packard, c. j. (2018) ldl cholesterol: how low to go? trends...
Post on 14-Sep-2020
0 Views
Preview:
TRANSCRIPT
Packard, C. J. (2018) LDL cholesterol: how low to go? Trends in
Cardiovascular Medicine, 28(5), pp. 348-354.
(doi:10.1016/j.tcm.2017.12.011)
This is the author’s final accepted version.
There may be differences between this version and the published version.
You are advised to consult the publisher’s version if you wish to cite from
it.
http://eprints.gla.ac.uk/156458/
Deposited on: 13 February 2018
Enlighten – Research publications by members of the University of Glasgow
http://eprints.gla.ac.uk
1
LDLcholesterol–Howlowtogo?ChrisJPackardInstituteofCardiovascularandMedicalSciences,UniversityofGlasgow,Glasgow,Scotland,UK,G128QQCorrespondenceto:ProfessorChrisJPackardMcGregorBuildingGroundFloor,RoomG31UniversityofGlasgowUniversityAvenueGlasgowG1238QQEmail:chris.j.packard@gmail.comTel:(44)1412110134Conflictofinterest:DrPackardhasreceivedgrants/honorariafromMerck,Sharp&Dohme,Pfizer,Amgen,Sanofi,Regeneron,Daiichi-Sankyo.
2
Abstract
Epidemiologyandtheresultsoflarge-scaleoutcometrialsindicatethattheassociationof
LDLwithatheroscleroticcardiovasculardiseaseiscausal,andcontinuousnotonlyacross
levelsseeninthegeneralpopulationbutalsodowntosub-physiologicalvalues.Thereisno
scientificbasis,therefore,tosetatargetor‘floor’forLDLcholesterollowering,andthis
presentsaclinicalandconceptualdilemmaforprescribers,patientsandpayers.Withthe
adventofpowerfulagentssuchasproproteinconvertase/subtilisinkexintype9(PCSK9)
inhibitors,LDLcholesterolcanbeloweredprofoundlybuthealtheconomicconstraints
mandatethatthistherapeuticapproachneedstobeselective.Basedontheneedto
maximisetheabsoluteriskreductionwhenprescribingcombinationlipid-loweringtherapy,
itisappropriatetoprioritisepatientswiththehighestrisk(aggressive,establishedCVD)who
willobtainthehighestbenefit,thatis,thosewithelevatedLDLcholesterolonoptimized
statintherapy.
3
Introduction
Fewtopicscurrentlyprovokeasmuchheateddebate-bothinthescientificliteratureandlaypress–
astheuseofcholesterolloweringtherapiestopreventcardiovasculardisease(CVD).Reviews,
editorialsandguidelinesprovideenthusiasticendorsementofevermoreaggressivegoalsfor
therapy(1-4),orcautionlestthereisadrivetoovertreatmentwithinsufficientattentionpaidtorisk
ofsideeffectsandtolerability(5,6),and,ofcourse,cost-effectiveness(7,8).Inthepre-statinera,this
wasnotanissuesincemedicationshadlimitedefficacy.Followingtheunequivocaltrialevidence
thatLDLcholesterol(LDLc)loweringwithstatinswasbeneficialinbothprimaryandsecondary
prevention(3,4,9),therewaswidespreadacceptanceofthistreatmentapproachbutconcernsraised
overtolerabilityespeciallyinprimaryprevention(6,10),andthemedicalizationofwhatwasseen,at
leastinasymptomaticindividuals,asalifestyleissue.Itisthedemonstrationofthesuccessof
combinedlipidloweringtreatmentswithezetimibe(11)and,particularly,proprotein
convertase/subtilisinkexin9(PCSK9)inhibitors(12)thathassharpenedthedebatesinceitisnow
possibletoachievepreviouslyunheraldedLDLclevels,wellbelowtherecommendedtargetsof70to
100mg/dladvocatedforexampleinEurope(4).Howlowdoyougo?Whatarethebenefit:riskand
benefit:cost/opportunityratios?WhichpatientsshouldbeprioritisedforintensiveLDLclowering
treatment?ThefollowingdiscussionsetsouttheconceptualframeworkforoptimisedLDLclowering,
summarizestheclinicaltrialevidenceforcombinedlipidloweringtherapy,andofferstherapeutic
strategiesthatmayaidintheappropriateuseofnewlymarketedandemergingdrugssuchasPCSK9
inhibitors,cholesterylestertransferprotein(CETP)inhibitors,andsmallRNA-oranti-sense
oligonucleotide-basedtherapies(13).
ContextandtherapeuticrationaleforLDLcholesterollowering.
UnderpinningtherationaleforevermoreaggressiveLDLcloweringinthepreventionofthefirstor
recurrentmajorcardiovasculareventsisourunderstandingoftherelationshipbetweenplasma
4
cholesterol(mainlycarriedinLDL)andatherosclerosis,thesilentdiseaseprocessthatleadsto
clinicalmanifestationsofMIandischemicstroke.Cholesterolisoneofthemajorriskfactors
alongsideraisedbloodpressure,smoking,anddiabetes.Considerationofthetotalityoftheevidence
hasledaninternationalexpertpaneltoconcludethatLDLisa(the?)majorcausalagentinthe
pathogenesisofthedisease(14)anddiffersconceptuallyfromotherssuchassmokingandhigh
bloodpressurewhichcanbeviewedasaggravatingfactorsthataccelerateplaqueprogressiononce
lesionformationisinitiated.Evidencetosupportthisviewcomesfromepidemiological
investigationswherepopulationswithlifelonglowcholesterollevelshavevirtuallynoCVDdespite
havinganelevatedinflammatorystate(14,15).Likewise,experimentsofnature–inherited
conditionsoflowandhighLDLc-revealreducedorelevatedincidenceofCVDindependentofthe
presenceorabsenceofotherriskfactors.HomozygotesforPCSK9loss-of-functionmutationshave
substantiallylowerlifetimeLDLclevelsandamuch-reducedriskforCVD(16),whileindividualswith
familialhypercholesterolemia(FH)haveraisedLDLcfrombirthand,ifuntreated,sufferaMItypically
inmid-lifeifheterozygous,andinchildhoodifhomozygotes(17,18).Shouldwethereforeconsider
LDLcasariskfactorthatisbestminimised(perhapsnottozero)inanalogywiththepromotionof
smokingabstinence,ratherthanaphysiologicalparameterthatneedstobemaintainedinan
optimalrange,likebloodpressureorbloodglucose?
Figure1providesaconceptualframeworkinwhichwecanunderstandtheimpactofLDLon
atherosclerosis,theopportunitiesforinterventionatvariousstagesofthedisease,andtherationale
forprofoundcholesterollowering.InconsideringthepotentialconsequencesofreducingLDLc
substantially,itshouldbeborneinmindthataschildrenwehadalowLDLc;themeanwasabout95
mg/dlandthe5thpercentileabout65mg/dl(19).Theselevels,analogoustothoseinprimates(14),
sawusthroughthedevelopmentalchallengesofpuberty,andapharmacologicalreturntosuch
valuesshouldnotofitselfbeproblematic.LDLcrisessubstantiallyinmenfromlateteenstomid-life
(Figure1)(19),probablyduetoareductionintheactivityofLDLreceptorswithageing(20).Itisthis
5
changeinLDLcthatlikelydrivesatherogenesis(asimilarriseoccursinwomenafterthemenopause).
Further,anemergingconcept,basedontheearlyCVDseeninFH(Figure1)(14,18),isthatwhat
mattersmostistheintegratedlengthofexposuretoelevatedlevelsi.e.accumulated‘LDLcxyears’.
GeneticanalysishasprovidedadditionalinsightintothepotentialeffectivenessofLDLclowering.
