Hypotheses and evidence related to intense sweeteners and effects on appetite and body weight

18 Pages·2017·6.52 MB·English

RESEARCHARTICLE
Hypotheses and evidence related to intense
sweeteners and effects on appetite and body
weight changes: A scoping review of reviews
AnnhildMosdøl1☯*,GunnElisabethVist1‡,CamillaSvendsen2‡,HubertDirven2‡,Inger
ThereseLaugsandLillegaard3‡,GroHaarklouMathisen3‡,TrineHusøy2☯
1 Divisionforhealthservices,NorwegianInstituteofPublicHealth,Oslo,Norway,2 Divisionforinfection
controlandenvironmentalhealth,NorwegianInstituteofPublicHealth,Oslo,Norway,3 TheNorwegian
a1111111111 ScientificCommitteeforFoodandEnvironment,Oslo,Norway
a1111111111
a1111111111 ☯Theseauthorscontributedequallytothiswork.
‡Theseauthorsalsocontributedequallytothiswork.
a1111111111
*[email protected]
a1111111111
Abstract
Observedassociationsbetweenconsumptionofdietfoodsandobesityhavesparkedcon-
OPENACCESS
troversyoverwhetherintensesweetenersmaypromoteweightgain,despitetheirnegligible
Citation:MosdølA,VistGE,SvendsenC,DirvenH,
LillegaardITL,MathisenGH,etal.(2018) energycontribution.Weconductedascopingreviewofreviews,toobtainanoverviewof
Hypothesesandevidencerelatedtointense hypotheses,researchapproachesandfeaturesoftheevidenceonintensesweeteners’
sweetenersandeffectsonappetiteandbody
potentialrelationshipstoappetiteandweightchanges.Wesearchedforreviewsofthesci-
weightchanges:Ascopingreviewofreviews.PLoS
entificliteraturepublishedfrom2006toMay2017.Tworeviewersindependentlyassessed
ONE13(7):e0199558.https://doi.org/10.1371/
journal.pone.0199558 titleandabstracts,andfulltextpublications.ArkseyandO’Malley’sframeworkforscoping
reviewsguidedtheprocess.Weextractedandcharteddataoncharacteristicsofthereviews
Editor:C.MarySchooling,CUNY,UNITEDSTATES
andtheevidencepresented.The40includedreviewspresenthypothesesbothonhow
Received:January22,2018
intensesweetenerscanreduceormaintainbodyweightandonhowthesecanpromote
Accepted:June8,2018
weightgain.Weclassifiedonlyfivepublicationsassystematicreviews;anotherninepre-
Published:July18,2018 sentedsomesystematicapproaches,while26reviewsdidnotdescribecriteriaforselecting
Copyright:©2018Mosdøletal.Thisisanopen orassessingtheprimarystudies.Evidencewasoftenpresentedforintensesweetenersas
accessarticledistributedunderthetermsofthe agrouporunspecified,andagainstseveralcomparators(e.g.sugar,water,placebo,intake
CreativeCommonsAttributionLicense,which
levels)withlimiteddiscussionontheinterpretationofdifferentcombinations.Apartfromthe
permitsunrestricteduse,distribution,and
observationalstudies,thepresentedprimaryevidenceinhumansisdominatedbysmall
reproductioninanymedium,providedtheoriginal
authorandsourcearecredited. studieswithshortfollow-up—consideredinsufficienttoassessweightchange.Systematic
reviewsofanimalstudiesarelackinginthistopicarea.Thesystematicevidenceonlypartly
DataAvailabilityStatement:Thedataunderlying
thisstudyarecollectedfrompublishedandpublicly exploreforwardedhypothesesfoundintheliterature.Primarystudiesinhumansseemtobe
availablereviews.Theauthorsdidnothavespecial availableforsystematicexplorationofsomehypotheses,butlong-termexperimentalstudies
accessprivileges.Informationrelatedtothe
inhumansappearsparse.Withfewexceptions,thereviewsonintensesweetenersand
reviewsisincludedinS1Table.Allotherrelevant
weightchangeunderusesystematicmethodology,andthus,theavailableevidence.Further
dataarewithinthepaperanditsSupporting
Informationfiles. studiesandsystematicreviewsshouldbeexplicitaboutthehypothesisexploredandeluci-
datepossibleunderlyingmechanisms.
