Do ketogenic diets really suppress appetite? PDF
Preview Do ketogenic diets really suppress appetite?
ToppanBest-setPremediaLimited OBR12230 bs_bs_query JournalCode:OBR Proofreader:Mony ArticleNo:OBR12230 Deliverydate:08Oct2014 PageExtent:13 obesity reviews doi:10.1111/obr.12230 Review 1 bs_bs_query 2 bs_bs_query Do ketogenic diets really suppress appetite? 3 12 4bbss__bbss__qquueerryy bs_bs_query A systematic review and meta-analysis 5 bs_bs_query 6 bs_bs_query 7 A.A.Gibson1,R.V.Seimon1,C.M.Y.Lee1,J.Ayre1,2,J.Franklin3,T.P.Markovic1,3,I.D.Caterson1,3 bs_bs_query 8 1 andA.Sainsbury1 bs_bs_query bs_bs_query 9 bs_bs_query 10 1TheBodenInstituteofObesity,Nutrition, Summary bs_bs_query 1112 ExerciseandEatingDisorders,Sydney Very-low-energy diets (VLEDs) and ketogenic low-carbohydrate diets (KLCDs) bbss__bbss__qquueerryy 1134 MedicalSchool,TheUniversityofSydney, aretwodietarystrategiesthathavebeenassociatedwithasuppressionofappetite. bbss__bbss__qquueerryy 1156 Camperdown,NSW,Australia;2Schoolof However,theresultsofclinicaltrialsinvestigatingtheeffectofketogenicdietson bbss__bbss__qquueerryy 1178 Psychology,FacultyofScience,The appetiteareinconsistent.Toevaluatequantitativelytheeffectofketogenicdietson bbss__bbss__qquueerryy 1290 UniversityofSydney,Camperdown,NSW, subjectiveappetiteratings,weconductedasystematicliteraturesearchandmeta- bbss__bbss__qquueerryy 2212 Australia;3MetabolismandObesityServices, analysis of studies that assessed appetite with visual analogue scales before (in bbss__bbss__qquueerryy 2234 RoyalPrinceAlfredHospital,Camperdown, energy balance) and during (while in ketosis) adherence to VLED or KLCD. bbss__bbss__qquueerryy 2256 NSW,Australia Individualswerelesshungryandexhibitedgreaterfullness/satietywhileadhering bbss__bbss__qquueerryy 27 toVLED,andindividualsadheringtoKLCDwerelesshungryandhadareduced bs_bs_query 2289 Received1August2014;revised5 desire to eat. Although these absolute changes in appetite were small, they bbss__bbss__qquueerryy 3301 September2014;accepted12September occurred within the context of energy restriction, which is known to increase bbss__bbss__qquueerryy 3323 2014 appetite in obese people. Thus, the clinical benefit of a ketogenic diet is in bbss__bbss__qquueerryy 34 preventinganincreaseinappetite,despiteweightloss,althoughindividualsmay bs_bs_query 3356 Addressforcorrespondence:AAGibson,The indeed feel slightly less hungry (or more full or satisfied). Ketosis appears to bbss__bbss__qquueerryy 3378 BodenInstituteofObesity,Nutrition,Exercise provide a plausible explanation for this suppression of appetite. Future studies bbss__bbss__qquueerryy 3490 andEatingDisorders,SydneyMedical should investigate the minimum level of ketosis required to achieve appetite bbss__bbss__qquueerryy 4412 School,TheUniversityofSydney,Ground suppressionduringketogenicweightlossdiets,asthiscouldenableinclusionofa bbss__bbss__qquueerryy 4434 Floor,MedicalFoundationBuilding,92–94 greatervarietyofhealthycarbohydrate-containingfoodsintothediet. bbss__bbss__qquueerryy 45 ParramattaRoad,Camperdown,NSW2050, bs_bs_query 4467 Australia. Keywords: Appetite, ketogenic diet, ketosis, low carbohydrate, very-low-energy bbss__bbss__qquueerryy 4489 2 E-mail:[email protected] diet,visualanaloguescale. bbss__bbss__qquueerryy bs_bs_query 50 bs_bs_query 51 Abbreviations: CCK, cholecystokinin; CHO, carbohydrate; KLCD, ketogenic bs_bs_query 52 3 low-carbohydrate diet; PYY, peptide YY; VAS, visual analogue scale; VLED, bs_bs_query bs_bs_query 53 very-low-energydiet. bs_bs_query 54 bs_bs_query 55 obesityreviews(2014) bs_bs_query 56 bs_bs_query tributetothehighrateofattritioninweightlossattempts 64 57 Introduction bs_bs_query bs_bs_query and the inability of individuals to maintain weight loss 65 bs_bs_query 58 Hungerisamajorsideeffectofweightlossattempts,and, (1–4). These compensatory changes in appetite during 66 bs_bs_query bs_bs_query 59 if the plethora of over-the-counter weight loss products weight loss are thought to be induced by alterations in 67 bs_bs_query bs_bs_query 60 and diet books claiming that you can ‘diet without expression of hypothalamic regulators of energy balance 68 bs_bs_query bs_bs_query 61 hunger’isanythingtogoby,itisalsothemostprofitable. (5) as well as adaptive changes in gut function, which 69 bs_bs_query bs_bs_query 62 Compensatory increases in hunger (and appetite gener- alter the concentration of appetite-regulating hormones, 70 bs_bs_query bs_bs_query 63 ally) in response to energy-restricted diets probably con- such as ghrelin (6–9), cholecystokinin (CCK) (8–10) and 71 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) 1 OBR12230 2 Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. obesity reviews 1 peptide YY (8,9,11). Thus, finding ways to ‘block’ the In light of current conjecture about the effect of 55 bs_bs_query bs_bs_query 2 compensatoryincreaseinappetiteassociatedwithenergy- ketogenic diets on appetite, the fact that VLEDs are fre- 56 bs_bs_query bs_bs_query 3 restricted diets represents the ‘holy grail’ of weight quently used and recommended for the treatment of 57 bs_bs_query bs_bs_query 4 management. obesity, as well as renewed interest in high protein, very- 58 bs_bs_query bs_bs_query 5 Two dietary strategies that may suppress appetite are low-carbohydratediets,cliniciansandpatientsneedclear, 59 bs_bs_query bs_bs_query 6 very-low-energy diets (VLEDs), which provide less than evidence-based information about what actually works 60 bs_bs_query bs_bs_query 7 3.4MJ (800kcal) per day (12), and ketogenic low- for appetite suppression during weight loss interventions. 