The Role of Nutrition and Nutritional Supplements in The Treatment of Dyslipidemia

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AbstractandIntroduction
Abstract
Thecombinationofalipidloweringdietandscientificallyprovennutraceuticalsupplementshavetheabilitytosignificantlyreduce
LDLcholesterol,decreaseLDLparticlenumber,increaseLDLparticlesize,lowertriglyceridesandVLDL,increasetotalandtype
2bHDLandimproveHDLfunctionality.However,eventhebestofdietsandpropernutritionmaynotbeenoughtoobtainthe
desiredlipidlevels,thusacombinationofnutritionandnutritionalsupplementsareusefulandeffectiveinreachingserumlipid
goals.Inaddition,inflammation,oxidativestressandvascularimmuneresponsesaredecreased.Inseveralprospectiveclinical
trials,coronaryheartdiseaseandcardiovasculardiseasehavebeenreducedwithoptimalnutritionand/oradministrationof
severalnutraceuticalsupplements,includingomega3fattyacids,redyeastrice,linolenicacidandniacin.Acombinedprogram
ofnutritionandnutraceuticalsupplementsrepresentsascientificallyvalidalternativeforpatientswhoarestatinintolerant,cannot
takeotherdrugsforthetreatmentofdyslipidemiaorinthosewhopreferalternativetherapies.Thisnewapproachtodecrease
dyslipidemicinducedvasculardiseaserecognizesandtreatsthemultiplestepsthatareinvolvedinthedevelopmentof
atherosclerosis.Thepurposeofthisreviewistoestablishthescientificvalidity,efficacyandsafetyofcombinednutritionand
nutraceuticalsupplementsfortreatingdyslipidemiawithoutdrugsforthosepatientsintolerantofpharmacologictherapiesorthose
whohavepreferencefornondrugtreatments.ThisextensivereviewwasdonethroughanalysisofallpublishedarticlesinEnglish
onthetopicofnutritionandnutraceuticalsupplementsforthetreatmentofdyslipidemiathatwereavailablethroughtheNIHand
NationalLibraryofCongresspublications(PubMed).
Background,NewConcepts&Perspectives
Dyslipidemiaisconsideredoneofthetopfiveriskfactorsforcardiovasculardisease(CVD),alongwithhypertension,diabetes
mellitus(DM),smokingandobesity.
[1]
Thereareaninfinitenumberofvascularinsultstothevascularsystemandbloodvessel,
butthevascularendothelium,vascularandcardiacsmoothmusclecanonlyrespondinonlythreefinitewaystotheseinsults.
Thesethreeresponsesincludeinflammation,oxidativestressandvascularimmunedysfunction.
[24]
Thesepathophysiologic
processesleadtoendothelialdysfunction(ED)andvascularsmoothmuscleandcardiacdysfunction.Thevascularconsequences
includeCVD,coronaryheartdisease(CHD),myocardialinfarction(MI)andcerebrovascularaccidents(CVA).
[4]
Genetics,epigenetics,chronicinflammatorymicroandmacronutrientintake,obesity(visceralobesity),chronicinfections,toxins
andsomespecificpharmacologicalagentsincludingsomeoftheolderblockersandthethiazideorthiazidelikediuretics,
tobaccoproducts,DMandlackofexercisecontributetodyslipidemia.
[5,6]
Severalgeneticphenotypes,suchasAPOE,resultinvariableserumlipidresponsestodiet,aswellascontributingtoCHDand
MIrisk.
[7,8]
Inaddition,HDLproteomicsthataffectPON1andSRBIincreaseCVD.
[9]
ThesortilinIallelevariantson
chromosome1p13increaseLDLandCHDriskby29%.
[10]
RecentstudiessuggestthatincreasingdietarycholesterolintakewillnotsignificantlyalterserumtotalorLDLcholesterollevelsor
CHDrisk.Somesaturatedfats,dependingontheircarbonchainlength,mayhaveminimalinfluencesonserumlipidsandCHD
risk,whereasmonounsaturatedandpolyunsaturatedfatshaveafavorableinfluenceonserumlipidsandCHDrisk.Increased
refinedcarbohydrateintakemaybemoreimportantinchangingserumlipidsandlipidsubfractionsthansaturatedfatsand
cholesterol.Refinedcarbohydrateshavemoreadverseeffectsoninsulinresistance,atherogenicLDL,smalldenseLDL,LDL
particlenumber(LDLP),VLDL,triglycerides,totalHDL,HDLsubfractionsandHDLparticlenumber,thuscontributingtoCHDrisk
morethansaturatedfats.
[5,1117]
Postprandialhyperglycemia,hypertriglyceridemiaandendotoxemiacoupledwithinflammation,oxidativestressandimmune
vasculardysfunctionarehighlyassociatedwithatherosclerosis.
[1821]
Activationofchylomicronandcholecystokinin,GLP1,low
nitricoxide(NO),elevatedasymmetricdimethylarginine,increasedlipidperoxidation,inflammatorycytokines,TNF,stimulation
ofNFB,patternrecognitionreceptors,Tolllikereceptors(TLR2and4),NODlikereceptors,caveolaeandlipidraftsincrease
TheRoleofNutritionandNutritionalSupplementsin
theTreatmentofDyslipidemia
MarkHouston
ClinLipidology.20149(3):333354.
11/9/2014 www.medscape.com/viewarticle/830034_print
theinflammatorypathwaysaftermealsinducingendothelialdysfunction.
[1821]
Increaseddietaryintakeofsodiumchloride,not
balancedwithpotassiumfurtherincreasesEDandasymmetricdimethylarginineandreducesNO.Manyphytoalexins,
phytonutrientsandpolyphenolsmayblocktheTLRandNODlikereceptorinflammatoryresponse.
[22,23]
Inaddition,a'metabolic
memory'ofcellsandthebloodvesselexistsduetoaninnateimmuneresponse,whichwillincreaseinflammation.These
responsesareperpetuatedlongaftertheoriginalinsultandareheightenedwithsmallerinsults.
[18]
Thevalidityofthe"DietHeartHypothesis"thatimpliesthatdietarysaturatedfats,dietarycholesterolandeggsincreasetheriskof
CHDhasbeenquestioned.
[1214]
TransfattyacidshavedefiniteadverseeffectsonserumlipidsandincreaseCVDandCHDrisk
butomega3fattyacidsandmonounsaturatedfatsimproveserumlipidsandreduceCVDrisk.
[5,1117]
TransfatssuppressTGF
responsiveness,whichincreasesthedepositionofcholesterolintocellularplasmamembranesinvasculartissue.
[16]
Expandedlipidprofilesthatmeasurelipids,lipidsubfractions,particlesizeandnumber,andApolipoproteinBandAarepreferred
tostandardlipidprofilesthatmeasureonlythetotalcholesterol,LDL,TGorHDL.Theseexpandedlipidprofilessuchasthe
lipoproteinparticles(SpectraCellLaboratories,TX,USA),nuclearmagneticresonance(Liposcience),BerkleyHeartLabs,Boston
HeartLabs,HealthDiagnosticsLabandverticalautoprofile(Atherotec),improveserumlipidanalysisandCHDriskprofiling.
[24,25]
ItisnowproventhatLDLPistheprimarylipidparameterthatdrivestheriskforCHDandMI,aswellascoronaryartery
calcificationasmeasuredbyCTangiogram..
[26,27]
DenseLDLtypeBorLDLtype3andtype4havesecondaryrolesinCHDonly
iftheLDLPiselevated.
DysfunctionalHDL
[2831]
maybeinflammatory,atherogenicandloseitsatheroprotectiveeffectsespeciallyinpatientswithDM,
metabolicsyndromeandobesityduetovascularinflammatoryeffects.
[31]
OxidationandinflammationofapolipoproteinA1often
resultsinhigherlevelsofHDLthataredysfunctionalandnotprotective.
[31]
TheabilitytoevaluateHDLfunctionality,eitherdirectly
orindirectly,measuringreversecholesteroltransport,cholesteroleffluxcapacity
[29]
ormyeloperoxidase
[30,31]
willimprovethe
assessmentofdyslipidemicinducedvasculardisease,CHDriskandtreatment.Anunderstandingofthepathophysiologicalsteps
indyslipidemicinducedvasculardamageismandatoryforoptimalandlogicaltreatment(Figure1).Theabilitytointerruptallof
thevariousstepsinthispathwaywillallowmorespecificpathophysiologicaltreatmentstoreducevascularinjury,improve
vascularrepairsystems,maintainandrestorevascularhealth.NativeLDL,especiallylargetypeALDLisnotusuallyatherogenic
untilmodified.However,thereexistsanalternatepinocytosismechanismthatallowsmacrophageingestionofnativeLDL,which
accountsforupto30%offoamcellformationinthesubendotheliumthatoccurduringchronicinflammationorinfections.
