10/10/2016 ManagementofDyslipidemiainAdultsAmericanFamilyPhysician

ManagementofDyslipidemiainAdults
SYEDM.AHMED,M.D.,M.P.H.,DR.P.H.,MARKE.CLASEN,M.D.,PH.D.,andJOHNF.DONNELLY,M.D.,WrightStateUniversitySchoolofMedicine,Dayton,Ohio
AmFamPhysician.1998May157(9):21922204.

Seerelatedpatientinformationhandoutonhighlipidlevels(http://www.aafp.org/afp/1998/0501/p2207.html),writtenbytheauthorsofthisarticle.

ThisarticleexemplifiestheAAFP199798AnnualClinicalFocusonpreventionandmanagementofcardiovasculardisease.

TheimportanceoftreatingdyslipidemiasbasedoncardiovascularriskfactorsishighlightedbytheNationalCholesterolEducationProgram
guidelines.Thefirststepinevaluationistoexcludesecondarycausesofhyperlipidemia.Assessmentofthepatient'sriskforcoronaryheartdisease
helpsdeterminewhichtreatmentshouldbeinitiatedandhowoftenlipidanalysisshouldbeperformed.Forprimarypreventionofcoronaryheart
disease,thetreatmentgoalistoachievealowdensitylipoprotein(LDL)cholesterolleveloflessthan160mgperdL(4.15mmolperL)inpatientswith
onlyoneriskfactor.ThetargetLDLlevelinpatientswithtwoormoreriskfactorsis130mgperdL(3.35mmolperL)orless.Forpatientswith
documentedcoronaryheartdisease,theLDLcholesterollevelshouldbereducedtolessthan100mgperdL(2.60mmolperL).AstepIIdiet,inwhich
thetotalfatcontentislessthan30percentoftotalcaloriesandsaturatedfatis8to10percentoftotalcalories,mayhelpreduceLDLcholesterol
levelstothetargetrangeinsomepatients.Ahighfiberdietisalsotherapeutic.Themostcommonlyusedoptionsforpharmacologictreatmentof
dyslipidemiaincludebileacidbindingresins,HMGCoAreductaseinhibitors,nicotinicacidandfibricacidderivatives.Otherpossibilitiesinselected
casesareestrogenreplacementtherapy,plasmapheresisandevensurgeryinsevere,refractorycases.

Dyslipidemiasaredisordersoflipoproteinmetabolism,includinglipoproteinoverproductionordeficiency.Thesedisordersmaybemanifestedbyelevationofthe
serumtotalcholesterol,lowdensitylipoprotein(LDL)cholesterolandtriglycerideconcentrations,andadecreaseinthehighdensitylipoprotein(HDL)cholesterol
concentration.

Epidemiologic,angiographicandpostmortemstudieshavedocumentedacausalrelationshipbetweenelevatedserumcholesterollevelsandthegenesisof
coronaryheartdisease.Angiographicstudiesshowthataggressivecholesterolreductionbyavarietyofmethods,asopposedtodietarymodificationsalone,results
inincreasedratesofplaqueregressionandstabilization.1Treatmentwithcholesterolloweringdrugsappearstobeaccompaniedbyareductioninthelipidcontent
ofatheroscleroticplaques,therebymakingthemmorestableandlesspronetorupture.2,3TheScandinavianSimvastatinSurvivalStudy4demonstrateda30
percentreductionintotalmortalityinsimvastatintreatedpatientswithcoronaryheartdiseaseascomparedwithpatientsnotreceivingthisagent.Inaprimary
preventiontrial,5patientstreatedwithpravastatinshoweda26percentreductioninLDLcholesterollevelsanda31percentreductionincoronaryevents(nonfatal
myocardialinfarctionordeathfromcoronaryheartdisease)ascomparedwiththeplacebogroup.

Evenafterrecognizingthecontroversiessurroundingcholesterolscreeningandtherapy,6,7mostexpertsemphasizetheimportanceoftreating
hypercholesterolemia.810Whileguidelinesfortreatingdyslipidemiasmaylackuniformity,muchcommongroundexistsforthemanagementofdyslipidemias.11The
recommendationsinthisarticleareprimarilybasedontheguidelinesfromtheNationalCholesterolEducationProgram(NCEP).12

DiagnosisandClassification
Secondarycausesofdyslipidemiaincludehypothyroidismandageneticpredisposition,suchasautosomaldominantfamilialhypercholesterolemia(Table1).13
Triglycerideelevationmayoccurinassociationwithdiabetesmellitus,alcoholism,obesityandhypothyroidism.Dyslipidemiashavebeentraditionallyclassifiedin
accordancewiththeelevatedlipoproteinclasses(Table2).14Currently,geneticdyslipidemiasareclassifiedasfamilialhypercholesterolemia,familialcombined
hyperlipidemiaandpolygenichypercholesterolemia.

