他汀作用副作用和治疗.docx

他汀作用副作用和治疗.docx

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他汀作用副作用和治疗

5他汀：

作用，副作用和治疗

Statins:

Actions,sideeffects,andadministration

Author

RobertSRosenson,MD

SectionEditor

MasonWFreeman,MD

DeputyEditor

DavidMRind,MD

Disclosures

Alltopicsareupdatedasnewevidencebecomesavailableandour peerreviewprocess iscomplete.

Literaturereviewcurrentthrough:

 Apr2013. | Thistopiclastupdated:

 四月11,2013.

INTRODUCTION — LipidalteringagentsencompassseveralclassesofdrugsthatincludeHMGCoAreductase（hydroxymethylglutarylCoAreductase）inhibitorsorstatins,fibricacidderivatives,bileacidsequestrants,cholesterolabsorptioninhibitors,andnicotinicacid.Thesedrugsdifferwithrespecttomechanismofactionandtothedegreeandtypeoflipidlowering.Thus,theindicationsforaparticulardrugareinfluencedbytheunderlyinglipidabnormality.Conventionaldosingregimensandcommonadversereactionsaredescribedinatable（table1）andtherangeofexpectedchangesinthelipidprofilearelistedinaseparatetable（table2）.

Lipidlowering,atleastwithstatins,isbeneficialinpatientswithdyslipidemiasforbothprimaryandsecondarypreventionofcoronaryheartdisease.（See "Clinicaltrialsofcholesterolloweringforprimarypreventionofcoronaryheartdisease" and "Clinicaltrialsofcholesterolloweringinpatientswithcoronaryheartdiseaseorcoronaryriskequivalents".）

Themechanismsofbenefitseenwithlipidloweringareincompletelyunderstood.Regressionofatherosclerosisoccursinonlyaminorityofpatients;furthermore,clinicalbenefitsoflipidloweringareseeninaslittleassixmonths,beforesignificantregressioncouldoccur.Thus,otherfactorsmustcontribute;theseincludeplaquestabilization,reversalofendothelialdysfunction,anddecreasedthrombogenicity.（See "Mechanismsofbenefitoflipid-loweringdrugsinpatientswithcoronaryheartdisease".）

Thecharacteristicsandefficacyofthestatinswillbereviewedhere（table3）.Possiblenoncardiovascularbenefitsofstatinsarediscussedseparately.（See "Statins:

Possiblenoncardiovascularbenefits".）Theefficacyoffibrates,lipidloweringdrugsotherthanstatinsandfibrates,anddietanddietarysupplementsarealsodiscussedseparately.（See "Lipidloweringwithfibricacidderivatives" and "Lipidloweringwithdrugsotherthanstatinsandfibrates" and "Lipidloweringwithdietordietarysupplements".）

Therapeuticdecisionmakinginpatientswithelevatedlipidlevels,includingindicationsforanddosingofstatins,isdiscussedindetailseparately:

▪（See "Treatmentoflipids（includinghypercholesterolemia）inprimaryprevention".）

▪（See "Treatmentoflipids（includinghypercholesterolemia）insecondaryprevention".）

▪（See "Intensityoflipidloweringtherapyinsecondarypreventionofcoronaryheartdisease".）

MECHANISMOFACTION — Currentlyavailablestatinsinclude lovastatin, pravastatin, simvastatin, fluvastatin,atorvastatin, rosuvastatin,and,insomecountries, pitavastatin （table3）.TheseagentsarecompetitiveinhibitorsofHMGCoAreductase,therate-limitingstepincholesterolbiosynthesis（figure1）.TheyoccupyaportionofthebindingsiteofHMGCoA,blockingaccessofthissubstratetotheactivesiteontheenzyme[1].

AreductioninintrahepaticcholesterolleadstoanincreaseinLDLreceptorturnoverthatresultsfromanenhancedrateofhepaticLDLreceptorcycling[2].StatinsalsoreduceVLDLproduction,viaaneffectmediatedbyhepaticapoBsecretion[3,4],anditisassociatedwithadiminishedrateofrecoveryofHMGCoAreductaseactivityafterdrugtreatment[5].

MostofthestatinshavemodestHDL-cholesterol（HDL-C）raisingproperties（about5percent）,althoughrosuvastatin hasalargereffect（see 'EffectonHDL' below）.Triglycerideconcentrationsfallbyanaverageof20to40percentdependinguponthestatinanddoseused（see 'Effectontriglycerides' below）.ThereductioninplasmatriglyceridesisduetoadecreaseinVLDLsynthesisandtoclearanceofVLDLremnantparticlesbyapo B/E（LDL）receptors.

Themechanismsbywhichstatinsmayaffectcardiovasculardiseasearediscussedseparately.（See"Mechanismsofbenefitoflipid-loweringdrugsinpatientswithcoronaryheartdisease".）

EFFICACY — Thestatinsarecommonlyusedinthetreatmentofhypercholesterolemiaandmixedhyperlipidemia.

EffectonLDLcholesterol

Potency — ThestatinsarethemostpowerfuldrugsforloweringLDL-cholesterol（LDL-C）,withreductionsintherangeof30to63percent（table3） [6-10].Whenswitchingbetweenstatindrugs,equipotentdoseswithregardtoLDL-Creductioncanbefoundinthefigure（figure2）.

Rosuvastatin issomewhatmorepotentthan atorvastatin [10,11],andboththeseagentsaresignificantlymorepotentthan simvastatin, lovastatin, pravastatin,and fluvastatin [11,12].Atmaximalprescribeddoses,LDL-Creductionisgreaterwithrosuvastatinandatorvastatinthanwiththeotheravailablestatins（figure2）.

