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//jn.nutrition.org

RUNNINGTITLE:

Fructoseandcholesterol

WORDCOUNT:

5618;

NUMBEROFFIGUREA:

3;

NUMBEROFTABLES:

2

SUPPLEMENTARYMATERIAL:

OnlineSupportingMaterials:

5

AUTHORLISTFORINDEXING:

An,Zhang,Zhang,Zhou,Huang,Zhang

1ThestudywassupportedbytheMinistryofScienceandTechnologyofChinawithgrantoftheNationalHigh-techResearchandDevelopmentProgramofChinatoDrJianZhang.

2Authordisclosures:

T.An,R.C.Zhang,Y.H.Zhang,Q.Zhou,Y.Hung,J.Zhanghavenoconflictsofinterest.

*Towhomcorrespondenceshouldbeaddressed.Mailingaddress:

HeartFailureCenter,CardiovascularInstituteandFuwaiHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,167Beilishilu,Beijing,China;

Zipcode:

100000;

Telephonenumber:

86-10-88396180;

Faxnumber:

E-mail:

Fwzhangjian62@

PROSPEROREGISTRATIONNUMBERS:

CRD42012003351

ABSTRACT

Fructoseiswidelyusedasasweetenerinproductionofmanyfoods,yettherelationbetweenfructoseintakeandcholesterolremainsuncertain.Weperformedasystematicreviewandmeta-analysisofhumancontrolledfeedingtrialsofisocaloricfructoseexchangeforothercarbohydratestoquantifytheeffectsoffructoseontotalcholesterol（TC）,LDLcholesterol（LDL-C）,andHDLcholesterol（HDL-C）inadulthumans.Weightedmeandifferenceswerecalculatedforchangesfrombaselinecholesterolconcentrationsbyusinggenericinversevariancerandom-effectsmodels.TheHeylandMethodologicalQualitywasusedtoassessstudyquality.Subgroupanalysesandmeta-regressionwereconductedtoexplorepossibleinfluenceofstudycharacteristics.Twenty-fourtrials（withatotalof474subjects）wereincludedinourmeta-analysis.Inanoverallpooledestimate,fructoseexertednoeffectonTC,LDL-CandHDL-C.Meta-regressionanalysisindicatedthatfructosedosewaspositivelycorrelatedwiththeeffectsizesofTCandLDL-C.SubgroupanalysesshowedthatisocaloricfructoseexchangeforcarbohydratescouldsignificantlyincreaseTCby12.97mg/dL（95%CI:

4.66,21.29;

P=0.002）andLDL-Cby11.59mg/dL（95%CI:

4.39,18.78;

P=0.002）at>

100gfructose/dbuthadnoeffectonTCandLDL-Cwhenfructoseintakewas≤100g/d.Inconclusion,veryhighfructoseintake（>

100g/d）couldleadtosignificantlyincreaseinserumLDL-CandTC.Larger,longerandhigher-qualityhumancontrolledfeedingtrialsareneededtoconfirmtheseresults.

Keywords:

fructose,cholesterol,meta-analysis

INTRODUCTION

Hyperlipidemiaisacommonriskfactorforcoronaryheartdisease（CHD）,with44.4%ofadultsintheUnitedStateshavingabnormalTCvaluesand32%havingelevatedLDL-Clevels

（1）.Comparedtosubjectswithnormalbloodlipid,thosewithhyperlipidemiahavea3-foldriskofheartattacks

（2）.LifestylemodificationshouldbeinitiatedinconjunctionbothprimaryandsecondarypreventionofCHD.Moreconsiderationexistsastowhatconstituteshealthyeating.

Fructoseisthemostnaturallyoccurringmonosaccharide,andhasbecomeamajorconstituentofourmoderndiet.Fruit,vegetables,andothernaturalsourcesprovidenearlyone-thirdofdietaryfructose,andtwo-thirdscomefrombeveragesandfoodsinthediets（eg,candies,jam,syrups,etc）（3）.Fructoseispreferredbymanypeople,especiallythosewithdiabetesmellitusbecauseofitslowglycemicindex（23%versusglucose100%）（4）.Afterintestinaluptake,fructoseismainlyremovedfromthebloodstreambytheliverinaninsulin-independentmanner,andisusedforintrahepaticproductionofglucose,fattyacidsorlactate.Cross-sectionalstudiesinhumansuggestthatexcessivefructoseconsumptioncanleadtoadversemetaboliceffects,suchasdyslipidemiaandincreasedvisceraladiposity（5-7）.TheDietaryGuidelinesforAmericans,2010,pointoutthatitislackofsufficientevidencetosetatolerableupperintakeofcarbohydratesforadults（8）.AlthoughTheCandianDiabetesAssociationsuggestsconsumptionofnomorethan60gofaddedfructoseperdaybypeoplewithdiabetesforitstriglyceride-raisingeffect（9）,thethresholddoseoffructoseatwhichtheadverseinfluenceoncholesteroliscontroversial.