Mendelianrandomisationstudiesbasedonmoderate-effectvariantsthatalterLDLclevels(14,21,22)
havesuccessfullypredictedtheoutcomeofclinicaltrials,andrevealthatthebenefitofreducing
LDLcbyagivenamountoveralifetimefarexceedsthatseenwhenthelipoproteinisdecreased
usingdrugsinclinicaltrialsat,onaverage,about62yearsofage;forexampletherelativerisk
reductionfora39mg/dllowerLDLcfrombirthisestimatedat54%comparedtothe22%seenfrom
meta-regressionofstatintreatmenttrialsof5yearsduration(21).Putanotherway,inorderto
achievea50%riskreductionLDLcneedstobedecreasedbyabout35mg/dliftreatmentisinitiated
inearlyadulthoodbutby100mg/dlifstartedlateinlife(Figure1).Thisdifferentialmaybeexplained
bythechangingnatureofthelesionswithage.Resolutionofearlyplaque/fattystreaksmaybe
moreeasilyachievedwithmoderateLDLcloweringwhilemuchmoreaggressivetreatmentisneeded
tostabiliseandregressmature,vulnerablelesionsseenlaterinlife.
ClinicaltrialevidenceforthebenefitsofprofoundLDLcholesterollowering.
ThefirstlandmarkLDLcloweringtrialsinsecondaryprevention(4Swith20-40mgsimvastatin;(23))
andprimaryprevention(WOSCOPSwith40mgpravastatin;(24))usedwhatisnowconsidered
‘moderateintensity’statintherapythatreducedCVDriskbyaboutone-third.Thebenefitofhigher
statindoseswassubsequentlyexaminedinaseriesofstudies,mostnotablyPROVE-IT(25)and
Treat-To-New-Targets(TNT(26))andthisledtotherecommendationthat‘highintensity’treatment
beusedinhigh-riskindividualswithestablishedCVD(3,4).Figure2A(adaptedfrom(14))
summarisestheoutcomeofclinicaltrialsofLDLcloweringinprimaryandsecondaryprevention
6
settings.ItcanbeseenthatthereisaconvincingcontinuousrelationshipbetweenachievedLDLc
levelinthetwoarmsofastudy(placebovsactivedrug,orhighervslowerstatindose)andriskofa
majorcoronaryevent.InEuropeanandCanadianguidelines,thisevidencebasewasinterpretedto
indicatethat‘lowerisbetter’andmoreaggressiveLDLctargetswerepromulgatedforhighrisk-
primaryandsecondaryprevention(4,27).Controversiallyinthemostrecentrevision,USguidelines
emphasisedtreatingpatientgroupsalignedwiththosetestedinthelandmarktrialsratherthan
focussingonachievementofgoals(3).Whilethisapproachhasmerits,therehavebeencallsforthe
reinstatementoftargetsespeciallywiththeintroductionofeffectiveadd-ontherapies(28).
Followingyearsof‘negative’trialsexaminingmainlythepotentialbenefitsofraisingHDLtoaddress
theresidualriskinpatientsonoptimisedstatintherapy(29,30),therehasbeenrecentlynotable
successindemonstratingincrementalriskreductionfromfurtherLDLcloweringusingcombination
therapywithacholesterolabsorptioninhibitor(ezetimibe),oraPCSK9inhibitor(suchas
evolocumab).IMPROVE-ITwasthefirstofthesuccessfulcombinedlipidloweringtrialstoreport
(11).Itshowedthatinwell-treatedsubjectsonstatintherapy,additionofezetimibeledtoafurther
decrementinLDLc–fromameanof74mg/dlto63mg/dl(with38%achievingLDLcholesterollevels
<50mg/dl(31))–andadecreaseinCVDriskof6.4%(P=0.016).Thiswasthefirstdemonstration
thatanon-statindrugcouldreducerisksignificantlyandsoreinforcedthecausalassociationofLDL
withCHD(14)thathadbeenquestionedonthebasisoftherepeatedobservationthatonlystatins
appearedtobeabletodecreaserisk(32).Therewerenosafetysignalsofconcerninthetrial
comparingthetwotreatmentarms(11),andwhenallsubjectsweregroupedtogetherandLDLc
acrosstherangeof<30to>70mg/dlrelatedtoarangeofemergentadverseeventsoverthetrial
period,therewereagainnosignalsthatverylowLDLcwaslinkedtoahigherfrequencyofadverse
events(31).Theinvestigatorspaidparticularattentiontonon-cardiovasculardeath,haemorrhagic
stroke,andneurocognitiveevents,allofwhichhadbeenraisedaspotentialissues.Anassociationof
cancerwithlowercholesterolwasobservedbutthiscanbeattributedtotheinclusionoftheplacebo
7
groupandtheknownrelationshipinthegeneralpopulationthatisunderstoodnottobecauseand
effect(i.e.peoplewithcancerdeveloplowcholesterollevelsratherthanviceversa).Thisanalysisin
verylowLDLcsubjectsmirrorsthemorecomprehensiveevaluationthatwasgeneratedusingmeta-
analysisoflipid-loweringtrials(33).
TheeagerlyawaitedFOURIERtrial(12)wasthefirstlarge-scaletestoftheabilityofPCSK9inhibitors
toreduceCVDrisk.ChangeinLDLcwasdramatic,fromameanof92mg/dlto30mg/dl;patientsin
thistrialhadthelowestlevelsofLDLcyetachievedwithpharmacologicalintervention.Incidenceof
theprimaryendpointwas15%lower(P<0.001),andthekeysecondaryendpoint20%lower,inthe
PCSK9inhibitortreatedgroupversusthosereceivingplacebo.AswithIMPROVE-IT,theclinical
benefitwasseenonabackgroundofstatintherapy(69.5%wereon‘high’and30.2%on‘moderate’
intensitystatinregimes).Thetrialhasbeencriticisedduetoitsshortdurationandlackof
demonstrationofaneffectoncardiovascularmortality(likelylinkedfeatures)butoverthemean2.2
yearsoffollowuptherewerenotreatment-emergentsafetysignals.Aconcernaboutneuro-
cognitivesideeffectsthathadarisenfromphase3trialsofPCSK9inhibitors(34,35)wasaddressedin
theEBBINGHAUSsub-study(36)whereabatteryofcognitiveassessmentswasundertakenandthe
resultsforsubjectsonevolocumabfoundtobeessentiallyidenticaltothoseonplacebo.The
FOURIERinvestigatorsembarkedonanexplorationoftheclinicalconsequencesofinducing
profoundlylowLDLclevelsusingthewholetrialdatasetinanapproach(37)thatmirroredthat
describedaboveforIMPROVE-IT(31).WhenachievedLDLcforthecombinedtreatmentgroupswas
relatedtoriskofcardiovascularendpoints,itwasseenthattherewasnolowerlimitofefficacy;
rather,therewasacontinuousrelationshipwithamonotonicdecreaseinincidenceofCVDfromthe
groupwithhighestLDLc(>100mg/dl)tothatwiththelowest(<20mg/dl)(Figure2B).Evengoing
below10mg/dlappearedtogivefurtherbenefit(37).Arangeofsafetyconcernswasaddressed-
includingliverdysfunction,creatinekinaselevels,worseningofdiabetescontrol,cataracts,
haemorrhagicstroke,cognition,andcancer–andtherewasnodiscernibleadversetrendwitheven
8
verylowLDLc.Inafurther,detailedanalysisoftherecognisedlinkbetweenLDLcloweringand
increasedriskofdevelopingdiabetes(38),itwasseeninFOURIERthatevolocumabtherapyon-top
ofstatinovertheperiodofthestudydidnotincreasetheincidenceoftype2diabetesinthewhole
cohortorthosewithpre-diabetes,nordiditappeartoworsenglycaemiccontrolinsubjectswith
diabetesatbaseline(39).ThisobservationcontrastswithfindingsfromMendelianrandomisation
studieswhichshowedthathavingalowerLDLcassociatedwithPCSK9variantswaslinkedto
increasedriskofdiabetesinamannersimilartothatseenforvariationinthegenefor3-hydroxy-3-
methyl-glutarylco-enzymeA(mimickingstatintherapy)(40).Thisdiscordancybetweengenotypic-
andclinicaltrial–findingsreflectsthestrengthsandweaknessesofeachapproachtodetermining
thebenefitsanddisadvantagesonanintervention(see(41)forareview).Asnoted,thedurationof
FOURIERatjustover2yearslimitstheabilitytodetectlate-appearingtreatment-emergentside
effects,andthegeneticobservationsleavethediabeteslinkanopenquestion.