61 bs_bs_query bs_bs_query 8 carbohydratediets(KLCDs),whichseverelyrestrictdietary Hence, we conducted a systematic review and meta- 62 bs_bs_query bs_bs_query 9 carbohydrateintakebutallowadlibitumconsumptionof analysistodeterminetheeffectofketogenicdietsonappe- 63 bs_bs_query bs_bs_query 10 proteinandfat.Paradoxically,despitesevereenergyrestric- tite. We specifically included dietary intervention studies 64 bs_bs_query bs_bs_query 11 tionandrapidweightloss(12),VLEDsarefrequentlycited thatemployedawithin-subject,repeatedmeasureofappe- 65 bs_bs_query bs_bs_query 12 intheliterature(13–18)andpromotedinthelaypress(19) tite before (when participants were in energy balance) 66 bs_bs_query bs_bs_query 13 assuppressingappetite.TheefficacyofKLCDsisalsooften andduring(whenparticipantswereinketosis)adherence 67 bs_bs_query bs_bs_query 14 attributedtoasuppressionofappetiteresultinginsponta- to VLED or KLCD. A secondary aim was to use meta- 68 bs_bs_query bs_bs_query 15 neousdecreaseinenergyintake(20–24).However,thereis regressiontoexplorewhetheradose–responseorthreshold 69 bs_bs_query bs_bs_query 16 conjecture in the literature regarding whether, and how, effect existed between circulating ketone levels and 70 bs_bs_query bs_bs_query 17 VLEDsorKLCDsalterappetite.Studieshavereportedan appetite. 71 bs_bs_query bs_bs_query 1189bs_bs_query idneccrreeaassee((1235,,1246,)2,0n,2o8,c3h1a–n3g3e)i(n10ap,1p7e,t2it4e,2d7u–ri3n0g)aadnhde/roerncae 72bs_bs_query bs_bs_query Methods 73 20 to such diets. Thus, there is a need for stronger evidence bs_bs_query bs_bs_query 74 21 basebeforewecanconcludethatVLEDsorKLCDsreally bs_bs_query bs_bs_query Selectioncriteriaofstudiesforthisreview 75 22 dosuppressappetite. bs_bs_query bs_bs_query 23 The supposed appetite suppression seen with both Studieswereincludediftheyassessedsubjectiveratingsof 76 bs_bs_query bs_bs_query 24 VLEDs and KLCDs is often hypothesized to be due to appetiteinadultsbefore(‘baseline’)andduringadherence 77 bs_bs_query bs_bs_query 25 ketosis (15,34–39). Ketosis is a condition where the pro- toVLEDorKLCDinatleastonestudyarm.Welimited 78 bs_bs_query bs_bs_query 26 ductionofketonebodiesor‘ketones’(β-hydroxybutyrate, studies to those that assessed subjective appetite using 79 bs_bs_query bs_bs_query 27 acetoacetateandacetonethatareproducedintheliverby visual analogue scale (VAS) questionnaires. VASs are a 80 bs_bs_query bs_bs_query 28 ß-oxidation of free fatty acids) is increased, leading to standardizedandvalidated(43)systemofappetiteassess- 81 bs_bs_query bs_bs_query 29 elevations in their circulating concentrations. Ketosis is a mentthatrequiresaresponsetoaquestionsuchas‘How 82 bs_bs_query bs_bs_query 30 coordinated metabolic response that provides an alterna- hungrydoyoufeelnow?’tobemarkedonaline(usually 83 bs_bs_query bs_bs_query 31 tivefuelsourcederivedfromfatwhenglucoseisinshort 100mm in length) anchored at each end with opposing 84 bs_bs_query bs_bs_query 32 supply.Thelevelofcirculatingketonesisprimarilydeter- statements such as ‘Not at all’ and ‘Extremely’ (44). For 85 bs_bs_query bs_bs_query 33 mined by carbohydrate intake and the action of insulin. inclusioninthemeta-analyses,thebaselineassessmenthad 86 bs_bs_query bs_bs_query 34 ModernVLEDsandKLCDs,respectively,provideapproxi- tobeperformedwhenparticipantswereinenergybalance 87 bs_bs_query bs_bs_query 35 mately 40–60 and 20g (initially) of dietary carbohydrate (e.g. had not been on an energy-restricted diet prior to 88 bs_bs_query bs_bs_query 36 per day. Although both VLEDs and KLCDs typically baseline assessment). We included randomized and non- 89 bs_bs_query bs_bs_query 37 result in ketosis, KLCDs can result in several fold randomized studies, provided that the study employed a 90 bs_bs_query bs_bs_query 38 higher circulating levels of ketones than VLEDs (20,29). within-subject, repeated measure for appetite assessment. 91 bs_bs_query bs_bs_query 39 Although ketosis is purported to be responsible for the The reason for this is that within-subject comparisons of 92 bs_bs_query bs_bs_query 40 appetite suppression associated with VLEDs and KLCDs, appetite are considered to be more sensitive and accurate 93 bs_bs_query bs_bs_query 41 carbohydrate-restricted diets are counter-intuitive to thanbetween-subjectcomparisons(45). 94 bs_bs_query bs_bs_query 42 evidence-based healthy eating guidelines as they involve We defined a ‘ketogenic’ diet as one that raised fasting 95 bs_bs_query bs_bs_query 43 elimination of whole groups of foods, and in particular bloodconcentrationsofβ-hydroxybutyrateto≥0.3mM(a 96 bs_bs_query bs_bs_query 44 thosethatarebeneficialforhealthand/orweightmanage- levelthatisgreaterthanthatinducedbyanovernightfast 97 bs_bs_query bs_bs_query 45 ment (i.e. whole grains, legumes, reduced-fat dairy, fruit) ∼0.1mMandthathasbeenassociatedwithappetitesup- 98 bs_bs_query bs_bs_query 46 (40–42).Thus,ifketosisisindeedassociatedwithsuppres- pression[29]),orinwhichparticipantstestedpositivefor 99 bs_bs_query bs_bs_query 47 sionofappetite,itispertinenttoexploreatwhatlevelof ketonesintheurineusingdipsticks.Toreducepublication 100 bs_bs_query bs_bs_query 48 carbohydrate intake and circulating ketone levels this bias, we also included studies that did not measure or 101 bs_bs_query bs_bs_query 49 occurs,becausesuchsevererestrictionofcarbohydratemay report blood or urinary ketone concentrations, but for 102 bs_bs_query bs_bs_query 50 not be necessary to prevent a compensatory increase in whichitwashighlylikelythatparticipantswereinketosis. 