VIDEO_DietDoctorPodcastwithDavidDiamond(Episode27)

Dr.BretScher:WelcomebacktotheDietDoctorpodcastwithDr.BretScher.TodayI'mjoinedbyDr.DavidDiamond.Now,Dr.DiamondhasaPhDinbiologyandheisaprofessoratthedepartmentofpsychologyattheUniversityofSouthFlorida.Now,interesFngly,hisworkisincogniFveandneuroscienceandhe'sdonethisfordecades.

Butbecauseofapersonaljourney,hehasnowgonedownthiswholepathofcholesterolandstaFnsandlow-carblifestyle,andreallytryingtosay,whatdoesthesciencesay,whatdoesthesciencesupportinthisrealm.Now,thisisapolarizingtopic,especiallywithmainstreammedicine,mainstreamcardiologybeingverymuchinthecampofLDLiscausaFveofheartdisease.

AndDr.Diamondisontheothersideofthat,sayingwaitasecond,Idon'tthinktheevidencesupportsthatstatement.Now,I'vegottobehonest,thisisaveryimportanttopicforme,apersonaltopicforme.IhadahugelistofnotesandIkindofwentaliKlebitallovertheplacebecauseIwasjustsointerestedintalkingtohimandtalkingaboutthedifferenttopicsandgeMnghisthoughtsondifferentthings.So,Iapologizeifthisinterviewdoesn'tflowasseamlesslyasIwouldhaveliked.

ButIthinkwecoveralotofdifferenttopics.Now,quickdisclaimer;ifyouhavehighcholesterol,ifyouareonastaFn,pleasedonotmakeanymedicaldecisionsorchangesbasedonthisdiscussion.Thisismerelytoexploresomeevidence,toexploreonesideofthisequaFon,hopefullyinabalancedway.ButifyouaregoingtomakeanychangesoranydecisionsaboutyourmedicaFonsoryourhealth,pleasetalktoyourdoctorfirst.Donotmakeanydecisionsbasedonthisdiscussionalone.

Now,withthatdisclaimer,wetalkalotaboutthescience,wetalkalotaboutthepracFcalityofhowthisimpliestoindividualsandalow-carblifestyle,andweexploreanumberofdifferenttopicsaboutcholesterol,LDL,staFns,andtheirbenefit.So,acoupleofquickdefiniFons,whichIthinkwegoover,butrelaFveriskreducFonversusabsoluteriskreducFon.

So,ifyouhaveaonepercentriskofsomethingandyoucanreduceitdowntoahalfofapercent,thedifference,theabsolutedifference,isahalfpercent,that'stheabsoluteriskreducFon.RelaFveriskreducFonhowever,Iwouldsaythat's50percentreducFonbecausehalfpercentishalfofonepercent.So,wetalkalotaboutthat,Dr.DiamondhasbeenveryvocalaboutsortoftruthinadverFsingbetweenthosetwothings.

WetalkaboutMendelianstudiesandbasicallythat'sjustanaturalhistoryexperimentofgeneFcmutaFonandfollowingwhathappenstopeopleoverFmewiththatgeneFcmutaFon,that'scalledaMendelianrandomizaFontrial,IthinkIusethattermaliKlebitinhere.Ithinkhopefullythat'sallthedefiniFonsyouneed,andIhopeyouenjoythisdiscussionwithprofessorDavidDiamond.Youcanseethefulltranscriptsondietdoctor.com.

Again,pleaserealizethisisnotmedicaladvice,thisisjustsimplyexploringafascinaFngtopicwithafascinaFnghumanbeing.So,enjoythisdiscussionwithDr.DavidDiamond.

Dr.DavidDiamond,thankssomuchforjoiningmeontheDietDoctorPodcast.

Dr.DavidDiamond:ThanksforinviFngme,Bret.

Bret:It'sapleasuretohaveyouherebecauseyouhavebeenaspearheadinthismovementofquesFoningtheroleofLDL,quesFoningtheroleofstaFnsandmoreimportantly,howdoesthatapplytoalow-carblifestyle.Butthis...thisisnotevenyourjob,thisisnotyourprofession.Imean,youhavearegularjobasaprofessorinthedepartmentofpsychology,sotellusaliKlebitabouthowyougotfrompointAtopointBhere.

David:Right,so,mytraining,myprimaryexperFseisinneuroscience,studyingthebrainandmemory,whichIstartedover40yearsago.Butwhathappenedabout20yearsagowasthatIfoundthatIhadextremelyhightriglycerides,Iwasactuallydiagnosedwithfamilialhypertriglyceridemia,whichhappenstoabout5%ofthepeopleinthepopulaFon.Ieatsomebreadandmytriglyceridesgoskyhigh.Mytriglycerideswereabout700,800andthesepeoplewhohavehightriglyceridesalsohavelowHDL.So,myraFooftriglyceridestoHDL,whichshouldideallybelike1:1,or2:1,minewasaboutover20:1.

Bret:Wow,that'samazing.

David:And,so...anditwasforabout10years.Mydoctor'skeepingtrackeveryyear,I'mgeMngbloodtests,I'mworkingoutlikecrazy,I'monalowfatdiet,andeveryyearIjustgotfaKerandfaKerandmytriglycerideswereup.Finally,mydoctorjustsatmedown,saidyouknow,you'vedoneyourbest,yourdietandexercisehavefailed,justliketheysayinthecommercial.You'vegottogoonastaFnaswellasothermedicaFon.

AndIjustfigured,well,youknow,I'vegotabackgroundinbiology.Iknowalotaboutthebrainbutnotmuchaboutheartdisease.LeastIcoulddoisreadafewpapersbeforeIgoonthemedicaFon.IreadafewpapersandbythisFme,I'venowreadafewthousandpapers.AndthathashelpedtoguidemeandmydecisionnottousemedicaFon.Instead,Ilearnedaboutthevalueoflow-carbdiet.Iwasabletocutmytriglyceridesby75%,raisemyHDL25%,loseagoodbitofweight,feelmuchhealthiernowthanIdid20yearsago.

So,I'mastrongadvocateforalow-carbdietbutalsorealizingthatmedicaFonwasn'tappropriate.Andintheprocess,I'vebeeninasenseindignantaboutthestaFnresearch.IactuallyexpressthiswhenIgivemytalksabouthowIrealizedthatthecholesteroltheory,whichischolesterolcausesheartdiseasethroughLDL,it'sreallynotwell-supportedandfrankly,whatIexpressistheobsceneprofitsthathavebeenmadethroughthefoodanddrugindustrythathavemaintainedahypothesisthathasfailed.

Bret:VerycontroversialandinteresFngtheorywhichyoubackupwithalotofresearch.So,IwanttotalkaboutthatbutIthinkyourexampleisaperfectexampleofwhat'shappeninginthislowcarb-worldandthemedicalworldingeneralthatwhetherit'sanengineerorwhetherit'sascienFst,frequentlyanoutsiderfromthemedicalprofessionhasapersonalexperience,butthentheyhavethetoolsandtheknowledgetodigdeeperandprovideuswithawholenewperspecFve.

AndIthinkthat'ssovaluablebecause,youknow,inthemedicalworld,ifyou'reinyourownechochamber,onlyhearingthesamepeople,thesameexperts,thesamedrugcompanies.Although,wefallintothatsameriskIguess,inalowcarbworld,right.Wecanbeourownechochambertoo,sowehavetoreachoutintootherareasandkeepourearsopenforotheropinions.

Now,oneofthethingsthatyou'reverycriFcalofisevidenceandhowweportrayevidence.Andwetalkaboutevidence-basedmedicinealltheFmeandwetalkaboutwhatistheevidenceforketo,againstketo.WhatisyourperspecFveasyou'velookedintothingsaboutthestateofevidenceinthemedicalworld?

David:Well,Ithinkit'sveryimportantthatIdon'tcomeinwithabias.Youknow,I'veactuallybeenverywell-fundedbydrugcompaniesinmyneuroscienceresearch,andI'mnotpersonallyorprofessionallyopposedtoanydrugcompanyresearch.IhadneverseenthedistorFonofdata...distorFonofthepresentaFonofdatabeforegoingintothecardiovascularfield,beforereadingpapersoneffecFvenessoftreatmentswithcardiovascular,parFcularlyloweringofcholesteroldrugs.

AndIhavetotellyouthatIwasastounded,IwasoffendedwhenIsawhowthedataweremanipulatedtogreatlyoverstatethebenefitofcholesterolloweringdrugs,whichactuallygoesbackdecades,originallytalkingaboutcholestyramineina1984paperinwhichyouhad,starFngoffwithabouthalfamillionmen,theygotthatworkdowntoabout600peopleatthehighestlevelsofcholesterol,andusinganolderdrugcholestyramine,whichloweredcholesterol.

Theamazingthingwasadersevenandahalfyears,therewasvirtuallynoeffectandtherewasnorealstaFsFcallysignificanteffect.Itwasa0.4%differencebetweentreatedanduntreatedmen.AndIlookatthat,andwhattheyshouldhavesaid,youknowsomething,wewerewrong...loweringcholesteroldidn'thaveanybenefitwhatsoever.

Buttheyturnedthat0.4%intoa24%improvementinoutcome.Andso,thismanipulaFonofthedataandthat'susingrelaFveriskratherthantheactualoutcomes.So,tome,thisisjustnotrightinhowyoureportthedatatothepublicandtothemedicalfield.