TheresultsofIMPROVE-ITandFOURIER,togetherwiththemorecomprehensiveevaluationfrom
meta-regression(33)providestrongevidencethatthereisnodiscernible‘floor’totheassociationof
LDLwithCVDrisk,andsofar,nosafetyconcernoverinducingprofoundlylowlevelsofthis
lipoprotein.TheeditorialaccompanyingtheFOURIERlowLDLcanalysistalkedofmovingfrom
targetstotheconceptofLDL‘eradication’(1).
Pooledfindingsfromphase3studieswithalirocumab(34,42)haverevealedthat,asfor
evolocumab,insubjectswithprofoundlyloweredLDLc(<15mg/dland<25mg/dl)thereappearsto
belittleofconcernregardingsafety,althoughagaindurationofexposureandthenumbersof
patientstreatedrenderthesepreliminaryconclusions.Therewasanimbalanceincataractfrequency
(42)thatintheorycouldhaveabasisinalteredcholesterolmetabolismintheeyesincecholesterol
isanimportantstructuralcomponentofthelens(43)andintheoryitsavailabilitymaybe
9
compromisedwhenLDLclevelsareverylow.Thisobservationneedstobeconfirmedorrefutedin
themajorODYSSEYOUTCOMEStrial(44).
OfespecialimportanceforbothIMPROVE-ITandFOURIERwasthefindingthattherelationship
betweenchangeinLDLcandreductioninCHDriskfellonthesameregressionlineasthatgenerated
bymeta-analysisofallthestatinbasedstudies(9,11,12,45).TheCholesterolTreatmentTrialists
Collaboration(CTTC)analysisshowedthatforeach39mg/dl(1.0mmol/l)lowerLDLcthereisa22%
decreaseinCHDriskovera5-yearexposuretodrugtherapy(9).Ezetimibetreatmentgavean
11mg/dldropinLDLcandaproportionate6.5%decreaseinriskinthe7-yeartrial(11).ForFOURIER,
itisnecessaryduetotheshortfollowuptotakeaccountofthefactthatonlyhalftheriskreduction
isseeninyear1andcorrectingfortriallengthshowedthatthePCSK9inhibitoryieldedthepredicted
magnitudeofbenefit(12,45).
DirectassessmentoftheextentofatherosclerosisanditsrelationshiptoLDLchasbeenexaminedin
imagingtrialswherelipidloweringinterventionshavebeenshowntoslowprogression,andinduce
regression,ofatheroscleroticlesions(46).Thefindingthatregressionoccursinthemajorityof
patientswhoachieveverylowLDLclevelsintheGLAGOVtrialofevolocumabtreatment(47)
reinforcestheviewthattheassociationofthislipoproteinwiththeunderlyingdiseaseprocessis
causal,andfurtherdemonstratesthatplaqueisamenabletoconsiderableremodelling,with
resultantbeneficialeffectsonclinicaloutcomes.
Thelatestlipidloweringadd-onoutcometrialtoshowasignificant(butmodest)CVDbenefitwas
theHPS-REVEALstudywithanacetrapib(48),adrugdesignedtoraiseHDL(whichitdoubles)but
thatalsoreducesLDLcby30%to40%(48).ThetrialwaspoweredtoseeaneffectofLDLclowering
incontrasttoearliercholesterylestertransferprotein(CETP)inhibitorstudiesthatweresmallerand
ofshorterduration(e.g30).Anacetrapibontopofoptimisedstatintherapyinsubjectswithalready
10
lowLDLc(baselineLDLcwas63mg/dl)gavea9%riskreductionforafurther29mg/dldecreasein
LDLcanda18mg/dldropinnon-HDLcholesterolandinapolipoproteinB(apoB)(48).Thisagenthas
beenshowntoaltertheratioofcholesteroltoproteininlipoproteinparticles,whichmakesaccurate
measurementofLDLcproblematic(49).Abetterguidetoefficacyinthesecircumstancesislikelyto
bechangeinapoB,thestructuralproteininatherogeniclipoproteins(49,50).(Notethatthe
manufacturerhasdecidednottoapplyforregistrationofanacetrapibduetoissuesassociatedwith
thepropertiesoftheagent–aparticularconcernwasthesubstantialaccumulationofthedrugin
adiposetissue(48)-anditisnotyetcleariftherewillbefurtherdevelopmentoftheCETPinhibitor
class).AconcomitantlyreportedMendelianRandomisation‘trial’–confirmedtheconceptthatCETP
inhibitioncombinedwithstatintherapywaslikelytoreduceCVDrisk,andagainthebenefitwas
predictedtobeproportionaltothedecreaseinapoB(LDLparticlenumber)notLDLcholesterol(51),
animportantfindingwhenconsideringinitiatingandmonitoringaggressivecholesterollowering
therapy.
TherearepotentialconcernsaboutverylowLDLclevelsbasedonobservationsinthehuman
disordersofabetalipoproteinemiaandhomozygoushypobetalipoproteinemia(52).HereLDLcand
apoBare<30mg/dl(orzero)andsymptomsappearassociatedwithfailuretotransportfatsoluble
vitaminsandwithdevelopmentofafattyliver.Inthiscontext,itiscriticaltonotethatthe
mechanismofLDLcloweringdiffersbetweenthesedeficiencystatesandtheactionsofstatins,
ezetimibeandPCSK9inhibitors.Inabetalipoproteinemiaandhomozygoushypobetalipoproteinemia,
thereisdefectivelipoproteinproductioninliverandgut(52).Statinsbyreducingintracellular
cholesterollevelsinduceexpressionofLDLreceptorsandsoaccelerateclearanceofLDLfromthe
circulation(14,53),similarlyezetimibereducescholesterolabsorptionandtransporttotheliverand
therebyincreasesLDLparticleclearance(14,53).PCSK9inhibitorspromoteclearanceofLDLand
otherapoB-containinglipoproteinsfromthebloodstreambyblockingtheactionofPCSK9onLDL
11
receptors(54).Noneofthethreedrugclassesappeartoalterlipoproteinproductionrates(14,54),
andsotransportoffattysubstancesislikelythereforebepreservedwiththeseagents.
TreatmentstrategiestoachieveverylowLDLcholesterol.
InlightofthelatestevidencefromtrialsexploringthebenefitsandrisksofprofoundLDLclowering
theanswertothequestion‘Howlowdoyougo?’is,arguably,astraightforward‘Aslowasyoucan!
Thereis,ofcourse,theneedformuchlongerfollowupdataforPCSK9inhibitortrials,asisnow
availableforstatinstudies(55).Therearealsomeasurementissuesthatarereviewedbelowsince
theyimpactonclinicalpractice(56),andcost-effectivenessconcernssincePCSK9inhibitorsare
expensive.