Atdosesofupto40 mg/day, fluvastatin istheleastpotentstatin（figure2）.However,atdosesof80 mg/day,fluvastatinisaseffectiveonloweringLDL-Casmoststatinsotherthan rosuvastatin and atorvastatin [13].Fluvastatinislesslikelytohavedruginteractionsorproducemuscletoxicitythansomeotherstatins.（See 'Sideeffects' below.）

Although simvastatin 80 mg/day isamoderately-potentdoseofstatin,givenhighratesofmyopathy[14]andtheavailabilityof rosuvastatin andgeneric atorvastatin,wesuggestnottreatingpatientswithdosesofsimvastatinabove40 mg/day. Additionally,cliniciansshouldstronglyconsiderswitchingevenpatientswhoarecurrentlytoleratingsimvastatin80 mg/day tooneoftheseotherstatinoptions,sincefuturemedicationtherapyorillnesscouldincreasetheriskfordevelopmentofmyopathyonhigh-dosesimvastatin.High-dosesimvastatinmaybeappropriateforasmallnumberofpatientswhohavetolerateditwellformanyyearsorwhoareintolerantofotherhigh-potencystatinoptions.

Thereisanadditivehypolipidemiceffectwhenanyofthestatinsisusedincombinationwithabileacidsequestrant（figure3）[15-17],orthecholesterolabsorptioninhibitor ezetimibe.（See "Lipidloweringwithdrugsotherthanstatinsandfibrates",sectionon'Ezetimibe'.）

LDLsubfractions — StatinsarethemosteffectiveagentsforloweringtotalLDLparticleconcentration,howevertheyarenonselectiveforreducingLDLsubclasses;theyreducethepredominantsubclass[18].Amongpatientswiththeatherogenicdyslipidemiaprofile,thereductioninthepredominantsubclassofsmall,denseLDLparticlesresultsinashiftoftheLDLsubfractionstomorebuoyant,andpotentiallylessatherogenic,LDL[19-21].（See "InheriteddisordersofLDL-cholesterolmetabolism",sectionon'SmalldenseLDL（LDLphenotypeB）' and"Lipoproteinclassification;metabolism;androleinatherosclerosis",sectionon'Intermediatedensitylipoprotein（remnantlipoproteins）' and "Lipoproteinclassification;metabolism;androleinatherosclerosis",sectionon'Lowdensitylipoprotein'.）

EffectonHDL — Simvastatin （40to80 mg/day） appearstobemoreeffectivethan atorvastatin （20to40 mg/day）forincreasingserumHDL-CandapolipoproteinA-Iconcentrations[22].However, rosuvastatin maybeevenmoreeffective,raisingHDL-Cbyupto10percent[11].Inmetabolicsyndromepatients,rosuvastatin（10to20 mg/day）wasmoreeffectivethanatorvastatin（10to20 mg/day） inincreasinglargeHDLparticles[18].Whetherthisisclinicallyimportantisuncertain.（See "HDLmetabolismandapproachtothepatientwithabnormalHDL-cholesterollevels".）

Effectontriglycerides — Atorvastatin and rosuvastatin aremoreeffectiveatloweringtriglycerides（14to33percent）thanotherstatinsinpatientswithhypercholesterolemia[11,23-25].Themagnitudeoftriglycerideloweringwithstatinsmaybelargerinpatientswithhypertriglyceridemia.

Theeffectsof atorvastatin and rosuvastatin onserumtriglyceridesaredose-dependent[11,23].Asanexample,inaseriesof56patientswithprimaryhypertriglyceridemiainwhomtheaveragetriglycerideconcentrationwas600mg/dL andLDL-Cconcentrationwas120 mg/dL （3.1 mmol/L）, theadministrationofatorvastatinatdosesof5,20,or80 mg/day producedreductionsintriglyceridesof27,32,and46percent,respectively,andinLDL-Cof17,33,and41percent,respectively[23].

Genetic/ethniceffects — Partofthevariabilityintheresponsetoandsideeffectswithstatinsmayberelatedtogeneticdifferencesintherateofdrugmetabolism.Asanexample,CYP2D6isamemberofthecytochromeP450superfamilyofdrugoxidizingenzymes.CYP2D6isfunctionallyabsentin7percentofCaucasiansandAfrican-Americans,whiledeficiencyisrareamongAsians.

TheCYP2D6phenotypeappearstobeimportantinpatientstreatedwith simvastatin,asitcanaffectboththedegreeoflipidloweringandtolerability[26].PolymorphismsinthegenecodingforHMGCoAreductasealsoappeartoaffecttheLDL-Cresponsetostatins,butnottheHDL-Cresponse[27].

ConcernshavebeenraisedthatAsiansmayhavegreaterresponsestolowdosesofstatinsthanCaucasians[28].Prescribinginformationfor rosuvastatin recommendsstartingtherapyatalowerinitialdoseinAsiansthaninothergroups,givenobserveddifferencesinpharmacokinetics[29].Thereisnostrongevidencesupportingsuchanapproachwithotherstatins.

Preventionofcardiovasculardisease — Themajoruseofstatinsisintheprimaryandsecondarypreventionofcardiovasculardisease.Thisuseisdiscussedextensivelyelsewhere:

▪（See "Treatmentoflipids（includinghypercholesterolemia）inprimaryprevention".）

▪（See "Treatmentoflipids（includinghypercholesterolemia）insecondaryprevention".）

▪（See "Intensityoflipidloweringtherapy