103 bs_bs_query bs_bs_query 51 appetite.Indeed,theremaybea‘threshold’foranappetite- Thiswasdeterminedbycomparingtherateofweightloss 104 bs_bs_query bs_bs_query 52 suppressive effect at lower levels of ketosis (and accord- inthestudywithratesofweightlossarisingfromknown 105 bs_bs_query bs_bs_query 53 inglyamoreliberalcarbohydrateintakecouldpotentially ketogenicdietsinsimilarpopulations,aswellasconsider- 106 bs_bs_query bs_bs_query 54 beallowedintheweightlossdiet). ingtheprescribedenergyandcarbohydratecompositionof 107 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 obesity reviews Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. 3 1 the intervention, or the circulating concentration of free and, if applicable, (v) methodology for assessing ketones 52 bs_bs_query bs_bs_query 2 fattyacids,whichisknowntobeincreasedduringketosis. and results (type [blood or urine; β-hydroxybutyrate, 53 bs_bs_query bs_bs_query 3 Thespecificrationaleforeachstudyincludedisdetailedin acetoacetateoracetone],timepoints,results).Whereinfor- 4 54 bs_bs_query bs_bs_query bs_bs_query 4 TableS1intheonlinesupplementaryfile. mation was missing, we contacted authors for further 55 bs_bs_query bs_bs_query 5 We excluded duplicate studies, studies where the inter- information. 56 bs_bs_query bs_bs_query 6 vention involved pharmacotherapy, if appetite was only 57 bs_bs_query bs_bs_query 7 assessed at baseline or if appetite was not assessed at Datasynthesis 58 bs_bs_query bs_bs_query 8 baseline. In studies that randomized participants after the point in 59 bs_bs_query bs_bs_query theinterventionthatwasofinterestforthismeta-analysis, 60 9 bs_bs_query bs_bs_query wepooledtheinterventiongroupsiftheyreceivedthesame 61 10bs_bs_query Searchstrategy ketogenicinterventionupuntiltherelevanttimepoint(i.e. 62bs_bs_query bs_bs_query 11 We searched electronic databases, namely, MEDLINE, if participants were randomized to a weight maintenance 63 bs_bs_query bs_bs_query 12 PreMEDLINE, PubMed, Embase and PsycINFO, from interventionafter4–6weeksonVLED,wewereonlyinter- 64 bs_bs_query bs_bs_query 13 inception until 13 December 2013 for original human estedinthedatabeforeandwhileadheringtotheVLED) 65 bs_bs_query bs_bs_query 14 researcharticlespublishedinEnglish.Thereferencelistsof (46–52). One study included multiple ketogenic interven- 66 bs_bs_query bs_bs_query 15 includedstudieswerealsosearched.Weemployedacom- tionarms(i.e.VLEDsdifferinginprotein,fatorcarbohy- 67 bs_bs_query bs_bs_query 16 prehensive search strategy combining two groups of key drate content), and we included all arms of that study as 68 bs_bs_query bs_bs_query 17 words(MeSHtermsand/orfreetext)relatedtothetypeof separatecomparisons(53).Weonlyidentifiedtwostudies 69 bs_bs_query bs_bs_query 18 interventionandoutcome: thatcomparedaketogenicdietwithanon-ketogenicdiet 70 bs_bs_query bs_bs_query thatalsometourotherinclusioncriteria(20,54).However, 71 19bs_bs_query • Lowcarb*ORDiet,carbohydrate-restrictedORdiet, thenon-ketogeniccomparisongroupsinthesetwostudies 72bs_bs_query 20bs_bs_query reducingORverylowenergydietORverylowcaloriediet weretoodissimilartobecombinedinameta-analysis,and 73bs_bs_query 21bs_bs_query OR protein sparing modified fast OR ketogenic diet OR onlyoneofthesestudies(20)usedparticipantsastheirown 74bs_bs_query 22bs_bs_query ketogenicORketosisORketonebodiesORketones control. Therefore, we only extracted information from 75bs_bs_query 23bs_bs_query • Appetite OR hunger OR satiation OR satiety OR ketogenicinterventionsandthus,allstudiesincludedinthis 76bs_bs_query 24bs_bs_query desiretoeatORvisualanaloguescale meta-analysisprovideddataof‘pre-test’vs.‘post-test’. 77bs_bs_query bs_bs_query 25 Itwasourintentiontoincludethefiveprimaryaspectsof 78 bs_bs_query bs_bs_query 26 Datacollectionandanalysis appetite as recommended by Blundell in 2010; fullness, 79bs_bs_query bs_bs_query satiety,hunger,desiretoeatandprospectiveconsumption 80 bs_bs_query 27 Selectionofstudies (44). However, due to inconsistencies in terminology and 81 bs_bs_query bs_bs_query 28 Recordswerescreenedindependentlybytwoinvestigators the lack of reporting of questions used to assess these 82 bs_bs_query bs_bs_query 29 (AAGandJA)attheabstractandtitlelevel.Thefulltexts aspectsofappetite,wehadtomakeadjustmentstothedata 83 bs_bs_query bs_bs_query 30 ofpotentiallyeligiblestudieswereobtainedandthesetwo from some studies. We combined analysis of studies that 84 bs_bs_query bs_bs_query 31 investigators applied the inclusion and exclusion criteria assessed ‘fullness’ (20,29,53) and those that assessed 85 bs_bs_query bs_bs_query 32 independently. Discrepancies were resolved by consensus ‘satiety’(47–52)intoasinglevariableof‘fullness/satiety’. 86 bs_bs_query bs_bs_query 33 withathirdauthor(RVS). Inonestudythatreportedbothfullnessandsatiety(55),we 87 bs_bs_query bs_bs_query 34 pooledtheresultsintoonevariable.Althoughfullnessand 88 bs_bs_query bs_bs_query 35 Dataextraction satiety may measure subtly different aspects of appetite, 89 bs_bs_query bs_bs_query 36 We developed a data extraction sheet, which was pilot theyarerelatedtoeachother(43)andwouldbeexpected 90 bs_bs_query bs_bs_query 37 tested and refined accordingly. One author (AAG) tochangeinthesamedirection. 91 bs_bs_query bs_bs_query 38 extractedthedatafromallstudiesandasecondauthor(JA) To calculate nutritional composition of interventions a 92 bs_bs_query bs_bs_query 39 checkedalldataentryforaccuracy. conversion of 17kJg−1 for protein and carbohydrate and 93 bs_bs_query bs_bs_query 40 Informationwasextractedfromeachincludedstudyon 37kJg−1forfatwasappliedtostudiesthatreportednutri- 94 bs_bs_query bs_bs_query 41 (i) study characteristics (primary author, year of publica- tionalcompositionasapercentageofenergy.Kilocalories 95 bs_bs_query bs_bs_query 42 tion,setting,duration[pointoffollow-upappetiteassess- wereconvertedtokJbymultiplyingby4.18.Forthedura- 96 bs_bs_query bs_bs_query 43 ment] and nutritional composition of intervention); (ii) tionofintervention,weassumed1monthtoequal4weeks. 