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TABLE1
SelectedCausesofSecondaryDyslipidemia

IncreasedLDLcholesterollevel

Diabetesmellitus

Hypothyroidism

Nephroticsyndrome

Obstructiveliverdisease

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Drugs

Anabolicsteroids

Progestins

Betaadrenergicblockers(withoutintrinsicsympathomimeticaction)

Thiazides

Increasedtriglyceridelevel

Alcoholism

Diabetesmellitus

Hypothyroidism

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TABLE2
FredricksonClassificationoftheDyslipidemias*
PHENOTYPE LIPOPROTEIN(S)ELEVATED SERUMCHOLESTEROLLEVEL SERUMTRIGLYCERIDELEVEL ATHEROGENICITY

I Chylomicrons Normalto Noneseen

IIa LDL Normal +++

IIb LDLandVLDL +++

III IDL +++

IV VLDL Normalto +

V VLDLandchylomicrons Normalto +

LDL=lowdensitylipoproteinIDL=intermediatedensitylipoproteinVLDL=verylowdensitylipoproteinHDL=highdensitylipoprotein=mildlyincreased=moderately
increased=severelyincreased=veryseverelyincreased+=mildtomoderateatherogenicity+++=severeatherogenicity.

*HDLcholesterollevelsarenotconsideredintheFredricksonclassification.

AdaptedfromFredricksonDS,LevyRI,LeesRS.Fattransportinlipoproteinsanintegratedapproachtomechanismsanddisorders.NEnglJMed1967276:3442,94103,148
56,21525,27381.

TheNCEPguidelines,however,arebasedonclinicalcutpointsthatindicaterelativeriskforcoronaryheartdisease.Includedintheguidelinesisthegeneral
recommendationthattotalcholesterolandHDLcholesterollevelsbemeasuredeveryfiveyearsbeginningatage20inpatientswhodonothavecoronaryheart
diseaseorotheratheroscleroticdisease.Bothofthesemeasurementsmaybeobtainedinthenonfastingstate.Theresultsofthesemeasurementsandthe
presenceofotherriskfactorsforcoronaryheartdiseasemaydemandamorecomprehensivelipoproteinanalysis(Table3).12

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TABLE3
CoronaryHeartDiseaseRiskBasedonRiskFactorsOtherThantheLDLLevel

Positiveriskfactors

Male45years

Female55yearsorpostmenopausalwithoutestrogenreplacementtherapy

Familyhistoryofprematurecoronaryheartdisease(definitemyocardialinfarctionorsuddendeathbeforeage55infatherorothermalefirstdegreerelativeorbeforeage65in
motherorotherfemalefirstdegreerelative)

Currentcigarettesmoking

Hypertension(bloodpressure140/90mmHgorpatientisreceivingantihypertensivedrugtherapy)

HDLcholesterollevel<35mgperdL(<0.90mmolperL)

Diabetesmellitus

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Negativeriskfactor*

HighHDLcholesterollevel(60mgperdL[1.60mmolperL])

LDL=lowdensitylipoproteinHDL=highdensitylipoprotein.

*Subtractonepositiveriskfactorifnegativeriskfactorispresent.

AdaptedfromNationalCholesterolEducationProgram.SecondreportoftheExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(adulttreatment
panelII).Bethesda,Md.:NationalCholesterolEducationProgram,NationalInstitutesofHealth,NationalHeart,Lung,andBloodInstitute,1993DHSSpublicationno.(NIH)933095:5.

TheLDLcholesterollevelcanbemeasureddirectlyorcanbe CALCULATED byusingtheFriedwaldformula(measurementisexpressedinmilligramsper

deciliter): Thisformulacannotbeusedwhenthetriglyceridelevelisgreaterthan400mgperdL(4.50mmolperL)orwhen
patientshavetypeIIIhyperlipoproteinemia.

Whilecholesterollevelsareclassifiedintodesirable,borderlinehighriskandhighriskcategories(Table4),12decisionsregardingthetreatmentof
hypercholesterolemiaarebasedontheLDLcholesterollevelandthepresenceorabsenceofotherriskfactorsforcoronaryheartdisease.Twoorthreefasting
LDLmeasurementsmustbeaveragedtoclassifythepatient'srisk.

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TABLE4
RiskClassificationofHypercholesterolemiainPatientsWithoutCoronaryHeartDisease
CLASSIFICATION TOTALCHOLESTEROLLEVEL LDLCHOLESTEROLLEVEL HDLCHOLESTEROLLEVEL

Desirable 200mgperdL(5.15mmolperL) <130mgperdL(<3.35mmolperL) 60mgperdL(1.55mmolperL)

Borderlinehigh 200to239mgperdL(5.15to6.20mmolper 130to159mgperdL(3.35to4.10mmolper 35to59mgperdL(0.90to1.55mmolper

risk L) L) L)

Highrisk 240mgperdL(6.20mmolperL) 160mgperdL(4.15mmolperL) <35mgperdL(<0.90mmolperL)

LDL=lowdensitylipoproteinHDL=highdensitylipoprotein.

ReprintedfromNationalCholesterolEducationProgram.SecondreportoftheExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(adulttreatment
panelII).Bethesda,Md.:NationalCholesterolEducationProgram,NationalInstitutesofHealth,NationalHeart,Lung,andBloodInstitute,1993DHSSpublicationno.(NIH)933095:5.