Bret:Yeah,you'vebeenveryvocalabouttherelaFveriskversusabsoluterisk.So,theabsoluteriskinthatseMngwouldhavebeenthe0.4%,butwhenyoudoitinapercentage,it'sarelaFverisk,soifyouhavea1%risk,youloweryourriskto0.5%percent,that'sa50%reducFon.Now,what'sinteresFngtome,asacardiologist,I'veinundatedwiththattypeofrelaFveriskreducFonpublicity,andtomeitwasjusthowitwasdone.

UnFlIstarted,youknow,diggingaliKlebitdeeperandrealizingit'sacompletelydifferentconversaFonifyouhavetheabsoluteriskreducFon.Butthefallbackisthereisachange,thereisadifference.So,eveninthestaFns,andIguessmaybewe'rejumpingaliKleaheadhere,buteveninthestaFntrials,ifthereisa1%difference,itcanbeastaFsFcallysignificant1%difference,whichthentheypublicizeasa36%difference.

Butit'shardtoargueifthereisadifference,sothequesFonbecomeswhenisitabigenoughdifferencetomakeaclinicallyusefulintervenFon,andthat'sahardquesFontoanswer,isn'tit?

David:Right,thefirstthingisthatweneedtruthinadverFsing,weneedaccuratereporFng.So,what'sveryimportantistoreportboth-theabsoluteriskandtherelaFverisk.Theyshouldbothbeintheabstracts,theyshouldbothbepresentedtodoctorsandtopaFents.Peopleshouldknowboth.

Whatisactuallythedifferenceintherateofeventsinpeopleofplaceboversusthetreatedpeople?Youshouldn'tonlybetoldtherelaFveriskbecausethat'sdecepFve,andweknowit'sbothindoctorsandthepublic.Whenyouhearabouta50%reducFoninriskandthat'sallyouhear,youthinkthathalfofallpeoplearenownotgoingtohaveaheartaKack.Andthat'sexactlywhatdoctorsinterpretthat.

So,again,first...I'mnotagainstreporFnga50%riskreducedwithstaFns,butthat'sgottocomealongwiththeabsoluteriskaswell.Peopleneedtohavebothdataforms.Andthesecondthingis,youareright.TherearenumerousstudiesshowingbenefitwithstaFns,andthatbenefittypicallyisontheorderofsingledigits.There'sneverbeenastaFnstudyIknowofinwhichyouactuallyhaveadouble-digitimprovement.

AndIhavetojustbrieflytellyou,inmyfieldofneurosciencewhereweactuallystudydepression,issuchagreatcontroversybecausepeoplewithmildtomoderatedepression,givenaplacebo,haveactuallyaratherdramaFceffectasabenefit.AndthecontroversyactuallyisthattheanFdepressantsonlyimproveoutcomeby10%comparedtoplacebo.

Well,there'sneverbeenareal10%improvementoutcomeofanykindwithstaFns.So,Iagreewithyoucompletely,therearestudiesthathaveshownthebenefitofstaFnswhenyou're

lookingatcoronaryevents,aswellascoronarymortalityandall-causemortalityandthosenumbersarerelaFvelysmall,buttheyarereal.

Bret:Yeah,Ithinkthat'sagreatperspecFvethatyoubringfromthefieldofpsychologyanddepressionandthey'relookingfora10%benefitandwe'retalkingabout0.5%to1%benefit.Andit'sinteresFngthatthephrasing,thewordingofthesestudies,thatthey'reblockbuster,thatthey'rerevoluFonary.Ithinkwe'vesortoflostperspecFveofwhatblockbusterandrevoluFonaryreallyare.LiketreaFngtuberculosis,thatwasrevoluFonary,thatwasblockbuster.SanitaFon,anesthesia,youknow,thosewereblockbuster.

Ahalfofapercentdifference,isthatablockbuster?Butthenpeoplesay,cardiovasculardiseaseisthenumberonekillerintheworld.Millionsofpeoplearegoingtosufferfromcardiovasculardisease,soifwecanmake1%differenceandthat'salotofpeople.Andinaway,that'savalidargumentwhenyou'retalkingaboutapopulaFonbasis.

David:Iagreecompletely.IfstaFnshadnoadverseeffectsandyousay1%ofthepeoplefromhavingaheartaKack,I'dbeallforit.MaybeI'dtakeitmyselfifwewereabsolutelycertaintherewerenoadverseeffects.Imean,thiskindofgrabsyou.Youthinkthatahundredpeoplearegoingtotakethedrugandlonepersonoutofa100--99takethedrugandthenthere'snobenefitwhatsoever,butagainitgetsdowntoadverseeffects.Now,whathashappenedispeoplearereallynotawareoftheadverseeffects.

They'vebeengreatlyminimizedbythekeyopinionleaders.AndI'vealsotalkedaboutthis.Now,weactuallywereinvitedtowriteacommentaryrecentlybyPlusOne.Andinthatcommentary,whichjustcameoutafewmonthsago,wereviewedtheliteratureonadversestaFneffects.Andit'snotsmall,it'sextensive.

Wereviewedabout60paperspublishedinpeer-reviewedmedicaljournalsofabout20differentcategoriesofadverseeffects.Themostobviousisdevelopmentoftype2diabetes.Andthishasreallybeenminimizedbythekeyopinionleaders.Butwhenyouactuallylookcarefully,andyouhaveanRCTandanactualtrialinwhichyougetbloodsamplesandyoulookattheA1clevelsandyoulookatfasFngglucoseandotherinsulinmeasures,youactuallyfindthatoverthecourseofsixyears-thisisinmen-thatthere'sa5%increaseinnewonsettype2diabetes.

So,thisparFcularonewasdoneinFinlandfundedbythegovernmentinwhichyouhaveaspontaneousincreaseintype2diabeteswithplaceboas5%.ButinthosethatwereonstaFns,itwasactually11%.Soit'sdoublingintherateoftype2diabetes,whichisarelaFveriskmeasure.Butwe'renottalkingabout1%,we'retalkingabouta6%increaseoverthecourseofaboutsixyears,andso,that'sjustoneadverseeffect.TherearereallywelldescribedcogniFveeffects.

We'vepublishedapaperoncogniFveeffectsinstaFns,andthere'sactuallyabeauFfulpaperthathasshownthatpeoplediagnosedwithdemenFa,olderpeoplediagnosedwithdemenFa,which,whentheyweretakenoffthestaFn,theirdemenFadisappeared.Putthembackonthe

staFn,thedemenFareturned.Thisisnotsomethingthatdoctorsareawareof,theextentoftheadverseeffectsofthestaFns.

Bret:Yeah,it'sveryinteresFng,becausewhenyoutalkaboutadverseeffectsofstaFns,themostcommonisthemuscleaches,that'swhateverybodytalksabout.Andtheargumentisyoucan'tcomparemuscleachestoheartaKacks,right?Thosearenotonthesamelevel,especiallywhenthevastmajorityofthemuscleachesdisappearwhenyoutake...whenyouremovethestaFn.

Butevenwiththemuscleaches,there'ssignificantcontroversy.Imean,youlookatthetrialsandtheyreportonein20000,youknow,riskofsignificantmuscleaches,andofcourse,thesearedesignedbythepharmaceuFcalcompaniessothere'saruninperiodwhichweedsoutalotoftheotherpeoplewhowouldbeintolerant,so,they'renotincludedinthetrial.

Butthen,myfavoriteishowyoucalledoutRoyCollinsand,youknow,howhewouldstatethere'sonein10000riskofstaFnsbutyethiscommerciallyavailableproducttotestforstaFnmyopathyrisk,quotesa29%risk.So,wheredoyouseeintryingtoevaluatetheevidence?Wheredoyouseethemuscleachesreallylie?Wheredoyouthinkthatis?Whatistherealnumber?

David:ThisisveryinteresFngbecauseyoulistentotheleadersofthefield.SteveNissen,forexample,callsitthenoceboeffect,inwhichthepaFentistoldthatthestaFncausesmuscleachesandtherefore,theysaytheyhavestaFn-inducedmuscleaches.Buthecallsitactuallyanocebo,meaningit'sallintheirhead.Andtherearesomeverypoorlydesignedstudiesthatsupportthat.

WhatIampresenFngtodayisactuallySteveNissenandChrisFeBallantyneandSteveNicholsstrongstaFnadvocates,talkingaboutmusclepaincausedbystaFns,they'renotcallingitanoceboeffect.AndtheiresFmateis40%ofthepeopletakingstaFnsstoptakingitinpartbecauseofmusclepain.So,Icaughtthemonavideoinwhichthey'rebeingcandidaboutwhatactuallyhappensintheclinic,whypeoplestoptakingstaFns.

Bret:InteresFng.

David:Yes.

Bret:Anditisdifficulttodecipherthereal-lifeeffect,thephysiologicaleffectversustheplaceboornoceboeffect.That'swhyyouneedarandomizedcontrol--placebocontrolledtrial,butthosetrialsfrequentlyexcludedpeoplewhowereatriskofhavingmuscleaches.So,Idon'tthinkweknowthetrueanswer.ButtheboKomlineisifyouthinkit'scausingyoumuscleachesandyou'renotgoingtoexercisebecauseofit,wehavetoaskisitimpacFngyourhealthfavorably.Andmakesyouwonder,doesn'tit?