Figure3summarizescurrentthinkingonthedeploymentofcombinationtherapytoachievelower
LDLclevels.Whileguidelinesadvocatetheuseofhighintensitystatintreatmentinhighrisksettings
suchassecondaryprevention,itshouldbenotedthatthe‘ruleof6%’appliesinthatdoublingthe
statindosewillonaveragelowerLDLconlybythisamount(3,4,57);dose-responsestudieshave
shownconsistentlythateachstatinhasacharacteristicresponseatthestartingdosee.g37%LDLc
loweringon10mgofatorvastatinandthatup-titrationtoa20mgor40mgdoseproducesaLDLc
reductionof43%and48%respectively(57).Thislimitationontheactionofstatinsisdue,itis
believed,tothecounter-regulatoryincreaseinPCSK9inducedbythesedrugswhichhastheeffectof
bluntingtheincreaseinLDLreceptorsandhencelimitingLDLcreduction(58).Internationalsurveys
revealthatwhileuseofhighintensitystatintherapyisarecommendedevidence-basedapproach,it
isnotsustainedinregularclinicalpractice(59).Further,statins,thoughstronglyrecommendedas
firstlinetherapyforlipidloweringhaveawell-characterisedsetofside-effectsincludingincreased
propensitytodevelopdiabetesespeciallyinpatientswithpre-diabetesorknownriskfactorsfor
12
diabetes(3,4,33,38).Statinintoleranceisalsoarecognisedphenomenonandisoftenlinkedto
myalgiaandothermuscle-relatedsymptoms(33,60).Theseadversereactionsaredosedependent
andcanbeareasonwhy‘highintensity’statintherapyrecommendedintheguidelinesisnotalways
usedinpractice.Combinationtherapynowtestedinmultipleclinicaltrialsoffersaneffective
alternativewithpotentiallyimprovedpatientacceptance,andenhancedefficacy.
Anumberofreportshaveappearedonthehealtheconomicsofcombinationlipidloweringtherapy
toachieveloworverylowLDLclevels.Thereisgeneralagreementthatwiththeincreased
availabilityofgenericezetimibe,additionofthisagentoffersacost-effectiveapproachtolowering
LDLcbeyondwhatcanbeachievedwithstatins(61).MarketedPCSK9inhibitors,however,cost
about$14,000peryearintheUSA,andabout€4,500inEurope,anddespitetheirconsiderable
impactonLDLcareconsideredacceptableintermsofcostperquality-adjustedlifeyear(QALY)only
whenthereisasubstantialdiscount,i.e.toapriceofabout$9,000perannumintheUSAorless
than£4,500intheUK(62-65).Inthiscontext,theeconomicsofCVDpreventionislinkeddirectlyto
thenumberofeventsprevented,thefrequencyoftreatment-emergentsideeffects,aswellasthe
priceofthemedication.TomaximiseeventreductionandsominimisethecostperQALY,itis
importanttounderstandthattheabsoluteriskreduction(numberofeventspreventedoveragiven
time)isconsideredbymanycommentatorstobethekeymetricindecidingwhenprofoundLDLc
loweringwithcombinationtherapyshouldbeused(64-67).Thisparameterisestimatedasthe
productofthepatient’songoingriskofaCVDeventandtherelativeriskreductionattributableto
furtherLDLclowering.ThelatterisderivedfromtheamountthatLDLcisdecreasedinmg/dlusing
the‘ruleofthumb’thatforeach39mg/dl(1.0mmol/l)fallinLDLcthereis22%decrementinrisk(9,
33,45).Forexample,bothalirocumabandevolocumabconsistentlylowerLDLcby60%onaverage
(regardlessofinitiallevel).IfthestartingLDLc(onstatin)is130mg/dlthenthistranslatesintoa
78mg/dl(2.0mmol/l)dropwhichinturnprovidesa44%decreaseinCVDrisk,andapotentiallylarge
absoluteriskreduction.If,however,thestartingLDLcis75mg/dlthentherelativeriskreductionis
13
onlyabout25%,andthedecrementinabsoluteriskproportionatelyless.(Thecommonlyusedterm
‘NNT’-thenumber-needed-to-treat-isthereciprocaloftheabsoluteriskreductionandhence
providesequivalentinformation(64)).Thus,NICE,theUKbodywhichrulesontheacceptabilityof
newagents,mandatedtheuseofPCSK9inhibitorsforthosewithhighbackgroundrisk–poly-
vasculardisease,multiplepastCHDevents–andelevatedLDLconmaximumtoleratedstatin
therapy(65).AsimilarapproachhasbeenrecommendedinupdatedguidancefromtheACCTask
Force(66)andtheESC/EASTaskForce(67).
AstrategyforprofoundLDLcloweringthattakesintoaccounttheeconomicrealitiesshould
thereforebebasedonriskstratificationofthepatientandanestimateofthebenefitthatwould
accompanytheinstitutionofcombinedlipidloweringtreatmentwithastatinandezetimibefirstand
thenadditionofaPCSK9inhibitor(Figure3)(66,67).Formalriskstratificationschemeshavebeen
devisedforacutecoronarysyndromepatientsfromdatasuchasthatfromIMPROVE-IT(68)but
moreworkisneededinthisareatoallowbettertargetingoftherapy.Inthissetting,itisunlikely
thatprimarypreventionsubjectswiththeexceptionofthosewithsevereFH(64-67)willexperience
enoughofanabsolutereductioninCVDrisktojustifyaddingaPCSK9inhibitortoastatin/ezetimibe
regimen.
ImplicationsandimplementationofprofoundLDLloweringparadigm.
Treatmenttargets:Animportantquestionthatarisesfromrecenttrialresultsis‘Ifatreatmentgoal
forallsecondaryprevention/highriskpatientsistobeused,shoulditnowbesetatalowervalue?’
Targetsforinterventionareatbestanartificialandidealisedconstructrecommendedbyexpert
committeesasausefulmetricoftherapeuticsuccess(4,27).Themonotonousrelationshipbetween
LDL(orapoB-containinglipoproteins)andCVDriskthatcontinuesdowntosub-physiologicallevels,
andindeedvirtuallytozero(Figure2)indicatesthattargetsiftheyareemployedaremorea
14
reflectionof‘willingnesstointervene’ratherthanpathophysiologicallyderivedlandmarks.
Internationalguidelinesagreeontheneedfora>50%reductioninLDLcrelativetooff-treatment
levels(3,4)andcurrentlyEuropeanandCanadiansocietiescontinuetorecommendatargetof
<70mg/dl(4,27).Othershaveintroduced<50mg/dlasagoalwhenriskisextremelyhigh(69).Thisis
acontinuingtopicofdebate–shouldwehaveamoreaggressivetargetthatreflectstheunderlying
pathologybutcreatesagreaterunmetneed,orshouldwemaintain<70mg/dl(incountrieswhereit
isrecommended)andnowensurethatthemajorityratherthanaminorityareabletoreachthis
levelwithacombinationofagents.
Measurementissues:ThereareanumberofapproachestothelaboratoryassessmentofLDLc
concentrationinthecirculation.‘Beta-quantification’whichusescentrifugationandprecipitationto
separatelipoproteinclassesphysicallyisthereferencemethod.DirectLDLctests,andthe
Friedewaldcalculation(basedonknowingtotalplasmacholesterolandtriglycerideandHDL
cholesterol)areconvenient,relativelyinexpensive,andprovideaccuratemeasurementsatnormal
andhighlevels(intherange70to300mg/dl).However,accuracyoftheFriedewaldequationfalls
offwhentriglycerideiselevatedorLDLcislow(<70mg/dl)(56).Thus,forpatientsoncombination
lipidloweringtreatment,thelaboratoryreportedLDLcmaybelowerthanthe‘true’concentration
(56).Analternative,morerobustapproachistomeasurenon-HDLcholesterol(totalminusHDL)or
apolipoproteinBlevelsthatcaptureallatherogeniclipoproteinsandtheseparametersarepromoted
inguidelinesandexpertopinion(4,27,50,70).TheapoB-containinglipoproteinspecieswithin‘non-
HDLcholesterol’include,inadditiontoLDL,lipoprotein(a)andthecholesterolenriched‘remnants’
oftriglyceride-transportingchylomicronsandverylowdensitylipoproteins.Recentevidencehas
linkedbothlipoprotein(a)(71)andremnants(72)toincreasedriskofcardiovasculardisease.