Funding:Theauthor(s)receivednospecific
fundingforthiswork.
Competinginterests:Theauthorshavedeclared
thatnocompetinginterestsexist.
PLOSONE|https://doi.org/10.1371/journal.pone.0199558 July18,2018 1/18
Intensesweeteners,appetiteandbodyweight
Introduction
Associationsseeninobservationalstudiesbetweentheconsumptionofdietproducts,predom-
inantlydietsoda,andprevalenceofobesityhasfuelledadebateoverwhetherintensesweeten-
erscanpromoteweightgain[1,2].Agroupofnon-caloriesweeteners,theintensesweeteners,
areupto700timessweeterthansucroseandcanprovidesweettastewhilecontributingnegli-
gibletopeople’senergyintake.Examplesoftheintensesweetenersaresaccharin,aspartame,
sucralose,cyclamateandsteviolglycoside.Explanationsforthiscontradictionhavebeen
suggested,butitremainsuncleariftheobservedassociationsarecausalrelationships.Some
intensesweetenershavebeenusedextensivelyfordecades,particularlyinbeverages.Increas-
ingly,intensesweetenerconsumptioncomesthroughfoods[3].ThenewWorldHealthOrga-
nization(WHO)guidelinerecommendaddedsugarstobebelow10%,andpreferably5%,of
thetotalenergyintake[4].Duetothisrecommendationandplannedtaxesonsugareddrinks
inmanycountries,sugarislikelytobereplacedwithintensesweetenersinmorefoodsand
beveragesahead[5].
Allpermittedfoodadditivesareconsideredsafeforhumanhealthwithinspecifiedintake
levels(acceptabledailyintake;ADI)asevaluatedbyNationalorInternationalfoodsafetyregu-
latoryagencies.StandardsafetyassessmentsdetermineanADIbasedoncomprehensivetoxi-
cologicaltestsconsideringnumerousendpoints,largelybasedonanimalstudies[6].These
includereportsonweightchangesinanimals,butsuchcontrolledfeedingstudiesmaynot
berelevanttonormalconsumptionpatternsinhumans.Weightlossesinstudyanimals,for
instance,maybeduetoreducedpalatabilityoffeedwhentestingveryhighdosesofintense
sweeteners.Inarecentre-evaluationofaspartame,apanelfromEuropeanFoodSafety
Authority(EFSA)alsoconsideredthatpotentialeffectsofintensesweetenersoneatingbehav-
iourwasoutsidetheremitofriskassessment[7].
Giventhecurrentobesityepidemicandseriousassociatedhealthrisks[8],itistimelyto
clarifyifintensesweetenersareeffectivetoolstolowersugarconsumptionandmaintaina
healthyweightor,onthecontrary,ifthesecompoundspromoteweightgain.Publishedreviews
canprovideanoverviewoftopics,hypothesesandresearchapproachesintheresearchfield.
Theaimofthisscopingreviewistodeterminetheextentandtypeofsummarizedevidence
publishedthelast10yearsregardingthepotentialeffectsofintensesweetenersonappetiteand
weightchange.Weparticularlyintendedtoidentifygapswherenewsystematicreviewsorpri-
maryresearchareneeded,includingwhichhypotheses,typesofintensesweetenersandout-
comesthatneedfurtherassessment.
Materialsandmethods
Weperformedascopingreviewusingapre-definedprotocol,guidedbytheframeworkfor
scopingreviewsproposedbyArkseyandO’Malley[9]withsuggestedenhancements[10–12]
andPRISMA(PreferredReportingItemsforSystematicReviewsandMeta-analyses)[13].In
scopingreviews,theresearcherssystematicallyexploretheliteratureonaspecifiedtopic,for
instancetoexaminetheextentandnatureofavailableresearch,thevalueofundertakingasys-
tematicreview,oridentifyresearchgaps[9].