David:Well,that'sanotherimportantpoint.WhathappensisweknowthatstaFnsinterferewithmetabolism,youhavelesscoq10,whichmusclesneedtobeabletohaveenergy.Andthere'ssomeveryniceworkfrom...outofUCSanDiego--Glome?...it'llcometomelater.ButveryniceworkshowingthatmanypeoplehavefaFguemuchmorerapidly,especiallyunderexerFoncondiFons,andso,wedohavelessenergy.

Peoplehavelessenergywhenthey'vetakenstaFns,andwedohavemusclesbreakingdown,whichcontributesthentokidneydisease,kidneyinjury.There'swell-establishedactuallypublicpapers.So,Ithinkwearelookingatveryrealphysiologicaleffectsthathaveadverseeffectsgloballyonthebody.

Bret:Yeah,so,westartedwiththemuscleachesandthen,diabetesisthenextbigone.Andwhat'sinteresFngaboutthediabetesispeoplesay,well,look,ifyou'rehavinganincreasedriskofdiabetes,butyou'resFllshowingareducFonincardiovascularevents,doesn'tmaKer.Andthat'sveryinteresFngwhenyou'reinafiveyeartrial.Butwhenpeopleareonthesedrugsfor20to30years,we'reledtodeterminehowarewegoingtointerpretthatdata?

Ontheonehand,peoplesay,well,ifthecardiovascularbenefitisoneyearorfiveyears,it'sgoingtobe2yearsor10yearsand4%at20years.Okay,maybewecanmakethatreach,buthowisthediabetesgoingtoimpactthat?Andwedon'tknowtheanswertothatquesFon,dowe?

David:No,wedon'tbecausemostofthetrialsarestoppedataboutthreeorfouryears.It'sBeatriceGolombbytheway--

Bret:Iknewyouweregoingtogetit.

David:Shecamebacktome,andshehaddonesomebeauFfulworklookingatstaFneffects.Whatyou'llfindwiththestaFnadvocates--Ilookatthis,reallyit'soutsidemyprimaryareainwhichIwasjustabasicscienFst.IamsFllabasicscienFstlookingabrainfuncFon.ButtoseepeoplewhoInowconsideradvocatesforstaFns,that'snotthewayscienceisdone.

Andwhat'shappenedwiththestaFnadvocatesistheyconsistentlytakethatnumberneededtotreat--whichmaybesmalladeroneyear--andtheysimplychangeit...oneoutof100peoplewillactuallyhaveabenefitfromstaFns.Andthenthey'llsay,wellader20years,youonlyhavetotreatfiveor10people.Becausethatbenefitwillaccrueover20years.Andtheyrefusetosaytheadverseeffectscanalsoaccrue.

So,ifyou'relookingat6%addiFonalpeoplewhodevelopdiabetesaderaboutfiveorsixyears,what'sgoingtohappenader20years?Andwhat'sgoingtohappenifthere'sactuallyanexponenFalincreaseinadverseeffects?ButonceFssuestartsbreakingdown,thenyou'vegottobeevenmoreconcernedwiththathappeningatanevenmorerapidpace,especiallywithelderlypeople.

Andbytheway,also,thewayIalsopresentthisisifthetobaccocompanieshadthecontrolthatthedrugcompanieshavenow,overlookingonlywiththeonsetofstarFngtotakethestaFnaderonlyaboutfouryears,youlookatthedevelopmentofcancer,it'sonlyfouryearsthatyou'vestartedsmoking,weneverwouldhaveknownaboutthelinkoflungcancertosmoking.So,understand,thesetrialswerestoppedreallybeforemostcancerscandevelop.

Butwhenyoulooklong-termandthere'sactuallyaniceepidemiologicalstudylookingover10years,youseetwicetherateofbreastcancerinwomenwhoareonstaFnschronicallycomparedtoequivalentgroupsofwomeneitherwithhighcholesterol,lowcholesterol.Andso,there'salsoevidenceofcancerinmenaswell,butyou'vegottolookatolderpopulaFonmorevulnerableoveralongerperiodofFme.

Bret:Andthat'sinteresFngbecausethat'swherethere'ssomecontradictoryevidence,becausethere'smeta-analysisshowingnoincreasedriskofcanceraswell,andallhastodowithwhichtrialsyou'llincludeandhowlongisthefollowup,anditbecomesconfusingandit'sdifficulttosaywithcertainty.Butthenyouhearthesestatements,thepreponderatesofevidence,right.

TakingtheevidenceasawholeshowsthatstaFnsreducecardiovascularevents.That'salsodifficultbecausewheredoesthepreponderatesofevidencecomefrom?It'smostlythePharmasponsoredtrials.SohowdoweinterpretPharmasponsoredtrials,ImeanthedataissFllthedata,wecan't--it'snotlikethey'refalsifyingthedata,butwhatistheimpactthepharmaceuFcalcompanieshaveonthedatawe'reseeing?

David:IactuallygivepharmaceuFcalcompaniesalotofcredit.Idon'tseeanyevidenceoffraud.ThedecepFonishowactuallytheclinicdirectorspresentthedatatothepublicandtothemedicalcommunity,andagain,thatgetsbacktotherelaFveriskversusabsoluterisk.Thefactthattheyreportsuchminisculebeneficialeffects...tome,Igivethemcredit.

Thatclearlytomedoesn'tappeartogivemeanyreasontoaccusethemoffraudbecausethey'reshowingsoliKlebenefit.Andagain,Idon'tthinkwewanttoautomaFcallydemonizestudiesthatarefundedbyPharma.Theseareveryexpensivestudiesandit'sverydifficulttogetgovernmentfundingforlong-termstudiesoncardiovasculardisease.Theotherchallengeisit'saverylowrateatwhichpeopledevelopheartaKacks.

AbouttheonlyFmeyouseeahighrateofdeathiswithheartfailure,ofwhichstaFnsareactuallynobenefitatall,peoplewithhighcholesterollivemuchlongerthanpeoplewithlowcholesterolfollowingheartfailure.Butwhenyou'relookingatheartaKacks,you'reactuallyseeinginthegeneralpopulaFonsuchalowratethatfrankly,togivethePharmacredit,it'sdifficulttomuchofareducFoninheartaKacks.

YoueventakepeoplewithhighriskofheartaKacksandyou'llonlygetabouttypically3,4,5%.whowillhaveheartaKacksandyou'llhavealowrateofmortality.So,thisispartofamethodologicalchallengeforthisareaofresearch.So,nowlikeinacancerstudyyoumayhave

50%ofthepeopledieinashortperiodofFme.ButintheseheartdiseasestudiesIdon'tthinkpeopleappreciatethattherereallyisrelaFvelyalowrateinplacebotreatedpeople.AndthisiswhyItellpeople...

IshowthemstudiessuchastheLipitorstudy,whichwasfamousintheLancetearly...around2000.OrtheBriFshHeartprotecFonstudy,you'reonlylookingatabout3%or4%ofthepeoplewhodied.They'reterriblyuncooperaFveasawaytoputit.Andabout97%ofthepeopledon'thaveheartdisease,andthewayIalsopresentthistopeople,Isay,listen,youcangotoyourdoctorandsay,ifIdon'ttakethestaFn,ifyougivemeaplacebo...what'sthelikelihoodinthenextfiveyearsthatI'llhaveaheartaKack?Andtheansweris97%likelythatyouwillnothaveaheartaKack.Andso,tome,that'stherealityofitaswell.

Bret:Yeah,so,thatgoesdowntothe--fromadoctorstandpoint,theshotgunapproachoflet'sgivethisdrugtoasmanypeopleaspossiblehopingoneisgoingtobenefitversusthemore...themorelaserbeamfocusoflet'sreallyfindoutwho'satthehighestriskandthenmaybeaddastaFnaspartoftheirregimen.So,howdoyouinterpretthecalciumscoringdatathat'scomeoutrecently?

Youknow,anotherbigstudy,WalterReed,thatshowedabsolutelynostaFnbenefitifyourcalciumscorewaszero.Itshowedaverysmallbenefitifyourcalciumscorewasbetweenoneand100.Ithinkitwas...thenumberneededtotreatwasabout100over10years.Butthen,asthatscoresgoover100,alloftheasuddenthenumberneededtotreattosaveonecardiovascularevent--notdeathbutcardiovascularevent--goesdownto12.So,howdoyouthinkaboutthatmorelaserfocusedapproachthantryingtobeKeridenFfywhomightbenefitfromastaFnasonepartoftheiroveralltreatmentprogram?

David:Right,soIthinkthereisevidence.Actually,goingbacktobeforethat,25yearsago,nowincludingthecalciumscoresforpeopleshowthatthepeoplemorevulnerabletodevelopheartdiseaseareactually...dobenefitfromthestaFns.And,soyou'reabsolutelyright.Thatstudyshowedthatthepeoplewhohaveahighcalciumscoreshowedabenefitofreducedcoronaryevents,nodifferenceinmortalityasyousayaswell.

AndIthinkit'sactuallyimportanttogobackthisrelates--Well,firstofall,whenwe'retalkingaboutcalciumscore,Iwanttopointout,everyoneagreeshighcalciumscoreisunhealthy.Imean,itisafact.TheinteresFngthingisnumerousstudieshavenowcomeoutshowingthatpeopleonstaFnshaveincreasedtheircalciumscore.Thisisalso--there'snodifferenceofopiniononthis--theremarkablethingtomeisnowthatwesay,well,thatmustbeagoodthingbecauseincreasingcalciumstabilizestheplaque.