Management
ThetargetLDLcholesterolvalueinpatientswithcoronaryheartdiseaseorotheratheroscleroticdiseaseis100mgperdL(2.60mmolperL)orlower.IftheLDL
leveldoesnotexceed100mgperdLinapatientwithcoronaryheartdisease,thepatientshouldbeginthestepIdiet,regularlyparticipateinphysicalactivityand
stopsmoking.Annuallipoproteinanalysisisindicatedforthisgroup.Premenopausal WOMEN andmen35yearsofageoryoungerwithdyslipidemiabutwithout
otherriskfactorsforcoronaryheartdiseaseorageneticpredispositionaregenerallyconsideredatlowrisk.

TheNCEPguidelinesrecommendthatpatientsathigherriskofcoronaryheartdiseasereceivemoreintensiveinterventionsfordyslipidemiathanpatientsatlower
risk.Personsathighestriskforfuturecoronaryeventshaveahistoryofcoronaryheartdiseaseorextracoronaryatheroscleroticdisease.Forallpracticalpurposes,
treatmentofpatientswithmultipleriskfactorsforcoronaryheartdiseasebutwithoutahistoryofcoronarydiseaseshouldbeasaggressiveasthatforpatientswith
coronaryheartdisease.AsOliverandcolleaguesstated,15Thereisprobablylittlerealisticdifferencebetweenthosewhohavehadaclinicaleventandthosewho
havenot.Thus,primaryandsecondarypreventionarecloselylinkedalongthisstrategiccontinuum.

LifestyleModifications
TheNCEPguidelinesrecommenddietarymodification,exerciseandweightcontrolasthefoundationoftreatmentofdyslipidemia.12Thesebasicinterventionsmay
providesufficienttreatmentforupto90percentofpersonswithdyslipidemiaaccordingtotheNCEPcutpoints.16Areductionintotalcholesterolby1percentmay
decreaseaperson'sriskofdevelopingcoronaryheartdiseaseby2percent.17Cessationofcigarettesmokingandreductionofothermodifiableriskfactorsare
essentialaspectsofpreventionofcoronaryheartdisease.

EXERCISEANDWEIGHTREDUCTION
Obesityfrequentlyelevatescholesterollevelsinbothverylowdensitylipoprotein(VLDL)andLDLfractions,raisestriglyceridelevels,lowersHDLcholesterollevels,
raisesbloodpressureand PROMOTES glucoseintolerance.WeightlosslowerstotalcholesterolanditsLDLandVLDLfractions,lowerstriglyceridesandraises
HDLcholesterol.18Weightlossalsolowersbloodpressureandimprovesglycemiccontrol.

Patientsaremorelikelytocomplywithexerciseprogramsthataretailoredtomeetindividualgoals,interestsandneeds.Mostpatientsbenefitfromaerobicexercise
thattargetslargemusclegroups,performedfor30minutesfourormoretimesaweek.18Shorter,butmorefrequent,aerobicexercisesessionsprovidesimilar
benefits.Overweightpatientsshouldengageinlowintensityexercisemorefrequentlyandforlongerdurations.

ALCOHOLINTAKE
Alcoholexertsseveraleffectsonlipidlevels,includingraisingtheserumtriglycerideandHDLcholesterollevels.ItseffectonLDLcholesterolappearstobeminimal.
Sinceexcessivealcoholcausesnumerousadverseeffects,includinghepatictoxicity,cardiomyopathy,motor VEHICLE crashesandextensivepsychosocial
consequences,itisnotrecommendedforthepreventionofcoronaryheartdisease.12

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STEPIANDSTEPIIDIETS
DietarytherapyshouldbeinitiatedinpatientswhohaveborderlinehighLDLcholesterollevels(130to159mgperdL[3.35to4.10mmolperL])andtwoormore
riskfactorsforcoronaryheartdiseaseandinpatientswhohaveLDLlevelsof160mgperdL(4.15mmolperL)orgreater.Theobjectiveofdietarytherapyin
primarypreventionistodecreasetheLDLcholesterollevelto160mgperdLifonlyoneriskfactorforcoronaryheartdiseaseispresentandtolessthan130mg
perdLiftwoormoreriskfactorsareidentified.Inthepresenceofdocumentedcoronaryheartdisease,dietarytherapyisindicatedinpatientswhohaveLDLvalues
exceeding100mgperdL(2.60mmolperL),withtheaimofloweringtheLDLlevelto100mgperdLorless.

ThegoalofdietarytherapyistoreduceelevatedtotalcholesterolandLDLcholesterollevelstothetargetvalueswhilemaintaininganutritiousdiet.Intheaverage
Americandiet,fatcomprisesabout35percentoftotalcalories,withsaturatedfataccountingfor13to14percent.12,18Cholesterolintakeaveragesabout360mg
perdayinAmericanmendailycholesterolintakeislessinAmerican WOMEN .12InapatientwithcoronaryheartdiseasewhoeatsanaverageAmericandietand
thenswitchestothestepIIdiet,LDLcholesterollevelscanbereducedby10to20percent.19However,somepatientswhostrictlyadheretodietarytherapyhave
onlyslightreductionsintotalcholesterollevels.Clinicaltrialsconsistentlyreportthatthelipidloweringeffectsofdietarymeasuresaregreatestinpersonswith
higherinitialvaluesoftotalcholesterol,LDLcholesterolandtriglycerides.12,16,18

StepIandstepIIdietsaredesignedtoprogressivelyreduceintakeofsaturatedfats,cholesterolandtotalcaloriestodecreaselipoproteinvaluesand PROMOTE
weightlossinoverweightpersons(Table5).12Complexcarbohydrates,ratherthansimplesugars,shouldbeemphasized.