Systematicsearchandinclusioncriteria
Anexperiencedresearchlibrarianconductedtheliteraturesearchandthesearchstrategywas
peerreviewed.Wesearchedwithoutlanguagerestrictionsforalltypesofreviewspublished
from2006toMay18th2017inthefollowingdatabases:MEDLINE(Ovid)andPubMed[sb],
Embase(Ovid),CochraneLibrary(CDSR,DARE,HTA),EpistemonikosandWebofScience.
TheliteraturesearchincludedMESHtermSweeteningagents,freetextwordsdescribingthe
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Intensesweeteners,appetiteandbodyweight
group(i.e.intensesweeten(cid:3),artificialsweeten(cid:3)etc.)andnamesofspecificintensesweeteners,
combinedwithMESHtermsandfreetextwordsrelatedtooverweight/obesity,weightchange
andappetite.Afilterforreviewslimitedthesearchandadjustmentsmadetosearchterms
andstructuretosuitdifferentdatabases(seeS1Appendixforsearchstrategy).Inaddition,
wesearchedforrelevantreportspublishedbyEFSA,JointFAO/WHOExpertCommitteeon
FoodAdditives(JECFA),U.S.FoodandDrugAdministration(FDA),NationalInstitutesof
Health(NIH,theU.S.),EuropeanMedicinesAgency(EMA),TheFederalInstituteforRisk
Assessment(BfR,Germany),InstitutNationaldel’EnvironnementIndustrieletdesRisques
(INERIS,France),RijksinstituutvoorVolksgezondheidenMilieu(RIVM,theNetherlands)
andTheEUJointResearchCentre(Italy).
Tworeviewersindependentlyscreenedtitleandabstracts,andconsideredpotentiallyrele-
vantreferencesinfulltext.Wedistributedtheworkamongpairsofauthors,andresolved
discrepancieswithathirdauthor.Inclusioncriteriawereanyreviewsoftheliteraturewhose
primaryfocuswastheeffectofconsumingintensesweeteners(eitherasagroupofsweeteners
orforspecificsweeteners)onweightchange,appetiteorrelatedoutcomes.Tofocustheevi-
denceonintensesweeteners,appetiteandweightspecifically,non-systematicreviewsthat
discussedseveralrelatedtopics(e.g.exposuretootherdietarycomponentsoroutcomessuch
asdiabetes,cardiovasculardiseasesorcancer)wereexcluded.Systematicreviewsofseveral
exposureswereincludedifthepublicationpresentedseparate,systematicanalysesforintense
sweetenersandourdefinedoutcomes.Eligiblereviewspresentedresultsfromempiricalstud-
iesofanyquantitativestudydesigninhumansandanimalmodelsonintensesweetenersor
specifiedforAcesulfamK,E950,Aspartame,E951,Cyclamat,E952,Saccharin,E954,Sucra-
lose,E955,NeohesperidinDC,E959,Steviolglycoside,E960,Neotame,E96.Weincluded
reviewsdiscussinganycomparatorwithoutcomerelevanttoappetiteandbodyweightchange,
includingeffectsthroughgutmicrobiota.
Dataextractionandanalyses
Allauthorscontributedtodataextractionusinganextractionformandanotherauthorvali-
datedtheextraction.Dataincludedcharacteristicsofthereview,itsobjectives,components
andanalysis,typesofincludedstudydesigns/experimentalmodels,studypopulations,intense
sweetenersexamined(includingdoseandformofintake),comparisonsandoutcomeswith
follow-uptime,andhypotheses.Wecharacterizedpublicationsassystematicreviewsbased
oursimplifiedversionofthedefinitionusedbytheCochranecollaboration[14].Publications
weresystematicreviewsiftheyhaddescribedorpresented1)asystematicliteraturesearch,2)
clearcriteriaforrelevantstudiestoinclude,and3)qualityassessmentoftheincludedstudies
(forinstanceCochraneRiskofBiasassessmentforRCTsorotherstudydesignspecificquality
assessmenttools).Wenotedifreviewshaddatasynthesisasmeta-analyses.
