BREHM RANDY J SEELEY STEPHEN R DANIELS AND DAVID A DALESSIO University of Cincinnati and Childrens Hospital Medical Center Cincinnati Ohio 45221 Untested alternative weight loss diets such as very low car bohydrate diets have unsubstantiated efficac ID: 13906
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ARandomizedTrialComparingaVeryLowCarbohydrateDietandaCalorie-RestrictedLowFatDietonBodyWeightandCardiovascularRiskFactorsinHealthyWomenBONNIEJ.BREHM,RANDYJ.SEELEY,STEPHENR.DANIELS,DAVIDA.DALESSIOUniversityofCincinnatiandChildrensHospitalMedicalCenter,Cincinnati,Ohio45221Untestedalternativeweightlossdiets,suchasverylowcar-bohydratediets,haveunsubstantiatedefficacyandthepo-tentialtoadverselyaffectcardiovascularriskfactors.There-fore,wedesignedarandomized,controlledtrialtodeterminetheeffectsofaverylowcarbohydratedietonbodycomposi-tionandcardiovascularriskfactors.Subjectswererandom- HEINCIDENCEOFobesityintheUnitedStateshasrisencontinuouslyoverthelastseveraldecades,andtheassociatedmedicalandeconomiccoststosocietyaresubstantial(13).Despiteconsiderabledesireonthepartofobeseindividualstoloseweight(4)andtheclearhealthbenefitsofdoingso(5),therearecurrentlynoproven,ef-fectiveapproachesformeaningfulandlong-termweightlossformostoverweightindividuals(2).Dietarystrategiessup-portedbythemajorityofphysiciansanddietitians,whichemphasizerestrictionoffatintake,areassociatedwithonlymodestweightlossandpoorlong-termcompliance(6,7). Abbreviations:DEXA,Dualenergyx-rayabsorptiometry;HDL,highdensitylipoprotein;LDL,lowdensitylipoprotein.TheJournalofClinicalEndocrinology&Metabolism88(4):16171623PrintedinU.S.A.Copyright©2003byTheEndocrineSocietydoi:10.1210/jc.2002-021480 SubjectassessmentswereconductedattheGeneralClinicalResearchCenterofCincinnatiChildrensHospitalMedicalCenterbytrainedresearchnurses.Subjectswerescreenedbymedicalhistoryandmea-surementsofheight,weight,bloodpressure,andfastingglucose,andeachwasgivenanelectrocardiogram.Bloodpressuremeasurementsweremadebyauscultationusinganappropriatesizecuffwiththesubjectseatedquietly.Individualsmeetingthecriteriaforstudypar-ticipationwereenrolledinthestudybytheresearchassistantortheprincipalinvestigator.Subjectsgaveasampleoffastingbloodandhadbodyfatmeasuredbydualenergyx-rayabsorptiometry(DEXA)usingatotalbodyscanner(4500A,Hologic,Inc.,SanFrancisco,CA).DEXAscanswereconductedatthebodycompositioncorelaboratoryoftheGeneralClinicalResearchCenterbytrainedtechnicians.Eachofthesemeasureswasrepeatedafter3and6monthsofdiet.StudydietsTheprimaryobjectiveofthestudywastocomparetheeffectsofaverylowcarbohydratedietandacalorie-restricted,lowfatdietonbodycompositionandcardiovascularriskfactors.Therefore,aftereachblockofsubjectswasassessed,theprincipalinvestigatorusedarandomnum-bertabletorandomlyassignthosesubjectstooneoftwodiets.Onegroupofdieterswasinstructedtofollowanadlibitumdietwithamaximumintakeof20gcarbohydrate/d(8).Itwasanticipatedthatthisdietwouldinduceketosis.After2wkofdieting,subjectswerepermittedtoincreasetheirintakeofcarbohydrateto4060g/donlyifself-testingofurinaryketonescontinuedtoindicateketosis.Theothergroupofdieterswasinstructedonacalorie-restricted,moderatelylowfatdietwitharecommendedmacronutrientdistributionof55%carbohydrate,15%protein,and30%fat.CalorieprescriptionswerebasedonbodysizeandcalculatedusingtheHarris-Benedictequation(24).Tworegistereddietitiansdelivereda3-monthinterventionaimedatpromotingdietarycompliance.GroupmeetingswithsubjectsonthesamedietwereheldbiweeklyontheUniversityofCincinnaticampusandaddressedcookingtips,stressmanagement,behaviormodification,andrelapseprevention.Onalternatingweeks,subjectsmetforindivid-ualcounselingsessionsduringwhichtheirassigneddietitianreviewedtheir3-dfoodrecordsfromthepreviousweek,analyzedbyNutritionistV(FirstDataBank,SanBruno,CA),andprovideddietaryrecommen-dationsandpositivereinforcement.Subjectswereadvisedtocontinuetheirbaselinelevelofactivity.Tocontrolforpossiblebias,eachdietitianwasassignedsubjectsfromeachdietgroupforcounselingandalter-natedasthemeetingfacilitatorforbothgroupsofdieters.Beforeeachweeklysession,subjectssubmitted3-dfoodrecordsandwereweighedonasingleelectronicscale(Tanita,ArlingtonHeights,IL).Bloodpres-surewasmeasured,andassessmentofurinaryketoneswasperformedusingKetostix(BayerCorp.,Elkhart,IN).Attheendofthe3-monthintervention,subjectswereinstructedtocontinuewiththeirweightlossefforts,butwithoutscheduledcontactwiththedietitiansuntilthe6-monthassessment.Determinationoftotalcholesterol,LDLcholesterol,highdensityli-poprotein(HDL)cholesterol,glucose,insulin,leptin,tyrate,andtriglyceridesinfastingplasmaweremadeusingconventionalmethods(2527).TheresultsofDEXAandbiochemicalanalysesweremadebypersonnelblindedtothegroupassignmentofthesubjects.Baselinecharacteristicswerecomparedbetweenthetwogroupsus-tests.Toassesstheeffectsofthediets,two-wayrepeatedmeasuresANOVA,withtimeastherepeatedfactor,wasperformedusingthesoftwarepackageSAS(version8.2,SASInstitute,Inc.,Cary,NC).Thelevelofsignificancewassetat0.05fortestingthemaineffectsofdietandtimeandtheinteractioneffect.Ifthemaineffectwassignificant,theBonferronimultiplecomparisonwasimplementedtodeterminethespecificdifferences.Iftheinteractionwassignificant,theBonferroniadjustmentwasusedtokeeptheoveralllevelofsignificanceat0.05.Differencesbetweengroupsareindicatedonlywhenthereisasignif-icantinteractionbetweendietandtime.Bodyweight,biochemicalpa-rameters,andDEXAmeasurementswereanalyzedforthe42subjectswhocompletedthestudy(thoseforwhomfollow-updatawereavailable).Bodyweightwasalsoanalyzedfortheentirerandomizedcohort.Inthisintentiontotreatanalysis,theinitialweightsforthesubjectswhowithdrewfromthestudywereusedastheirfollow-upweightsat3and6months(anassumptionof0kgofweightloss).Dataarepresentedasthemeanandunlessdesignatedotherwise.SubjectswererecruitedthroughadvertisementsfromMay2000throughJanuary2001.Fifty-threeobesefemales(13African-Americansand40Caucasians)wereenrolledinthestudy.Volunteerswereenrolledin3successivegroupsof14,20,and19subjectsat3-to4-monthintervals.Forty-twoofthe53subjects(79%)completedthe6-monthstudy,with4drop-outsfromtheverylowcarbohydratedietgroupand7drop-outsfromthelowfatdietgroup(Fig.1).Themajorityofsubjectsdiscontinuingthestudyciteddifficultymaintainingthescheduledvisitsastheprimaryreason,andfollow-upmeasurementswereobtainedforonly1ofthethesewomen.Onesubjectfromeachdietgroupdroppedoutduetodislikefortheirassigneddiet.Ageandanthropometriccharacter-isticsofthosesubjectscompletingthestudyareincludedinTable1.NutrientintakeSubjectsrandomizedtothelowfat(n20)andtheverylowcarbohydrate(n22)dietgroupsconsumedsimilaramountsofcaloriesattheinitiationofthediets(1707and1608123kcalrespectively)withsimilardistributionofmacronutrients(Fig.2).Basedontheresultsoftheweeklyfoodrecords,subjectscompliedwiththeirassigneddiets.Althoughsubjectsonthecarbohydrate-restricteddietwere .1.Flowchartofsubjectsinthecontrolled,randomizedweightlosstrial.JClinEndocrinolMetab,April2003,88(4):16171623Brehmetal.TrialofaVeryLowCarbohydrateDiet notspecificallyaskedtolimitcaloricintakeaswerethoseonthelowfatdiet,bothgroupsreportedadecreaseincaloricintakeofapproximately450caloriescomparedwithbaseline.Althoughcaloricintakesinthetwogroupsweresimilar,theproportionsofcarbohydrate,protein,andfatconsumeddif-fereddramatically.At3months,caloricintakeintheverylowcarbohydratedietgroupwasdistributedas15%carbo-hydrate,28%protein,and57%fat.Incontrast,thelowfatdietgrouphaddailycaloriesdistributedas54%carbohydrate,18%protein,and28%fat.At3months,theverylowcarbo-hydratedietgroupconsumedsignificantlylesscarbohy-drate,vitaminC,andfiberandsignificantlymoreprotein,totalfat,saturatedfat,monounsaturatedfat,polyunsatu-ratedfat,andcholesterolthanthelowfatdietgroup(forallcomparisons).At6months,thetwogroupsstilldif-feredsignificantlyformostofthesemeasures(Table2).WeightandbodycompositionBodyweightandbodyfatinthelowfatandverylowcarbohydrategroupsweresimilaratbaseline(Table1).Aftertheinitiationofthediets,bothgroupshadadecreaseinbodyweightthatwasmorerapidintheearlierweeksofobser-vationandbecamelesspronouncedasthestudyprogressed(Fig.3).Thewomenintheverylowcarbohydrategrouplostanaverageof7.60.7kgafter3monthsand8.51.0kgafter6monthsofdiet.Womenfollowingthelowfatdietlost0.8and3.91.0kgat3and6months,respectively.Theamountofweightlostwassignificantlygreaterintheverylowcarbohydrategroupcomparedwiththelowfatgroup,whetheranalyzedasintentiontotreatwithallrandomizedsubjectsintheanalysis(0.001at3and6months)orwithonlythesubjectswhocompletedthetrial(Fig.3;at3and6months).BodycompositiondataforthetwogroupsofwomenareshowninTable3.Bothfatmassandfat-freemassdecreasedsignificantly(0.001)inthetwogroupsoverthecourseofthetrial.However,similartobodyweight,fatmassandleanbodymassdecreasedsignificantlymoreintheverylowcarbohydrategroupcomparedwiththelowfatgroupatboth3and6months(0.01).Thereducedfatmasscomprised60%oftheweightlostinbothgroups.Therewerenochangesinbonemineralcontentoverthecourseofthestudy. .2.Meancaloricintakeanddistributionofmacronutrients(aspercentageoftotalkilocalories)ofwomenbeforeandat3and6monthsofeitherverylowcarbohydrateorlowfatdiets.Graylines,Carbohydrate;,protein;,fat.TABLE1.Ageandanthropometriccharacteristicsbeforedietinitiationofsubjectswhocompletedthe6-monthstudy Lowfatdietgroup(n20)Verylowcarbohydratedietgroup(nMean()RangeMean()RangeAge(yr)43.10(8.56)31.0858.5544.22(6.84)29.0153.490.64Height(m)1.65(0.05)1.581.751.66(0.07)1.541.790.58Weight(kg)92.31(6.0)83.4105.291.20(8.4)76.9113.70.6134.04(1.83)29.5736.0533.17(1.83)30.8737.030.13Bodyfat(%)41.34(2.70)37.347.641.26(3.67)36.250.10.93Bodymassindex(BMI)weight(kg)/height(m)etal.TrialofaVeryLowCarbohydrateDietJClinEndocrinolMetab,April2003,88(4):1617 