This,tome,cameoutofnowhere.It'slikeincreasedcalciumscoreisbadunlessit'sinducedbythestaFn.Thenitbecomesagoodthing.So,that'sremarkabletome.So,whatIwillyieldhere

isthatthereisevidenceofbenefitofstaFnsgiventopeoplewithhighrisk.Andtheimportantthingactuallyisthere'sananalysisofpeopleinthe4Sstudythatwasdone25yearsagousingsomeoneonstaFnandactually,thatwasoneofthebiggesteffectseverinwhichactuallyhada4%reducFoninmortality.AndforsecondaryprevenFon,peoplealreadyhadaheartaKack.

David:Andfrankly,Ihadtogoback25yearstofindanystudyasgoodasthe4Sstudy.Itshowshowweaktheeffectshavebeensincethen.ButevenaccepFngitwasastudyrunbyPharma,thedatawereanalyzedbyPharma.It'sokay,a4%reducFoninmortalityforpeopleathighrisk.AreanalysisofthatstudycameoutsevenyearslaterpublishedinCirculaFonanditshowedtheenFrebenefitwasinpeoplethatbasicallyhadmetabolicsyndrome,peoplewhohadlowHDL,hightriglyceridesandhighLDL,theenFrebenefit.

Now,whenyoulookinthe4Sstudy,whichissoimportant,thepeoplethathadthesamehighLDLbuthighHDLandlowtriglycerides,secondaryprevenFon,nobenefitwhatsoever.Andthisissoimportant,geMngbacktolow-carb,becausethat'sexactlywhathappenswhenpeoplegolow-carb.TheirHDLrises,theirtriglyceridesdropjustlikeitdidforme.So,whatthisissayingisyouhaveachoice,okay.YoucantakeastaFnandbasicallyhaveacrappymetabolicsyndrome,oryoucangolow-carb,makeallthoseimprovementsandthestaFnwon'thaveanybenefitoverthat.

Bret:Ithinkthat'sagreatperspecFve,I'lltalkaboutthatrealquickly,goingbacktothestaFnscausinganincreaseincalcium.Ithinkthat'sagreatpoint.TheimmediatereacFonfromthecommunitywasoh,thisisagoodthing.Andtobehonest,wedon'tknow,couldbeperfectlycorrect.Well,there'samechanisFcwaytothinkthatthatiscorrectbuttonothavetheevidenceandjustdismissitbecauseofamechanism.Wouldgetthrownoutifitwascontrarytothecommonbelief.ItshowshowacommonbeliefcanreallydirectaconversaFon.Maynotbe-mayberight,maybewrongbutit'sjustaperfectexample.

So,thatwasgood.Right,nowgeMngbacktotheLDLandtheenvironmentit'sin,andthat'ssomethingIthinkwereallyloseperspecFveofbecauseevengoingbacktotheFraminghamdata,samething.TherewasanassociaFon,all--acomplete,totalassociaFonbetweenrisingLDLandrisingcholesterolandriskofcardiovasculardisease.

ButwhenyouseetheFraminghamoffspringdataandtheybreakitdownaccordingtoHDLlevels,allofasudden,thatassociaFonislostathigherHDL.So,itshowsthere'ssomethingtothismorethanjustLDL,anditprobablyhastodowithmetabolichealthlikeyousaid,arevaluaFonofthe4Strial,saysthat.Now,thatbeingsaidthough,youknow,LDLiscausaFveofcardiovasculardisease.Wehearditin1980swithBrownandGoldstein,wehearditagainlastyearwiththeEuropeansocietyofcardiology.

ThedefiniFonofcardiovasculardiseaseasanAPO-Bcontaininglipoproteininamacrophageinarterialwall,therefore,itiscausaFve.Now,withsomanypeoplecertaininthemedicalcommunitythatitiscausaFve,whataretheymissing?

David:So,whenyousayit'scausaFve,you'rejustquoFng--Idon'tknowyouropiniononthat-

Bret:Sorry,IshouldsayIamquoFngtheliterature,right.IamnotstaFngmyopinion;IamquoFngwhatIseeinpaperaderpaperaderpaper.

David:Sure.AndjusttomenFonBrownandGoldstein,theystatedasafactthatLDLcausesheartdiseaseinacompleteabsenceofanyevidence.heydidanelegantworklinkingLDLabnormaliFestofamilialhypercholesterolemia,buttheynevershowedthatLDLwasactuallycausaFveofheartdisease.Thisisagainwherewehavetoreallylookattheevidence.It'sallIreallycareabout.So,wehaveadrugthatlowersLDLasmuchasstaFnsandalsoraisesHDL,thisisCETPinhibitors.

So,thegreatthingaboutthisdrugisacompletelydifferentmechanismfromstaFns,andiniFallykilledpeople,andsothosetrialswerestopped.So,peoplearedyingwithlowerLDLandhigherHDL,butaderthattheywereabletocleanupthedrug,soithasalmostnosideeffects.TheCETPinhibitors,drugcompanyhasinvestedoverabilliondollars.Thiswastobeablockbuster,becausenotonlydiditlowerLDL,itraisedHDL.

ThisisoneofthebiggestfailureseverinPharmahistory.So,thesearethepeoplewhoprimary,secondarytreatmentwiththedrug,dramaFcallylowerLDL,andabsolutelynodifferencetocoronaryeventsormortality,sonobenefit,noharm.This,tome,issortofthedeathnotefortheLDLhypothesis.

Thisissaying,no,you'reloweringLDLandyou'remakingnodifferenceincoronaryevents.So,that'sthefirstthing.Thesecondiswehavetorealizethere's...there'salotofmoneyinvolvedinblamingLDLforheartdisease.WhatwegotisanewgeneraFonofdrugs.Well,letmebackoff,alotofpeoplesayitdoesn'tmaKerwhetherstaFnslowerLDLornot,aslongasstaFnsprovideabenefit,wedon'tcareaboutthemechanism.

Andthat'sonesideoftheargumentwhichactuallywecantalkabout.IfstaFnshaveabenefitandtheydon'thaveanyadverseeffects,fine,whocareshowtheywork.ButwhathashappenediswehavethisnewgeneraFonofdrugs,that'sthePCSK9inhibitors.ThisdrugspecificallytargetsLDL.

So,ifweactuallylookobjecFvelyattheresearchandwedropLDLandwesimplyacceptthatLDLdoesn'treallycauseheartdiseaseandstaFnsworkandwestoprightthere,thatwouldbefine.ButbecausethedrugcompanieshaveinvestedoverabilliondollarsinthePCSK9inhibitors,we'vegottoconFnuetotargetLDL.Now,partofthisisIjustwanttotalkaboutfamilialhypercholesterolemia.

ThesearepeoplewithextremelyhighLDLlevels,two,threeFmesnormal.AndinmypapersthatI'vewriKenwhichI'mcoveringinmytalktoday,I'mcoveringhowpeoplewithFH,peoplewithLDL,200to300ormore,liveahealthynormallife...thattheyhaveanormallifespan.Thesearepeoplewholiveintotheir70sand80swithtotalcholesterolof400andtheirLDL300.Well,that'sclearlycountertotheideathatLDLiskillingpeople.Itdoesn'tmakesense.

Bret:Yetthere'sasubsetthatclearlydevelopcardiovasculardiseaseatayoungageanddieatayoungage,butwhentakenasawhole,theoveralllifeexpectancyisnotthatmuchdifferent.Andwhenyoucomparethosewhogetearlycardiovasculardiseasetothosewhodon't,itdoesn'tseemthatLDListhepredictor,doesit?

David:Right,absolutely.So,again,andlet'sbeclearonthenumbers.Whenyoulookat-it'saraFo-oftheageofdeathversusdecadeoflife...sothefirstthingis,onlyabout1%ofpeopledieintheirfirst20years.Inmodernsociety,wehaveverylowmortalityrate,first20years.AndwhenyoulookatrateofdeathforpeoplewithFH,thatthatisnotstaFsFcallydifferentfrompeoplein20years,20to30,20to40.Thereisnooveralldifferenceindeathrate.

Itisremarkable;thereisagreaterincrease,therearegreaterincidentsofcoronaryevents,buttheactualdeathrate,thisgoesbackwhetheryou'relookingatthe1960s,toHarland'swork...thoughthedecadestherehavebeenadozenofpaperspublished.AndMundaletal,thisisbeauFfulworkoutofNorwayinwhichyou'relookingatabout5000peopledocumentedFHinwhichyouhavenoincreasedrateofdeathall-causemortalityatanyage.

Andinfact-thisisuntreated,sothisisnotlookingatstaFnshavinganeffectforpeople70yearsofagewithFH,theyhaveasignificantlylowerrateofdeathforthenextdecadecomparedtothegeneralpopulaFon.

Bret:Yeah,andthat's--

David:So,LDLisclearlynotrelaFve.Now,wepublishedapaper.MymedicalcolleaguesandIpublishedapaperonmedicalhypothesesinwhichwereviewedtheFHliterature,andthisissoimportantandit'signoredbythestaFnadvocates.YouhavesomanypapersthathaveshownthatwhatkillspeoplewithFHiscoagulaFonfactors.Thesepeoplenaturally,itcomesalongwithhighLDL,theyalsohaveageneFcanomalyinwhichtheyhavesignificantlyhighercoagulaFonfactors,higherfibrinogen,higherfactor8.

AndtheirplateletsaremuchmorereacFvetoepinephrine.So,youputsomeepinephrineinadishwithplatelets,plateletscoagulate,okay,theyaggregate.SomeonewithFH,puttheirplateletsinadish,putinsomeepinephrine,they're100FmesmoresensiFvetoepinephrinethanacontrolledpopulaFon.Now,youdon'thearmuchaboutthatbecausenoone'sexcitedaboutreducingplateletaggregaFon,Imeanwhowantstogiveaspirintosomeonewho'sgotFH,right?There'snomoneyinplateletaggregaFon,farmoremoneyintargeFngLDL.

Bret:Yeah,so,what'sinteresFngaboutthatispeoplehaveaproblemmechanisFcallyunderstandingthatbecausetherecanbe,youknow,20ormoredifferentgeneFcmutaFonsthantheLDLreceptortocauseFH.So,howcantheyallindividuallyalsoeffectcoagulaFon?Itseemslikeadisconnect.TheLDLreceptorgenesalsoaffecFngcoagulaFongenes.So,peoplehavearealhardFmemechanisFcallyunderstandingthat.Areyouabletoexplainthat?

David:Ithinkthatit'sadifferentgene.There'sactuallyaverynicestudyshowingdifferentgeneformsforprothrombin,whichisinvolvedincoagulaFon.Andit'sthesubsetofthosealsohaveFHandequallyhighLDLbetweenthosewhohavecardiovasculardiseaseandthosewhodon't.Butasubsetofthosealsohavethegeneanomaly,whichdramaFcallyincreasesprothrombinandthosearethepeoplewhohavecardiovasculardisease.So,itlookslikeitispotenFallylinkedtotheLDLgeneanomaly,butitisaseparategene.

AndsoonlyasubsetofpeoplewithFHnowhavethisreacFve,andthosearetheones.Theotherthingtokeepinmind,peoplewithFHarejustlikeeverybodyelse.TheyaresuscepFbletothesameriskfactors.So,peoplewithFHthatsmokehaveadramaFcallyhigherrateofheartdisease,muchmorethanthegeneralpopulaFon.Andifyoutalkaboutstressreducingheartdisease,well,theFHpersonisgoingtobemoresensiFvetostress.

Anddiabetes,sohigherbloodsugarisgoingtotriggerplateletaggregaFon,sothatFHpersonwillbemoresensiFve.Buttotheindividualsthatdon'thavetheseriskfactorsandyethaveskyhighLDL,noheartdisease.

Bret:Yeah,Ithinkthat'soneofthemostimportantpointstothemake.It'sthattheaugmentedfacts,weknowsmokingisbad,weknowdiabetes,hypertension,metabolicsyndromearedangerousforyourcardiovascularhealth.ButforthosewithFH,itisamagnitudeorahigherriskfortheaverageperson.

David:AndIthinkit'simportantforthepersonwithFHtorealizethatthisisacrosstheenFrepopulaFon,thatitappearsthattheyallhavethisincreasedsusceptabilitytoplateletaggregaFon.Butit'sthesubsetthenthathadtheaddiFonalriskfactors.Suchasthehighbloodsugar.ButyouknowwhatisdisturbingtomeisthatIreadthereviewsonFH,IreadabouttreatmentforFH,andwe'retalkingabout20,30authorswriFngamassivereviewonFH.Theword"platelet"doesnotcomeuponce.CoagulaFondoesnotcomeuponce.TotalfocusinonLDL.

Bret:Yeah,that'sinteresFng,dotheyjustnot--theyjustdisregardthatit'sevenanissuebecausethepapersarethere,thescienceisthere.Youmightsay,Idon'tbelieveit'ssuchabigissue,butyoucan'tignorethatthescienceisthere,andtheyhavetoaddressit.

David:Yeah,that'swhattheydo.Andit'snotjustoneortwopapershereandtherewherepeoplecan'tfindit,andyouknow,we'retalkingabout50yearsofresearchlookingatpeoplewithFH.Andthere'ssomeanomalies,kindofinteresFngandpeoplewhogettheirFH,it's

heterozygoussoit'seitherfromoneparentortheother.Itjustturnsoutthatthere'samaternalinfluence.PeoplewhogettheirFHfromtheirmotheraremuchmorelikelytodevelopheartdiseasethanpeoplewhogetitfromtheirfather.

Bret:Really?Ihaven'tseenthat.

David:Yeah,it'soutthere,it'sconfirmedLDLlevelsappeartobeequivalent.It'sinteresFnganditsaysthatmaybe--ImeanI'vehypothesizedthatcoagulaFonfactorscomealongwithmaternalFHandnotwithpaternalFH.TheymaybemorereacFvebutnobody'stalkingaboutthis.

Bret:Yeah,there'snomoneyinstudyingitandthere'snorealbenefitinstudyingitbecausewehavethebogeyman,wehavethetreatment,sowhycomplicatetheissue.

David:Well,that'salsotheotherthing.TherehasneverbeenastudyonFHgoingback50years.NeverbeenastudyonFHwithaplacebo-controlledtrial.Andthere'salotofmodelingthatyouwillsee,nooneever--fromthebeginningtheythoughtitwasethicalandwegotpeoplewithFH,wegottogivethemtreatment,twodifferenttreatmentsbecausewe'vegottobeabletosavethem.

Andthewaytolookatitisthere'snoevidencethatstaFnshaveanybenefitsoranyotherbenefitasatreatmentinFHbecauseit'sneverbeencomparedtoplacebo.

Bret:Right,buthistoricaldatashowsinthestaFnera,riskofcardiovasculardiseasehasdecreasedtenfoldiswhatyouwouldreadinmostpaperssincestaFntreatmenthasbeeninsFtuted.Now,asweknowfromepidemiologicalstudies,therearelotsofotherthingsthatcanhappenandcoincidewiththat.TherelaFveriskdropsincestaFnshavebeenintroducedisimpressive.Imean,whenlookingatdatafromthatstandpoint,butmyguessisyouhaveadifferentinterpretaFonofthat.

David:Well,no,it'sjustamaKeroflookingwhenisitthatdeathfromcoronaryheartdiseasehasdeclined,itactuallybeganinthe1960s.Deathpeakedinthe1950sandyoucanactuallyseethatdeclinebeganinthe1960s,andreally,theslopeinthedeclinehasn'tchangedmuchwithstaFns.

AndthestaFnresearchhasshownaveryloweffectonoverallmortality.So,there'snoreasontobelievethatthestaFnshaveanyeffectonpopulaFonmortalityfromcardiovasculardisease.So,clearly,andtherearepaperstoreadinthe1970squesFoningwhyisitsomuchfewerpeoplearedyingfromheartdiseasenowthantheydid20yearsago.ThatmayverywellbethatitisbeKercareandit'sactuallypost-coronarycarethatmaybereducing--it'sdeathfromheartdiseasethathasdeclinedoverthelast40yearsorso.

Butprobablytheincidentsofheartdiseasemaybeincreasingwithobesityanddiabetes.Butactually,whatitshouldbepotenFallytheuseofanFbioFcs.It'sactuallyveryimportantbecauseyoudoseealinkageofinfecFousdiseasewithheartdisease.

Bret:Yeah,wehearaboutsmoking,wehearaboutbloodpressuremanagement.

David:Oh,yeah,youknow,that'ssoimportant.Thedeclineofdeathfromheartdiseasehascomewiththedeclineinsmokingtoo,whichisagainpeakedinthe1940sand1950s.

Bret:CouldhavealsobeentreaFngtoothabscessesortreaFng,youknow,chronicsmallerinfecFons.Thepointiswedon'tknowtheanswer.Wecouldcomeupwithlotsofhypotheses.

David:ButstaFnsdon'tdeservethecreditforreducingitbecauseitprecededstaFndevelopmentbydecades.

Bret:Yeah,oh,okay.So,wejustwentdownaliKlerabbithole.IthinkI'mgoingtodoalotwithyouherebecausethere'ssomuchtotalkabout.ButIwasstarFngfromthepointofaskingisLDLcausaFveofcardiovasculardisease,andsomeFmesIdogetintroubleofmakingstatementsthatmakeitsoundlikeIsupportthemwhenI'mreallyquoFngtheliteratureandtryingtoplaydevil'sadvocate.

ButIthinkthere'ssomuchcontroversyaboutbeinginvolvedandbeingcausaFveandweblurthelinesfartoooden.So,Imean,wouldyouagreethatAPO-BcontaininglipoproteinslikeLDLlipoproteinareinvolvedintheatherogenicprocessandinvolvedindevelopingcardiovasculardisease?

David:It'scertainlypossibleandIamopentoanypossibility;I'dliketolearnmoreaboutit.Butwhatjustdoesn'tmakesensetomeiswhenyoulookatpeoplethathaveastronomicallyhighLDLandtheydon'thaveheartdisease.ifwe'retalkingaboutitbeingcausaFve,Imeanwhyisitnotbeingcausedoutbyitself?We'lltalkabouttheenvironment,themetabolicenvironment.