[32,33]
Forexample,decreasingLDLmodification,theatherogenicformofLDLcholesterol,bydecreasingoxidized(oxLDL),glycated
(glyLDL),glycooxidizedLDL(glyoxLDL)andacetylatedLDL(acLDL),decreasingtheuptakeofmodifiedLDLintomacrophages
bythescavengerreceptors(CD36SR),decreasingtheinflammatory,oxidativestressandautoimmuneresponseswillreduce
vasculardamagebeyondtreatingtheLDLcholesterollevel.
[3440]
Thereareatleast38mechanisticpathwaysthatcanbetreated
tointerruptthedyslipidemicinducedvasculardamageanddisease().ReductioninHSCRP,aninflammatorymarker,reduces
vasculareventsindependentofreductionsinLDLcholesterolthroughnumerousmechanisms.
[39]
Manypatientscannotorwillnot
usepharmacologictreatmentssuchasstatins,fibrates,bileacidresinbindersorezetimibetotreatdyslipidemia.
[5]
Statininduced
orfibrateinducedmusclediseasewithmyalgiasormuscleweakness,abnormal,liverfunctiontests,neuropathy,memoryloss,
mentalstatuschanges,gastrointestinaldisturbances,glucoseintoleranceordiabetesmellitusaresomeofthereasonsthat
patientsmayneedtousenutritionalsupplements.
[4145]
Manypatientshaveotherclinicalsymptomsorlaboratoryabnormalities
suchaschronicfatigue,exerciseinducedfatigue,decreaseinleanmusclemass,reducedexercisetolerance,reductionsin
coenzymeQ10,carnitine,vitaminE,vitaminD,omega3fattyacids,seleniumandfreeT3levels(hypothyroidism)withprolonged
usageortheadministrationofhighdosestatins.
[5,4153]
Box1.38mechanismsfortreatmentofdyslipidemiainducedvasculardisease.
Decreaseendothelialpermeability,gapjunctions,endothelialdysfunctionandimproveendothelialrepair:aged
garlic.IncreaseNO,reduceAIIeffects,increaseEPC's,BPcontrol,reduceinflammation,oxidativestressand
vascularimmunedysfunction
Modifycaveolae,caveolin1,lipidrafts,membranemicrodomains,unesterifiedcholesterolandcholesterolcrystals.
Lycopene,omega3fattyacidsandstatins
IncreaseeNOSandnitricoxide.Arginine/citrullene,resveratrol,flaxseed,omega3fattyacids,coenzymeQ10,
Rlipoicacid,NAC,taurine,pycnogenol,grapeseedextract,pomegranate,agedgarlic
ModifyPRRactivationandtolllikereceptors.Niacin,EGCG,pantethine,resveratrol,MUFA,curcumin,
pomegranate,agedgarlic,sesame,/tocotrienols,lycopene
Decreasecholesterolcrystals,LDLphospholipids,oxLDL,APOBandsevenketosteroidsthatactivatePRR.
Omega3fattyacidsandstatins
DecreaseLDLburden(Box4)
Reducecholesterolabsorption(Box6)
Increasecholesterolbileexcretion(Box17)
DecreaseLDLparticlenumber(Box13)
DecreaseAPOB(Box15)
DecreaseLDLmodification/oxidation:(Box2)
InhibitLDLglycation(Box3)
IncreaseLDLsize(Box5)
ModifyLDLcomposition.Omega3fattyacids,MUFA,reduceinflammation,oxidativestressandimmune
dysfunction
UpregulateLDLreceptor(Box17)
RegulatesortilinsandSORLA
DeactivatetheLOX1receptor.ReduceBP,reducehsCRP
DecreasemodifiedLDLmacrophageuptakebyscavengerreceptors(Box11)
DecreasenativeLDLmacrophageuptakebypinocytosis.Decreaseinfectionsandinflammation,decrease
modifiedLDL
DecreaseLDLsignaling.Plantsterols
DecreaseCAMs,macrophagerecruitmentandmigration.NAC,resveratrol,luteolin,glutathione,andcurcumin.
Altermacrophagephenotype.Omega3fattyacid,plantsterols,sterolinsandglycosides
ModifysignalingpathwaysPlantsterolsandphytosterolins
Increasereversecholesteroltransport(Box12)
IncreaseHDLandincreaseHDLsize(Box10)
ImproveHDLfunction.Reduceinflammation,oxidativestressandimmunedysfunction,quercetin,pomegranate,
EGCG,resveratrol,glutathione,lycopene
IncreaseAPOA1(Box16)
IncreasePON1andPON(Box18)
Reduceinflammation(Box14)
Reduceoxidativestress
Modulateimmunedysfunction.Plantsterolsandsterolins
DecreaseVLDLandTG(Box9)
LowerLp(a)(Box8)
Reducefoamcellandfattystreakformation.Resveratrol,NAC,phytosterolins
Reducetrappingoffoamcellsinthesubendothelium.Resveratrol,NAC
Stabilizeplaque.Omega3fattyacids,vitaminK2MK7,agedgarlic
ReduceLpPLA2.Omega3fattyacids,niacin
Reduceplaqueburden,progressionandincreaseregression.Omega3fattyacids,vitaminK2MK7,agedgarlic,
pomegranate
BP:BloodpressureCAM:CelladhesionmoleculeEGCG:EpigallocatechingallateeNOS:Endothelialnitricoxide
synthaseEPC:EndothelialprogenitorcellMUFA:MonounsaturatedfatsNAC:NacetylcysteineNO:Nitricoxide
PRR:Patternrecognitionreceptor.
Figure1.
Lipoproteinsandatherosclerosis:itmatterswhatyouhave.ThevariousstepsintheuptakeofLDLcholesterol,modification,
macrophageingestionwithscavengerreceptors,foamcellformation,oxidativestress,inflammationandautoimmunecytokines
andchemokineproduction.
?:Probablebutnotcompletelyconfirmed.
Newtreatmentapproachesthatcombineweightloss,reductioninvisceralandtotalbodyfat,increaseinleanmusclemass,
optimalaerobicandresistanceexercise,scientificallyprovennutritionanduseofnutraceuticalsupplementsthatmaybe
integratedwithdrugtherapiesoffernotonlyimprovementinserumlipidsbutalsoreductionsininflammation,oxidativestress,
immunedysfunction,endothelialandvascularsmoothmuscledysfunction.Inaddition,surrogatemarkersforvasculardiseaseor
clinicalvasculartargetorgandamagesuchasCHDandcarotidIMTarereducedinmanyclinicaltrialsusinganonpharmacologic
approach.
[5]
NutraceuticalSupplements&theManagementofDyslipidemia
Nutraceuticalsupplementmanagementofdyslipidemiahasbeeninfrequentlyreviewed.
[56,54]
Newimportantscientific
informationandclinicalstudiesarerequiredtounderstandthepresentroleofthesenaturalagentsinthemanagementof
dyslipidemia.
[56,54]
ClinicaltrialsshowexcellentreductionsinserumlipidsandCHDwithniacin,omega3fattyacids,redyeast
rice,fiberandalphalinolenicacid.SmallerstudiesshowimprovementsinvariousbiomarkersforCVDsuchasinflammation,
oxidativestress,vascularimmunefunction,plaquestability,progressionandregression.
[5,5455]
Inadditionstudieshaveused
surrogatevascularmarkers,showimprovementinarterialstiffnessandimprovedelasticity,reductioninpulsewavevelocityand
augmentationindex,decreasedcarotidintimalmedialthickness(CIMT)andobstruction,coronaryarteryplaqueprogression,
coronaryarterycalciumscorebyelectronbeamtomography(EBT)andCTangiogramaswellasdecreaseingeneralized
atherosclerosisandimprovementinendothelialfunction.
[5,5456]
Theproposedmechanismsofactionofsomeofthenutraceuticalsupplementsonthemammaliancholesterolpathwayareshown
inFigure2.Virtuallyallstudieshaveshownveryhighsafetyprofilesfornutritionalsupplementsinthetreatmentofdyslipidemia.In
thesectionbelow,alltheefficacystudies,adverseeffectsandsafetyprofileswillbereviewedforeachnutraceuticalsupplement.
Inaddition,themechanismsofactionofeachsupplementwillbereviewedandadetaileddiscussionofCVDoutcomedata,
surrogateCVDoutcomes,serumbiomarkersforCVD,improvementsinnoninvasiveandinvasivevasculartestswillbeprovided
whereavailable.
Figure2.
Proposedmechanismsofactionsofnutraceuticalsandstatinsinthecholesterolpathway.
Niacin(VitaminRef3)
Niacinhasadoserelatedeffect(14gperday)inreducingtotalcholesterol(TC),LDL,apolipoproteinB(APOB),LDLparticle
number,triglycerides(TG),VLDL,increasingLDLsizefromsmalltypeBtolargetypeA,increasingHDLespeciallytheprotective
andlargerHDL2bparticleandapolipoprotein(APOA1).