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TABLE5
ExamplesofFoodstoEatandFoodstoAvoidintheStepIandStepIIDiets
FOODGROUP FOODSTOEAT FOODSTOAVOID

Leanmeat,poultryandfish(6oz Beef,pork,lambleancuts,welltrimmedbeforecooking Beef,pork,lambregular,groundbeef,fattycuts,spareribs,

aday) ORGANMEATS

Poultry,withoutskin Poultrywithskin,friedchicken

Fish,shellfish Friedfish,friedshellfish

Processedmeatpreparedfromleanmeat Regularluncheonmeat

Eggs(stepI:4yolksperweek Eggwhites,cholesterolfreeeggsubstitute Eggyolks(includingeggsusedincookingandbaking)

stepII:2yolksperweek)

Lowfatdairyproducts(2to3 Milkskim,%or1%lowfatmilk,buttermilk Wholemilk,2%lowfatmilk,imitationmilk

servingsaday)
Nonfatorlowfatyogurt Wholemilkyogurt

Lowfatorprocessedcheese Regularcheese

Nonfatorlowfatcottagecheese Regularcottagecheese(4%fat)

Frozenyogurt,icemilk Icecream

Lowfat COFFEE creamer,nonfatorlowfatsour Cream,half&half,whippingcream,regularsourcream

cream

Fatsandoils(6to8teaspoonsa Unsaturatedoilssafflower,sunflower,corn,soybean, Coconutoil,palmoil

day) canola,olive,peanut
ThestepIdietlimitscaloriesderivedfromsaturatedfatsto8to10percentoftotalcaloriesandcholesteroltolessthan300mgperday.ThestepIIdietfurther
restrictscaloriesfromsaturatedfatstolessthan7percentoftotalcaloriesandrestrictscholesterolintaketolessthan200mgperday.Forbothdiets,itis
recommendedthatmonounsaturatedfatsconstitutenomorethan15percentoftotalcaloriesandpolyunsaturatedfatsnomorethan10percentoftotalcalories.
Monounsaturatedfats,suchasthosefoundinpeanuts,almondsandcanolaoil,appeartohavelessofanadverseeffectontheHDLcholesterollevelthan
polyunsaturatedfats.Omega3fattyacids,whicharepolyunsaturatedfattyacidsfoundinmanyfish,havebeenshowntoreduceserumtriglycerideconcentrations.
TheyhaveonlyaminoreffectonLDLcholesterolinpatientswithnormaltriglyceridelevels.Thebenefitsoffishoilsandotheromega3fattyacidsupplementsare
presentlyunderinvestigation.TheNCEPguidelinesdonotroutinelyrecommenduseoffishoils,althoughtheconsumptionoffishisrecommendedinbothstepI
andstepIIdiets.

ManypatientswithhyperlipidemiamayalreadyhaveadoptedeatingpatternssimilartothoseofthestepIdiet.ThecholesterolloweringeffectsofthestepIdietin
suchpatientswilllikelybemodest.ThemorestringentstepIIdietrequirescloseinspectiontoensurethatthepatientmaintainsanutritiousdiet.TheNCEP
guidelinesrecommendconsultationwitharegistereddietitianforpatientsfollowingthestepIIdiet.

ThestepIdiethasbeenshowntolowerthetotalserumcholesterollevelby3to14percent,whilethestepIIdietmaylowerthetotalcholesterollevelanadditional
3to7percent.12Notallstudies,however,havereportedsimilarreductions.Hence,patientsshouldbeinformedthatevenwithstrictadherencetothestepIdiet,a
stepIIdietmaybeneededtoeffectsignificantimprovementinthelipidprofile.Obesepatientswholoseweightmayhavegreaterreductionsinthetotalcholesterol
level.TheNCEPrecommendsevaluatingthepatient'sresponsetodietarytherapybymonitoringthetotalcholesterollevelaftersixweeksand12weeksofthestep
Idiet.

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Inprimarypreventionofcoronaryheartdisease(thatis,inpatientswithoutevidenceofcoronaryheartdisease),dietarytherapyshouldbemaintainedforsix
monthsbeforedrugtherapyisinitiated.ReferraltoaregistereddietitianisindicatedinpatientswhoarealreadyadheringtothestepIdietatthetimeofthe
diagnosisofdyslipidemiaorwhoareunabletoachievethegoalsofdietarytherapywhileadheringtothestepIdiet.Inpatientsathighriskofcoronaryheart
diseaseorwithahightotalcholesterolorLDLvalue,drugtherapyshouldbeinitiatedatanearlierstage.InpatientswithcoronaryheartdiseaseandanLDL
cholesterolvalueabove100mgperdL(2.60mmolperL),therapyshouldbeginwiththestepIIdiet.