Assessmentofnon-HDLcholesterolorapoBwhenLDLchasbeenloweredprofoundlywithsaya
PCSK9inhibitormayhelpreassurethepatientthatthereisstillasufficiencyoflipoproteinspresent
15
toperformtherequiredmetabolictransporttasks(thedecreaseinthesevariablesislessthanthat
seenforLDLc(12,34,35)),andmaybeabettermarkerofongoingrisk(70).
Patientprioritization:ProfoundLDLcloweringismostlikelytobeneededinpatientswith
establisheddisease,eitherthosewhohavehadanevent,orthosewithadvancedplaquepresenton
imaging.Asnotedabove,riskstratificationinsecondarypreventionneedstobeimprovedbutat
presentthosewithstablediseasecouldbemanagedwithhighintensitystatin,orincreasinglya
combinationofstatinplusezetimibetoachievea50%LDLcdecreaseandalevel<70mg/dl.A
‘highestrisk-highestbenefit’approachforpatientswithanaggressivediseasecourseisauseful
strategyfordecidingwhentoaddaPCSK9inhibitor(64-67,73).Insuchpatients,thehighriskand
elevatedLDLclevelonoptimisedstatintherapyprovidesasubstantialabsoluteriskreduction(low
NNT)andsatisfactorycost-effectiveness.Theupdated2017ESC/EASguidelinessetoutthresholdsof
140mg/dlforPCSK9inhibitorinitiationinpatientswithclinicalatheroscleroticCVDand100mg/dlin
thosesevere,aggressivedisease(67)(Figure3).OncethedecisionhasbeenmadetoaddaPCSK9
inhibitorthereis,accordingtotheemergingparadigm,notargetandneitheristhereaconcernthat
theLDLcistoolow.Datafromtrialsindicatethatthemajoritytreatedwiththiscombinationwill
haveLDLcbelow50mg/dlgiventhepotencyoftheagents.Inconclusion,inlightofthisemerging
consensusonthemostappropriatestrategyforfurtherLDLcloweringinveryhighriskpatients,the
pressingneednowistomovetoimplementation.
16
References
1. HovinghGK,BoekholdtSM,StroesES.VerylowLDL-cholesterolconcentrationsachieved:
whichtargetisnext?Lancet.2017.pii:S0140-6736(17)32292-4.doi:10.1016/S0140-
6736(17)32292-4.
2. SabatineMS,GiuglianoRP.Low-DensityLipoproteinCholesterolTreatmentintheProprotein
ConvertaseSubtilisin/KexinType9InhibitorEra:GettingBackonTarget.JAMACardiol.2017
Aug2.doi:10.1001/jamacardio.2017.2293.
3. StoneNJ,RobinsonJG,LichtensteinAH,BaireyMerzCN,BlumCB,EckelRH,GoldbergAC,
GordonD,LevyD,Lloyd-JonesDM,McBrideP,SchwartzJS,SheroST,SmithSC,Jr.,Watson
K,WilsonPW,EddlemanKM,JarrettNM,LaBreshK,NevoL,WnekJ,AndersonJL,Halperin
JL,AlbertNM,BozkurtB,BrindisRG,CurtisLH,DeMetsD,HochmanJS,KovacsRJ,Ohman
EM,PresslerSJ,SellkeFW,ShenWK,SmithSC,Jr.,TomaselliGF.2013ACC/AHAguidelineon
thetreatmentofbloodcholesteroltoreduceatheroscleroticcardiovascularriskinadults:a
reportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceon
PracticeGuidelines.Circulation2014;129:S1-45.
4. PiepoliMF,HoesAW,AgewallS,AlbusC,BrotonsC,CatapanoAL,CooneyMT,CorraU,
CosynsB,DeatonC,GrahamI,HallMS,HobbsFD,LochenML,LollgenH,Marques-VidalP,
PerkJ,PrescottE,RedonJ,RichterDJ,SattarN,SmuldersY,TiberiM,vanderWorpHB,van
DisI,VerschurenWM,DeBackerG,RoffiM,AboyansV,BachlN,BuenoH,CarerjS,ChoL,
CoxJ,DeSutterJ,EgidiG,FisherM,FitzsimonsD,FrancoOH,GuenounM,JenningsC,JugB,
KirchhofP,KotsevaK,LipGY,MachF,ManciaG,BermudoFM,MezzaniA,NiessnerA,
PonikowskiP,RauchB,RydenL,StauderA,TurcG,WiklundO,WindeckerS,ZamoranoJL.
2016EuropeanGuidelinesoncardiovasculardiseasepreventioninclinicalpractice.EurJ
PrevCardiol.2016;23:Np1-np96.
5. IoannidisJPA.InconsistentGuidelineRecommendationsforCardiovascularPreventionand
theDebateAboutZeroinginonandZeroingLDL-CLevelsWithPCSK9Inhibitors.JAMA.
2017;318:419-420.
6. KrumholzHM.TreatmentofCholesterolin2017.JAMA.2017;318:417-418.
17
7. PandyaA,SyS,ChoS,WeinsteinMC,GazianoTA.Cost-effectivenessof10-yearrisk
thresholdsforinitiationofstatintherapyforprimarypreventionofcardiovascular
disease.JAMA.2015;314:142-150.
8. KaziDS,PenkoJ,CoxsonPG,MoranAE,OllendorfDA,TiceJA,Bibbins-DomingoK.Updated
cost-effectivenessanalysisofPCSK9inhibitorsbasedontheresultsoftheFOURIERtrial
(letter).JAMA2017;318:748-750.
9. BaigentC,BlackwellL,EmbersonJ,HollandLE,ReithC,BhalaN,PetoR,BarnesEH,KeechA,
SimesJ,CollinsREfficacyandsafetyofmoreintensiveloweringofLDLcholesterol:ameta-
analysisofdatafrom170,000participantsin26randomisedtrials.Lancet2010;376:1670–
81.
10. RedbergRF,KatzMH.Statinsforprimaryprevention:Thedebateisintensebutthedataare
weak.JAMA2016;316:1979-81.
11. CannonCP,BlazingMA,GiuglianoRP,McCaggA,WhiteJA,TherouxP,DariusH,LewisBS,
OphuisTO,JukemaJW,DeFerrariGM,RuzylloW,DeLuccaP,ImK,BohulaEA,ReistC,
WiviottSD,TershakovecAM,MuslinerTA,BraunwaldE,CaliffRM;IMPROVE-IT
Investigators.Ezetimibeaddedtostatintherapyafteracutecoronarysyndromes.NEnglJ
Med2015;372:2387-2397.
12. SabatineMS,GiuglianoRP,KeechAC,HonarpourN,WiviottSD,MurphySA,KuderJF,Wang
H,LiuT,WassermanSM,SeverPS,PedersenTR;FOURIERSteeringCommitteeand
Investigators.EvolocumabandClinicalOutcomesinPatientswithCardiovascularDisease.N
EnglJMed.2017;376:1713-1722.
13. ParhoferKG.Newapproachestoaddressdyslipidemia.CurrOpinLipidol.2017doi:
10.1097/MOL.0000000000000456
14. FerenceBA,GinsbergHN,GrahamI,RayKK,PackardCJ,BruckertE,HegeleRA,KraussRM,
RaalFJ,SchunkertH,WattsGF,BorénJ,FazioS,HortonJD,MasanaL,NichollsSJ,
NordestgaardBG,vandeSluisB,TaskinenMR,TokgözogluL,LandmesserU,LaufsU,
WiklundO,StockJK,ChapmanMJ,CatapanoAL.Low-densitylipoproteinscause
atheroscleroticcardiovasculardisease.1.Evidencefromgenetic,epidemiologic,andclinical
studies.AconsensusstatementfromtheEuropeanAtherosclerosisSocietyConsensusPanel.