[5]
NiacinmayalsoincreasetheHDLparticlenumber(thepredominant
protectivelipidparameter)andHDLfunctionwithimprovementsinreversecholesteroltransport.
[5759]
Niacinhasalogarithmic
doseresponseonHDL,withsmallerdoseshavingalargeeffect.TheeffectonLDLreductionisalineardoseresponsethat
requireshigherdoses.
[57]
Thechangesaredoserelatedandvaryfromapproximately1030%foreachlipidlevelasnotedabove.
[5,6061]
Niacininhibits
LDLoxidation,increasesTGlipolysisinadiposetissue,increasesAPOBdegradation,reducesthefractionalcatabolicrateof
HDLAPOA1,inhibitsplateletfunction,inducesfibrinolysis,decreasescytokinesandcelladhesionmolecules(CAMs),lowers
Lp(a),increasesadiponectin,whichprovidesantioxidantactivity,inhibitsCETPandincreasesreversecholesteroltransport.
[5,57
61]
However,despiteanimprovedlipidprofile,thereisavariableimprovementinendothelialandmicrovascularfunction.
[62]
RandomizedclinicaltrialssuchastheCoronaryDrugProject,HATStrial,ARBITOR2,OxfordNiaspanStudy,FATS,CLASIand
CLASIIandAFRShaveshownreductionincoronaryevents,decreasesincoronaryatheroma(plaque)anddecreasesincarotid
IMT.
[5,6066]
TherecentnegativefindingsintheAIMHIGHstudy
[67,68]
donotdetractfromthesepositiveclinicaltrials,asthis
studyhasnumerousmethodologicaldesignflawsandwasnotpoweredtostatisticallydetermineCVDendpoints.
TherecentTHRIVEtrialof26,000patientsusing2gofextendedreleaseniacinplustheantiflushingagentlaropiprantdailyor
placeboontopofabackgroundtherapyofsimvastatinwithorwithoutezetimibedidnotreducecardiovasculareventsdespitean
increasedHDLof17%anddecreasedLDLof20%.
[69,70]
Whethertheinhibitionofflushingbylaropiprantorsomeotherunknown
effectofthisagentinterferedwiththeHDLfunctionandtheCVoutcomesisnotclear.However,therecommendationbysomenot
touseniacininfaceoftheothermanypositivestudiesisclearlyprematureandincorrect.Theeffectivedosingrangeisfrom500
to4000mgperday.Onlyvitaminref3niaciniseffectiveindyslipidemia.Thenonflushniacin(inositolhexanicotinate)doesnot
improvelipidprofiles,andisnotrecommended..
[5,71]
Thesideeffectsofniacinincludehyperglycemia,hyperuricemia,gout,
hepatitis,flushing,rash,pruritus,hyperpigmentation,hyperhomocysteinemia,gastritis,ulcers,bruising,tachycardiaand
palpitations.
[5,6061]
Elevationsinhomocysteineshouldbetreatedwithvitaminref6,ref12andfolate.Niacininducedflushingis
minimizedbyincreasingthedosegradually,takingonaregularbasiswithoutmissingdoses,takingwithmeals,avoidingalcohol
within4hofingestionofniacin,consumptionof81mgbabyaspirinandsupplementalquercetin,applesorapplepectinorsauce.
[5]
Policosanol
Policosanolisasugarcaneextractofeightaliphaticalcoholsthathasundergoneextensiveclinicalstudieswithvariableresults.
[5]
MostoftheearlierstudiesthatshowedpositiveresultsperformedinCubahavebeenquestionedastotheirvalidity.
[5,54,7273]
Themorerecentdoubleblindplacebocontrolledclinicaltrialshavenotshownanysignificantimprovementinanymeasuredlipids
includingTC,LDL,TGorHDL.Policosanolisnotrecommendedatthistimeforthetreatmentofanyformofdyslipidemia.
[5,54,72
73]
RedYeastRice
Redyeastrice(RYRMonascusPurpureus)isafermentedproductofricethatcontainsmonocolins,whichinhibitcholesterol
synthesisviaHMGCoAreductaseandthushas'statinlike'properties(13naturalstatins).
[5,54,7496]
RYRalsocontains
ergosterol,aminoacids,flavonoids,traceelements,alkaloids,sterols,isoflavonesandmonounsaturatedfattyacidsthatimprove
thelipidprofile.RYRadministeredorallytoadultssubjectswithdyslipidemiaat2400mgperdayreducedLDLCby22%(p<
0.001),TGby12%withlittlechangeinHDL.
[5,54,74]
RYRreducestheriskofabdominalaorticaneurysmsbysuppressing
angiotensinIIlevels.
[75]
RYRalsoiseffectiveinmousemodelsagainstobesityrelatedinflammation,insulinresistanceand
nonalcoholicfattyliverdisease.
[76]
RYRinconjunctionwithberberineimprovesinsulinresistance,glucoseandlipidsinsubjects
withorwithoutmetabolicsyndrome.
[86,89,95]
RYR,policosanolandartichokeleafextractdecreaseLDLCsignificantly
[77,84]
as
didRYRwithplantstanols.
[83]
RYRwithberberine,policosanol,astaxanthin,coenzymeQ10andfolicacidreduceLDLCby
21.1%similartopravastatin10mgperdaywitha4.8%increaseinHDLCover8weeks.
[92]
RYRinhibitsTNFandMMP2andMMP9(metalloproteinases),
[79]
suppressescaveolin1,increaseseNOS(endothelialnitric
oxidesynthase)expression,improvesabnormalhemorheology,
[78]
increasesadiponectin,
[85]
improvestheleptintoadiponectin
ratio,
[92]
lowersHSCRP(highsensitivityCRP)andimprovesvascularremodelingparameterssuchasMMP2andMMP9,
[87]
reducesexpressionoftissuefactor,oxLDLandreducesthrombosisinanimalmodelsbysuppressingNADPHoxidaseand
extracellularsignalregulatedkinasesactivation.
[90]
InarecentplacebocontrolledChinesestudyof5000subjectsover4.5years,
anextractofRYRreducedLDL17.6%(p<0.001)andincreasedHDL4.2%(p<0.001).
[96]
CVmortalityfell30%(p<0.005)and
totalmortalityfell33%(p<0.0003)inthetreatedsubjects.TheoverallprimaryendpointforMIanddeathwasreducedby45%(p
<0.001).RecentmetaanalysisandclinicaltrialsofRYRfordyslipidemiaandCVDendpointsconfirmedthesepositivefindings.
[81,82,9394]
AhighlypurifiedandcertifiedRYRmustbeusedtoavoidpotentialrenaldamageinducedbyamycotoxin,citrinin.
[5,54,74]
Therecommendeddoseis24004800mg/dayofastandardizedRYR.Noadverseeffectshavebeenreportedsuchas
myalgiasorliverdysfunctionwithlongtermusenoristhereanyinterferencewiththeCYP450enzymes.
[90]
Althoughreductions
incoenzymeQ10mayoccurinpredisposedpatientsandthoseonprolongedhighdoseRYR,duetoitsweaker'statinlike'effect
thisisnotaslikelyaswithstatins.RYRisanexcellentalternativetopatientswithstatininducedmyopathy
[5,54,74,88,96]
andin
statinintolerantpatientswithorwithoutType2DMinconjunctionwiththeMediterraneandiettoeffectivelymanagetheir
dyslipidemia.
[91]
PlantSterols(Phytosterols)
TheplantsterolsarenaturallyoccurringsterolsofplantoriginthatincludeBsitosterol(themostabundant),campesteroland
stigmasterol(4desmethylsterolsofthecholestaneseries)andthesaturatedstanols.
[5,54,97101]
Theplantsterolsaremuch
betterabsorbedthantheplantstanols.ThedailyintakeofplantsterolsintheUSAisapproximately150400mgperdaymostly
fromsoybeanoil,variousnutsandtallpinetreeoil.
[54]
Thesehaveadosedependentreductioninserumlipids.
[98]
Total
cholesterolisdecreased8%,LDLisdecreased10%(range:615%)withnochangeinTGandHDLondosesof23gramsper
dayindivideddoseswithmeals.
[5,54,97101]
Arecentmetaanalysisof84trialsshowedthatanaverageintakeof2.15gperday
reducedLDLby8.8%withnoimprovementwithhigherdoses.
[98]
Themechanismofactionisprimarilytodecreasethe
incorporationofdietaryandbiliarycholesterolintomicellesduetolowermicellarsolubilityofcholesterol,whichreduces
cholesterolabsorptionandincreasesbileacidsecretion.Inaddition,thereisaninteractionwithenterocyteATPbindingcassette
transportproteins(ABCG8andABCG5)thatdirectscholesterolbackintotheintestinallumen.