DIETARYFIBER
SolublefiberhasbeenshowntomodestlyreducetotalcholesterolandLDLcholesterollevels.12Currentdietaryguidelinesrecommendatotaldailyfiberintakeofat
least20to30gforadults,with25percentofthefiberbeingsolublefiber.12Theselevelscanbeattainedwiththeproposedsixormoredailyservingsofgrain
productsandfiveormoredailyservingsoffruitsandvegetables.Adding3gperdayofsolublefiberfromoatbrancanreducetotalcholesterolby5to6mgper
dL.18Higherdailyintakeofsolublefiber PROMOTES afurthermodestreductionofcholesterolvalues.

TheAmericanHeartAssociationdietmaylowertotalcholesterolby5to7percent,whereassimilardietsthatemphasizedietaryfibermayreducetotalcholesterol
by11to32percentandmayexertbeneficialeffectsonLDLandHDLcholesterollevelsaswell.20Moreover,ahighcarbohydrate,lowfiberdiettypicallyraises
serumtriglyceridelevelsandlowersHDLcholesterollevels.Conversely,ahighcarbohydrate,highfiberdietmaylowertheserumtriglyceridelevelandraisethe
HDLcholesterollevel.20Ahighfiber,lowfatdietalsoprovidesotherbeneficialeffects,includingimprovedglycemiccontrol,weightreductionandearliersatiety,
preventionofdiverticulardiseaseand,possibly,preventionofcolorectalcancer.20

Highintakeofsolublefibercontributestogastrointestinalsideeffectssuchasbloatingandflatulence.Excessiveintakeoffibermaybeassociatedwithimpaired
absorptionofimportantnutrientssuchascalcium.Supplementationwithadailymultivitaministhereforerecommendedforpatientsconsumingahighfiberdietand
highfibersupplements.20

ANTIOXIDANTS
Atherogenicityis PROMOTED byoxidationandglycosylationofLDLcholesterol.12Severalvitamins,includingvitaminC,vitaminEandbetacarotene,have
antioxidantproperties,whichmayprovideprotectionagainstatherogenesis.Fruits,anddarkgreenanddeepyellowvegetablesarerichsourcesofantioxidant
vitamins.

DrugTherapy
BecausedietarymodificationrarelyreducesLDLcholesterollevelsbymorethan10to20percent,theNCEPguidelinesrecommendthatconsiderationbegivento
theuseofcholesterolloweringagentsiflipidlevelsremainelevatedaftersixmonthsofintensivedietarytherapyorsoonerundercertaincircumstances.

ApatientwithaveryhighLDLcholesterollevelmayneedtostartdrugtherapysooner,21becauseitisunlikelythatapatientwithanLDLlevelof130mgperdL
(3.35mmolperL)orgreaterwillbeabletoachievethegoalof100mgperdL(2.60mmolperL)withdietalone.19Patientsshouldbegiventheclearmessagethat
drugtherapyisnotasubstituteforappropriatedietandexercise.Addressingothermodifiableriskfactorsisvitaltotheoverallsuccessofanytreatmentplan.

Inmostpatientswithhypercholesterolemia,HMGCoAreductaseinhibitorsarethedrugsofchoicebecausetheyreduceLDLcholesterolmosteffectively(Tables6
and7).18,22Gemfibrozil(Lopid)ornicotinicacidmaybebetterchoicesinpatientswithsignificanthypertriglyceridemia.

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TABLE6
CholesterolLoweringAgents,TheirDosagesandCost
AGENT MAINTENANCEDOSAGE COST*

Bileacidbindingresins

Cholestyramine(Questran,QuestranLite) 4g,8g,12gor16gtwicedaily $89.00(packets)

70.00(generic)

Colestipol(Colestid) 5gtwicedailyor30gperday,individeddoses 81.00(packets)

HMGCoAreductaseinhibitors(statins)

Atorvastatin(Lipitor) 10to80mgperdayanytime 55.00

Cerivastatin(Baycol) 0.3mgintheevening 40.00

Fluvastatin(Lescol) 20mgor40mgatbedtime,or20mgtwicedaily 41.00

Lovastatin(Mevacor) 20mg,40mgor80mgwitheveningmeal 67.00

Pravastatin(Pravachol) 10mg,20mgor40mgatbedtime 55.00

Simvastatin(Zocor) 5mg,10mg,20mgor40mgatbedtime 53.00

Fibricacidanalogs

Clofibrate(Atromid5) 500mgfourtimesdaily 115.00

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TOTALCHOLESTEROL
DRUGCLASS LDLLEVELS HDLLEVELS TRIGLYCERIDES SIDEEFFECTS View/PrintTable
LEVELS
TABLE7
ChangesinSerumLipidValueswithDifferentClassesofCholesterolLoweringDrugsandSomeofTheirSideEffects
TOTALCHOLESTEROL
DRUGCLASS LDLLEVELS HDLLEVELS TRIGLYCERIDES SIDEEFFECTS
LEVELS

Bileacidbindingresins 20% 10%to 3%to5% Neutralor Unpalatability,bloating,constipation,heartburn

20%

Nicotinicacid 25% 10%to 15%to 20%to50% Flushing,nausea,glucoseintolerance,abnormalliver

25% 35% functiontest

Fibricacidanalogs 15% 5%to 14%to 20%to50% Nausea,skinrash

15% 20%

HMGCoAreductase 15%to30% 20%to 5%to 10%to40% Myositis,myalgia,elevatedhepatictransaminases

Inhibitors 60% 15%

LDL=lowdensitylipoproteinHDL=highdensitylipoprotein.