Forsystematicreviewsandreviewswithsomedescriptionofsystematicapproachtostudy
selection(relatedtocriteria1and2above),wepresentedcharacteristicsofthereview.For
otherreviews,wechartedsuchinformationinasimplifiedformat.Wesearchedallreviewsfor
explicitorimplicitreferencestohypothesesonhowintensesweetenersinfluenceappetiteand
bodyweightchange.Formulatedhypotheses,suggestedmechanisms,explanationsforaneffect
orsimilarstatementswerenotedforeachreview.Basedonourinterpretationoftheircontent,
wesortedtopicsacrosspublications.Theauthorsdiscussedthepropositionsfoundandcom-
binedtheseintomainhypotheseswithsimilarcontent.Theexperimentalevidencefromsys-
tematicreviews/reviewswithsomesystematicapproachestostudyselectionweremapped
accordingtowhichmainhypothesistheyprovidedinsightinto.Thiscategorizationwasbased
onourjudgementoftheaim,researchquestionorhypothesespresentedforeachreview,study
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Intensesweeteners,appetiteandbodyweight
Fig1.Literaturesearchandselectionprocess.
https://doi.org/10.1371/journal.pone.0199558.g001
inclusioncriteriaandanalysespresented.Observationalstudieswereexcludedfromthismap-
ping,asweconsidertheseinadequatetoelucidatethehypothesesfurther.Basedonthereviews
thatprovidedcharacteristicsonallincludedprimarystudies,weextractedandchartedthe
numberofparticipantsandlongestfollow-uptimeincategoriesdefinedbyintensesweeteners
versuscomparatorstudied,forobservationalandexperimentalstudiesrespectively.
Results
Thesearchreturned991referencesthatweprocessedasshowninFig1.Inaddition,wecon-
sidered11referencesfromrelevantagencies.Of102provisionallyeligiblereferences,we
excluded62basedonfull-textscreening(S1Table).Twoofthesewereprotocolsforplanned
Cochranesystematicreviewsthatwilladdressthescopeofourreview[15,16].Weincluded40
reviews.Thenumberofreviewspublishedonthistopicincreasedovertime,with31ofthe
reviewspublishedfrom2012onwards,andninein2016only.
Systematicreviewsandreviewswithasystematicapproach
Amongtheincludedpublications,wecategorizedfive[17–21]assystematicreviews.Another
ninepublications[22–30]hadsomedescriptionofaliteraturesearchstrategyforstudies,
althoughwithvaryinglevelofdetailoncriteriaforeligiblestudydesigns,exposures,compari-
sonsandoutcomes.However,theseninedidnotdescribeanyqualityassessmentofthe
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Intensesweeteners,appetiteandbodyweight
includedstudies—criteriaNo3forbeingasystematicreview.Characteristicsofthefourteen
reviewswithasystematicapproachtostudyselectionarepresentedinTable1.
Theevidenceinthesereviewswaspredominantlyfromhumanstudies.ThereviewbyRog-
ersetal.[19]hadasystematicsearchandseparateanalysesofanimalstudies,whiletwopubli-
cationspresentssomeevidencefromanimalstudies[24,27].Fourreviews[17,21,22,30]
restrictedtheiranalysestocontrolledtrialsinhumans.Theremainingtenreviewspresented
bothobservationalandexperimentalevidence.Tworeviewshadaspecificfocusonaspartame
[21,22].Otherwise,mostofthesereviewsincludedseveralintensesweeteners,usuallyexamin-
ingtheeffectofintensesweetenersasonespecifiedorunspecifiedgroup.Asawhole,these
reviewsexaminedtheeffectofintensesweetenerconsumptionagainstmultiplecomparators:
nointake,water,sucrose,othercaloricsweetener,unsweeteneddrinksorplacebo,orby
comparingdifferentintakelevelsofintensesweetenersinobservationalstudies.Allfourteen
reviewsconsideredmultipleoutcomes,primarilyrelatedtoweightchangeorbodycomposi-
tion.Thereviewsalsovariedgreatlyinhowtheyhandledlengthoffollow-up,bothinthestudy
selectionprocessandintheanalyses.Seven[20,21,23,24,26,27,30]hadnomentionoffol-
low-uptimeintheirinclusioncriteria.Whendefined,eligiblyregardingfollow-upvariedfrom
beingopen[19]toincludingstudieswithminimumsixmonthsfollow-up[18,25,28,29].