CardiovascularriskfactorsTherewerenoelectrocardiographicabnormalitiesinanyofthesubjectsduringthestudy.Bloodpressure.Thebloodpressuresinthetwogroupswerewithinthenormalrangeattheoutsetofthestudyandre-mainedsothroughoutthestudy(Table4).Significantdif-ferencesinbloodpressurewerenotfoundbetweenthegroupsduringthestudy.Plasmalipids.Meanplasmaconcentrationsoftotalcholes-terol,triglycerides,LDLcholesterol,andHDLcholesterolwerenormalineachofthetwogroupsbeforestartingthediets.Asignificantinteraction(0.05)wasfoundforplasmatriglycerides,butthiswasprobablyduetoadiffer-encebetweenthegroupsatbaseline.Differencesinplasmalipidsbetweenthegroupswerenotdetectedatthe3-or6-monthassessments(Table4).Significanttimeeffects(0.01)foralloftheplasmalipidsindicatedthatthesubjectsimprovedtheirlipidprofilesduringthecourseofthestudy,withsignificantdecreasesintotalcholesterol,LDLcholes-terol,andtriglyceridesat3monthsandsignificantincreasesinHDLcholesterolat6months(Table4).Fastinghormonesandsubstrates.Fastingglucoseandinsulindidnotdifferbetweenthetwogroupsatthe3-or6-monthassessments.However,significanttimeeffectsforglucose0.001)andinsulin(0.0001)indicatethattheglucoseandinsulinlevelsdecreasedsignificantlyinthewomenonbothdietsoverthe6-monthstudy(Table5).Therewerenodifferencesinleptinlevelsbetweenthetwogroups(Table5).Yetasignificanttimeeffect(0.0001)showsthatplasmaleptinlevelsdecreasedsignificantlyinbothgroupsofsub-jectsat3months(Table5).Asignificantdifferencebetweenthegroupswasdetectedforplasma-hydroxybutyrate,withthisketoneincreasingsignificantlymoreintheverylowcarbohydrategroupat3months(0.0005;Table5).Weeklytestingofurinaryketoneswaspositiveinthema-jorityofsubjectsontheverylowcarbohydratedietandnegativeinthoseonthelowfatdiet.Theresultsofthisstudydemonstratethataverylowcarbohydratediet,takenwithoutaspecifiedrestrictionof .3.Meanbodyweightofwomenrandomizedtoverylowcarbo-hydrateandlowfatdietsoverthecourseofthe6-monthtrial.Thefirsttimepoint(wk1)representsthesubjectsbodyweightsimmediatelybeforerandomization.Follow-upforthe2groupsincluded17subjectsinthelowfatgroupand1922subjectsintheverylowcarbohydrategroup.Forsubjectsmissingafollow-upvisit,theirlastrecordedweightisincludedinthecalculationofthegroupmean.*,Valuedifferentfromverylowcarbohydratedietgroup(icantinteractionoftimeanddiet),TABLE2.Meannutrientintakeofwomenbeforeandafter3and6monthsofdieting Baseline3months6monthsRecommendedintakeVerylowcarbohydratedietgroup(nCarbohydrate(g)188.9241.1355%totalkcalProtein(g)63.3278.1515%totalkcalTotalfat(g)65.7971.3230%totalkcalSaturatedfat(%)12.420.710%totalkcalMonounsaturatedfat(%)10.120.610%totalkcalPolyunsaturatedfat(%)6.29.010%totalkcalCholesterol(mg)215.25460.87VitaminC(mg)70.2835.6558.4675Folate(g)155.14139.65195.89400Calcium(mg)590.81444.20739.011000Fiber(g)12.035.27Lowfatdietgroup(nCarbohydrate(g)200.06169.40162.8855%totalkcalProtein(g)66.0655.9354.741015%totalkcalTotalfat(g)71.6039.7743.1330%totalkcalSaturatedfat(%)12.39.911.110%totalkcalMonounsaturatedfat(%)10.19.07.310%totalkcalPolyunsaturatedfat(%)5.84.53.710%totalkcalCholesterol(mg)273.51169.00182.21VitaminC(mg)76.9294.1853.1475Folate(g)170.95221.72193.90400Calcium(mg)607.25567.19662.621000Fiber(g)12.4813.3112.3520Recommendedintakeforfemales,1950yrofage.Denotesvaluesdifferentfromthelowfatdietgroup,Denotesvaluesdifferentfromthelowfatdietgroup,JClinEndocrinolMetab,April2003,88(4):16171623Brehmetal.TrialofaVeryLowCarbohydrateDiet