Whatyou'vegotisaharmfulmetabolicenvironmentandyou'vegotpeoplewhohavehighbloodsugarandhighbloodpressure,whichiscausingdamagetotheendothelial,it'scausingdamagetothevasavasorum,andpotenFallyonecouldsayisthenyou'vegotinfecFon,thattheLDLisfoundatthesceneofthecrime.

AndagainitgetstotheassociaFonversuscausaFon.Imean,thepolicearealwaysfoundatthesceneofthecrime,andsoonecanmakeanargumentthatpolicehavecausedthecrime.It'sthesamekindofargument.There'sgoodevidencethatLDLworkswithwhitebloodcells,withmacrophagestotargetpathogens...totargetandbeabletokillbadvirusesandbacteriaandthatiswhy,infact,youfindLDLindamagedartery.Andyoualsofindwhitebloodcells.Wow,thisguyissayingthatthesewhitebloodcellsobviouslymustbeatherogenic.

Youfindcalciuminyourartery,well,calciummustbecausingheartdiseaseandyoufindlotsofbacteriainthesearteries,well,bacteriamustbecausing.LDLisfoundalongwithotherthingsinsidethearteriesandessenFally,there'ssomuchworkshowingthatLDLisapartoftheimmunesystem.Andwhenyoufindactuallybacterialremnants,thisisverycommonintheplaque,youfindbacterialremnants.

InfecFonisodenassociatedwithheartdisease.Andso,LDLisfoundwhereyouhaveinfecFon.AndsothathelpstounderstandLDL'srole,whichisapartofourimmunesystem.So,Iwouldsayatthispoint,thereisnoevidenceofcausaFon.And,infact,totakeittoanotherlevel,therearedifferentkindsofLDL.Andthisissoimportanttothelow-carbcommunitybecausewehavetoseethatissoobviousisthattheLDLchangesdependingontheenvironment.Andso,whatyoufindis--andthere'ssomuchworkbyRonKraussandothers--isthattheLDLchangesunderthecondiFonoflowbloodsugar.

So,youdon'thavethatabnormalLDL.Imean,natural,naFveLDLislarge--asIsay--largeandfluffy.Andwhenyousurrounditbysugarthatisglycatedandoxidized,well,youendupwithwhat'scalledsmall,denseLDL.Ithasmuchlesscholesterolinitandit'smuchmorereacFve.ThewaytothinkaboutthisisthatisnotthewayLDLissupposedtobe.

Thatsmall,denseLDLisassociatedwithanendothelium,withtheliningofthearterywallthat'sdamaged.Andso,whatyougotinconjuncFonwithtoomuchbloodsugar,toomuchbloodpressure,andthenyou'vegotdamagetothewall,theLDLitselfisdamaged.So,Iwouldactuallysayatthispoint,Ithinksmall,denseLDLispotenFally...thinkofitasatherogenic.Butthat'sbecauseit'scontribuFngtothenoise,it'scontribuFngtothedamage.ButthenaFveLDLinahealthypersonisnotcontribuFngtothedamage.

Bret:So,herewehavealifestyleintervenFonthatcanimprovemetabolicdisease,improveinsulinlevels,improveglucoselevels,cantakesmall,denseLDLandmakeitthelargerfluffyLDL,canlowertriglycerides,raiseHDL,lowerbloodpressure,itcandoalltheseimpressivethings.Yet,themedicalcommunityisafraidthatitcanalsoraiseLDL.So,wouldyousaythisisacompletelydifferentparadigmandenvironmentthanhasbeenstudiedbeforeandwe'reoutsideofanyrealmofevidencethatmedicinecanpointto?

David:Right,andwhatI'llbetalkingabouttodayisthatthere'ssoliKleworkrelaFngketogenicdiettosomanyfactorsthatpeopleassumehavetodowithheartdiseaseaswellasotherdisease.Imean,wecouldtalkaboutthemicrobiome.Peoplesayyou'vegottohavefiber;you'vegottohavevegetablesbecausethisbacteriamustfeedonthefiber.Well,noonethatIknowhaseverlookedatketogenicdiet-themicrobiome--So,wedon'tknowwhatreallyahealthymicrobiomelookslikeinsomeonethat'sketogenic.

ThesamewaywithLDL,there'sbeensufficientworklookingatLDLinpeoplewhoareketogenic.There'snoworkIknowoflookingatstaFneffectsinpeoplethatgolow-carb,andmy

guessiswhowantstofundthatstudy,becausethelow-carbwillblowawaystaFnsandthebenefits.So,thepersonwho'sgoinglow-carbinasense-andIsaythis-andyoudon'tknowwhattheoutcomewillbebecausethere'sneverbeenastudyonlow-carbandketogenicdietandcoronaryoutcome.

AndsomeFmespeople...reallyatrociousworksayingthatlow-carbactuallyincreasemortality,peoplediefromlow-carb...Trulyawfulepidemiologicalwork.Buttheansweriswedon'tknowthatketogenicdietwillreducecoronaryeventsbecausenoone'severshownthat.It'sreasonabletoassumethatbecausethebiomarkersallmoveintherightdirecFon,itshouldallbeprotectedfromcoronaryevents.AndtheLDLwillturnouttobecompletelyirrelevant.

Bret:So,theargumentofcoursesayingtheLDLsFllmaKers.Letmerephrasethatbecausethere'stwoarguments.Oneistheoneyoujustmade,wedon'tknowandwehavereasonstobelieveit'sgoingtobeprotecFve.

Theotheriswedon'tknow,sowereallyshouldn'ttreatthisasaspecialcircumstanceunFlwedoknow,andweshouldlumpitalltogether.Andthenwhenyou...ifyougothatrouteandthat'ssortofthemainstreammedicalcommunitywouldgothatroute,theyreallypointtothreeversionsofevidencetosupportthatanyelevatedLDLisgoingtoincreaseyourrisk.

There'stheMendelianrandomizaFon,thegeneFctrialswhichwesortoftalkedaboutwithFH,butthere'salsothePCSK9gain-of-funcFon,which...so,PCSK9basicallyisinvolvedinthedegradaFonoftheLDLreceptors.So,ifyouhaveahigherfuncFoningPCSK9,you'regoingtoactuallyhavemoreLDLreceptors,you'regoingtocleartheLDLfaster.

So,there'sapopulaFonthathadalowerriskofcardiovasculardiseasewiththatgain-of-funcFon,andthus,thedevelopmentofthePCSK9inhibitordrugs.So,justastudylikethatshowingbenefitfromlowerLDLwithhigherreceptoracFon,Imeanisthatenoughtosay,okay,thereismoreevidencetheretosaythatalowerLDLisbeneficialforsomepeople,sotherefore,weshouldaironthatside.

David:Yeah,theoriginalPCSK9workwasbasedonpeoplewhohadabnormalPCSK9andsotheyhadsignificantlyhigherLDLreceptordensitythereforelowerlevelsofLDLandsomewhatlowerlevelsofcoronaryevents.ButthatwasreallyrelatedtoarelaFvelysmallnumberofpeopleshowingnooverallmortalitydifferencebetweenthosewiththePCSK9abnormaliFesandthecontrols.Now,thereasonwas--andagain,targetisLDLbecausethat'swhereallthemoneyis.

TherecentworkhastargetedthePCSK9inhibiFngdrugs.Thethingthat'ssoimportanttorealizeiswhensomeonetakesthisdrug,whatthey'redoingisincreasingtheirLDLreceptordensity,okay,whichisabnormal.TherearebeauFfulnegaFvefeedbacksystemstomaintainLDLreceptorjusttotherightlevel.ThisdrugblockstheneaFvefeedbacksoyou'reincreasingLDL

receptors,meaningwhereisthatLDLgoingtogo?It'sgoingtobuyintothesereceptorsandgointothecell.

So,thecellwillbecomechockfullofLDLthatshouldn'tbethere.ThecardiologistslovethisbecausenowtheLDListakenoutoftheblood,soyoudropLDLlevelsby70%.ButthatLDLdoesn'tdisappear.TheLDLisbeingcrammedintolivercells,andulFmately-mypredicFon,they'veonlylookedliketwoyearsnow,andthere'snorealdifferenceincardiaceventswhenyoulookatthePCSK9trials.

MypredicFonisyou'regoingtoseeareallyscrewedupliver.You'regoingtoseeliverdamageinthesecellsthathavetoomuchcholesterolinsidethem,andso5,10yearsdowntheline,you'llbelookingatpeoplethatwillbeharmedbythisdrug.

Bret:Wow,that'sagreathypothesis.Andweneedlongertermstudiesbecausesofar,they'vebeenonlytwoyears.IndefenceofthePCSK9inhibitors,theytakethehighestriskpaFentsalreadyonastaFn,theygivethemthePCSK9inhibitors...theydroptheirLDLfurther,twobigstudies,oneshowedabouta1%reducFonincardiovasculareventswithnomortalitydifference.

Oneshoweda1.5%reducFonwithasmallmortalitybenefitattwoyears.So,theproponentssay,well,ifwehadthiseffectintwoyears,thinkoftheeffectwe'regoingtohaveat10years.Andofcourse,yourresponseiswhatarethesideeffectsandtheriskswillbeat10yearsandwedon'tknowtheanswertothatquesFon.

David:Wedon'tknowthatanswer.