Sevenofthesereviewspresentedresultsasmeta-analysesbasedonajudgementifthestudies
weresimilarenoughtocombine[17–22,28],sometimescombinedwithnarrativesynthesisof
theevidence.
Wedidnotextractinformationondosesorexposureofintensesweeteners,thebaseline
energyintakeordifferencesinenergyintakeofstudyarmsasintended.Fewreviewpapers
reportedinformationonthedoseorexposuretointensesweetenersinasystematicway.
Unlesschangeinenergyintakewasanoutcome,informationonenergyintakeinstudyarms
wasgenerallylackinginthereviews.
Narrativereviewswithoutdescriptionofstudyselection
Weidentifiedanother26reviewswithprimaryfocusonintensesweeteners’effectonappetite
orweightchange[2,3,31–54](Fig2),butthesehadnodescriptionofhowtheevidencehad
beenselected.Allhadnarrativesynthesesofthefindings.ComparedtothereviewsinTable1,
thesereviewsreferredtoawiderrangeofevidence:Observationalhumanstudies(nearlyall
reviews),experimentalstudies,bothhumanandanimal(19of26reviews)andfindingsfrom
experimentsincellcultures(threereviews).Often,thereviewspresentedevidencefromonly
oneorafewstudieswithineachcategory.Inadditiontolackofclarityabouthowthestudies
hadbeenselected,thereviewsprovidedlimitedornoinformationconcerningthecharacteris-
ticsofthestudies,studydesigns,numberofparticipants/experimentalanimals,comparisons
made,effectsizesandqualityoftheprimarystudies.Tenreviewsdiscussedfindingsfrom
otherreviewsaspartoftheirevidencesynthesis.
SimilartothereviewsinTable1,allpublicationsinFig2referredtoeffectsofunspecified
intensesweetenersortheseasagroup.Sixofthe26reviewsdiscussedfindingswithoutspecify-
inganyintensesweeteners,butmostreviewsalsoprovidedevidenceononeorseveralnamed
compounds.Anothercharacteristicofthesereviewsisthattheeffectswereexaminedagainst
severaldifferentcomparators(e.g.comparedtointakeofsugar,water,differentintakelevels,
placebo),ofteninthesamelineofreasoning.Sometimesthecomparatorforastatedeffectwas
unclearfromthetext[33,35,36,39,42,44,48,53].Theonlyexceptionwasthescientificstate-
mentpaperfromEFSA2011,whichonlydiscussedintensesweetenersincomparisontointake
ofglucose[32].Themostcommonoutcomediscussedinthesereviewswasmeasuresofbody
weight,butthereviewsinFig2referredtoagreaterrangeofoutcomemeasures,suchas
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Intensesweeteners,appetiteandbodyweight
Table1. Characteristicsofincludedsystematicreviewsandreviewswithsomedescriptionofsystematicapproachtostudyselection.
First Literaturesearch Inclusioncriteria(ifnotpre-specified,descriptionofwhatwasincluded.Authors’ Quality Data Included
author, (endsearch) termspresented) assessmentof synthesis studies
published studies
Typesofstudies Intensesweeteners Comparison Outcomesandfollow-
andpopulations considered upperiod
Wiebe, Medline,Embase, RCTs. Anynon-caloric Anystudy Weightchange,energy 4RCT-specific Narrative, 6a
2011[17] CENTRAL,CAB Humans(cid:21)16 sweetener. comparing intake,clinical domainsfor network
Global(toJanuary years.Healthy, againstanother outcomesFollow-up: riskofbias meta-
2011) overweightor sweetener,caloric >1week analysis
diabetic. ornon-caloric.
Reid,2016 Medline,Embase, Prospectivecohorts Allnon-nutritive Nutritive Primaryoutcomes: CochraneRisk Narrative, 8
[18] CochraneLibrary, andRCTs. sweeteners. sweeteners, BMI/BMIZ-score. ofBiastool meta-
referencelist,grey Humans,pregnant placebo;regular Secondaryoutcomes: (RCTs), analysis
literature(toJuly women,infantsand diet Birthweight,growth Newcastle-
2015) children<12years velocity,adiposity, OttawaScale
only. clinicaloutcomes. (Cohorts).