EurHeartJ.2017;38:2459-2472
18
15. KaplanH,ThompsonRC,TrumbleBC,WannLS,AllamAH,BeheimB,FrohlichB,Sutherland
ML,SutherlandJD,StieglitzJ,RodriguezDE,MichalikDE,RowanCJ,LombardiGP,BediR,
GarciaAR,MinJK,NarulaJ,FinchCE,GurvenM,ThomasGS.Coronaryatherosclerosisin
indigenousSouthAmericanTsimane:across-sectionalcohortstudy.Lancet(2017)
dx.doi.org/10.1016/S0140-6736(17)30752-3
16. CohenJC,BoerwinkleE,MosleyTHJr,HobbsHH.SequencevariationsinPCSK9,lowLDL,and
protectionagainstcoronaryheartdisease.NEnglJMed2006;354:1264–1272
17. RaalFJ,PilcherGJ,WaisbergR,ButheleziEP,VellerMG,JoffeBI.Low-densitylipoprotein
cholesterolbulkisthepivotaldeterminantofatherosclerosisinfamilial
hypercholesterolemia.AmJCardiol1999;83:1330-1333.
18. RifkindBM,SegalP.LipidResearchClinicsProgramreferencevaluesforhyperlipidemiaand
hypolipemia.JAMA1983:250:1869-72.
19. NordestgaardBG,ChapmanMJ,HumphriesSE,GinsbergHN,MasanaL,DescampsOS,
WiklundO,HegeleRA,RaalFJ,DefescheJC,WiegmanA,SantosRD,WattsGF,ParhoferKG,
HovinghGK,KovanenPT,BoileauC,AvernaM,BorénJ,BruckertE,CatapanoAL,
KuivenhovenJA,PajukantaP,RayK,StalenhoefAF,StroesE,TaskinenMR,Tybjærg-Hansen
A;EuropeanAtherosclerosisSocietyConsensusPanel.Familialhypercholesterolaemiais
underdiagnosedandundertreatedinthegeneralpopulation:guidanceforcliniciansto
preventcoronaryheartdisease.ConsensusStatementoftheEuropeanAtherosclerosis
Society.EurHeartJ2013;34:3478-3490.
20. FerenceBA,YooW,AleshI,MahajanN,MirowskaKK,MewadaA,KahnJ,AfonsoL,Williams
KASr,FlackJMEffectoflong-termexposuretolowerlow-densitylipoproteincholesterol
beginningearlyinlifeontheriskofcoronaryheartdisease:aMendelianrandomization
analysis.JAmCollCardiol.2012;60:2631-9
21. FerenceBA,RobinsonJG,BrookRD,CatapanoAL,ChapmanMJ,NeffDR,VorosS,Giugliano
RP,DaveySmithG,FazioS,SabatineMS.VariationinPCSK9andHMGCRandRiskof
CardiovascularDiseaseandDiabetes.NEnglJMed.2016;375:2144-2153.
22. ScandinavianSimvastatinSurvivalStudyGroup.Randomisedtrialofcholesterolloweringin
4444patientswithcoronaryheartdisease:theScandinavianSimvastatinSurvivalStudy.
Lancet1994;344:1883-9.
19
23. ShepherdJ,CobbeSM,FordI,IslesCG,LorimerAR,MacfarlanePW,McKillopJH,PackardCJ.
Preventionofcoronaryheartdiseasewithpravastatininmenwithhypercholesterolemia.N
EnglJMed.1995;333:1301-07.
24. CannonCP,BraunwaldE,McCabeCH,etal.Intensiveversusmoderatelipidloweringwith
statinsafteracutecoronarysyndromes.NEnglJMed2004;350:1495-504.
25. LaRosaJC,GrundySM,WatersDD,etal.Intensivelipidloweringwithatorvastatininpatients
withstablecoronarydisease.NEnglJMed2005;352:1425-35.
26. AndersonTJ,GrégoireJ,PearsonGJ,BarryAR,CoutureP,DawesM,FrancisGA,GenestJJr,
GroverS,GuptaM,HegeleRA,LauDC,LeiterLA,LonnE,ManciniGB,McPhersonR,NguiD,
PoirierP,SievenpiperJL,StoneJA,ThanassoulisG,WardR.2016CanadianCardiovascular
SocietyGuidelinesfortheManagementofDyslipidemiaforthePreventionofCardiovascular
DiseaseintheAdult.CanJCardiol.2016;32:1263-1282
27. ShrankWH,BarlowJF,BrennanTA.Newtherapiesinthetreatmentofhighcholesterol:An
argumenttoreturntogoal-basedlipidguidelines.JAMA2015;314:1443-4
28. JarchoJA,KeaneyJF.Proofthatlowerisbetter:LDLcholesterolandIMPROVE-IT.N.Eng.J
Med.2015;372:2448-50.
29. GiuglianoRP,WiviottSD,BlazingMA,DeFerrariGM,ParkJG,MurphySA,WhiteJA,
TershakovecAM,CannonCP,BraunwaldE.Long-termSafetyandEfficacyofAchievingVery
LowLevelsofLow-DensityLipoproteinCholesterol:APre-specifiedAnalysisoftheIMPROVE-
ITTrial.JAMACardiol.2017;2:547-555.
30. CollinsR,ReithC,EmbersonJ,ArmitageJ,BaigentC,BlackwellL,BlumenthalR,DaneshJ,
SmithGD5,DeMetsD,EvansS,LawM,MacMahonS,MartinS,NealB,PoulterN,PreissD,
RidkerP,RobertsI,RodgersA,SandercockP,SchulzK,SeverP,SimesJ,SmeethL,WaldN,
YusufS,PetoR.Interpretationoftheevidencefortheefficacyandsafetyofstatintherapy.
Lancet2016doi:10.1016/S0140-6736(16)31357-5.
31. GiuglianoRP,MachF,ZavitzK,KurtzC,ImK,KanevskyE,SchneiderJ,WangH,KeechA,
PedersenTR,SabatineMS,SeverPS,RobinsonJG,HonarpourN,WassermanSM,OttBR;
EBBINGHAUSInvestigators.CognitiveFunctioninaRandomizedTrialofEvolocumab.NEngl
JMed.2017;377:633-643
20
32. GiuglianoRP,PedersenTR,ParkJG,DeFerrariGM,GaciongZA,CeskaR,TothK,Gouni-
BertholdI,Lopez-MirandaJ,SchieleF,MachF,OttBR,KanevskyE,PinedaAL,SomaratneR,
WassermanSM,KeechAC,SeverPS,SabatineMS;FOURIERInvestigators.Clinicalefficacy
andsafetyofachievingverylowLDL-cholesterolconcentrationswiththePCSK9inhibitor
evolocumab:aprespecifiedsecondaryanalysisoftheFOURIERtrialLancet.2017pii:S0140-
6736(17)32290-0.
33. PreissD,SattarN.Pharmacotherapy:Statinsandnew-onsetdiabetes--theimportant
questions.NatRevCardiol.2012;9:190-2.
34. SabatineMS,LeiterLA,WiviottSD,GiuglianoRP,DeedwaniaP,DeFerrariGM,MurphySA,
KuderJF,Gouni-BertholdI,LewisBS,HandelsmanY,PinedaAL,HonarpourN,KeechAC,
SeverPS,PedersenTRCardiovascularsafetyandefficacyofthePCSK9inhibitorevolocumab
inpatientswithandwithoutdiabetesandtheeffectofevolocumabonglycaemiaandriskof
new-onsetdiabetes:apre-specifiedanalysisoftheFOURIERrandomisedcontrolledtrial..
LancetDiabetesEndocrinol.2017pii:S2213-8587(17)30313-3.doi:10.1016/S2213-
8587(17)30313-3.