caloricintake,iseffectiveforweightlossovera6-monthperiodinhealthy,obesewomen.Comparedwiththelowfatgroup,whofollowedadietconformingtocurrentlyrecom-mendeddistributionsofmacronutrientcalories,theverylowcarbohydrategrouplostsignificantlymoreweight,afindingthatwasapparentbothwhenthewomencompletingthedietwereconsideredaloneandwhenthedatawereanalyzedusingintenttotreatprinciples.Inaddition,despiteeatingahighpercentageofcaloriesasfatandhavingrelativelyhighintakesofsaturatedfatandcholesterol,thewomenintheverylowcarbohydrategroupmaintainednormallevelsofbloodpressure,plasmalipids,glucose,andinsulin.Thesedatasuggestthatthedeleteriouseffectsofdietscontainingahighpercentageoffatonbodyweightandcardiacriskfactorsaremitigatedbyrestrictionofcaloricintakeandas-sociatedweightloss.Thesubjectsrecruitedforthisstudywerehealthyadultwomenwhoweremoderatelyobesebycurrentstandards.AssuchtheywererepresentativeofmanyAmericanwomenwhoembarkonweightlosseffortseachyearusingtheal-ternativedietaryplanscurrentlymarketedinthiscountry.Althoughcompliancewiththedietswasassessedprimarilybydietaryrecords,thesedataaresupportedbymoreobjec-tivemeasures.Forexample,theaverage3-monthweightlossinthelowfatdietgroup(4kg)iswhatwouldbeexpectedforindividualsdecreasingtheirdailycaloricconsumptionbyabout400kcal(28),approximatelytherestrictionthesewomenreportedmaking.Inaddition,therewasasignificantcorrelationbetweenreportedchangesincaloricintakeandweightloss(r0.001).Finally,thepresenceofmeasurableketonemiaandketonuriaintheverylowcar-bohydrategroupisconsistentwithseverecarbohydratere-strictionandwasnotseeninthelowfatdieters.Thus,webelievethattheoutcomesofthisstudycanbeattributedprimarilytodifferencesintheprescribeddietsofthetwogroupsandareapplicabletothelargenumberofobese,butotherwisehealthy,Americanwomenexploringverylowcar-bohydratediets.Oneconclusionofpreviousreportsonlowcarbohydratedietswasthattheincreasedweightlosswasduetothediuresisthataccompaniesseverecaloricrestrictionorwasduetodecreasedbodywater,presumablyaccompanyingdepletionofstoredglycogen(29,30).However,thesestudieswereofveryshortduration,from12wkinlength.Mostdietsthathaveasignificantrestrictionofcaloriescauseasodiumdiuresisthatoccursoverthefirstwkor2oftheiruse,andinfact,wenotedthemostrapidweightlossinbothgroupsoverthisperiod.Thelowfatdietgrouplost1.6kginthefirst2wk,representing38%oftheirmeanweightlossduringthefirst3monthsofthestudy.Theverylowcarbo-hydrategrouplost3.0kgduringthefirst2wk,or39%oftheirmean3-monthweightloss.Weanalyzedbodycompositionat3and6monthsofdieting,wellaftertheexpectedperiodofdiuresis.Ouranalysisofbodycompositionshowedthattheweightlostintheverylowcarbohydratedietgroupconsistedofasimilarpercentageoffatmassasinthelowfatdietgroup.Thus,wethinkitisveryunlikelythatdifferencesinweightbetweenthetwogroupsat3and6monthsarearesultofdisproportionatechangesinbodywaterintheverylowcarbohydratedieters.Themechanismoftheenhancedweightlossintheverylowcarbohydratedietgrouprelativetothelowfatdietgroupisnotclear.Basedondietaryrecords,thereductionindailycaloricintakewassimilarinthetwogroups.Forthegreaterweightlossintheverylowcarbohydrategrouptobestrictlyaresultofdecreasedcaloricconsumption,theywouldhavehadtoconsumeapproximately300fewercalories/doverthefirst3monthsrelativetothelowfatdietgroup(28).Althoughtheinaccuracyofdietaryrecordsforobeseindividualsiswelldocumented(31,32),itseemsunlikelythatasystematicdiscrepancyofthismagnitudeoccurredbetweengroupsofsubjectswhowerecomparablyoverweight.Therefore,itisdifficulttoexplainthedifferencesinweightlossbetweenthetwogroupsprimarilyasafunctionofdifferingcaloricintake.Despiteinstructionstomaintainbaselinelevelsofactivity,itispossiblethatthewomenintheverylowcarbohydratedietgroupexercisedmorethanthoseinthelowfatdietgroup.Additionally,itispossiblethatconsumingaverylowcar-bohydratedietincreasesrestingorpostprandialenergyex-penditure.Thepossibilitythatdifferencesinthemacronu-trientcompositionofthedietalterenergyexpenditureisaninterestingquestionthatbearsfurtherinvestigation.Anotherunexplained,butimportant,observationwasthespontaneousrestrictionoffoodintakeintheverylowcar-bohydratedietgrouptoalevelequaltothatofthecontrolsubjectswhowerefollowingaprescribedrestrictionofcal-ories.Thisraisesthepossibilitythattheverylowcarbohy-dratedietmayhavebeenmoresatiating.Previousstudieshavesuggestedthat,calorieforcalorie,proteinismoresa-tiatingthaneithercarbohydrateorfat(33,34),anditmaybethatthehigherconsumptionofproteinintheverylowcar-bohydratedietgroupplayedaroleinlimitingfoodintake.Anotherexplanationforrestrictedfoodintakeintheverylowcarbohydrategroupisthatfoodchoiceswereprobablygreatlylimitedbytherequirementsofminimizingcarbohy-drateintake,andthatdietaryadherencepersemayhaveforcedcaloricrestrictionduetopracticalfactors.Althoughithasbeenproposedthatketosisdevelopingfromseverecar-bohydrateintakecontributestoadecreaseinappetite(8),thisdoesnotseemlikelybasedonourdata.AlthoughthewomenTABLE3.Means(and)ofbodycompositionmeasuresofwomenbeforeandafter3and6monthsofdieting Verylowcarbohydratedietgroup(n22)Lowfatdietgroup(nBaseline3months6monthsBaseline3months6monthsBodyfat(g)37,327.0(4,787.7)33,035.237,827.9(2,651.8)35,305.5(3,602.4)35,853.3(4,125.2)Bonemineralcontent(g)2,782.8(321.2)2,799.2(313.7)2,775.7(312.7)2,819.7(284.7)2,827.7(288.2)2,792.8(296.7)Leanbodymass(g)50,385.9(5,999.9)47,565.351,026.8(5,010.4)50,181.3(5,124.9)50,295.9(5,197.5)Denotesvaluedifferentfromthelowfatgroup(,significantinteractionoftimeanddiet),etal.TrialofaVeryLowCarbohydrateDietJClinEndocrinolMetab,April2003,88(4):1617 followingtheverylowcarbohydratedietdevelopedsignif-icantketonemia,theelevationofcirculatingtyratewasmild,wellbelowwhatisseeninotherclinicalstatesofketosis,suchasstarvationanddiabeticketoacidosis(26,35),andwasnotedonlyat3months.Inaddition,therewasnocorrelationbetweenthelevelofplasmabutyrateandweightloss(rThisstudyprovidesasurprisingchallengetoprevailingdietarypractice.Thecurrentstandardsforhealthyeatingincludereducingtotalfatintaketolessthan30%oftotalcaloriesanddecreasingsaturatedfatintaketolessthan10%.Thisrecommendationisbasedonalargebodyofprimarilyepidemiologicaldataandisintendedtolowerplasmacho-lesterol(23),buthasbeenextendedbysomeexpertsasameanstodecreasetheriskofobesity.However,thesubjectsontheverylowcarbohydratedietexperiencedsignificantlymoreweightlossthanthelowfatgroupandmaintainedcomparablelevelsofplasmalipidsandothercardiovascularriskfactorswhileconsumingmorethan50%oftheircaloriesasfatand20%assaturatedfat.Thesedataindicatethattheroleofmacronutrientdistributioninindividualswhoareonweightlossdietsneedstobefurtherinvestigated.Inpartic-ular,itseemslikelythatintheshortterm,adecreaseintotalcaloricintakewithaccompanyingweightlosshasagreaterimpactonnutritionallysensitiveparameterssuchasplasmalipidsthandothemacronutrientconstituentsofthediet.Theresultsofthisstudyareapplicabletohealthypersons,butextensionofourfindingstosubjectswithestablishedcardiovascularriskfactorsshouldnotbemadewithoutfur-thercarefulinvestigation.Themeanlevelsofbloodpressure,glucose,andplasmalipidsinoursubjectswerenormaland,infact,lowerthantheaveragevaluesforAmericanadults(36).Itispossiblethatverylowcarbohydratediets,withhighrelativeintakesofproteinandfat,wouldhavedeleteriouseffectsinsubjectswithhyperlipidemia,diabetes,orothermetabolicdisorders.Althoughadvocatesforverylowcarbohydratedietsarelikelytoembracetheresultsofthisstudy,severalpointsofcautionneedtobeemphasized.First,asinglestudyofaspecificdietaryregimencannotprovideafullassessmentofsafetyandefficacy.Despitethisstudybeingthelongestran-domized,controlledtrialofaverylowcarbohydratedietreported,ourresultsarestilllimitedbythe6-monthtimeframe.Whethertheverylowcarbohydratedietwillproducesustainedweightlossandcontinuedimprovementincar-diovascularriskfactorsoverlongerperiodsoftimeremainstobedetermined;thegradualincreaseincarbohydratecon-sumptioninthefinal3monthsofthestudysuggeststhatsomedegreeofrecidivismislikelyinpersonsonthisdiet.Inaddition,increaseddietaryfathasbeenlinkedtocertaintypesofcancer(37)andmayhaveeffectsoncardiovascularhealthbeyondtheriskfactorsassessedinthisstudy.Therewasalsoalowintakeofcalciumandfiberintheverylowcarbohydrategroupthatwouldneedtobeaddressedifthisdietweretobeusedforlongerperiods.Finally,long-stand-ingketosishasbeenassociatedwithmyocardialdysfunctioninchildrenafteraketogenicdiettotreatintractableseizures(38).Despitetheseconcerns,thepresentresultsindicatethatthereareimportant,interesting,andpoorlyunderstoodef-fectsofseverecarbohydraterestrictionthatwarrantfurtherTABLE4.Means(and)ofbloodpressureandplasmalipidconcentrationsofwomenbeforeandafter3and6monthsofdieting Verylowcarbohydratedietgroup(n22)Lowfatdietgroup(nBaseline3months6monthsBaseline3months6monthsBloodpressure(mmHg)116/79(3.23/2.69)112/72(2.36/2.06)114/74(2.82/2.23)115/75(2.47/1.99)116/75(2.01/1.79)113/74(2.41/1.62)Totalcholesterol(mg/dl)206.32(6.63)185.68(5.64)205.46(6.79)184.45(6.07)176.25(5.87)182.85(6.21)Triglycerides(mg/dl)148.7392.41(8.74)113.86(15.25)109.25(9.49)101.80(6.71)111.00(12.37)LDL(mg/dl)124.86(5.39)113.00(5.34)124.00(5.81)113.80(6.36)104.90(5.97)107.80(5.86)HDL(mg/dl)51.77(2.82)54.09(2.77)58.73(2.57)48.75(2.23)51.05(3.49)52.85(2.58)ToconverttoSIunits,multiplytotalcholesterol,LDL-cholesterol,HDL-cholesterol(mg/dl)mmol/liter;multiplytriglycerides(mg/dl)Denotesvaluedifferentfromthelowfatgroup(,significantinteractionoftimeanddiet),JClinEndocrinolMetab,April2003,88(4):16171623Brehmetal.TrialofaVeryLowCarbohydrateDiet 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Verylowcarbohydratedietgroup(n22)Lowfatdietgroup(nBaseline3months6monthsBaseline3months6monthsGlucose(mg/dl)99.1(2.6)93.8(2.7)90.1(2.1)91.1(2.1)90.5(2.5)87.5(2.0)Insulin(U/ml)16.9(1.8)11.6(1.2)14.4(1.4)23.9(2.34)18.1(2.5)18.4(2.1)Leptin(ng/ml)25.43(1.49)16.23(1.09)21.68(1.49)30.08(1.88)25.35(1.82)29.40(2.58)-hydroxybutyrate(mg/dl)1.04(0.31)4.301.52(0.51)1.01(0.40)1.17(0.27)1.14(0.44)ToconverttoSIunits,multiplyglucose(mg/dl)mmol/liter;multiplyinsulin(pmol/liter;multiplybutyrate(mg/dl)Denotesvaluedifferentfromthelowfatgroup(,significantinteractionoftimeanddiet),etal.TrialofaVeryLowCarbohydrateDietJClinEndocrinolMetab,April2003,88(4):1617