Follow-up:>6months
Rogers, Medline,Embase, Severalstudy Low-energy Notpre-specified. Energyintake,body CochraneRisk Narrative, 147
2016[19] WebofScience designs.Animal, sweeteners(intense Includedsugar, weight,bodymass ofBiastool meta-
(toFebruary human sweetenersand water, index.Follow-up:open usedfor analysis
2015) observational,short sugaralcohols). unsweetened, sustained
andsustained nothing,placebo human
interventionstudies intervention
analyzedseparately. studies
Ruanpeng, Medline,Embase, RCTs, Sugar-sweetenedor Nosoda Obesity,weightgain Newcastle- Meta- 3a
2017[20] Cochrane observational artificially consumption Follow-up:Notpre- Ottawaquality analysis
databases(toMay studies(cohort, sweetenedsodas specified.Included scale.
2015) case-control,cross- onlycross-sectional.(cid:3)
sectional).Humans,
adults.
Santos, Cochrane, Controlledtrials. Aspartame. Control(water, Primaryoutcomes: CochraneRisk Narrative, 29
2017[21] LILACS,PubMed, Humans,adults. placebo,nothing) bloodglucose,obesity. ofBiastool meta-
Scopus,Webof orsucrose. Secondaryoutcomes: analysis
Science,grey glycemiccontrol,
literature(toApril overweight,energy
2016) intake,clinical
measures.Follow-up:
Notpre-specifiedand
unclear.Singledoseto
twoyearsincludedin
sameanalyses.
dela Nosearch RCTs.Human, Aspartame,aloneor Primary Energyintake,Body No. Meta- 16
Hunty, strategy.“All adultsonly. incombination comparison weightFollow-up:> analysis
2006[22] studies[...]were withotherintense sucrose, 24hours
identified”. sweeteners. secondarywater
and“other”.
Brown, PubMed,Webof Notpre-specified: Artificialsweeteners Notpre-specified. Foodintake,weight No. Narrative 18
2010[23] Science,EMBASE Mixofstudy Includedsugar, change,clinical
(endsearch designs.Humans, water,placebo, outcomesFollow-up:
unclear) children0–18years. differentintake Notpre-specified.
levels. Included20minto10
years.
Gardner Pubmed, Prospectivecohorts FDAapprovednon- Caloric Partlypre-specified. No. Narrative 32
2012[24] EvidenceAnalysis andcontrolled nutritivesweeteners sweeteners. Includedenergyintake
Libraryofthe trials.Systematic (aspartame, Sucrose. compensation,
AmericanDietetic reviews.Humans. acesulfame-K, appetite,hunger,body
Association,hand Animalstudies neotame,saccharin weight.Follow-up:
search(from presented. sucralose,stevia) Unclear.Included
2000,unclearend shortupto5years.
date)
(Continued)
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Intensesweeteners,appetiteandbodyweight
Table1. (Continued)
First Literaturesearch Inclusioncriteria(ifnotpre-specified,descriptionofwhatwasincluded.Authors’ Quality Data Included
author, (endsearch) termspresented) assessmentof synthesis studies
published studies
Typesofstudies Intensesweeteners Comparison Outcomesandfollow-
andpopulations considered upperiod
Pereira, Medline(to Unclearstudy Unclear:Artificially Notpre-specified Bodyweight,obesity No. Narrative 14
2013a[25] September2011), designcriteria. sweetened andunclear. risk,clinicaloutcomes.
referencelists Humans. beverages. Includedmultiple Follow-up:Notpre-
comparisons. specified.Included
cross-sectionalupto
sixyears.
Pereira, Medline(from Prospectivecohorts Unclear:Artificially Notpre-specified Bodyweight,bodyfat, No. Narrative 17
2013b[26] 1990toMay andRCTs. sweetened andunclear. clinicaloutcomes.