[5,54,97]
Theonlydifference
betweencholesterolandsitosterolconsistsofanadditionalethylgroupatpositionC24insitosterol,whichisresponsibleforits
poorabsorption.Theplantsterolshaveahigheraffinitythancholesterolforthemicelles.Theplantsterolsarealsoanti
inflammatoryanddecreasethelevelsofproinflammatorycytokinessuchashsCRP,IL6,IL1b,TNF,PLA2andfibrinogen,but
theseeffectsvaryamongthevariousphytosterols.
[101,102]
Otherpotentialmechanismsincludemodulationofsignalingpathways,
activationofcellularstressresponses,growtharrest,reductionofApoB48secretionfromintestinalandhepaticcells,reduction
ofcholesterolsynthesiswithsuppressionofHMGCOAreductaseandCYP7A1,interferencewithSREBPandpromotionof
reversecholesteroltransportviaABCA1andABCG1.
[102]
Thebiologicalactivityofphytosterolsisbothcelltypeandsterol
specific.
[102]
Theplantsterolscaninterferewithabsorptionoflipidsolublecompoundssuchasfatsolublevitaminsandcarotenoidslikevitamin
D,E,Kandcarotene.
[5,54]
Somestudieshaveshownreductioninatherosclerosisprogression,reductioninprogressionof
carotidIMTandcarotidplaquebuttheresultshavebeenconflicting.
[5,54]
Patientsthathavetherarehomozygotemutationsofthe
ATPbindingcassettearehyperabsorbersofsitosterol(absorb1560%insteadofthenormal5%)andwilldeveloppremature
atherosclerosis.
[54]
Thisisarareautosomalrecessivedisordertermedsitosterolemia.TherearenostudiesonCHDorotherCVD
outcomestodatewithphytosterols.Therecommendeddoseisapproximately22.5gperday(average2.15gperday).
Soy
Numerousstudieshaveshownmildimprovementsinserumlipidswithsoyatdosesofabout3050gperday.
[5,54,103104]
Total
cholesterolfalls29.3%,LDLdecreases412.9%,TGdecreases10.5%andHDLincreasesupto2.4%.However,thestudiesare
conflictingowingtodifferencesinthetypeanddoseofsoyusedinthestudies,aswellasnonstandardizedmethodology.
[5,54,103
104]
Soydecreasesthemicellarcontentandabsorptionoflipidsthroughacombinationoffiber,isoflavones(genistin,glycitinand
diadzin)andphytoestrogens.
[5,54,103104]
SoyalsoreducesSREBP,HMGCOAreductase,increasesLDLreceptordensityand
increasestheantioxidantactivityofSODandcatalase.
[105]
Thegreatestreductionisseenwithsoyenrichedisoflavoneswithsoy
protein.Fermentedsoyispreferred.
GreenTeaExtract&GreenTea(EGCG)
Catechins,especiallyEGCG,mayimprovethelipidprofilebyinterferingwithmicellarsolubilizationofcholesterolintheGItract
andreduceabsorption.
[5]
Inaddition,EGCGreducesthefattyacidgeneexpression,inhibitsHMGCoAreductase,increases
mitochondrialenergyexpenditure,reducesoxLDL,increasesPON1,upregulatestheLDLreceptor,decreasesAPOB
lipoproteinsecretionfromcells,mimicstheactionofinsulin,improvesendothelialdysfunction,activatesNrf2,increasesHO1
expression,decreasesinflammation,displacescaveolin1fromcellmembranes,increasesnitricoxide,reducesendothelial
inflammationanddecreasesbodyfat.
[5,106109]
Ametaanalysisofhumanstudiesof14trialsshowthatEGCGat224674mgperdayor60ozofgreenteaperdayreducedTC
7.2mg/dlandLDL2.19mg/dl(p<0.001forboth).TherewasnosignificantchangeinHDLorTGlevels.
[110]
Therecommended
doseisastandardizedEGCGextractat5001000mgperday.
Omega3FattyAcids
Observational,epidemiologicandcontrolledclinicaltrialshaveshownsignificantreductionsinserumTG,VLDL,decreasedLDL
particlenumberandincreasedLDLandHDLparticlesizeaswellasmajorreductionsinallCVDevents.
[5,111118]
TheDARTtrial
demonstratedadecreaseinmortalityof29%inmenpostMIandtheGISSIpreventiontrialfoundadecreaseintotalmortalityof
20%,CVdeathsof30%andsuddendeathof45%.TheKuppioHeartStudydemonstrateda44%reductioninfatalandnonfatal
CHDinsubjectsinthehighestquintileofomega3intakecomparedwiththelowestquintile.
[5,111112]
Omega3FAreduceCHD
progression,stabilizeplaque,reducecoronaryarterystentrestenosisandCABGocclusion.
[5,113]
IntheJELISstudy,theaddition
of1.8gofomegaEPAtoastatinresultedinanadditional19%RRRinmajorcoronaryeventsandnonfatalMIanda20%
decreaseinCVA.
[5,114]
ThereisadoserelatedreductioninVLDLofupto50%,TGofupto50%,withlittletonochangeordecreaseintotalTC,LDL,
APOBandnochangetoslightincreaseinHDL.
[5,115118]
However,thenumberofLDLparticlesdecreasesandLDLparticlesize
increasesfromsmalltypeBtolargetypeA(increaseof0.25nm).TheantiatherogenicHDL2bisalsoincreasedbyupto29%.
TherateofentryofVLDLparticlesintothecirculationisdecreasedandAPOCIIIisreduced,whichallowslipoproteinlipasetobe
moreactive.
[27]
Thereisadecreaseinremnantchylomicronsandremnantlipoproteins.
[5,116]
PatientswithLDLover100mg/dl
havereductionsintotalLDLandthosethatarebelow80mg/dlhavemildincreases.
[117]
However,inbothcasestheLDLparticle
numberdecreases,thedenseLDLBincreasesinsizetothelessatherogenicLDLAparticleandAPOBlevelsdecrease.There
isanetdecreaseintheconcentrationofcholesterolcarriedbyallatherogenicparticlesanddecreasesinnonHDLcholesterol.
Omega3FAareantiinflammatory,antithrombotic,lowerBPandheartrate,improveheartratevariability,
[5,111]
decreasefatty
acidsynthesis,increaseinfattyacidoxidationandreducebodyfatandweight.
[5]
Omega3fattyacidsareoneoftheonly
substancesthatlowerLpLPA2.
[27]
Insulinresistanceisimprovedandtherearenosignificantchangesinfastingglucoseor
hemoglobinA1Cwithlongtermtreatment.
[119]
Dosesof3gperdayofcombinedEPAandDHAata3:2ratiowithGLAat50%of
thetotalEPAandDHAcontentand700mgof/tocopherolat80and20%tocopherolper3gofDHAandEPAare
recommended.
[5]
DHAandEPAmayhavevariablebutfavorableeffectsonthevariouslipidlevels.
[5,115116,119]
EPAdoesnot
usuallyincreaseLDL,islesseffectiveinloweringTGthanDHAanddoesnotaltertheLDLandHDLparticlesize.AlthoughDHA
mayincreasetotalLDL,itincreasesLDLandHDLsizeandlowersTGmore.
[118]
Thecombinationofplantsterolsandomega3
fattyacidsissynergisticinimprovinglipidsandinflammation.
[70]
Newfreefattyacidformsofomega3fattyacidshaveafourfold
greaterareaundertheplasman3PUFAcurvethanprescriptionLovazaandthusamorepotentreductioninTGlevels.
[119]
The
dataofkrilloilondyslipidemiaislimitedtoonlytwostudiesinhumans.
[120,121]
Thefirststudy
[120]
showedadoserelated
responseofLDLCreductionupto39%,TGreductionof27%andHDLelevationof60%.
[120]
Anotherstudy
[121]
showedminimal
reductionsinTGof10%,butthedecreasewasnotsustainedduringlongtermtreatment.Thesefindingswithkrilloilarevery
disparateandthestudiesarenotconfirmatory.Krilloilisnotrecommendedatthistimeforthetreatmentofdyslipidemia.
Flax
FlaxseedsandflaxlignancomplexwithsecoisolariciresinoldiglucosideandincreasedintakeofALAfromothersourcessuchas
walnutshavebeenshowninseveralmetaanalysestoreduceTCandLDLby515%,Lp(a)by14%,TGbyupto36%witheither
nochangeoraslightreductioninHDL.
[5,122124]
Thesepropertiesdonotapplytoflaxseedoil.IntheSevenCountriesstudy
CHDwasreducedwithincreasedconsumptionofALA.IntheLyondiettrialattheendof4years,intakeofflaxreducedCHDand
totaldeathsby5070%.
[5]
Flaxseedscontainfiber,ligninsandphytoestrogensanddecreasethelevelsof7hydroylaseand
acylCoAcholesteroltransferase.
[5,122124]
FlaxseedsandALAareantiinflammatory,reduceHSCRP,decreaseTG,increase
HDL,decreaseinsulinresistanceandriskofType2DM,reducevisceralobesityandsystolicBP,increaseeNOSandimprove
endothelialdysfunction.Flaxdecreasesvascularsmoothmusclehypertrophy,reducesoxidativestress,increasescholesterol
effluxinmacrophagederivedfoamcellsbydecreasingstearoylCoAdesaturase1expressionsandfarnesoidXreceptor's
mechanismsofactionwhich,retardthedevelopmentofatherosclerosis..
[5,122126]
Thedoserequiredfortheseeffectsisbetween
14to40gramsofflaxseedperday.
[5,122126]
Chiaseeds(Salviahispanica)aretherichestbotanicalsourceofALAat60%
weight/volume.
[125]
ThedoseofChiaseedsis25gperday.
MonounsaturatedFats
Monounsaturatedfats(MUFA)suchasolives,oliveoilandnutsreduceLDLby510%,lowerTG1015%,increaseHDL5%,
decreaseoxLDL,reduceoxidationandinflammation,improveED,lowerBP,decreasethrombosisandreducetheincidenceof
CHD(Mediterraneandiet).
[5,127131]
MUFAreducesCD40Lgeneexpressionanditsdownstreamproducts(IL23a,adrenergicB2
receptor,oxLDLreceptor1andIL8receptor)andrelatedgenesinvolvedinatherogenicandinflammatoryprocessinvivoin
humans.
[131]
MUFAareoneofthemostpotentagentstoreduceoxLDLinhumans.Theequivalentofthreetofourtablespoons
(3040g)perdayofextravirginoliveoil(EVOO)inMUFAcontentisrecommendedforthemaximumeffectinconjunctionwith
omega3fattyacids.ThecaloricintakeofthisamountofMUFAdidnotresultinanyweightgaininthePREDIMEDstudyand
resultedinasignificantreductioninCVD.
[132]
Sesame
Sesameat40gperdayreducesLDLby9%throughinhibitionofintestinalabsorption,increasingbiliarysecretion,decreasing
HMGCoAreductaseactivity,upregulatingtheLDLreceptorgeneexpression,7hydroxylasegeneexpressionandtheSREBP2
geneexpression.
[133,134]
Arandomizedplacebocontrolledcrossoverstudyof26postmenopausalwomenwhoconsumed50gof
sesamepowderdailyfor5weekshada5%decreaseintotalcholesterolanda10%decreaseinLDLC.
[133]
Tocotrienols
TocotrienolsareafamilyofunsaturatedformsofvitaminEtermed,,and.
[5]
TheandtocotrienolslowerTCupto17%,
LDL24%,APOB15%,andLp(a)17%withminimalchangesinHDLorAPOA1in50%ofsubjectsatdosesof200mgperday
givenatnightwithfood.
[5,135137]
The/formoftocotrienolsinhibitscholesterolsynthesisbysuppressionofHMGCoA
reductaseactivitybytwoposttranscriptionalactions.
[5,135137]
Theseincludeincreasedcontrolleddegradationofthereductase
proteinanddecreasedefficiencyoftranslationofHMGCoAreductasemRNA.Theseeffectsaremediatedbysterolbindingofthe
reductaseenzymetotheendoplasmicreticulummembraneproteinscalledINSIGS.
[136]
Thetocotrienolshavenatural
farnesylatedanalogsoftocopherolsthatgivethemtheireffectsonHMGCoAreductase.
[136]
Inaddition,theLDLreceptoris
augmentedandtheyexhibitantioxidantactivity.
Thetocotrienoldoseisveryimportant,asincreaseddosingwillinduceitsownmetabolismandreduceeffectiveness,whereas
lowerdosesarenotaseffective.
[5]
Alsoconcomitantintake(lessthan12h)oftocopherolreducestocotrienolabsorption.
Increasedintakeofalphatocopherolover20%oftotaltocopherolsmayinterferewiththelipidloweringeffect.
[5,135]
TocotrienolsaremetabolizedbysuccessiveoxidationthencatalyzedbytheCYP450enzymes3A4andCYP4F2.
[5]
The
combinationofastatinwith/tocotrienolsfurtherreducesLDLcholesterolby10%.
[135]
Thetocotrienolsblocktheadaptive
responseofupregulationofHMGCoAreductasesecondarytocompetitiveinhibitionbythestatins.
[5,135]
Carotidarterystenosis
regressionhasbeenreportedinapproximately30%ofsubjectsgiventocotrienolsover18months.Theyalsoslowprogressionof
generalizedatherosclerosis.
[5,137]
Therecommendeddoseis200mgoftocotrienolatnightwithfood.
Pantethine
PantethineisthedisulfidederivativeofpantothenicacidandismetabolizedtocystamineSHwhichistheactiveformintreating
dyslipidemia.
[5,138142]
Over28clinicaltrialshaveshownconsistentandsignificantimprovementinserumlipids.TCisdecreased
15%,LDLby20%,APOBby27.6%,andTGby36.5%over49months.HDLandAPOA1areincreased8%.
[5,138143]
The
effectsonlipidsareslowwithpeakeffectsat4monthsbutmaytakeupto69months.
[5,138143]
Inaddition,pantethinereduces
lipidperoxidationofLDL,decreaseslipiddeposition,intimalthickeningandfattystreakformationintheaortaandcoronary
arteries.
[5,138143]
Pantethineinhibitscholesterolsynthesisandacceleratesfattyacidmetabolisminthemitochondriabyinhibiting
hepaticacetylCoAcarboxylase,increasesCoAinthecytoplasmwhichstimulatestheoxidationofacetateattheexpenseoffatty
acidandcholesterolsynthesis,andincreasestheKrebscycleactivity.
[5,138143]
Inaddition,cholesterolesteraseactivity
increasesandHMGCoAreductaseactivitydecreases.
[5,138143]
Thereis50%inhibitionofFAsynthesisand80%inhibitionof
cholesterolsynthesis.
[5]
Itslipideffectsareadditivetostatins,niacinandfibrates.Therecommendedeffectivedoseis300mg
threetimesperdayor450mgtwiceperdaywithorwithoutfood.
[5,138143]
Guggulipids
Guggulipids(Commiphoramukul)areresinsfromthemukulmyrrhtreethatcontainactivelipidloweringcompoundscalled
guggulsterones.
[5,144146]
TheseincreasehepaticLDLreceptors,bileacidsecretionanddecreasecholesterolsynthesisinanimal
experiments.
[5,144]
However,controlledhumanclinicaltrialshavenotshowntheseagentstobeeffectiveinimprovingserum
lipids.
[144146]
Onestudyof103subjectson5075mgofguggulsteronesperdayfor8weeksactuallyhada5%increaseinLDL,
nochangeinTC,TGorHDL,andinsignificantreductionsinLp(a)andHSCRP.
[144]
Guggulipidsarenotrecommendedatthis
timetotreatdyslipidemia.
Garlic
NumerousplacebocontrolledclinicaltrialsandmetaanalysisinhumansshowreductionsinTCof175mg/dlandreductionsof
LDLofabout96mg/dlatdosesof600900mgperdayover2monthswithastandardizedextractofallicinandajoene.
[5,147
154]
Manystudieshavebeenpoorlycontrolledandusevariabletypesanddosesofgarlic,whichhavegiveninconsistentresults.
[5,147148]
Agedgarlic(AGE)hasshownthebestresultsrelatedtoimprovementinserumlipidsaswellasloweringBP,improving
endothelialfunctionandarterialelasticity,decreasingcoronaryarterycalciumandplaqueprogression,andloweringHSCRP.
[5,55,147154]
Garlicreducesintestinalcholesterolabsorption,inhibitsenzymesinvolvedincholesterolsynthesisanddeactivates
HMGCOAreductase.
[5,147]
Inaddition,agedgarlicreducesvascularsmoothmuscleproliferationandtransformation,decreases
oxidativestressandinflammation,decreasesoxLDL,preventsentryoflipidsintothearterialwallandmacrophages,increases
eNOSandNO,increasesglutathione,glutathionereductaseandsuperoxidedismutase,hasfibrinolyticactivityandantiplatelet
activity.
[5,55,147]
AgedgarlichasbeenusedinthesestudiesaloneorinconjunctionwithBvitamins,folate,arginineandstatins.
[148151]
Thepreferreddoseofagedgarlic(Kyolicgarlic)is600mgtwiceperday.
Resveratrol
ResveratrolreducesoxLDL,inhibitsACATactivityandcholesterolesterformation,increasesbileacidexcretion,reducesTC,TG
andLDL,increasesPON1activityandHDL,inhibitsNADPHoxidaseinmacrophagesandblockstheuptakeofmodifiedLDLby
CD36SR(scavengerreceptors).
[155,156]
NAcetylCysteine(NAC)hasthissameeffectonCD36DRandshouldbeusedin
conjunctionwithresveratrol.