Todeterminetheeffectoffructoseoncholesterol,asubstantialnumberofclinicaltrialshavebeenperformedonadulthumanswithdifferenthealthstatus（diabetic,obese,overweight,hyperinsulinemic,impairedglucose-tolerantandhealthy）.Thesetrialsusedvariousintakelevelsoffructoseanddifferentprotocols.Thus,itisdifficulttoreachaconsistentconclusionacrossthesestudies.Therefore,weconductedasystematicreviewofthescientificliteratureandmeta-analysisofcontrolledfeedingtrialstoevaluatetheeffectofisocaloricoralfructoseexchangeforcarbohydratesoncholesterolandtoclarifytheactivefactorsoffructose.

MaterialsandMethods

Thismeta-analysisfollowedthePreferredReportingItemsforSystematicReviewsandMeta-analyses（PRISMA）criteria（10）.

Searchstrategy.WesearchedPubMed（http:

//www.ncbi.nlm.nih.gov/pubmed;

from1966toDecember2012）,Embase（;

from1966toDecember2012）andtheCochraneLibrarydatabase（http:

//www.cochrane.org）byusingthefollowingsearchterms:

fructoseand（lipemiaorlipaemiaorlipidsorcholesterolor“totalcholesterol”or“LDLcholesterol”or“HDLcholesterol”）inEnglish.WealsosearchedChinaNationalKnowledgeInfrastructure（）andWangfangdatabase（）inChineseaccordingtothesearchstrategy.Thesearchwasrestrictedtoreportsoftrialsonhumans.

Studyselection.Allclinicaltrialsusingfructoseandindexedwithintheabovedatabaseswerecollected.Twoindependentreviewers（T.A.,R.C.Z）screenedtheabstractsandtitlesforinitialinclusion.Ifthiswasnotsufficient,fulltextsarticleswereobtainedandreviewedbyatleasttwoindependentreviewers（T.A.,R.C.Z,Q.Z.,Y.H.）.Thereferencelistsofretrievedarticlesalsousedtosupplementthedatabase.Anydisagreementswereresolvedthroughdiscussion.Weincludedcontrolledfeedingtrialsinvestigatingthechroniceffectoffructoseonbloodcholesterol,frombothrandomizedandnonrandomizedstudies,iftheymetthefollowingcriteria:

subjectsmusthavebeenadministeredfructoseforatleast2weeks;

studiesinvestigatedtheeffectoforalfree（unbound,monosaccharide）fructosewhencomparedwithisocaloriccontroldietwithanothercarbohydrateinplaceoffructose;

studieswereperformedinhumanadultswitheitheraparallelorcrossoverdesign;

subjectsinbothexperimentalgroupsandcontrolgroupswereinstructedtoconsumeisocaloricdiets.Ifthestudyreportedanycomparisons,weincludedallsuchcomparisonsinthemeta-analysis.

Dataextractionandqualityassessment.Tworeviewers（T.A.,R.C.Z）independentlyextractedrelevantdatafromeligiblestudies.Disagreementswereresolvedbyoneofthetwoauthors（Y.H.Z.,J.Z.）.Thesedataincludedinformationonstudyfeatures（author,yearofpublication,studydesign,randomization,blinding,samplesize,comparator,fructoseform,dose,follow-upandmacronutrientprofileofthebackgrounddiet）,participantcharacteristics（gender,ageandhealthystatus）andbaselineandfinalconcentrationsornetchangesoftotalcholesterol,LDL-CandHDL-C.Datainitiallyextractedwereconvertedtosysteminternationalunit（eg,TC:

1mmol/Lconvertedto38.6mg/dL）.Formulti-armstudies,onlyinterventiongroupsthatmetinclusioncriteriawereusedinthisanalysis.Ifbloodlipidconcentrationsweremeasuredseveraltimesatdifferentstagesoftrials,onlyfinalrecordsoflipidconcentrationsattheendofthetrialswereextractedforthismeta-analysis.

ThequalityofeachstudywasassessedwiththeHeylandMethodologicalQualityScore（MQS）（11）,generalizedasfollows:

randomization;

analysis;

blinding;

patientselection;

comparabilityofgroupsatbaseline;

extentoffollowup;

treatmentprotocol;

co-intervention;

outcomes.Thehighestscoreforeachareawastwopoints.Highernumbersrepresentedabetterquality（MQS≥8）.

Datasynthesis.StatisticalanalyseswereperformedwithStatasoftware（version11.0;

StataCorporation,TX,USA）andREVMANsoftware（version5.2;

CochraneCollaboration,Oxford,UnitedKingdom）.Separatepooledanalyseswereconductedbyusingthegenericinversevariancerandom-effectsmodelsevenwheretherewasnoevidenceofbetween-studyheterogeneitybecausethesemodelsgivemoreconservativesummaryeffectestimatesinthepresenceofundetectedresidualheterogeneitythanfixed-effectsmodels.Thedifferentchangesfrombaselinebetweenfructoseandcarbohydratecomparatorsfortotalcholesterol,LDLcholesterolandHDLcholesterolwereusedtoestimatetheprincipleeffect.WeappliedpairedanalysestoallcrossovertrialsaccordingtothemethodsofElbourneandcolleagues（12）.Weightedmeandifferencesoffructoseconsumptiononcholesterolconcentrationsandcorresponding95%CIswerecalculated.A2-sidedPvalue<

0.05wassetasthelevelofsignificanceforaneffect.Thevariancesfornetchangesinserumcholesterolwereonlyreporteddirectlyintwotrials（29,31）.Wecalculatenetchangesfor