97 bs_bs_query bs_bs_query 4445bs_bs_query bsiazsee,lsinexe,cahgaer,abcotedryismticasssoinfdtehxe);s(tiuiid)ywepiogphutllaotsisonou(tscaommpelse; 98bs_bs_query bs_bs_query Datasynthesisandanalysis 99 46 (iv) appetite assessment method and results (aspects bs_bs_query bs_bs_query 47 [hunger, fullness etc.], time of day, frequency, reference Primaryoutcomes 100 bs_bs_query bs_bs_query 48 period [i.e. ‘present’ – how hungry do you feel now; or Theprimaryoutcomesweretheweightedmeandifference 101 bs_bs_query bs_bs_query 49 ‘retrospective’ – how hungry did you feel today/this in change in appetite (mm on a 100-mm scale) between 102 bs_bs_query bs_bs_query 50 week?]),reportingformat(i.e.singletimepointoraverage baseline (when participants were in energy balance) and 103 bs_bs_query bs_bs_query 51 of several time points), results (all in mm out of 100); during adherence to VLED or KLCD (when participants 104 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 4 Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. obesity reviews 1 were in ketosis). A random effects model was used to bs_bs_query 2 estimate separate effect sizes for fullness/satiety, hunger, bs_bs_query 3 desire to eat and prospective consumption. Changes in bs_bs_query 4 appetitevariableswerecalculatedbysubtractingthemean bs_bs_query 5 ratingmeasuredduringadherencetoVLEDorKLCDfrom bs_bs_query 6 themeanratingmeasuredatbaseline,sothatthedifference bs_bs_query 7 (positiveornegative)wouldreflectthedirectionofchange bs_bs_query 8 inappetite.Forexample,anegativedifferenceforhunger bs_bs_query 9 andapositivedifferenceforfullness/satietybothrepresent bs_bs_query 10 adecreaseinappetite. bs_bs_query 11 bs_bs_query 12 Secondaryoutcome bs_bs_query 13 Meta-regressionaimstorelatethesizeofaneffecttochar- bs_bs_query 14 acteristics (potential ‘effect modifiers’) of the studies bs_bs_query 15 involved (56). Therefore, a secondary outcome was to bs_bs_query 16 use meta-regression to determine whether the change in bs_bs_query 17 appetite (as calculated above) was associated with the bs_bs_query 18 level of ketosis, i.e. whether higher circulating levels of bs_bs_query 19 β-hydroxybutyrateresultedinagreaterdifferenceinappe- bs_bs_query 20 tite. Meta-regression was to be performed only if hetero- bs_bs_query 21 geneity was found to be present among studies, as this bs_bs_query 22 would indicate whether differences in the effect in each bs_bs_query 23 studyexisted. bs_bs_query 24 bs_bs_query 25 Heterogeneity,riskofbiasandqualityassessment bs_bs_query 26 Heterogeneity between studies was assessed using the I2 bs_bs_query 27 statistic.Egger’stestwasusedtoinvestigatepossiblepub- bs_bs_query 28 lication bias. Statistical significance was set at P<0.10. bs_bs_query 29 Theusualqualityfiltersforrandomizedtrialsorobserva- bs_bs_query 30 tionalepidemiologicstudieswerenotappliedtothestudies bs_bs_query 31 selectedforthiswork,asonly‘pre-test’vs.‘post-test’data bs_bs_query Figure1 Flowchartofpublicationselectionforthesystematicreview 54 3323bs_bs_query weArellasstasetisssteidca.lanalyseswereconductedusingSTATAsoft- andmeta-analysis.VAS,visualanaloguescale. 55bbss__bbss__qquueerryy bs_bs_query 34bs_bs_query wareversion13.0(StataCorp,CollegeStation,TX,USA). 56bs_bs_query 35bs_bs_query was conducted entirely in an outpatient setting, with the 57 36bs_bs_query Results durationofalltheketogenicinterventionsrangingfrom4 58bbss__bbss__qquueerryy 3378bbss__bbss__qquueerryy Studyselection tdoesc1r2ibweetehkes.inTtehrevesnttuidoiness,uasneddfdoirffecroennstistteernmcyintohloegtyertmo 5690bbss__bbss__qquueerryy 39 Thesystematicsearchresultedin26publicationsthatmet VLED is used to refer to all interventions providing less 61bs_bs_query 40bs_bs_query the inclusion criteria, 12 of which were included in the than3.3MJ(800kcal)perday,andthetermKLCDisused 62bs_bs_query 41bs_bs_query meta-analysis(Fig.1).Fourteenpublicationswereincluded whenreferringtointerventionsthatrestrictedcarbohydrate 63bs_bs_query 42bs_bs_query in the review but were not included in the meta-analysis, intaketo<10%ofenergyor≤50gday–1,butthatallowed 64bs_bs_query 43bs_bs_query nine did not have the required data (13,17,24–26,30,32) ad libitum consumption of energy, protein and fat. Ten 65bs_bs_query 44bs_bs_query and five conducted baseline assessment of appetite when studiesinvolvedVLEDinterventions,andtheyprescribed 66bs_bs_query 45bs_bs_query participantswerenotinenergybalance(14,27,28,31,33). similardailyintakesofenergy(∼2.1–2.4MJ),protein(50– 67bs_bs_query 46bs_bs_query These publications excluded from the meta-analysis were 60g), carbohydrate (45–52g) and fat (<10g) (29,30,46– 68bs_bs_query 47bs_bs_query reviewedqualitatively. 52). There were slight differences in one study that 69bs_bs_query bs_bs_query providedvaryingdailyprotein(64–97g),fat(2–23g)and 70 48 bs_bs_query bs_bs_query carbohydrate(28–42g)intakesintheinterventiongroups 71 49 Characteristicsofstudiesincludedin bs_bs_query bs_bs_query (53).Nostudiesreportedthefibrecontentofthediet.Allof 72 50 themeta-analysis bs_bs_query bs_bs_query theVLEDstudiesallowedadditionalservingsoffruitand 73 bs_bs_query 51 Interventions vegetables (46,48–52), but more specific information was 74 bs_bs_query bs_bs_query 52 Thecharacteristicsofstudiesincludedinthemeta-analysis not reported; therefore, dietary prescriptions reported 75 bs_bs_query bs_bs_query 53 (n=12)areshowninTable1.Allbutoneofthesestudies in Table1 do not include these allowances. All studies 76 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 obesity reviews Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. 