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.

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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