AdaptedwithpermissionfromGottoAMJr.Managementoflipidandlipoproteindisorders.In:GottoAMJr,PownallHJ,eds.Manualoflipiddisorders.Baltimore:Williams&Wilkins,
1992.

HMGCOAREDUCTASEINHIBITORS
Lovastatin(Mevacor),pravastatin(Pravachol),simvastatin(Zocor),fluvastatin(Lescol),atorvastatin(Lipitor)andcerivastatin(Baycol)areHMGCoAreductase
inhibitors,orstatins,thatinhibitcholesterolsynthesis.Tovaryingdegrees,alloftheseagentslowertotal,LDLandtriglyceridecholesterolcomponentsandslightly
raisetheHDLfraction.Whiletheseagentsaregenerallywelltolerated,asmallpercentageofpatients(fewerthan1percent)maydevelopelevatedhepatic
transaminaselevels,whichmaynecessitatediscontinuationofthedrug.21Otheradverseeffectsincludemyopathy(fewerthan0.1percentofcases)and
gastrointestinalcomplaints.Thegastrointestinaleffectsoftensubsidewithcontinuedtherapy.

Evidencesuggeststhattheseagentsreduceuntowardcardiovascularevents4,5andworkbymechanismsbeyondthesimplereductionintheLDLcholesterol
level.23TheresultsofthePrimaryPreventionofCoronaryHeartDiseasewithPravastatintrialdemonstratedreductionsof31percentinfirstmyocardialinfarctions,
32percentincardiovascularmortality,22percentintotalmortalityand37percentintheneedforrevascularizationprocedures.5

Therearedifferencesamongthestatins.Forexample,atorvastatinhasaslightlydifferentsideeffectprofilethantheotherstatins.Itmayexertagreatereffecton
loweringLDLcholesterol,totalcholesterolandtriglycerides,buthigherdosesofotherstatinsmayproducethesameresponse.However,atorvastatinasasingle
agentmayobviatetheneedformultipledrugtherapyinhighriskpatients.24In VIEW ofthenumerousothermechanismsbeinginvestigated,suchasplaque
stabilization,antiplateletaggregationactivityandantiarterialspasmodiceffects,thisparticulardifferencemaybelessimportantthanotherfactors.Todate,no
comparativestudiesofthestatinshavebeenperformedtodelineatealloftheclinicallyimportantdifferences.However,analysisoftheScandanavianSimvastatin
SurvivalStudyshowedthathospitalizationcostsforpatientshospitalizedbecauseofcardiovasculardiseasewerereducedbyapproximately31percent,making
statinsquitecosteffective.25

StatinsshouldgenerallybetakeninasingledosewiththeeveningmealoratbedtimetomaximizetheLDLloweringeffect.

BILEACIDBINDINGRESINS
Theanionexchangeresinscholestyramine(Questran)andcolestipol(Colestid)bindcholesterolcontainingbileacidsintheintestines,producinganinsoluble
complexthatpreventsreabsorption.Thisresultsinincreasedhepaticoxidationofcholesteroltobileacids,fecalcholesterolexcretionandLDLreceptoractivity.26
TheseagentsdecreaseLDLcholesterollevelsbyupto20percent.Theymaybeagoodchoiceinpatientswithhepaticdiseasebecausetheydonotaffecthepatic
metabolism.Theyarealsoagoodchoiceinveryyoungpatientsand WOMEN ofchildbearingage.11

Bileacidbindingresinsmaycauseanincreaseintriglyceridelevels.Becauseoftheirgrittytextureandsideeffects,compliancemaybeaproblem.Sideeffects
includeconstipation,abdominaldiscomfort,flatulence,nausea,bloatingandheartburn.Adosagereduction,increaseddietaryfiber,takingbileacidsequestrants
withmealsandlettingtheresinstandinliquidfor10minutesbeforetakingitarestrategiesthatminimizethesideeffects.

Bileacidsequestrantscanbindwithwarfarin,digitalis,thyroxine,thiazides,furosemide,tetracycline,penicillinG,phenobarbital,iron,propranolol(Inderal),
acetaminophenandnonsteroidalantiinflammatoryagents,aswellasoralphosphatesupplementsandhydrocortisone.Ingestingsuchagentsatleastanhour
beforeorfourtosixhoursafteraresindosereducesthepotentialfordruginteractions.27

NICOTINICACID
Nicotinicacid,orniacin,decreasesthesynthesisofLDLcholesterolbyreducingthehepaticsynthesisofVLDLcholesterol,byincreasingthesynthesisofHDL
cholesterol,byinhibitinglipolysisinadiposetissueandbyincreasinglipaseactivity.ThisagentincreasestheHDLlevelby15to35percent,reducestotalandLDL
cholesterollevelsby10to25percent,anddecreasesthetriglyceridelevelby20to50percent.21