5 ective Outcome Weightloss(kg)* 7.77.1 6.36.46.66.29.56.35.05.05.912.56.35.9 bj u s D on S± ED, ketogenicdiets eline BMI(meanorrange) 28.72.0±29.62.0± 35.13.8±29.72.6±29.42.6±29.42.6±36.13.3±25–3731.74.7±29.92.6±32.36.1±34.73.5±29.52.6±29.62.4± ••;SSP,••;VL alysisofeffectsof participantsatbas Age(meanSD±orrange) 40.89.5±442± 3810±18,6018–6018–6045.89.3±40–7018–80 54.410.9±44.210.3±18–60 darddeviation;SP, udedinthemeta-an Characteristicsof SampleSexsize(%F) 501008055 1701047591NR113NR134672803482256828753968148NR76NR outpatient;SD,stan ncl m mm O, 2studiesi Fat–1(gday) 88 Adlibitu888AdlibituAdlibitu22236.988 shown. reported; ne,aswellasweightlossoutcome,inthe1 CHOProteinEnergy–1–1–1)(gday)(gday)(MJday 2.152542.15254 Adlibitum4%ofEnAdlibitum2.152542.152542.15254Adlibitum20gAdlibitum<Adlibitum10%ofEnAdlibitum<2.44295∼2.44397∼2.42864∼2.245522.152542.15254 asnotincludedinthenutritionalinformation etal.(49). D,ketogeniclow-carbohydratediet;NR,not CharacteristicsofdietaryinterventionsandparticipantsatbaseliTable1appetite StudyPrescribeddietaryintervention SettingKetogenicDurationdiettype(weeks)* †OVLED6Diepvensetal.(46)OVLED4HurselandWesterterp-†Plantenga(47)‡Johnstoneetal.(20)I/OKLCD4†§OVLED4Kovacsetal.(48)†§OVLED4Lejeuneetal.(50)†OVLED4Lejeuneetal.(49)Martinetal.(54)**OKLCD12¶OKLCD12Ratliffetal.(55)†OVLED(lac)4Soenenetal.(53)αVLED(SSP)4VLED(SP)4†OVLED8Sumithranetal.(29)†§OVLED4Westerterp-Platengaetal.(51)†OVLED4Westerterp-Platengaetal.(52) *Atthetimeofassessmentofappetitewhileontheketogenicdiet.†Interventionincludedanallowanceoffruitand/orvegetables,andthisw‡Allowedtoleavehospitaltogotowork.§NutritionalinformationassumedtobethesameasdescribedinLejeune¶Nutritionalinformationobtainedfromanotherreference(77).**Weightoutcomesobtainedfromanotherreference(78).BMI,bodymassindex;CHO,carbohydrate;En,energy;I,inpatient;KLCvery-low-energydiet. ©2014InternationalAssociationfortheStudyofObes5itybs_bs_query (IASO) 6bs_bs_query 12 3 45 678901234567890 12345678 11111111112 22222222 OBR12230 6 Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. obesity reviews 1 involvingVLEDreportedaverageweightlossesofgreater and reported area under the curve, but only the fasted 59 bs_bs_query bs_bs_query 2 than 1kgweek–1 and most commonly reported a mean appetitevaluewasincludedinthemeta-analysesforcom- 60 bs_bs_query bs_bs_query 3 weightlossof∼6kg(range5.0–12.5kg)atthetimeofthe parison with the other studies (29). Most VAS questions 61 bs_bs_query bs_bs_query 4 appetite assessment. The remaining three studies used were asked in reference to the present state (e.g. ‘How 62 bs_bs_query bs_bs_query 5 KLCDintervention(20,54,55).Althoughparticipantswere hungry do you feel now?’) (n=11) vs. retrospective 63 bs_bs_query bs_bs_query 6 not instructed to restrict their energy intake, it appeared enquiry (e.g. ‘How hungry were you this week?’) (n=1). 64 bs_bs_query bs_bs_query 7 thattheydidsoinallthreeKLCDstudies,asevidencedby Theresultsweretypicallyreportedintheformatofasingle 65 bs_bs_query bs_bs_query 8 mean weight losses of 6.3–9.5kg. One study was a well- timepoint(n=9)or,dependingonthetimepointsatwhich 66 bs_bs_query bs_bs_query 9 controlled in-patient study, where participants reduced appetitewasassessed,asanaverageofseveraltimepoints 67 bs_bs_query bs_bs_query 10 their daily energy intake by 5.4MJ (20), while the other on the same day (n=3) or over several days (n=1). All 68 bs_bs_query bs_bs_query 11 twodidnotreportenergyintake. studiesreportedresultsinmmona100-mmscaleorcmon 69 bs_bs_query bs_bs_query 12 a10-cmscale(whichwereconvertedtommforthecurrent 70 bs_bs_query bs_bs_query 13 Participants meta-analysis). 71 bs_bs_query bs_bs_query 14 Samplesizesinthedifferentstudiesrangedfrom17to148. 72 bs_bs_query bs_bs_query 15 Where reported, studies had a greater proportion of Ketones 73 bs_bs_query bs_bs_query 16 womenthanmen.Participantsinthe12studieshadsimilar In studies included in the meta-analysis, ketosis was con- 74 bs_bs_query bs_bs_query 17 ages(rangingfrom30to55years)andwereoverweightor firmed through objectively measured blood or urinary 75 bs_bs_query bs_bs_query 18 obese(bodymassindex≥25kgm−2).Informationrelating parameters.Table3showsthelevelsofβ-hydroxybutyrate 76 bs_bs_query bs_bs_query 19 totheparticipantsineachstudyisprovidedinTable1. inthebloodofparticipantsatthetimeofappetiteassess- 77 bs_bs_query bs_bs_query 20 ment while on the ketogenic diet, in the nine studies in 78 bs_bs_query bs_bs_query 21 Appetitemethodology which it was reported. All but one of these studies 79 bs_bs_query bs_bs_query 22 Methods of appetite assessment used in the 12 studies involved VLEDs, and the prescribed daily carbohydrate 80 bs_bs_query bs_bs_query 23 includedinthismeta-analysis,andtheaspectsofappetite intake ranged from 45 to 52g (not including fruit 81 bs_bs_query bs_bs_query 24 assessed, are shown in Table2. The majority of studies andvegetableallowances),resultinginsimilar(∼0.5mM) 82 bs_bs_query bs_bs_query 25 (n=8)assessedappetiteinthemorninginthefastedstate. blood β-hydroxybutyrate levels. Levels of blood 83 bs_bs_query bs_bs_query 26 Onestudyalsoassessedappetiteafterastandardizedmeal β-hydroxybutyrate were several fold higher in the KLCD 84 bs_bs_query bs_bs_query 27 bs_bs_query 28 Table2 Protocolforappetiteassessmentviavisualanaloguescalesinthe12studiesincludedinthemeta-analysisofeffectsofketogenicdietson bs_bs_query 29 subjectiveappetite bs_bs_query 30 bs_bs_query 31 Study Aspectsofappetite Timeofday Reference Reportingformat Assessmenttime bs_bs_query 32 points bs_bs_query 33 bs_bs_query 34 Diepvensetal.