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1.Thefailureofahigh-profilecholesteroldrughasthrownaspotlightonthecomplicatedmachinerythatregulatescholesterollevels.Butmanyresearchersremainconfidentthatdrugstoboostlevelsof'good'cholesterolarestilloneofthemostpromisingmeanstocombatspirallingheartdisease.

2.DrugcompanyPfizerannouncedon2Decemberthatitwascancellingallclinicaltrialsoftorcetrapib,adrugdesignedtoraiseheart-protectivehigh-densitylipoproteins(HDLs).Inatrialof15000patients,asafetyboardfoundthatmorepeoplediedorsufferedcardiovascularproblemsaftertakingthedrugplusacholesterol-loweringstatinthanthoseinacontrolgroupwhotookthestatinalone.

3.Thenewscameasakickintheteethtomanycardiologistsbecauseearliertestsinanimalsandpeoplesuggesteditwouldlowerratesofcardiovasculardisease."Therehavebeennoredflagstomyknowledge,"saysJohnChapman,aspecialistinlipoproteinsandatherosclerosisattheNationalInstituteforHealthandMedicalResearch(INSERM)inPariswhohasalsostudiedtorcetrapib."Thiscancellationcameasacompleteshock."

4.TorcetrapibisoneofthemostadvancedofanewbreedofdrugsdesignedtoraiselevelsofHDLs,whichferrycholesteroloutofartery-cloggingplaquestotheliverforremovalfromthebody.Specifically,torcetrapibblocksaproteincalledcholesterolestertransferprotein(CETP),whichnormallytransfersthecholesterolfromhigh-densitylipoproteinstolowdensity,plaque-promotingones.Statins,incontrast,mainlyworkbyloweringthe'bad'low-densitylipoproteins.

Underpressure

5.Researchersarenowtryingtoworkoutwhyandhowthedrugbackfired,somethingthatwillnotbecomeclearuntiltheclinicaldetailsarereleasedbyPfizer.Onehintliesinevidencefromearliertrialsthatitslightlyraisesbloodpressureinsomepatients.Itwasthoughtthatthismildproblemwouldbeoffsetbytheheartbenefitsofthedrug.Butitispossiblethatitactuallyprovedfatalinsomepatientswhoalreadysufferedhighbloodpressure.Ifbloodpressureistheexplanation,itwouldactuallybegoodnewsfordrugdevelopersbecauseitsuggeststhattheproblemsarespecifictothiscompound.OtherprototypedrugsthatarebeingdevelopedtoblockCETPworkinaslightlydifferentwayandmightnotsufferthesamedownfall.

6.ButitisalsopossiblethatthewholeideaofblockingCETPisflawed,saysMotiKashyap,whodirectsatherosclerosisresearchattheVAMedicalCenterinLongBeach,California.WhenHDLsexcretecholesterolintheliver,theyactuallyrelyonLDLsforpartofthisprocess.SoinhibitingCETP,whichpreventsthetransferofcholesterolfromHDLtoLDL,mightactuallycauseanabnormalandirreversibleaccumulationofcholesterolinthebody."You'reblockingaphysiologicmechanismtoeliminatecholesterolandeffectivelyconstipatingthepathway,"saysKashyap.Goingup

7.Mostresearchersremainconfidentthatelevatinghighdensitylipoproteinslevelsbyonemeansoranotherisoneofthebestroutesforhelpingheartdiseasepatients.ButHDLsarecomplexandnotentirelyunderstood.Oneapproveddrug,calledniacin,isknowntobothraiseHDLandreducecardiovascularriskbutalsocausesanunpleasantsensationofheatandtingling.Researchersareexploringwhethertheycanbypassthissideeffectandwhetherniacincanlowerdiseaseriskmorethanstatinsalone.Scientistsarealsoworkingonseveralothermeanstobumpuphigh-densitylipoproteinsby,forexample,introducingsyntheticHDLs."Theonlythingw

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