2013) Humans. beverages. Includedmultiple Follow-up:RCTsnot
comparisons. restricted,(cid:21)6months
forcohorts
Shankar Medline, Notpre-specified. Notpre-specified. Notpre-specified Notpre-specifiedand No. Narrative 15
2013[27] PubMed,websites Includedhuman Includednon- andunclear. unclear.Relatedto
(from1987to andanimalstudies, nutritivesweeteners weight,obesityand
2012) variousdesigns. combined, energycompensation.
saccharin,
aspartame,
acesulfame-K,
tagalose,sucralose,
stevia.
Miller,2014 Medline, Prospectivecohorts Anylow-calorie Notpre-specified. Anymeasureofbody No. Meta- 23
[28] referencelists(to andRCTs.Healthy sweetener Includedsugar, weightorcomposition. analysis
September2013) populations. (nonnutritive lactosecapsules, Follow-up:(cid:21)3weeks
Humans. sweeteneror usualdiet, forRCTs,(cid:21)6months
polyol). differentintake forcohorts
levels.
Pereira, Medline, Prospectivecohorts Unclear:Sugar- Notpre-specified Bodyweight,bodyfat. No Narrative 18
2014[29] referencelists andRCTs. Sweetenedand andunclear. Follow-up:RCTsnot
(from1946to Humans. artificially Includedintake restricted,(cid:21)6months
March2012) sweetened levels,sugar. forcohorts
beverages,
presented
separately.
Romo- PubMed,The Observational Non-nutritive Notpre-specified. Outcomesrelatedto No. Narrative 28a
Romo,2016 Cochranelibrary, studies.Clinical sweeteners.Six Includedwater, glucosemetabolism,
[30] TripDatabase, trials.Humans. specificintense simple appetiteregulating
handsearch(to sweeteners saccharides, hormonesandhunger.
April2015) presentedintrials. placebo,corn Follow-up:Notpre-
Saccharin, flour,milk. specified.Included7–8
aspartame, yearsforcohorts,
acesulfame-K singledoseto18weeks
intrials(cid:3)
RCTs:Randomizedcontrolledtrials,
aRelevanttotheaimofthisscopingreview(Thepublicationalsopresentsseparateanalysesofothercomparisonsoroutcomes)
https://doi.org/10.1371/journal.pone.0199558.t001
appetiteandhungerscores,hormonesecretion,intestinalglucoseabsorptionandintestinal
microbiome.
Mainhypothesismappedagainstavailablesystematicevidence
Wesearchedthroughall40reviewsincludedinTable1andFig2fordescriptionsofhypotheses
onhowintensesweetenersinfluenceappetiteandbodyweightchanges.Explicitorimplicit
hypotheseswereidentifiedinthepapers’introduction,aspartoftheaims,innarrativeevidence
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Intensesweeteners,appetiteandbodyweight
Fig2.Featuresofincludedreviewswithoutdescriptionofstudyselection,allnarrativeanalyses.
https://doi.org/10.1371/journal.pone.0199558.g002
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Intensesweeteners,appetiteandbodyweight
syntheses,andparticularlyinthediscussionsectionsaspartofsuggestedmechanismsorinter-
pretationoffindings.Althoughthesehypotheseswereformulatedindifferentways,weconsid-
eredthatallcouldbesummarizedinfivemainhypothesespresentedinFig3.Thefirsttwo
hypothesisassumethatuseofintensesweetenersmaylowersugarconsumptionandsubse-
quentlytotalenergyintaketoreduceormaintainbodyweight.Theotherthreehypothesescon-
siderhowintensesweetenersmaypromoteweightgain.
Wemappedexperimentalevidencefromthesystematicreviewsandreviewswithasystem-
aticapproach(fromTable1)againstwhethertheyprovidedevidencetoexplorethesefive
hypotheses.Elevenreviews[17–19,21–25,27–29]hadevidenceofrelevancetothemain
hypothesisNo.1;thatsubstitutionofsugarwithintensesweetenersinbeveragesandfoodswill
reducethetotalenergyintake,andsubsequentlyaffectbodyweight.Onlytwoofthesereviews
[18]hadseparateanalysesforstudieswithlonger-termfollow-up(>6months).Fourreviews
[21,23,24,27]hadpooledallfollow-upperiodstogether,fromsingledoseexposuretolonger-
termfollow-up,orhadnodescriptionofthefollow-up.Wedidnotfindanysystematicevi-
dencespecificregardinghypothesisNo.2:Beverageswithintensesweetenersareasprotective,
ormoreprotective,thanwaterinpreventionofobesitywhencomparedtoconsumptionof
sugar-sweetenedbeverages.However,singlestudiesaddressingthishypothesiswereembed-
dedinanalysesrelatedtomainhypothesisNo.1.