(46) Hunger Morning/fastedandat60, Present Averageover4h(five Baseline,week6 bs_bs_query 35 120,180and240min measurements) bs_bs_query 36 after1MJofyoghurt bs_bs_query 37 Hurseland Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 38 Westerterp- bs_bs_query 39 Plantenga(47) bs_bs_query 40 Johnstoneetal.(20) Fullness,hunger,desiretoeat, Hourlyduringwaking Present Averageof15daily Dailyfor4weeks bs_bs_query 41 prospectiveconsumption hours(08:00–22:00h) measurements bs_bs_query 42 Kovacsetal.(48) Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 43 Lejeuneetal.(50) Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 44 Lejeuneetal.(49) Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 45 Martinetal.(54) Hunger NR Retrospective Singlemeasurement Baseline,week12 bs_bs_query 46 (1week) bs_bs_query 47 Ratliffetal.(55) Fullness,satiety,hunger,desire NR Present Averageof5days Baseline,week12 bs_bs_query 48 toeat bs_bs_query 49 Soenenetal.(53) Fullness,hunger,desiretoeat, Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 50 prospectiveconsumption bs_bs_query 51 Sumithranetal.(29) Fullness,hunger,desiretoeat, Morning/fasted Present Singlemeasurement Baseline,week8 bs_bs_query 52 prospectiveconsumption bs_bs_query 53 Westerterp-Platenga Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 54 etal.(51) bs_bs_query 55 Westerterp-Platenga Satiety,hunger Morning/fasted Present Singlemeasurement Baseline,week4 bs_bs_query 56 etal.(52) bs_bs_query 57 bs_bs_query 58 NR,notreported. bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 obesity reviews Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. 7 1 Table3 Degreeofketosisattainedintheninestudiesincludedinthemeta-analysisthatalsoreportedbloodconcentrationsofβ-hydroxybutyrate bs_bs_query 2 bs_bs_query 3 Study Ketogenic PrescribedCHO Timepoint n β-Hydroxybutyrate bs_bs_query 4 diettype intake(gday–1) (weeks) mM(mean±SD) bs_bs_query 5 bs_bs_query 6 Diepvensetal.(46)* VLED 52 6 50 0.49±0.38 bs_bs_query 7 HurselandWesterterp-Plantenga(47)* VLED 52 4 80 0.56±0.24 bs_bs_query 8 Johnstoneetal.(20) KLCD 22 4 17 1.52±1.64 bs_bs_query 9 Kovacetal.(48)* VLED 52 4 104 0.50±0.30 bs_bs_query 10 Lejeuneetal.(50)* VLED 52 4 91 0.53±0.31 bs_bs_query 11 Lejeuneetal.(49)* VLED 52 4 113 0.51±0.32 bs_bs_query 12 Sumithranetal.(29)* VLED 45 8 39 0.48±0.44 bs_bs_query 13 Westerterp-Platengaetal.(51)* VLED 52 4 148 0.50±0.32 bs_bs_query 14 Westerterp-Platengaetal.(52)* VLED 52 4 76 0.50±0.08 bs_bs_query 15 bs_bs_query 16 *Interventionincludedfruitand/orvegetableallowance,andthiswasnotincludedinthecarbohydrateinformationshown. bs_bs_query 17 CHO,carbohydrate;KLCD,ketogeniclow-carbohydratediet;SD,standarddeviation;VLED,very-low-energydiet. bs_bs_query 18 bs_bs_query 19 intervention,inwhichparticipantsconsumed22gofcar- by 8.9mm (95% CI: −16.0, −1.8). No heterogeneity 55 bs_bs_query bs_bs_query 20 bohydrate per day (20). In the three studies included (I2=0.0%)orpublicationbiaswasdetectedinanyofthe 56 bs_bs_query bs_bs_query 21 in the meta-analysis that did not report on blood analyses. 57 bs_bs_query bs_bs_query 22 β-hydroxybutyrate levels, two confirmed ketosis using 58 bs_bs_query bs_bs_query 22223456bbbbssss____bbbbssss____qqqquuuueeeerrrryyyy ukcwireriittcnohuanltraehystoindwsgeieprrfseertaeicenckhofsetadt(mt5dye4ua,ar5sciu5nidr)ge.dkcI,oentnbocousenitnse.ttrhareetimroenapisonriwnteegdresitncucodrnyesais(s5ete3ni)nt, MMβd-ieehestytaad--(rrr∼oee0xgg.ryr5eebssmussitMoiyonrn)atewanawdsasnoonstliympioleanrrfeoramKmLeodCngDasadllitehtVeLmEleeDvaeslusrteoudf- 56669012bbbbssss____bbbbssss____qqqquuuueeeerrrryyyy 27 β-hydroxybutyrate. 63 bs_bs_query bs_bs_query 28 Mainfindingsfromthemeta-analyses 64 bs_bs_query bs_bs_query 2390bbss__bbss__qquueerryy VAefroy-rleoswt-pelnoetrgoyf tdhieetnsitnuedisetsudies examining the effect of Qthueamliteattaiv-eaneavlaylsuisationofstudiesnotincludedin 6656bbss__bbss__qquueerryy 33333333344444441234567890123456bbbbbbbbbbbbbbbbssssssssssssssss________________bbbbbbbbbbbbbbbbssssssssssssssss________________qqqqqqqqqqqqqqqquuuuuuuuuuuuuuuueeeeeeeeeeeeeeeerrrrrrrrrrrrrrrryyyyyyyyyyyyyyyy VVwfci8nhadsw(t(nuIePtol.oue2uLLselhc8lncnntlr=rdEEi=)rnsseceeg.eitfDDie0hae0eduAoaoss.sr.seodrs0nle0osea/rlfddi6dslt%deepnsyouaiu)dssdu.tftbdre)afhbibisitoyienpneieyhslwtnnuisgpesyec6oerad.tea2.aathVstt5Hts.ddishei6stLtsodeutmhecoeeuEsnmemhdewsimdtiDrarsimsemeeeebieencetsvndiesda(gtstaetct9eoet-e(usarehdfa95p,fu-dena5o%iwatwaslicitaol%nueinttanghlsefanysatenocedladahsnsyoniuCisnssefidssniins/ynicgIdsaefiVsd:poaanas,doFrLntsvit−asieofieafietEoei4gndlscgrtsvyDtf..pcaayni.9hrehge.2len.oirl,eunfic.,taImNWitnincn−laAifihflagvdot0onhcoanleeeil.araeflvwrrt2lu.cnnlvhioy)ddoelIstae.fdlsnevtcunnlteiuesoedetOnasesic[hdrrnuir.lscC,rvolneiessmryeeiEsg/Iihle,dassdy]etpeagua:suoetnwsgtentnhart4ieeieoiwgeieeeli.nrnlriiett3rnay’onngyyeeesrt,,, TdcrmffidhoistHnnrohetheeuraouesgoreNtacbnpstmmdsayswrralagaeiieiae-anleteetcoarsectaiistrvteehesfedt,niSeeeptdutveaa2yrsyrtoeis,in(tlihmdnely1surbiadyewdntfts3denu,nioeiocth,isotdodhmr3aeosn.emtnes,s-2fneeSiarsesg)ate3i(nus1aganste.motapi-4tnniuiioOaruglnfipeiddynnhfidcaonsfsytatcaytsirohtuoslaunrtahytVeednnrtspdhtespeiihtLoispuedgedsoteeEnseenehia,rntclDfiiaetp2tiisfitrcetnosnphe,eecrdhiedveaaenautoetinastnhtsnnpinneaesouttegaosweeresypsvssvccssistepehhteKanuocr-srlniiaaopeedLsneflhtnnammprriiCtuebggeaoehoheesnDeenxinerwunlngdctisi)(nttmteneuala1iyaudgarswpn0erfdelomapyaadtl,ereyaa1fsnnordefit-7epddroita(aslnt,haa3enni2fveiggortrt0na4exhaptondlh)Vcri,ceyrm.ic5aoriufiloLsineug7lfipTnicvoaEesd)naagttwisgDhhdeondaneieyndoeeerssft-t., 