[155]
Thedoseoftransresveratrolis250mgperdayandNACis1000mgtwiceperday.
Curcumin
Curcumin,phenoliccompoundintumericandcurry,
[5,157]
induceschangesintheexpressionofgenesinvolvedincholesterol
synthesissuchastheLDLreceptormRNA,HMGCoAreductase,SREBP,cholesterol7hydrolyze,PPAR,LXR,affectsthe
expressionofgenesinvolvedinleukocyteadhesionandtransdendothelialmigrationtoinhibitatherosclerosis.
[5,157160]
Inone
humanstudyoftenpatientsconsuming500mgperdayofcurcumin,theHDLincreased29%andtotalcholesterolfell12%.
[5,157]
Arecentmetaanalysisoffivestudiesof133subjectsdidnotindicateasignificanteffectofcurcuminonanyofthelipid
parameters.
[160]
LargerrandomizedclinicaltrialsareneededtodeterminethelipidloweringeffectsandpotentialreductioninCV
effectswithcurcumin.
Pomegranate
PomegranateincreasesPON1bindingtoHDLandlevelsofPON2inmacrophages.Itisapotentantioxidantthatincreasestotal
antioxidantstatus,lowersoxLDL,decreasesantibodiestooxLDL,inhibitsplateletfunction,reducesglycosylatedLDL,decreases
macrophageLDLuptakeandreduceslipiddepositioninthearterialwall.
[161166]
Thesechangesimpedetheprogressionof
carotidarteryIMTandlowerbloodpressureespeciallyinsubjectswiththehighestoxidativestress,knowncarotidarteryplaque
andthegreatestabnormalitiesinTGandHDLlevels.
[161166]
Consumingabout8ozofpomegranatejuiceperdayoronetotwo
cupsofpomegranateseedsisrecommended.
OrangeJuice
Inonehumanstudy,750mlofconcentratedorangejuiceperdayover2monthsdecreasedLDL11%withreductionsinAPOB,
TGandincreasedHDLby21%.
[167]
Theeffectsareduetopolymethoxylatedflavones,hesperitin,naringin,pectinandessential
oils.
[167]
Additionalstudiesareneededtoverifythisdata.
CitrusBergamot
Citrusbergamothasbeenevaluatedinseveralclinicalprospectivetrialsinhumans.Indosesof1000mgperdaythiscompound
lowersLDLupto36%,TG39%andincreasesHDL40%.
[168171]
CitrusbergamotinhibitsHMGCoAreductase,increases
cholesterolandbileacidexcretion,bindstotheACATreceptor,andlowersoxLDL.
[168171]
Favorableeffectsonglycemic
parametersincludereductionsinglucoseviaAMPKandGLUT4receptorreductioninROSandweightloss.Theactive
ingredientsincludenaringin,neroeriocitrin,neohesperidin,poncerin,rutin,neodesmin,rhoifolin,melitidineandbrutelidine.
[168171]
VitaminC
VitaminCsupplementationlowersserumlowdensitylipoproteincholesterolandtriglycerides.
[172]
Ametaanalysisof13
randomizedcontrolledtrialsinsubjectsgivenatleast500mgofvitaminCdailyfor3to24weeksfoundareductioninLDL
cholesterolof7.9mg/dl(p<0.0001)TGreductionof20.1mg/dl(p<0.003).HDLdidnotchange.ThereductionsinLDLandTG
weregreatestinthosewiththehighestinitiallipidlevelsandthelowestserumvitaminClevels.
[173]
Lycopene
Lycopeneisanacycliccarotenoidwithahighconcentrationintomatoes.IthasbeenshownintissueculturetoinhibitHMGCoA
reductase,induceRhoinactivation,increasePPAR,LXRreceptorandRXRactivities,increasereversecholesteroltransport
andeffluxwithABCA1,apoAIexpressionandcaveolin1expression,increaseHDL2and3,improveHDLfunctionality,reduce
SAA,decreaseCETP,increasePON1andreduceinflammationinhumans..
[174176]
Thisreducesintracellularcholesteroland
lowerscholesterolinlipiddomains,whichaltersmembraneinducedcellularsignaltransduction.Thetwounconjugateddouble
bondsinthelycopenemoleculehavehighactivityagainstROS.Higherserumlycopenelevelsareassociatedwithreductionin
carotidIMTandcarotidatherosclerosis.
[177]
Wogonin&Flavonoids
Wogoninisaflavonoid(ScutellariabaicalensisGeorgiextract)thatenhancesreversecholesteroltransport..
[178]
Wogonin
increasestheproteinexpression,levelandhalflifeoftheABCA1transporter(ATPbindingcassettetransporterA1).Thiseffect
islinkedtoitsabilitytostimulatePP2B,whichisaproteinSer/ThrphosphatasethatregulatesthestabilityofABCA1protein.In
addition,Wogonininhibitstheexpressionofproatherogenicmoleculesinendothelialcellsandvascularsmoothmusclecells.
Otherflavonoidssuchasprocyanidins,quercetin,catechins,redwine,resveratrol,grapeseedextract,tangerineextractand
anthocyaninsmayhavesimilareffects.
Probiotics
Mixedhighdoseprobioticsat60to100billionorganismsperdayreduceTC9%,LDLC8%andTG10%.
[179182]
Probiotics
precipitatebilesalts,deconjugatebilesaltswithbilesalthydrolyaseandareincorporatedintocellmembranes,aswellasbeing
assimilatedintocholesterolitself.
BerberineHCL
BerberineHCLisanalkaloidpresentinroots,rhizomesandstembarksofselectedplants.
[183185]
Inastudyof32dyslipidemic
patients,500mgperdayofberberineHCLdecreasedTC29%,LDLC25%andTG35%in3months.
[184]
Berberineincreases
hepaticLDLRandsuppressesPCSK9expressionthatincreaseshepaticLDLexcretionandisadditivetostatinsinitslipid
loweringeffect.
[183,184]
Therecommendeddoseis500mgq.d.tob.i.d.BerberinehasadditiveLDLloweringeffectswith
statins
[183]
andezetimibe.
[185]
Ametaanalysisofberberinethatincludedelevenrandomizedtrialsof874subjectsshowed
significantreductioninTC,LDL,TGandincreaseinHDLwithoutanyseriousadverseeffects.
[186]
Berberineismoreeffectiveand
hasfeweradverseeffectscomparedwithezetimibemonotherapy.
[185]
Combinations
Aprospectiveopenlabelhumanclinicaltrialof30patientsfor2monthsshowedsignificantimprovementinserumlipidsusinga
proprietaryproductwithacombinationofpantethine,plantsterols,EGCG,/tocotrienolsandphytolens.
[187]
TheTCfell14%,
LDLdecreased14%,VLDLdropped20%andsmalldenseLDLparticlesfell25%(typeIIIandIV).
[187]
Inanotherstudyusingthe
sameproprietaryproductwithRYR2400mgperdayandniacin500mgperday,theTCfell34%,LDLdecreasedby34%,LDL
particlenumberfell35%,VLDLdropped27%andHDLincreased10%[HoustonMC,UnpublishedData].Studiesindicatea
relativeriskreductionofCVDmortalitywithomega3fattyacidsof0.68,withresinsof0.70andwithstatinsof0.78.
[188,189]
Combiningstatinswithomega3fattyacids(EFA)decreasesCHD19%more.
[114]
Thecombinationof/tocotrienolsandastatin
reducesLDLcholesterolanadditional10%.
[135]
Plantsterolswithomega3fattyacidshavesynergisticlipidloweringandanti
inflammatoryeffects.
[118]
Acombinationofredyeastrice,bittergourd,chlorella,soyproteinandlicoriceresultedinsignificant
reductionsinTC,TGandLDL,aswellasBPin228subjectsinacontrolledclinicaltrial.
[190]
Agedgarlicaloneorincombination
withBvitamins,folate,arginine,coenzymeQ10orstatinsimproveslipidsandothermarkersofendothelialfunction,vascular
elasticity,NO,inflammation,HSCRP,CACandplaqueregression.
[5,55,147151]
Futurestudiesareneededtoevaluatevarious
othercombinationsonserumlipids,surrogatevascularendpointsandCHDandCVDmorbidityandmortality.
NutritionalManagementofDyslipidemia
Nutritionisanimportanttreatmentfordyslipidemia,CHDriskfactorsandforthepreventionandtreatmentofCVD.Numerous
epidemiologicalstudiesandprospectiveclinicaltrialsincludingtheFraminghamHeartStudy,
[191,192]
SevenCountriesStudy,
[193,194]
Pritikindietstudies,
[195197]
OrnishLifestyleHeartTrial,
[198201]
OmniHeartTrial,
[192]
Portfoliodiet,
[202205]
Mediterraneandiet,
[206210]
LyonDietHeartStudy,
[209]
IndianHeartStudy,
[211]
Predimedstudy
[210213]
andPaleolithicdiethave
clearlyestablishedtherelationshipbetweendiet,serumlipids,inflammationandCVDsincludingcoronaryheartdiseaseand
stroke.
