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