66677777777778887890123456789012bbbbbbbbbbbbbbbbssssssssssssssss________________bbbbbbbbbbbbbbbbssssssssssssssss________________qqqqqqqqqqqqqqqquuuuuuuuuuuuuuuueeeeeeeeeeeeeeeerrrrrrrrrrrrrrrryyyyyyyyyyyyyyyy 47 scorestakenover2weeks,whichincludedthefirstfewdays 83 bs_bs_query bs_bs_query 48 Ketogeniclow-carbohydratedietstudies ontheVLED,inwhichappetiteisknowntobeincreased 84 bs_bs_query bs_bs_query 49 A forest plot of the three studies examining the effect of (25). In the other of these two VLED studies, despite 85 bs_bs_query bs_bs_query 50 KLCDsonappetiteisdepictedinFig.3.Onlytwoofthe reportingasignificantincreaseinhunger,participantsdid 86 bs_bs_query bs_bs_query 51 studies assessed fullness/satiety, which did not increase notexhibitgreaterenergyintakeatabreakfastmeal(26). 87 bs_bs_query bs_bs_query 52 significantly. All three studies assessed hunger, which Five studies (all VLEDs) were excluded from the 88 bs_bs_query bs_bs_query 53 decreased significantly by 5.5mm (95% CI: −8.5, −2.5). meta-analysis because the baseline assessment of appetite 89 bs_bs_query bs_bs_query 54 Two studies assessed desire to eat, which decreased was not conducted under conditions of energy balance, 90 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 8 Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. obesity reviews W in print & Colour online, B bs_bs_query Figure2 Forestplotofchangeinappetite 13 17 assessedwithvisualanaloguescales bs_bs_query 18bs_bs_query bs_bs_query betweenbaselineandinresponsetoa 19 bs_bs_query very-low-energydiet.Eightstudies(10 20 bs_bs_query comparisons;n=738)assessed 21 bs_bs_query fullness/satiety,ninestudies(11comparisons; 22 bs_bs_query n=788)assessedhunger,twostudies(four 23 bs_bs_query comparisons;n=126)assesseddesiretoeat 24 bs_bs_query andtwostudies(fourcomparisons;n=126) 25 bs_bs_query assessedprospectiveconsumption.Plotted 26 bs_bs_query valuesareweightedmeandifferences(WMD) 27 bs_bs_query fromarandomeffectsmodel.Errorbars 28 bs_bs_query depict95%confidenceintervals(CI).TheI2 29 bs_bs_query statisticreferstoheterogeneity. 30 bs_bs_query 31 bs_bs_query 1 but was instead preceded by an energy-restricted diet bs_bs_query Discussion 32 2 (14,27,28,31,33).Comparedwiththebaselineassessment bs_bs_query bs_bs_query 3 of hunger measured during moderate-energy restriction, This study showed that individuals are significantly less 33 bs_bs_query bs_bs_query 4 while adhering to VLED, participants in three studies hungry and exhibit significantly greater fullness/satiety 34 bs_bs_query bs_bs_query 5 showedsignificantlydecreasedhunger(14,31,33),partici- whileadheringtoVLEDcomparedwithwhentheyarein 35 bs_bs_query bs_bs_query 6 pantsinonestudyshowednochangeinhunger(27)and energy balance at baseline. This work also showed that 36 bs_bs_query bs_bs_query 7 participantsinanotherstudyonaliquidVLEDshowedno individualsadheringtoKLCDaresignificantlylesshungry 37 bs_bs_query bs_bs_query 8 changeinhungerandparticipantsonthefood-basedVLED and have a significantly reduced desire to eat compared 38 bs_bs_query bs_bs_query 9 showedasignificantdecreaseinhunger(28).Thatis,inall withbaselinemeasures.Althoughtheabsolutechangesin 39 bs_bs_query bs_bs_query 10 five of these excluded VLED studies, participants were subjectiveappetitemeasuresduringVLEDorKLCDmay 40 bs_bs_query bs_bs_query 11 eitherlesshungryorwerenohungrierwhileontheVLED be considered small, and for some aspects of appetite 41 bs_bs_query bs_bs_query 12 comparedwithafterthemoderatelyenergy-restricteddiet. were not significant, the more remarkable finding from 42 bs_bs_query bs_bs_query 13 Although these studies are not directly comparable, with this work, from a clinical perspective, is the clear lack 43 bs_bs_query bs_bs_query 14 thoseincludedinthemeta-analysis,theysupportthefind- of increase in hunger despite participants consuming 44 bs_bs_query bs_bs_query 15 ings of the meta-analysis by showing that there was no a severely (in the case of VLEDs) or moderately (in the 45 bs_bs_query bs_bs_query 16 increaseinappetitewhileadheringtoVLED. case of KLCDs) energy-restricted diet, and having lost 46 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 obesity reviews Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. 9 W in print & Colour online, B bs_bs_query 1 Figure3 Forestplotofchangeinappetite bs_bs_query 2 assessedwithvisualanaloguescales bs_bs_query 3 betweenbaselineandinresponsetoa bs_bs_query 4 ketogeniclow-carbohydratediet.Twostudies bs_bs_query 5 (twocomparisons;n=45)assessed bs_bs_query 6 fullness/satiety,threestudies(three bs_bs_query 7 comparisons;n=179)assessedhungerand bs_bs_query 8 twostudies(twocomparisons;n=45) bs_bs_query 9 assesseddesiretoeat.Plottedvaluesare bs_bs_query 10 weightedmeandifferences(WMD)froma bs_bs_query 11 randomeffectsmodel.Errorbarsdepict95% bs_bs_query 12 confidenceintervals(CI).TheI2statistic bs_bs_query 13 referstoheterogeneity. bs_bs_query 14 bs_bs_query 15 significantamountsofweight.Thus,forcliniciansseeking of ketosis (17,33,35,57,58), as indicated by circulating 49 bs_bs_query bs_bs_query 16 an effective method of weight loss that does not increase β-hydroxybutyrateconcentrationsof∼3.7or0.5–0.7mM, 50 bs_bs_query bs_bs_query 17 hunger, this meta-analysis provides clear evidence that respectively (17,57). The question whether appetite 51 