Bret:So,there'stheMendelianstudy,thegeneFcpredisposiFon,andthenthere'stheepidemiologicalstudies,whichwesortoftouchedonbutstudieslikeMr.Fit,likeFraminghamwhichshowedtheassociaFonbetweentotalcholesterolandLDLandcardiovascularrisk.Although,asmallassociaFonbutanassociaFon...nowwhatabout--?

David:CanIinterruptyou?

Bret:Yes.

David:I'mgoingtobetalkingaboutMr.Fittoday.ThisisanamazingstudybecauseMr.Fitshoweda400%increaseincoronarymortalitybasedoncholesterollevelsgoingfromthelowesttohighest.Andit'sactuallyrightnowattheUniversityofMinnesotawebsite,youcanseeMr.Fit.

Andthisislookingatabout400,000middleagedmenandthey'vegottheircholesterollevelsandtheyhadfollowedthemforquiteafewyears,sevenyears.Themortalityratefromthelowesttothehighestmanwas1%,theactualmortalityratewas1%.Andtheyhavedistortedthistoturnitintoa400%mortalityrate.So,youmenFonedMrFit.ThatwasanabominaFonofscience.Framingham,Ithinkit'sallveryclear.

Whenyoulookatunhealthypeople,youlookatLDLinanunhealthyenvironment.PotenFally,it'seithertryingtosavetheunhealthyenvironmentorit'sapartofit.Butagain,itmeansthepaFentneedstosortoftakehislifeintohisownhandsorherownhands.Theyneedtotakecontroloftheirownenvironment,they'renotgoingtofindhealthinapillhasbeenmypoint.

Andso,thepersonwhohasdiabetesandisobesethinksthey'regoingtobeprotectedbytakingastaFn,welltheanswerissFllthey'regoingtobeveryunhealthy.

Bret:Yeah,andthat'soneofthetrapswefallintoasamedicalcommunity,justtryingtomakethingssosimpleforthepaFent.Makeiteasyforthem,andthateasydoesn'talwayswork.

David:Right,andso,forthepersonwho'sgoinglow-carb,improvingallthebiomarkers,andyetthey'resFllconcernedabouttheLDL.So,whenwelookagain,geMngbackto4S,whichIthinkissoincrediblyimportant.The4Strial,againrunbythedrugcompanies,andsoeventhoughI'mskepFcallookingatthedatagoingwow,thisisamazing.

Thepeoplehavethekindofbiomarkersyouseewithsomeoneonalowcarb-dietshowednobenefitwhatsoeverwithstaFntreatment.ThattellsyoualiKlesomethingaboutwhattopredictwhenwehavesomeonethatislow-carb,andtherefore,theydon'tneedthestaFnbecausethereisnobenefit.

Bret:Right,notprovingthatthelowcarbis--thelowcarbeliminatesthebenefit,becausethatwasn'ttestedbutyoucandrawahypothesiswiththatevidenceifyouwant.

David:Yeah,andthere'severyreasontobelievethatadverseeffectsdon'tdiscriminate.There'snoreasonwhythereshouldn'tbeadverseeffectsinsomeoneonlow-carb.AndsotheadverseeffectsarejustthestaFneffectsinphysiology.So,potenFally,they'relookingatthecogniFveeffectsandthemuscledamageandtheliverandkidneyeffectsaswell.

Bret:So,what'sinteresFng,though,whenyouspecificallythecogniFveeffectsandtheriskofdiabetes,Imeanthat'swhatlow-carbispurportedtobeabletobenefit,soIwouldliketothinkthatthatwouldbeasafetymechanismtohopefullyreducethosesideeffects;again,nodatabehindit.

Butitcertainlymakesempiricsense.So,ifIhavesomeoneonastaFn,Iwouldactuallywantthemonalow-carbdiet.OneforthemetabolicbenefitandtohelpwiththeLDLbeyondwhatastaFncoulddobutalsotoreducepotenFalsideeffects.Now,you'vepointedouttomethattherewasactuallyapapershowingsomebetacelldysfuncFoninthepancreas,somaybelow-carbisn'tgoingtobeenoughtohelpreducetheriskofdiabetes.Whatdoyouthink?

David:No,notatall.WhenyouthinkcogniFveeffects,thebrainmakesitsowncholesterolanditneedsthecholesteroltomakenewbraincellstomakememories.Well,weactuallypublishedapapershowingthatthestaFnsthatactuallyarelipophilic,whichmeanstheycangetintothe

brain,aretheonesassociatedwithadversecogniFveeffects.AndsothatstaFnisgoinginthebrainindependentofwhatevertheperson'sdietis.

Itinterfereswithbraincholesterolsynthesis,whichisessenFalformakingmemories.Andso,no,Idon'tthinkithasanythingtodowiththeperson'sdiet,thisisnowjustsimplephysiology.YouinterferewithcholesterolproducFoninthebrain,you'regoingtointerferewithbrainfuncFoning.

Bret:Yeah,andthecriFcssayit'sdifficulttomeasurethatbecauseifstaFnsarebeingusedinanelderlypopulaFon,elderlypeoplearegoingtogetreducedmemoryfuncFonanyway,howdowequanFfyitwithoutatrial,samething.Butitcomesdowntowhatareyoumostworriedabout.AreyoumostworriedaboutdevelopingAlzheimer'sdiseaseandcogniFvedeclineoraheartaKack,andasweagethatmaychange?

AndageissuchafascinaFngtopicwhenitcomestocholesterolandLDLingeneralbecausewhetherit'sFraminghamstudyorwhetherit'stheHonoluluHeartstudy,thereareanumberofdifferentstages.Takingittogethersuggeststhereisagainmaybeabimodalresponseinthe50sandyounger,there'saFghterassociaFonbetweenLDLandcardiovascularrisk,butinthe70sandover,thatassociaFonseemstoflip.Andyou'vebeenverybigaboutpoinFngthatout.So,tellusaboutthatdifference.

David:Yeah,so,whatIwouldsFllgowithisriskfactors.Whatyou'vegotthereareriskfactorsthatkillpeoplerelaFvelyyoung;smokersanddiabetes.TheseriskfactorspotenFallyinteractwithoxidizedandsmalldenseLDLatayoungerage.Youmakeitintoyour70sand80s,thenyoubasicallydon'thavethoseriskfactors,you'llmuchlesslikelyhavetheriskfactors.Andso,youdon'tseeobesepeopletypicallylivingintotheir80sand90s.

Andinfact,whatyoudofindisthatpeoplewiththehighestLDL--andthere'smorethan50yearsofstudies--peoplewiththehighestLDLactuallylivelongerthanthosewithlowLDL.Soagain,it'scompletelyinconsistentwiththeideathatLDLcausesharmonitsown.AndwepublishedthispaperinBMJOpenafewyearsago.

WereviewedandlookedateverypaperthatlookedatmortalityinrelaFontoLDLlevels.Therewasn'tasinglepaperthatshowedincreasemortalityinrelaFontothegeneralpopulaFoninolderpeople,that'sover60,withthehighestLDL,comparedtolowerLDL.So,that'scompletelyinconsistentwiththehypothesisthatLDLitselfiscausaltoheartdisease.Becauseit'snotkillingolderpeoplewhoareatthehighestriskofdeathfromstrokeandcoronaryheartdisease.

Bret:Yeah,thecomebackthereisthataspeoplegetsicker,theirLDLdeclines,soasthey'reontheirdeathbed,theirLDLisgoingtolower.

David:That'sreallythereversecausalityargument,whichreallycompletelyfailsbecauseit'snotlookingoneyearadersomeonehashadabloodtest,whichactuallydoeshappen.Someone

diesandyoufindtheyearbeforedeath,especiallyifit'sacancerdeath,LDLlevelsdodecline.Buttheseare10,20,30,even40year-longinsFtuFonalstudies.

Yougotabloodsamplefromsomeoneinthe50sor60s,and20yearslateryoulookatwho'sdiedandso,you'relookingyearsbeyondandthesearepeoplewhohadgoodhealthtobeginwithandyoueliminateanypeoplethathaddiedinthefirstcoupleofyears.You'resFlllooking20yearslater.ThosewhohadthehighLDLintheir50sand60saresFlllivinginthe80sand90s.

Bret:Yeah,so,again,observaFonaldatadoesn'tprovethatthehighLDLiswhatisimprovingtheirhealth,butcertainlyfliesinthefaceofhighLDLisdangerousandgoingtokillyou.

David:ThesearecompletelyinconsistentwiththeideathatLDLiscausal.It'ssosimple;essenFallyitrelatesmealsototheveganversuscarnivorediet.Veganslovetosayhowbadredmeatisforyou.IfonlythepeoplewhowereeaFngredmeatintheir40swoulddieofaheartaKack,itwouldbesosimple.

Well,ifthepeoplewhodemonizeLDLandsay,wellitcausesheartdiseaseandpeopledie,well,ifpeoplewithhighLDLwouldjustdie,intheir30sor40s,itwouldbesosimple.Buttheydon't.ThepeoplewithhighLDLarelivingintotheir80sand90sandeven100;we'regoingtohearthattodaythatthepeoplewhoare100yearsoldhavethehighestLDLofthosemeasured.Itjustsimplydoesn'tmakesensetothinkofthisascausingheartdisease.

