CK=creatinekinase;ULN=upperlimitofnormal.
upperlimitofnormal,oriffrankrhabdomyolysisdevelops,statinsshouldbediscontinued.Rhab-domyolysispromptsin-hospitalsupportivetreat-mentconsistingofintravenoushydrationandmonitoringforpotentialcomplications.[117]Intolerablemusclesymptoms,regardlessofCKlevels,requiretemporarystatininterruption.Oncesymptomsresolve,thesameorlowerdoseofthesameoradifferentstatincanberestarted.Alternativestatinregimenswithanostensiblylowermyopathicpotentialmayincludefluvasta-tinextendedrelease,[118]low-doserosuvastatin,[119]andnon-dailyregimenswithatorvastatin[120-122]orrosuvastatin.[123-126]Ifsymptomsreoccur,statinsuspensionshouldbepermanent.Non-statinlipid-loweringagentsthathaveshownef-ficacyandsafetyinpatientsintoleranttostatins
ª2010AdisDataInformationBV.Allrightsreserved.
includeezetimibe,[118,127]aloneorincombinationwithbileacid-bindingresin.[128]7.Conclusions
StatinsrepresentthemosteffectiveclassofmedicationsforreductionofLDL-Candthere-foreforthepreventionofcardiovascularathero-scleroticdisease.Althoughmyopathyistheirmostcommonadverseeffect,severemuscle-relatedcomplicationsareveryrareandshouldnotdeterphysiciansfromprescribingthesegen-erallysafeandwelltoleratedagents.Severalfac-torsthatmaypredisposeto,ortrigger,myopathiceventsinstatin-receivingpatientshavebeenwellcharacterized.Individualriskstratification,takingintoconsiderationpatientcharacteristics,
DrugSaf2010;33(3)
Statin-InducedMyopathy:RiskFactorsandDrugInteractionscoadministeredmedicationsandstatinpharma-cologicalproperties,shoulddetermineclinicaldecisionmaking.Consideringthedose-dependentnatureofstatin-relatedmyopathy,physiciansshouldstartcautiouslywithlowerdosesinthepresenceofpredisposingconditionsandweighthebenefitoflipidloweringversusthepotentialofexcessriskwhenuptitratingdoses.Combina-tiontherapywithotherclassesofhypolipidaemicagentsmaybeoptedforwhenaggressivelipid-loweringtherapyisrequired.Sincemostpatientseligibleforstatinsreceivemultipleconcomitantmedications,oftensharingthemetabolicpath-wayoftheCYPsystem,recognitionofpotentialdruginteractionsiscritical.Knowledgeofthepharmacokineticpropertiesofcurrentlyavailablestatinsmayallowtheidentificationofthestatinatthepresumablylowestriskfordruginter-actions.Intheclinicalsetting,counsellingpatientsontheriskandwarningsignsofmyopathywillincreaseawarenessandallowpromptrecogni-tionandappropriatemanagementofmyopathicevents.Inordertoaccuratelyestimatethetrueincidenceofstatin-inducedmyopathyanden-hanceourunderstandingofpotentialriskfactors,amorecompleteandformalreportingoftheentirespectrumofmuscle-relatedeventsattribu-tabletostatinsisrequired.Acknowledgements
Nosourcesoffundingwereusedtoassistintheprepara-tionofthisreview.Theauthorshavenoconflictsofinteresttodeclare.Y.S.ChatzizisisandK.C.Koskinascontributedequallytothiswork.
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Correspondence:ProfessorGeorgeD.Giannoglou,1stCardiologyDepartment,AHEPAUniversityHospital,AristotleUniversityMedicalSchool,1StKyriakidiStreet,54636Thessaloniki,Greece.E-mail:yan@med.auth.gr
DrugSaf2010;33(3)
Reproducedwithpermissionofthecopyrightowner.Furtherreproductionprohibitedwithoutpermission.
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