ThreecohortsoftheFraminghamHeartStudywithover10,000subjectshavedemonstratedimprovedCVriskonlipidlowering
dietsthatdecreasetotalandLDLcholesterol,TGandincreaseHDL.
[191,192]
TheSevenCountriesStudywasaninternational
studythatinvestigatedlifestyleanddiet.
[193,194]
AhighfatdietincreasedprevalenceofCVD.ThePritikinPrincipleDiet,which
includedlowfatdiet(10%oftotalcalories)withprimarilyvegetables,grains,andfruits,combinedwithexercise,improvedthelipid
profile.
[195197]
Ornishetal.evaluatedanintensivetherapeuticapproachthatcombinedalowfat(10%totalcalories,lowcholesterolof10mgper
day,complexcarbohydrate,lowrefinedcarbohydratevegetariandiet,exercise,andotherlifestylechangessuchasstress
reduction,smokingcessationandgrouppsychosocialsupport.
[198201]
Theexperimentalgroupcomparedwiththecontrolgroup
hadstatisticallysignificantreductionsinLDLC,frequencyofanginaepisodes,andregressionincoronaryarterystenosisatyears
1and5.TheOptimalMacronutrientIntakeforHeartHealthTrial(OmniHeartTrial)wasarandomizedcontrolledintervention
crossoverstudyof164adultsusingaMediterraneanstylediettoevaluateplasmalipidsandbloodpressure.
[192]
Threedietswere
includedacarbohydraterichdiet,aproteinrichdietwith50%fromplantsources,andadietrichinmonounsaturatedfat.The
monounsaturatedfatrichdietincreasedHDLClevels,loweredTG,withnochangeinLDLC.Theproteinrichdietdecreased
LDLC,TGandHDLCcomparedwiththecarbohydratediet.Substitutionofthecarbohydrateswitheitherproteinsor
monounsaturatedfatloweredbloodpressure,improvedserumlipidlevelsandreducedcardiovascularrisk.
[205]
ThePortfolioDietStudywasarandomizedcontroltrialof14dyslipidemicsubjects
[202]
givenavegetariandiet,withadditional
solublefiber,nuts,soyproteinandplantsterols.At4weekstheLDLCfell29.6%andTGfell9.3%inthedietgroupversus8.5%
inthecontrolgroup.Therewasa33.3%decreaseinLDLCand11%decreaseinTGinthosegivenastatindrug.Inafollowup
studyoftheportfoliodietin66dyslipidemicadultsfor1year,31participantshadreductionsinLDLC>20%relatedtocompliance
withthediet.
[203]
ThemostrecentPortfoliodietof351subjectsshowedanLDLCreductionof13.8vs3%inthecontrolgroup.
[204,205]
IncreasingthemonounsaturatedfatcontentincreasedserumHDLClevelsbutmaintainedthereductioninLDLC.
[204,205]
TheMediterraneanstylediet
[206]
consistsofahighintakeofvegetablesandfruits,breadandothercerealgrains,potatoes,
legumes,nuts,seeds,monounsaturatedfatasoliveproducts(1520%oftotalcalories),animalproducts(meat,poultry,fish,dairy
andeggs)atalowtomoderatelevelandredwine.TheLyonDietHeartStudywasthefirstrandomizedsingleblindsecondary
preventiontrial600participantsover4yearswithapriormyocardialinfarction(MI)toinvestigatetheeffectofaMediterranean
styledietonCVD.
[207209]
TheprimaryoutcomemeasurementoffatalornonfatalMIwassignificantlyreduced.Forexample,the
totalfatintheexperimentaldietwas30.5%fatbutonly12.5%MUFAandwasenrichedinlinolenicacid,anomega3
polyunsaturatedfat.Therecent4.8yearstudyof7447subjectsgiventheMediterraneandietinprimarypreventionofCVDfound
a2830%reductioninmajorCVeventsinthoseontheMDwithextravirginoliveoilornuts.
[210]
TheIndianHeartStudywasa1
yearevaluationofaMediterraneanstyledietenrichedinlinolenicacidadministeredtothetreatedgroup,whilethecontrolgroup
wasadvisedonsmokingcessation,stressmanagement,regularexercise,reductionofdietaryfatandalcohol.
[211]
Comparedwith
thecontrolgroup,thetreatedgrouphada38%reductioninnonfatalMIanda32%reductioninfatalMI.
PREDIMED
[210,212]
wasa3monthrandomizedcrosssectionalstudyof772asymptomaticSpanishadultsathighriskfor
cardiovasculardiseasetreatedwithoneofthreediets.AcontrolgroupandtwoexperimentalarmsthatusedaMediterranean
stylediets,differingonlyintheprimaryfatsource:EVOOat1lperweekormixednutsat30gperday.Thetreatedgroups
showedareductioninthetotalcholesterol:HDLCratio,at0.38(95%CI:0.55to0.22)forthoseontheMediterranean/EVOO
dietandof0.26(95%CI:0.42to0.10)forthoseontheMediterranean/nutsdiet.Inaddition,fourinflammatorymarkerswere
significantlyreducedintheEVOOgroupincludingHSCRP,IL6,ICAM1andVCAM1.AllbuttheHSCRPwerereducedinthe
nutconsumptiongroup.
[210217]
Thehuntergathererdiet,orPaleolithicdiet,
[214217]
isconsideredtobeclosetoMan'sancestraldietandconsistedofadiethigh
infoliage,leafyvegetables,fruits,seeds,nuts,plantsterols,vegetableprotein,fiberandomega3fattyacidsandleananimal
protein,whichimproveslipidsandCVDrisk.
SummaryofNutrition,Dyslipidemia&CVD
Althoughmanyquestionsstillexistregardingtheoptimalintakeoffats,whichtypesoffats,typesandqualityofprotein,aswellas
thedietaryintakeofcomplexandrefinedcarbohydrates,moststudiesclearlyindicatethattransfattyacidsandrefined
carbohydrateshaveanadverseeffectonserumlipidsandcardiovascularoutcomes.
[217]
Somesaturatedfatsmaybeadverse,
othersneutralandsomepotentiallybeneficial.TheMUFAandomega3fattyacidsareconsistentlybeneficialfordyslipidemiaand
CVD.Thevegetariandietwithincreasedcomplexcarbohydratesandfiberwithlowerdietarycholesterolisalsobeneficial.Protein
intakeoflean,wildandorganictypesofproteinandcoldwaterfishimproveslipidsandCHDriskfactors.
Summary,Conclusion&FuturePerspective
Thecombinationofalipidloweringdietandselectedscientificallyprovennutraceuticalsupplementshavetheabilitytoreduce
LDLCbyupto50%,increaseLDLparticlesize,decreaseLDLparticlenumber,lowerTGandVLDLandincreasetotalandtype2
bHDLandimproveHDLfunctionalityandreversecholesteroltransport.Inadditioninflammation,oxidativestressandimmune
responsesaredecreased.Manysurrogatesforvasculartargetorgandamageareimproved,suchascarotidIMTandplaque,
aorticfattystreaks,CAC,plaqueregressionandmorphologychanges,endothelialfunction,vascularsmoothmusclehypertrophy
andelasticity,CABGandstentocclusion,andheartratevariability.HardCVendpointsarealsoimprovedsuchas
atherosclerosis,CVA,CVD,CHD,MI,abdominalaorticaneurysms,suddendeath,andtotalmortality.Inseveralprospective
clinicaltrials,CHDandCVDhavebeenreducedwithmanyofthenutraceuticalsupplementssuchasomega3fattyacids,RYR,
ALAandniacin.Thisnutritionalandnutraceuticalsupplementtreatmentisavalidalternativeforpatientsthatarestatinintolerant,
cannottakeotherdrugsforthetreatmentofdyslipidemiaorinthosewhopreferalternativetreatments.Thisnewapproachtolipid
managementtodecreasevasculardiseaseutilizesamorefunctionalandmetabolicmedicineapproachwithabroadertreatment
programthataddressesthemultitudeofstepsinvolvedindyslipidemiainducedvasculardamage(,,,,,,,,,,,,,,,,,,&).
Box1.38mechanismsfortreatmentofdyslipidemiainducedvasculardisease.
Decreaseendothelialpermeability,gapjunctions,endothelialdysfunctionandimproveendothelialrepair:aged
garlic.IncreaseNO,reduceAIIeffects,increaseEPC's,BPcontrol,reduceinflammation,oxidativestressand
vascularimmunedysfunction
Modifycaveolae,caveolin1,lipidrafts,membranemicrodomains,unesterifiedcholesterolandcholesterolcrystals.