Thereisanenvironment,atoxicenvironmentwhereyouwillfindLDL,especiallyintheyoungerpeople.Atoxicenvironmenthastodowithsmokingandhighbloodpressure.Andsoagain,ifwethinkofhighLDLcomingtotherescue,now,thereasonwhywewanttothinkofLDLbeingbeneficialisthatpeoplewithFHhavealowerrateofdeath.

Again,gottoemphasize,it'snotstaFns.Peopleintheir70shavea40%reducedrateofdeathbecausetheyhaveanormalrateofdeathfromcoronaryheartdiseasebutalowerrateofdeathfromnon-coronaryheartdiseaseintheir70s.LessdeathfrominfecFousdisease,lessdeathfromcancer.Thisishowyoulookatit;ifyouliveuptoyour70swithhighLDL,you'vegotamoreprotecFveimmunesystem,andnodifferenceincardiovasculardeath.

Bret:Yeah,it'sinteresFngtoseeit'scertainlynottalkedaboutitfromthatstandpoint.

David:There'snomoneyintalkingaboutLDLasprotecFve.

Bret:Right,andthenthere'stheconcernaboutFmeofexposure,thathassomethingtodowithit.WhetheryouhaveLDLinyour40sorLDLinyour70s,thatit'sadifferent...awholedifferentFmeofenvironment,adifferentFmeofexposure.butmorethanFmeofexposure,islikelywhatelseisgoingonfromotherriskfactorsandmetabolichealth.

David:ThepersonthathasFHandisintheir70shavehad70yearsofexposure.Andsoagain,theycallthatlifeFmeLDLburden.Andifyouactuallylookatsomeoftheworkyoucitedearlier,

they'resayingthatFHuntreated,youcanexpectpeopletobedyingintheir30sor40s.Andagainitsimplydoesn'thappen.

Bret:Right,right.Whereelsetogo?There'ssomuchtotalkabouthere,somuchmore.YouhavebeencriFcizedandanyFmeanybodygoesagainstthemainstreammedicine,ofcoursethey'regoingtobecriFcized.ButoneofthecriFcismshasbeenthatyou'recherrypickingyourstudiesandcherry-pickingthedata.Howdoyourespondtothat?

David:Yeah,IthinkthepeoplewhohavecriFcizestaFnsarecalledstaFndeniersarecherry-pickingthedataandactuallytheircriFcismgoesbeyondthat.TheyareactuallysayingthatthisisaninternetcultandtheysaythesepeoplearenoscienFsts.Ihavenobiaswhatsoever.Andagain,I'mjustascienFst.

Myfirstprioritywastoimprovemyownhealth.Ihavenoreasontobebiasedtopickthestudiesthatwouldbasicallymakeapointforme.IfIwanttobeshowingthatLDLisnotharmfulandIpickedthosestudies,butulFmatelyIdon'tcareaboutmyownhighLDL.Imean,itharmsmyownhealth.So,Ihavenobias.Ihavenointerestinthisotherthanlookingatgoodscience.IwanttolookatallthescienceandcometovalidconclusionsasascienFst.

BecauseIgetnomoneyfromthis,Ihavenopay,Ihavenofundingformyinterestincardiovascularwork.It'spurelyapersonalventureforme.Idon'twanttobebiased,Idon'twanttocherry-pickthedata.I'mlookingattheenFretyoftheliteratureandthencomingtoconclusions.

Bret:Yeah,andso,itleavesusasdoctorsandcliniciansfacingsomeonewho'simprovedtheirhealth,improvedtheirbloodpressure,improvedtheirmetabolicparametersbuthaveahighLDL,beingconfusedwhattodo.Theaveragedoctorouttherewhodoesn'tseethiseverydayisgoingtohavetheknee-jerkreacFonthatthisisdangerous.

SomeonesayignoretheLDLcompletelyandyoudon'thavetoworryaboutitandsomearetryingtoreallyputitintocontext.Butit'sbecauseofworklikeyou,becauseofZoeHarcombeandAseemMalhotraandMalcolmKendrick.PeoplearewillingtogoagainstthejuggernautofthemedicalcommunityandBigPharmatosaywait,weneedtolookatthisdifferently,thatallowsclinicianstheabilitytosay,okaythisissomethingdifferent,thereissomethingtothis.You'veputyourselfouttheretoreallyhelpmovethisforwardandyou'vegoKenalotofaKacksforit.Imean,hasyourskinreallythickenedfromthis?

David:Actually,I'mnotsurewhataKacksyou'retalkingabout.IthinkingeneralthestaFnadvocateshaveignoredtoagreatextentthepeoplewhohavebeencriFcs.IknowitcameoutthereanarFcleintheUKpaperrecentlyspecificallycriFcisingZoeHarcombe,MalcolmKendrick,UffeRavnskov.

TheyledmeoutofthisbecauseI'mnotaUKperson,butthatarFclewastrulyawful.Imean,aKackingthemandsaying,youknow,howwrongtheyare.Butreally,Idon'teventhink...we'renotcomingoutagainstPharma,speakingforthemaswell,thereisnobiaswhatsoever.IamnotlookingtopraiseLDLandIwouldgrantthatthesmalldenseLDL,whichisanabnormalLDL,maybecontribuFngtodiseasealongwith--it'salmostlikeLDL,smalldenseLDLmayverywellbethegasonthefire,butitdidn'tmakethefire.

So,Idon'ttakeitpersonally.Andoh,IactuallydorecallthattherewasacardiologistatDukeUniversity,whowroteanotespecificallyaboutmesayingthatIwascausingharmtoherpaFents,thatpeoplewouldalldiebecauseIwasexplaininghowstaFnshaveadverseeffectsandhowoveralltheadverseeffectsaregreaterthanthebenefits,towhichIwrotearebuKaltothatcardiologisttoreply.

Soyes,therewasoneexampleIcanthinkofwhichI'vepersonallybeenaKacked.Butthenagaintome,it'salljustscience,it'snotsomethingItakepersonally.

Bret:Ithinkthat'sagoodperspecFve,it'sallscience.Andactually,justtotalkquicklyaboutthatarFcleintheDailyMailwheretheycomparedLDLcholesteroldenierstotheanF-vaccinemovement.WhichIthinkisfascinaFngbecausetheydrewthatcomparisontothedoctorwhowasfalsifyingdataaboutthevaccines.

AndIthoughtthatwasawful,Ithoughtthatwasclearlyoversteppingtheboundsbecauseyouarenotfalsifyinganytdata.Youarehelpingusseedatathatexists,thatotherpeopledid,that'seitherbeingignoredorbeenpromotedinadifferentway,you'rejusthelpingusre-seethatdata;there'snofalsificaFonthere.

David:Well,there'sastrategyincombat,whichistodehumanizeyourenemy.Andwhatpeopledoissay,they'renotrealscienFsts,soyoucancallthemaninternetcult.Youcansaythatthey'rejustliketheanF-vaccinepeople.Andthatway,inasense,youdehumanizethem,youdenigratethemandthereforethey'llhavelesscredibilityandthat'sjustwrong.WhatwehavetodoistalkaboutscienceandI'mopentoanyaspectofthescience.

Fromtheverybeginning,IjustwantedtolearnhowisitIcanmakemyselfhealthier.AndwhatIrealizeisthatIdidignoretheLDLandIdidignoremyLDLnow,whichisquitehighandwhatIreallycareaboutandwhatmaKersisbloodsugartriglycerides,HDLisimportantbutitisthecanaryinthecoalmine.Youdon'twanttotakeadrugthat'llraiseyourHDL.HDLtellsyouaboutyourlifestyle,triglyceridestellyouaboutyourlifestyletellingyouyou'reconsumingtoomanycarbohydrates.LDLdoesn'ttellyoumuch.

Bret:Yeah,andIthinkthat'sagreatpointandagreatwaytosortofsummarizethis,isarewetalkingaboutcausaFonorarewetalkingaboutmarkersofourunderlyinghealthandourunderlyinglifestyle?Thatimproveswithalow-carblifestyle.Yourmarkersimproveandthenthatshouldgiveustheevidencethatourhealthdowntheroadimproves.Ihopethatweget

thatlong-termevidenceandintheabsenceofitthere'scertainlyreasontobelieveit'sgoingtobeso.

David:That'sagreatsummary.

Bret:Okay,good.Well,thankyouforjoiningme,Ireallyappreciateit,andwherecanpeoplehearmoreaboutyou,aboutyourthoughtsandyourresearch?

David:Well,youknow,Idon'tsellbooks.Idon'thaveabook,Idon'thaveablog,Idon'thaveawebsite.ThisformeissFll,it'spersonal.IhavemydayjobinwhichIsFlldomyneuroscienceresearch.Iwillbe...Iactuallydon'thaveanytalksplannedforthefuture.Forme,it'simportanttowritemedicalpublicaFons,soI'mintheprocessofwriFngmorepaperstobepublishedinmedicaljournals.

So,I'mreallyapproachingthisasascienFst.Idon'tpromotemyselfasanything,Iamnotmakinganymoneyfromthis,soIwelcometheopportunitytotalkaboutitwithyou,thankyousomuchforinviFngme,butfrankly,Idon'thaveanythingtoshareasfaraspromoFngmyself.

Bret:That'sabreathoffreshair,wedon'thearthatveryoden.Thankyoufordoingthat.

David:You'reverywelcome.