SevenreviewsprovidedsomesystematicevidencetoexploremainhypothesisNo.4:Intense
sweetenersaffectsweettastereceptors,hormonalsignalling,rewardsystemsandlearned
energysensingperceptionsinamannerthatinterfereswithnutrientabsorption,appetitecon-
trolorotherweightregulationmechanisms.However,thisevidencewasscatteredandcover-
ingonlysomerelevantoutcomes.Noneofthesereviewsconsideredaspectsoffollow-uptime
specifically.Wedidnotfindanysystematicevidencesynthesesrelatingtomainhypothesis
No.3“Deliberateconsumptionofbeveragesandfoodswithintensesweetenersisassociated
withweightgainthroughmechanismsofgivingpsychologicaljustificationtoovereat,being
partofanunhealthydietarypatternordietinghistory”;norhypothesisNo.5“Intensesweeten-
ersaltergutmicrobiotawithpossiblesecondaryeffectsinvolvingchangesinglucosetolerance,
appetite-regulatinghormonesorotherfactorsthatalterriskofobesitydevelopment”.
Characteristicsofunderlyingprimarystudies
Tomapthehumanprimaryevidenceusedsystematically,weextractedinformationfrom
reviewsthatdescribedcorecharacteristicsonalltheirincludedprimarystudies,including
numberofparticipants,follow-uptime,exposureandcomparator.Studiesweresortedaccord-
ingtothecombinationofexposure(includingintensesweetenersasagroup)andcomparator.
Chartsshowthenumberofparticipantsandfollow-uptimewithincategoriesdefinedby
intensesweetenersversuscomparatorstudied.Sevenreviews[18–20,25,28–30]provided
suchcharacteristicsonobservationalstudies(presentedinFig4)andninereviews[17–19,21–
23,28–30]providedcharacteristicsonhumanexperimentalstudies(presentedinFig5).These
reviewspresentedfindingsfromintotal24observationalstudies,fiveanalysedascross-sec-
tionalstudiesand19ascohortstudies.Thenumberofparticipantsintheobservationalstudies
variedgreatly,fromunder100upto53000participants.Manyhadseveralyearsfollow-up
time,includingninestudieswithfollow-upfrom4yearsupto20years(Fig4).Amongthe118
humanexperimentalstudiesfoundinthesereviews’datasynthesis(Fig5),themoststudied
sweetenerwasaspartamewithresultsreportedfrom96studies,mostoftencommonlycom-
paredagainstconsumptionofsucrose.Ahighnumberofprimarystudieswerealsoreported
resultsforsucralose(n=30)andmixtureofintensesweeteners(n=31),whilefewexperimen-
talprimarystudieswerereportedfortheintensesweetenersacesulfameK,cyclamate,
PLOSONE|https://doi.org/10.1371/journal.pone.0199558 July18,2018 9/18
Intensesweeteners,appetiteandbodyweight
Fig3.Mainhypothesesidentifiedfromallincludedreviewsmappedagainsttheevidencefoundinsystematicreviewsandreviewswithsystematic
approachtostudyselection.aDataextractedfromsystematicreviewsandreviewswithdescriptionofsystematicapproach(fromTable1).
Categorisationisbasedonourjudgementoftheaim,researchquestionorhypothesespresented,studyinclusioncriteriaandanalysespresentedineach
reviewagainstthehypothesis.Evidencesummariesofobservationalstudieswerenotconsideredforthispresentation.A:Animalstudies.
https://doi.org/10.1371/journal.pone.0199558.g003
PLOSONE|https://doi.org/10.1371/journal.pone.0199558 July18,2018 10/18