Lycopene,omega3fattyacidsandstatins
IncreaseeNOSandnitricoxide.Arginine/citrullene,resveratrol,flaxseed,omega3fattyacids,coenzymeQ10,
Rlipoicacid,NAC,taurine,pycnogenol,grapeseedextract,pomegranate,agedgarlic
ModifyPRRactivationandtolllikereceptors.Niacin,EGCG,pantethine,resveratrol,MUFA,curcumin,
pomegranate,agedgarlic,sesame,/tocotrienols,lycopene
Decreasecholesterolcrystals,LDLphospholipids,oxLDL,APOBandsevenketosteroidsthatactivatePRR.
Omega3fattyacidsandstatins
DecreaseLDLburden(Box4)
Reducecholesterolabsorption(Box6)
Increasecholesterolbileexcretion(Box17)
DecreaseLDLparticlenumber(Box13)
DecreaseAPOB(Box15)
DecreaseLDLmodification/oxidation:(Box2)
InhibitLDLglycation(Box3)
IncreaseLDLsize(Box5)
ModifyLDLcomposition.Omega3fattyacids,MUFA,reduceinflammation,oxidativestressandimmune
dysfunction
UpregulateLDLreceptor(Box17)
RegulatesortilinsandSORLA
DeactivatetheLOX1receptor.ReduceBP,reducehsCRP
DecreasemodifiedLDLmacrophageuptakebyscavengerreceptors(Box11)
DecreasenativeLDLmacrophageuptakebypinocytosis.Decreaseinfectionsandinflammation,decrease
modifiedLDL
DecreaseLDLsignaling.Plantsterols
DecreaseCAMs,macrophagerecruitmentandmigration.NAC,resveratrol,luteolin,glutathione,andcurcumin.
Altermacrophagephenotype.Omega3fattyacid,plantsterols,sterolinsandglycosides
ModifysignalingpathwaysPlantsterolsandphytosterolins
Increasereversecholesteroltransport(Box12)
IncreaseHDLandincreaseHDLsize(Box10)
ImproveHDLfunction.Reduceinflammation,oxidativestressandimmunedysfunction,quercetin,pomegranate,
EGCG,resveratrol,glutathione,lycopene
IncreaseAPOA1(Box16)
IncreasePON1andPON(Box18)
Reduceinflammation(Box14)
Reduceoxidativestress
Modulateimmunedysfunction.Plantsterolsandsterolins
DecreaseVLDLandTG(Box9)
LowerLp(a)(Box8)
Reducefoamcellandfattystreakformation.Resveratrol,NAC,phytosterolins
Reducetrappingoffoamcellsinthesubendothelium.Resveratrol,NAC
Stabilizeplaque.Omega3fattyacids,vitaminK2MK7,agedgarlic
ReduceLpPLA2.Omega3fattyacids,niacin
Reduceplaqueburden,progressionandincreaseregression.Omega3fattyacids,vitaminK2MK7,agedgarlic,
pomegranate
BP:BloodpressureCAM:CelladhesionmoleculeEGCG:EpigallocatechingallateeNOS:Endothelialnitricoxide
synthaseEPC:EndothelialprogenitorcellMUFA:MonounsaturatedfatsNAC:NacetylcysteineNO:Nitricoxide
PRR:Patternrecognitionreceptor.
Box2.InhibitionofLDL.
Oxidation
Niacin
EGCGandcatechins
Quercetin
Pantethine
Resveratrol
RedWineGrapeSeedextract
MUFA
Curcumin
Pomegranate
Garlic
Sesame
/tocotrienols
Lycopene
Polyphenols
Flavonoids
Oleicacid
Glutathione
Citrusbergamot
Tangerineextract
Policosanol
RBO(ferulicacidgammaoryzanol)
CoenzymeQ10
VitaminE
Polyphenolsandflavonoids
ECGC:EpigallocatechingallateMUFA:Monounsaturatedfats.
Box3.InhibitionofLDLglycation.
Carnosine
Histidine
Myricetin
Kaempferol
Rutin
Morin
Pomegranate
Organosulfurcompounds
Box4.LowerLDL.
Niacin
RYR
Plantsterols
Sesame
Tocotrienols(/)
Pantethine
GLA
Citrusbergamot
EGCG
Omega3fattyacids
FlaxSeed
MUFA
Agedgarlic
Resveratrol
Curcumin
Orangejuice
Solublefiber
Soy
Lycopene
Fiber
ECGC:EpigallocatechingallateMUFA:MonounsaturatedfatsRYR:Redyeastrice.
Box5.ConvertdenseLDLBtolargeLDLA.
Niacin
Omega3fattyacids
Plantsterols
Box6.Reduceintestinalcholesterolabsorption.
Plantsterols
Soy
EGCG
FlaxSeeds
Sesame
Garlic
Fiber
EGCG:Epigallocatechingallate.
Box7.HMGCoAreductaseinhibition.
RYR
Pantethine
//tocotrienols
Sesame
EGCG
Omega3fattyacids
Citrusbergamot
Garlic
Curcumin
GLA
Plantsterols
Lycopene
Soy
EGCG:EpigallocatechingallateRYR:Redyeastrice.
Box8.LowerLp(a).
Niacin
Nacetylcysteine
/tocotrienols
Omega3fattyacids
Flaxseed
CoenzymeQ10
VitaminC
LCarnitine
LLysine
LArginine
Almonds
Box9.Lowertriglycerides.
Niacin
RYR
Omega3fattyacids
Pantethine
Citrusbergamot
Flaxseed
MUFA
Resveratrol
Orangejuice
MUFA:MonounsaturatedfatsRYR:Redyeastrice.
Box10.IncreasetotalHDLandHDL2blevelsandconvertHDL3toHDL2and2b.
Niacin
Omega3fattyacids
Pantethine
Redyeastrice
MUFA
Resveratrol
Curcumin
Pomegranate
Orangejuice
Citrusbergamot
MUFA:Monounsaturatedfats.
Box11.AlterscavengerreceptorNADPHoxidaseandoxidizedLDLuptakeintomacrophages.
Resveratrol
Nacetylcysteine
Agedgarlic
Box12.AlterscavengerreceptorNADPHoxidaseandoxidizedLDLuptakeintomacrophages.
Niacin
Plantsterols
Glutathione
Wogonin
Resveratrol
Variousflavonoidsandanthocyanins
Alphalinolenicacid
Box13.DecreaseLDLparticlenumber.
Niacin
Omega3fattyacids
Box14.Reduceinflammation.
Niacin
Omega3fattyacids
Flaxseed
MUFA
Plantsterols
Guggulipids
Resveratrol
Glutathione
Quercetin
Curcumin
Agedgarlic
MUFA:Monounsaturatedfats.
Box15.LowerAPOBlipoprotein.
Niacin
Omega3fattyacids
Plantsterols
EGCG
Box16.IncreaseAPOA1lipoprotein.
Niacin
Box17.UpregulatetheLDLreceptor.
EGCG
Sesame
Tocotrienols
Curcumin
Policosanol
Plantsterols
Box18.IncreasePON1andPON2.
EGCG
Ouercetin
Pomegranate
Resveratrol
Glutathione
Box19.Increasebileacidexcretion.
Resveratrol
Citrusbergamot
Fiber
Probiotics
Plantsterols
Sesame
Table1.Summaryofnutraceuticalsupplementrecommenddosesforthetreatmentofdyslipidemia.
Supplement Dailydose
Niacin:vitaminB3 5004000mgindivideddoses
Phytosterols 2.15g
Soy(fermented) 3050g
EGCG 5001000mg
Omega3fattyacids 30005000mg
Flaxseed 40g
Monounsaturatedfats 2040g
Sesame 40g
/tocotrienols 200mg
Pantethine 900mgindivideddoses
Resveratrol(transform) 250mg
Nacetylcysteine 2000mgindivideddoses
Curcumin 20005000mgindivideddoses
Pomegranatejuice 8ounces
Pomegranateseeds 1cup
Citrusbergamot 1000mg
VitaminC 500mg
Quercetin 5001000mg
Sidebar
ExecutiveSummary
Advancedlipidtestingisrecommendedforproperdiagnosisandtreatmentofdyslipidemia.
Treatmentshouldbedirectedattheabnormalitiesintheadvancedlipidtesting,aswellasthe38mechanismsof
dyslipidemicinducedvasculardisease.
Nutritionandnutritionalsupplementswillprovidedramaticimprovementsinserumlipidlevelsthatcancompetewithdrug
therapies.
Combinationsofdrugsandnutritionalsupplementsarescientificallyvalidtreatmentstoachievegoallipidlevelsandreduce
vasculardisease.
Inpatientsthatareintoleranttostatins,thesenondrugapproachesareclinicallyvaluabletopropertreatmentoflipid
disorders.
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stockownershiporoptions,experttestimony,grantsorpatentsreceivedorpending,orroyalties.
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