Sideeffectsofnicotinicacidincludeflushing,pruritus,gastrointestinaldiscomfort,hyperuricemia,gout,elevatedliverfunctiontestsandglucoseintolerance.Taking
325mgofaspirin30minutesbeforethedrugisingestedmayminimizeflushing.28Frequently,however,flushingandpruritusresolvespontaneouslywithcontinued
use.Nicotinicacidshouldbetakenwithmealstoreducetheoccurrenceofgastrointestinalupset.Hepatotoxicsideeffectsaremorecommonwithsustainedrelease
nicotinicacidpreparationsthanwithregularformulations.Ahepatitislikesyndrome,manifestedbyweaknessandalackofappetite,maydevelopinpatients
receivingsustainedreleasepreparations.16Othersideeffectsofnicotinicacidincludeatrialfibrillation,hypotension,transientheadachesandactivationofpeptic
ulcerdisease.Nicotinicacidtherapyshouldbeavoidedinpatientswithdiabetesmellitusbecauseittendstoworsenglycemiccontrol.27

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FIBRICACIDDERIVATIVES
Fibricacidderivatives,orfibrates,increasethe CLEARANCE ofVLDLcholesterolbyenhancinglipolysisandreducinghepaticcholesterolsynthesis.These
agentshavebeenreportedtolowertriglyceridelevelsby20to50percent,raiseHDLlevelsbyupto20percentandreduceLDLlevelsbyapproximately5to15
percent.2931SomepatientswithhypertriglyceridemiamayhaveanincreaseinLDLlevels,sosuchpatientsshouldbeverycloselymonitorediffibratesareused.
Gemfibrozil(Lopid)isparticularlyusefulinpatientswithdiabetesandfamilialdysbetalipoproteinemia.

Sideeffectsofgemfibrozilincludenausea,bloating,flatulence,abdominaldistressandmildliverfunctionabnormalities.Myositis,gallstonesandelevationofthe
LDLcholesterollevelhavealsobeenreported.21,31Clofibrate(AtromidS)hasbeenassociatedwithformationofgallstonesandseriousgastrointestinaldisease,
includinghepaticmalignancy,21andthereforeshouldonlybeusedincertainselectpatientswithtypesII,IVorVhyperlipidemia.Inaddition,clofibratehasnotbeen
showntopreventcoronaryheartdisease.FibratesshouldgenerallynotbeusedwithHMGCoAreductaseinhibitorsbecausetheriskofseveremyopathyisgreatly
increased.19

MULTIPLEDRUGTHERAPY
Asmentionedpreviously,theNCEPguidelinesdefineatargetLDLcholesterollevelof100mgperdL(2.60mmolperL)asagoalforhighriskpatientswith
establishedcoronaryheartdisease.Butthispopulation,evenwithastepIIdiet,oftencannotachievesuchalowLDLlevel.AnLDLlevelgreaterthan130mgper
dL(3.35mmolperL)requiresfurtherreductioninpatientswithcoronaryheartdisease,andcombinationdrugregimensaresometimesrequired(Table8).19An
additionalcholesterolloweringdrugisprobablyrequirediftheLDLcholesterollevelremainsabovethetargetlevelafterthreemonthsofsingledrugtherapy.In
patientswithcoronaryheartdiseaseandLDLlevelsbetween100and130mgperdL(2.60and3.35mmolperL),clinicaljudgmentisneededtodecidewhetherto
initiatecholesterolloweringmedication(oraddasecondmedication)inconjunctionwithdietarytherapy.Althoughdrugtherapyisnotusuallystarteduntilpatients
haveundergoneathreetosixmonthtrialofdietarytherapy,insomepatientswithmarkedhypercholesterolemiaorcoronaryheartdisease,itisreasonableto
initiatedrugtherapyearlier.11

View/PrintTable

TABLE8
PossibleCombinationTherapiesIfSingleAgentTherapyIsNotEffectiveinReducingLipidLevels
LIPIDLEVELS FIRSTDRUGDRUGTOADD

ElevatedLDLlevelandtriglyceridelevel<200mgperdL Statinbileacidbindingresin

Nicotinicacid*statin*

Bileacidbindingresinnicotinicacid

ElevatedLDLlevelandtriglyceridelevel200to400mgperdL Statin*nicotinicacid*

Statin*gemfibrozil(Lopid)

Nicotinicacidstatin

Nicotinicacidgemfibrozil

LDL=lowdensitylipoprotein.

*Possibleincreasedriskofmyopathyandhepatitis.

Increasedriskofseveremyopathy.

Thecombinationofnicotinicacidandlovastatin(Mevacor)mayinducerhabdomyolysis,arareadversedruginteraction.

AdaptedfromNationalCholesterolEducationProgram.Cholesterolloweringinthepatientwithcoronaryheartdisease.Bethesda,Md.:NationalInstitutesofHealth,NationalHeart,
Lung,andBloodInstitute,1997DHHSpublicationno.(NIH)973794.

FOLLOWUPOFDRUGTHERAPY
Becauseofbiologicandanalyticvariabilityoflipoproteinlevels,itisadvisabletoobtainatleasttwolipoproteinlevelsduringonetotwomonthsofmaximumdietary
therapybeforebeginningdrugtherapy.11Ifitseemslikelythatpharmacotherapywillbeneeded,baselineliverfunctiontestsshouldalsobeperformed.

Afterstartingdrugtherapy,theLDLcholesterollevelshouldbemeasuredinaboutsixweeksandagainin12weeks.11Liverfunctionandothertestsfordrugtoxicity
canbedoneatthesetimes.IftheLDLgoalisreached,lipidlevelsshouldbecheckedeverysixto12months.32Followupanalysisshouldoccursixtoeightweeks
afterachangeindrugtherapy.Inpatientsreceivingnicotinicacid,followupmeasurementsshouldbeobtainedfourtosixweeksafterastabledosehasbeen
reached.19

SpecialConsiderations
ROLEOFLIPOPROTEIN(A)
Lipoprotein(a),orLp(a),isa SPECIALIZED formofglycoproteinLDLcholesterolcomplex.ElevatedLp(a)(over30mgperdL[300mgperL])canbean
independentriskfactorforthedevelopmentofearlycoronarydiseaseinmen.33,34ControversyexistsoverwhetherelevatedLp(a)isthecauseortheeffectof
coronaryarterydamage.35Nicotinicacid(givenatdosagesofatleast3gperday)andestrogenhavebeenfoundtoreduceelevatedLp(a)levels.36Arecenttrial
suggeststhatpostmenopausalhormonereplacementtherapylowerstheLp(a)level,37andpreliminaryclinicaltrialshaveshownthattheexperimentaldruglifibrol
alsolowersLp(a)levels.33

ESTROGENREPLACEMENTTHERAPY

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Althoughestrogenshavenotyetreceivedanindicationforthetreatmentofdyslipidemia,theNCEPrecommendsthatconsiderationbegiventoestrogen
replacementtherapyasameansofdecreasing(byabout15percent)LDLcholesterollevelsandincreasing(byabout22percent)HDLcholesterollevelsin
postmenopausal WOMEN .Arecentstudyshowedareductioninmortalityamongwomenwhoreceivedpostmenopausalhormonereplacementtherapy,although
thesurvivalbenefitswerenotedtodiminishwithalongerdurationofuse.38Hormonereplacementtherapymaybecombinedwithothercholesterollowering
interventionstoachieveanevenmorefavorablealterationofthelipidprofile.IthasbeenreportedthatpravastatinplusconjugatedestrogenimprovesLDL
cholesterollevelsmorethaneitheragentusedalone.39

OtherTherapeuticModalities
LIFIBROL
Lifibrolisalipidloweringagentpresentlyunderinvestigation.ClinicaltrialshaveshownthatlifibrollowerstotalcholesterolandLDLcholesterollevelswithapotency
similartothatofhighdosestatins.33LifibrolhasalsobeenshowntoreduceLp(a),fibrinogenanduricacidlevels.33ItseffectsonHDLcholesterolandtriglyceride
levelsarelessconsistent.

Themechanismofactionofthisagentiscomplexandprobablymultimodal.Itappearstoactatanearlierlevelofthecholesterolsynthesispathwaythandothe
statins.Sideeffectsareprimarilygastrointestinal.

GENETHERAPY
Genetherapyisseveralyearsfromclinicaluse.Itmayproveidealforuseinpatientswithgeneticdisorderssuchasfamilialhypercholesterolemia.Genetherapywill
probablynotbeappropriateindyslipidemicpatientswhosepredominantrisksforcoronaryheartdiseaseareexogenous.10

PLASMAPHERESIS
Plasmapheresishasbecomethemostcommonnonpharmacologic,nondietarytreatmentofseverehypercholesterolemia.40Innonselectiveplasmapheresis,the
patient'splasmaisreplacedwithsaltfreehumanalbumin.Thisactionreducestriglyceridelevelsdramaticallyanddecreasestheriskofpancreatitis.Inpatientswith
severe,refractoryformsoffamilialhypercholesterolemia,ahighlyspecificLDLcholesterolabsorptionsystemisutilizedforextendeduse.40

SURGICALMODALITIES
Partialilealbypassthateliminatesthereabsorptionofbileacidsatthedistalportionoftheileumhasbeenshowntobeaviabletreatmentinsomecasesofsevere
dyslipidemia.41Portacavalshuntandlivertransplantationhavebeenshowntobeeffectiveintreatingseverehypercholesterolemia.Theseproceures,ofcourse,are
notfirstlinetreatments.

TheAuthors showallauthorinfo
SYEDM.AHMED,M.D.,M.P.H.,DR.P.H.,isanassistantprofessoroffamilymedicineatWrightStateUniversitySchoolofMedicineandtheMiamiValleyHospital
familymedicineresidencyprogram,bothinDayton,Ohio.HeisagraduateofSir.SalimullahMedicalCollege,DhakaUniversity,Dhaka.Hecompletedaresidency
andfellowshipinfamilymedicineatBaylorCollegeofMedicine,Houston.HeobtainedbothamastersdegreeandadoctorateinpublichealthfromtheUniversityof
TexasSchoolofPublicHealth,Houston....

REFERENCES showallreferences
1.SuperkoHR,KraussRM.Coronaryarterydiseaseregression.Convincingevidenceforthebenefitofaggressivelipoproteinmanagement.Circulation.
199490:105669....

EachyearmembersofadifferentmedicalfacultypreparearticlesforPracticalTherapeutics.ThisseriesiscoordinatedbytheDepartmentofFamilyMedicineat
WrightStateUniversitySchoolofMedicine,Dayton,Ohio.GuesteditorsoftheseriesareCynthiaG.Olsen,M.D.,andGordonS.Walbroehl,M.D.

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