35. RobinsonJG,FarnierM,KrempfM,BergeronJ,LucG,AvernaM,StroesES,LangsletG,Raal
FJ,ElShahawyM,KorenMJ,LeporNE,LorenzatoC,PordyR,ChaudhariU,KasteleinJJ,
ODYSSEYLONGTERMInvestigators.Efficacyandsafetyofalirocumabinreducinglipidsand
cardiovascularevents.NEnglJMed2015;372:1489–1499.
36. SchwartzGG,BessacL,BerdanLG,BhattDL,BittnerV,DiazR,GoodmanSG,HanotinC,
HarringtonRA,JukemaJW,MahaffeyKW,MoryusefA,PordyR,RoeMT,RorickT,Sasiela
WJ,ShirodariaC,SzarekM,TambyJF,TricociP,WhiteH,ZeiherA,StegPG.Effectof
alirocumab,amonoclonalantibodytoPCSK9,onlongtermcardiovascularoutcomes
followingacutecoronarysyndromes:rationaleanddesignoftheODYSSEYoutcomestrial.
AmHeartJ2014;168:682–689.
37. FerenceBA,CannonCP,LandmesserU,LüscherTF,CatapanoAL,RayKK.Reductionoflow
densitylipoprotein-cholesterolandcardiovasculareventswithproproteinconvertase
subtilisin-kexintype9(PCSK9)inhibitorsandstatins:ananalysisofFOURIER,SPIRE,andthe
CholesterolTreatmentTrialistsCollaboration.FerenceBA,CannonCP,LandmesserU,
LüscherTF,CatapanoAL,RayKK.EurHeartJ.2017doi:10.1093/eurheartj/ehx450
38. BowmanL,HopewellJC,ChenF,WallendszusK,StevensW,CollinsR,WiviottSD,CannonCP,
BraunwaldE,SammonsE,LandrayMJ.EffectsofAnacetrapibinPatientswith
21
AtheroscleroticVascularDisease.HPS3/TIMI55–REVEALCollaborativeGroup,NEnglJMed.
2017;377:1217-1227
39. LincoffAM,NichollsSJ,RiesmeyerJS,BarterPJ,BrewerHB,FoxKAA,GibsonCM,GrangerC,
MenonV,MontalescotG,RaderD,TallAR,McErleanE,WolskiK,RuotoloG,VangerowB,
WeerakkodyG,GoodmanSG,CondeD,McGuireDK,NicolauJC,Leiva-PonsJL,PesantY,Li
W,KandathD,KouzS,TahirkheliN,MasonD,NissenSE;EvacetrapibandCardiovascular
OutcomesinHigh-RiskVascularDisease.NEnglJMed.2017;376:1933-1942
40. DavidsonM,LiuSX,BarterP,BrintonEA,CannonCP,GottoAMJr,LearyET,ShahS,
StepanavageM,MitchelY,DanskyHM.MeasurementofLDL-Caftertreatmentwiththe
CETPinhibitoranacetrapib.JLipidRes.2013;54:467-72.
41. SnidermanAD,PetersonEDGeneticStudiesHelpClarifytheComplexitiesofLipidBiology
andTreatment..JAMA.2017;318:915-917.
42. FerenceBA,KasteleinJJP,GinsbergHN,ChapmanMJ,NichollsSJ,RayKK,PackardCJ,Laufs
U,BrookRD,Oliver-WilliamsC,ButterworthAS,DaneshJ,SmithGD,CatapanoAL,Sabatine
MS.AssociationofGeneticVariantsRelatedtoCETPInhibitorsandStatinsWithLipoprotein
LevelsandCardiovascularRisk.FerenceBA,KasteleinJJP,GinsbergHN,ChapmanMJ,
NichollsSJ,RayKK,PackardCJ,LaufsU,BrookRD,Oliver-WilliamsC,ButterworthAS,Danesh
J,SmithGD,CatapanoAL,SabatineMS.JAMA.2017;318:947-956
43. ShapiroMD.RareGeneticDisordersAlteringLipoproteins.In:DeGrootLJ,ChrousosG,
DunganK,FeingoldKR,GrossmanA,HershmanJM,KochC,KorbonitsM,McLachlanR,New
M,PurnellJ,RebarR,SingerF,VinikA,editors.Endotext[Internet].SouthDartmouth(MA):
MDText.com,Inc.;2000-2015Dec6.
44. PackardCJ.UnpackingandUnderstandingtheImpactofProproteinConvertase
Subtilisin/KexinType9InhibitorsonApolipoproteinBMetabolism.Circulation.
2017;135:363-365.
45. PackardC,FordI.Longtermfollowupoflipidloweringtrials.Curr.Opin.Lipidol.
2015;26:572-9.
46. WheltonSP,MeeusenJW,DonatoLJ,JaffeAS,SaengerA,SokollLJ,BlumenthalRS,JonesSR,
MartinSS.EvaluatingtheatherogenicburdenofindividualswithaFriedewald-estimated
22
low-densitylipoproteincholesterol<70mg/dLcomparedwithanovellow-density
lipoproteinestimationmethod.JClinLipidol.2017;11:1065-1072.
47. KotsevaK,WoodDDeBacquerDetal.EUROASPIREIV:AEuropeanSocietyofCardiology
surveyonthelifestyle,riskfactorandtherapeuticmanagementofcoronarypatientsfrom24
Europeancountries.Europ.J.ofPreventativeCardiol.2015DOI:
10.1177/2047487315569401.
48. PokharelY,ChinnakondepalliK,VilainK,WangK,MarkDB,DaviesG,BlazingMA,Giugliano
RP,Braunwald,E,CannonCP,CohenDJ,MagnussonEA.Impactofezetimibeontherateof
cardiovascular-relatedhospitalizationsandassociatedcostsamongpatientswitharecent
acutecoronarysyndrome.Circ.Cardiovasc.Qual.Outcomes.2017
;10:e003201.DOI:10.1161/CIRCOUTCOMES.116.003201.
49. SabatineMS.Proproteinconvertasesubtilisin/kexintype9(PCSK9)inhibitors:comparing
andcontrastingguidanceacrosstheAtlantic.EurHeartJ.
2017;https://doi.org/10.1093/eurheartj/ehw572.
50. KaziDS,PenkoJ,CoxsonPG,MoranAE,OllendorfDA,TiceJA,Bibbins-DomingoK.Updated
cost-effectivenessanalysisofPCSK9inhibitorsbasedontheresultsoftheFOURIERtrial
(letter).JAMA2017;318:748-750.
51. RobinsonJG,HuijgenR,RayK,PersonsJ,KasteleinJJ,PencinaMJ.Determiningwhentoadd
nonstatintherapy:aquantitativeapproach.JAmCollCardiol2016;68:2412-2421.
52. NationalInstituteforHealthandCareExcellence.Alirocumabfortreatingprimary
hypercholesterolaemiaandmixeddyslipidaemia.Technologyappraisalguidance[TA393].
2016.https://www.nice.org.uk/guidance/ta393.
53. Lloyd-JonesDM,MorrisPB,BallantyneCM,BirtcherKK,DalyDDJr,DePalmaSM,Minissian
MB,OrringerCE,SmithSCJr2017FocusedUpdateofthe2016ACCExpertConsensus
DecisionPathwayontheRoleofNon-StatinTherapiesforLDL-CholesterolLoweringinthe
ManagementofAtheroscleroticCardiovascularDiseaseRisk:AReportoftheAmerican
CollegeofCardiologyTaskForceonExpertConsensusDecisionPathways.Lloyd-JonesDM,
MorrisPB,BallantyneCM,BirtcherKK,DalyDDJr,DePalmaSM,MinissianMB,OrringerCE,
SmithSCJr.JAmCollCardiol.2017;70:1785-1822.
23
54. LandmesserU,ChapmanMJ,StockJK,AmarencoA,BelchJJF,BorenJ,FarnierMF,Ference
BA,GielenS,GrahamI,GrobbeeDE,HovinghGK,LuscherTF,PiepoliMF,RayKK,StroesES,
WiklundO,WindeckerS,ZamoranoJL,PintoF,TokgozogluL,BaxJJ,andCatapanoAL.2017
UpdateofESC/EASTaskForceonpracticalclinicalguidanceforproproteinconvertase
subtilisin/kexintype9inhibitioninpatientswithatheroscleroticcardiovasculardiseaseorin
familialhypercholesterolaemia.Europ.HeartJ.2017;doi:10.1093/eurheartj/ehx549
55. BohulaEA,MorrowDA,GiuglianoRP,BlazingMA,HeP,ParkJG,MurphySA,WhiteJA,
KesaniemiYA,PedersenTR,BradyAJ,MitchelY,CannonCP,BraunwaldE.Atherothrombotic
riskstratificationandezetimibeforsecondaryprevention.JAmCollCardiol2017;69:911-
921.
56. JellingerPS,HandelsmanY,RosenblitPD,BloomgardenZT,FonsecaVA,GarberAJ,
GrunbergerG,GuerinCK,BellDSH,MechanickJI,Pessah-PollackR,WyneK,SmithD,Brinton
EA,FazioS,DavidsonM.AmericanAssociationofClinicalEndocrinologistspreventionof
cardiovasculardisease.EndocrPract.2017;23(Suppl2):1-87.
57. BoekholdtSM,ArsenaultBJ,MoraS,PedersenTR,LaRosaJC,NestelPJ,SimesRJ,Durrington
P,HitmanGA,WelchKM,DeMiccoDA,ZwindermanAH,ClearfieldMB,DownsJR,Tonkin
AM,ColhounHM,GottoAMJr,RidkerPM,KasteleinJJ.AssociationofLDLcholesterol,non-
HDLcholesterol,andapolipoproteinBlevelswithriskofcardiovasculareventsamong
patientstreatedwithstatins:ameta-analysis.JAMA2012;307:1302-1309.
58. AnnemansL,PackardCJ,BriggsA,RayKK.‘Highestrisk-highestbenefit’strategy:a
pragmatic,cost-effectiveapproachtotargetinguseofPCSK9inhibitortherapies.Europ
HeartJ.2018(inpress).
59. RidkerPM,EverettBM,ThurenT,MacFadyenJG,ChangWH,BallantyneC,FonsecaF,
NicolauJ,KoenigW,AnkerSD,KasteleinJJP,CornelJH,PaisP,PellaD,GenestJ,CifkovaR,
LorenzattiA,ForsterT,KobalavaZ,Vida-SimitiL,FlatherM,ShimokawaH,OgawaH,
DellborgM,RossiPRF,TroquayRPT,LibbyP,GlynnRJ;CANTOSTrialGroup.
AntiinflammatoryTherapywithCanakinumabforAtheroscleroticDisease.NEnglJMed.
2017;377:1119-1131.
24
Figurelegends
Figure1.ContextandrationaleforLDLloweringstrategies.
TheschematicdepictsthechangeinLDLcholesteroloveralifecourseinmales(adaptedfrom
reference19;forfemales,theriseinadulthoodislargelydelayeduntilthemenopause).LDLcin
familialhypercholesterolemiaiselevatedfrombirthandthosewiththisconditionhaveanenhanced
integratedLDLexposure(‘LDLcxyears’)andearlyatheroscleroticCVD(18).Theriskreduction
associatedwithadecrementinLDLcispredictedtobegreaterifaninterventiontolowerthis
lipoproteinisinitiatedearlier(21).Itisspeculatedthatthisisduetothenatureofthelesions
presentacrossthedecadesoflife.TheriskreductionsrelativetoLDLloweringareextrapolatedfrom
reference21.
Figure2.AssociationofachievedLDLcwithCVDriskinlipidloweringtrials.
Figure2A(adaptedfromreference14)showsfortrialsofstatinversusplacebo,ormorevsless
intensestatintreatment,achievedLDLcinthetwoarmsofthestudy(linkedbysolidbar)and
observedongoingriskofacoronaryevent(fatalCHDplusnon-fatalmyocardialinfarction).The
verticalaxesareadjustedtoallowprimaryandsecondarypreventionstudiestobeexamined
together.
Figure2BistakenfromtheFOURIERtrial(reference37supplementarydata).Itshowsforall
subjects(i.e.inbothtreatmentarms)groupedinto5categoriesofincreasingLDLctherelationship
betweenmeanachievedLDLcandeventrate.Theassociationismonotonous(P<0.001fortrend)
withnoattenuationatevenverylowLDLc.Thesub-groupoflowestLDLc(<10mg/dl)isalso
depicted;ithadacommensuratelylowCVDrisk.
25
Figure3.TherapeuticstrategiesforprofoundLDLlowering.
Thisflowchartisillustrativeofdevelopingparadigmsofcombinationlipid-loweringtherapy
(presentedinmuchgreaterdetailinreferences66,67).Itisenvisagedthatmanypatientswith
atheroscleroticvasculardisease(ASCVD)willrequireup-titrationoftheirstatindosetoachieve
guidelinetargetswherethesearerecommended(e.g.inEuropean/Canadianguidelines4,27).
Thereisalimittowhatcanbeachievedwithhighintensitystatintherapy.TheneedforfurtherLDL
lowering(andpossiblypatientpreference)leadstoroutineadditionofezetimibe(51,66,67).Where
thereisapredictedveryhighCVDriskandanelevatedLDLcthenaPCSK9inhibitorcanbe
considered(64-67,73).Herethegoalistoachieveasubstantialabsoluteriskreduction(lowNNT)
personalizedforthepatientandacceptabletothepayer.Annualrisks(%/y)arequotedfor
illustrativepurposesonly;moredetailonthetypeofCVDpatientthatwillreachanappropriaterisk
thresholdisgiveninreferences64-67.
26
Figure1
2.0
3.0
4.0
5.0
6.0
1 3 5 7 9 11 13
LD
L c
ho
l(m
mo
l/l)
7 17 27 37 47 57 67Age (years)
LDLc rise with age (in men).
FH
Integrated LDL exposure
Artery wall disease
Response to initiation of LDL lowering
Greater RRR per mmol/l reductionPlaque resolution
Lesser RRRPlaque stabilisation
LDL depositionFatty streaks
Complex lesionsPlaque ruptureClinical event
LDLc reduction needed for 50% CVD risk reduction
35 mg/dl(0.9 mmol/l)
100mg/dl(3.0 mmol/l)
Trea
tmen
t st
rate
gie
s
27
Figure2
0.0
2.0
4.0
6.0
8.0
10.0
0.0
5.0
10.0
15.0
20.0
25.0
0 50 100 150 200 250
Prim
arypreventio
ntrials(%
with
event)
Secondarypreventio
ntrials(%
with
event)
AchievedLDLcholesterol (mg/dl)
WOSCOPS
JUPITER
4S
AFCAPS
ASCOTLIPIDPROSPERCARE
HPSIDEAL
TNT
CHD event rate per 5 years
0.0
2.0
4.0
6.0
8.0
10.0
0 20 40 60 80 100 120
FOURIERCVDdeath,MI,stroke
Achieved LDLc (mg/dl)
Perc
ent w
ith e
vent
(10)
( )
A
B
28
Figure3
Patient not at goal for LDL-C
Further LDL reduction indicated clinically
Increase statin dose‘Rule of ‘6%’;Tolerability; Side effects
Combination therapy options
Statin + ezetimibe Additional 20-25% LDLc decrease
Target of <70mg/dl LDLc; <100mg/dl non-HDLc
Statin (+ Eze) + PCSK9i Additional 60% LDLc decrease
No target; maximise absolute risk reduction
ASCVD risk>3%/y; LDLc>100mg/dl ASCVD risk>2%/y; LDLc>140mg/dl
- Aggressive, established/ polyvascular CVD- CVD, PAD, stroke
top related