bs_bs_query bs_bs_query 18 VLEDsachievethistarget.KLCDsalsoappearpromising canbesuppressedduringweightlossatalowthresholdof 52 bs_bs_query bs_bs_query 19 but,duetothelimitednumberofthesestudiesavailablefor ketosiswarrantsinvestigation,asitwouldenabledevelop- 53 bs_bs_query bs_bs_query 20 thepresentreview,furtherinvestigationisneeded. mentofKLCDsthataremorealignedwithevidence-based 54 bs_bs_query bs_bs_query 21 Asecondaryaimofthisworkwastodeterminewhether healthy eating recommendations through inclusion of 55 bs_bs_query bs_bs_query 22 thereisadose–responseor‘threshold’ofcirculatingketone healthy(i.e.lowglycaemicindex)carbohydrate-containing 56 bs_bs_query bs_bs_query 23 levels for appetite suppression. However, it was not pos- foodssuchaswholegrains,legumes,reduced-fatdairyand 57 bs_bs_query bs_bs_query 24 sibletorealizethisaimbecausetherewasalackofdiffer- fruit. 58 bs_bs_query bs_bs_query 25 enceinβ-hydroxybutyratelevelsamongVLEDstudiesand Fromthecurrentstudies,itwasnotpossibletodetermine 59 bs_bs_query bs_bs_query 26 there was only one KLCD study that reported blood whethertheappetitesuppressionseenwithketogenicdiets 60 bs_bs_query bs_bs_query 27 β-hydroxybutyrate levels. Nevertheless, it is important is indeed due to ketosis, or due to other factors such as 61 bs_bs_query bs_bs_query 28 to note that the VLED studies that measured circulating anincreasedordecreasedcontentofproteinorfatinthe 62 bs_bs_query bs_bs_query 29 ketone levels included in the meta-analysis showed blood dietortherestrictionofcarbohydrate.Thisisbecausethe 63 bs_bs_query bs_bs_query 30 β-hydroxybutyrate levels of ∼0.5mM, and none reported dietary intake of one particular macronutrient cannot be 64 bs_bs_query bs_bs_query 31 an increase in appetite. This finding suggests that if a variedindependentlyoftheothermacronutrientswithout 65 bs_bs_query bs_bs_query 32 threshold of circulating β-hydroxybutyrate for appetite affecting energy. For instance, the appetite suppression of 66 bs_bs_query bs_bs_query 33 control exists, it may be lower than 0.5mM, and that KLCDs has been attributed to their high protein content 67 bs_bs_query bs_bs_query 34 higher levels (and accordingly more severe dietary carbo- (59).However,KLCDsinvolveonlymodestornoincreases 68 bs_bs_query bs_bs_query 35 hydrate restriction) may not be necessary to prevent an inabsoluteproteinintakerelativetonormaldiets(34,60). 69 bs_bs_query bs_bs_query 36 increaseinappetiteinresponsetoenergyrestriction.Unfor- Moreover, increased protein intake cannot explain why 70 bs_bs_query bs_bs_query 37 tunately, the carbohydrate intake required to achieve this appetite is suppressed during VLEDs, which, while rela- 71 bs_bs_query bs_bs_query 38 levelofketosiscannotbeinferredfromthecurrentdataset. tivelyhighinprotein,provideabsoluteproteinintakesof 72 bs_bs_query bs_bs_query 39 AlthoughallVLEDstudiesprovidedapproximately50gof only∼50–60gday–1(whichforobesepersonsislowerthan 73 bs_bs_query bs_bs_query 40 carbohydrate per day (in formulated meal replacement thesuggestednormalintakeof0.8–1.2gkg−1bodyweight 74 bs_bs_query bs_bs_query 41 products), these interventions also included additional perday[39]).Additionally,increasedproteinintakecannot 75 bs_bs_query bs_bs_query 42 allowances of fruits and vegetables, for which the nutri- explain the observation of an ‘absence of hunger’ during 76 bs_bs_query bs_bs_query 43 tional information was not provided. Further support starvationorfastingregimes(35,61)–anobservationthat 77 bs_bs_query bs_bs_query 44 forthenotionofathresholdofcirculatingketoneconcen- historicallyledtotheinitialdevelopmentVLEDstomimic 78 bs_bs_query bs_bs_query 45 trations for the effect on appetite comes from studies this benefit (15). Further, well-controlled studies have 79 bs_bs_query bs_bs_query 46 that have investigated appetite in response to varying shown that when protein intake is matched, a ketogenic 80 bs_bs_query bs_bs_query 47 levels of ketosis. These studies found no difference in high-proteindietsuppressesappetitemoresothananon- 81 bs_bs_query bs_bs_query 48 appetite between groups with higher or lower levels ketogenic high-protein diet in obese (20) and in lean 82 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO) OBR12230 10 Doketogenicdietsreallysuppressappetite? A.A.Gibsonetal. obesity reviews 1 subjects (62), highlighting ketosis as a plausible factor ketone esters (72,73). Although synthetic ketone esters 55 bs_bs_query bs_bs_query 2 commontobothVLEDsandKLCDsthatcouldsuppress werenotdevelopedforthepurposeofappetitesuppression, 56 bs_bs_query bs_bs_query 3 appetite.Besidesprotein,anotherfactorthatcouldconceiv- using them to artificially induce mild ketosis could be a 57 bs_bs_query bs_bs_query 4 ably explain the effect of ketogenic diets on appetite is novel strategy for weight management. For instance, if 58 bs_bs_query bs_bs_query 5 dietary fat (63). However, the contrasting low levels of patientswereabletoreapthebenefitsofappetitesuppres- 59 bs_bs_query bs_bs_query 6 dietaryfatintakeduringVLEDswiththerelativelyhigher sion with ketosis while consuming a more balanced and 60 bs_bs_query bs_bs_query 7 levels consumed during KLCDs suggest that dietary fat sustainabledietaryregimethanaKCLD,theycouldpoten- 61 bs_bs_query bs_bs_query 8 intake is not a common factor explaining the appetite- tially benefit from improved weight outcomes as well as 62 bs_bs_query bs_bs_query 9 suppressiveeffectofbothdiets. avoidingpotentialsideeffectsoflong-termdietaryimbal- 63 bs_bs_query bs_bs_query 10 Onelineofevidencethatketosisplaysaroleinappetite ances (37,74,75). After all, VLEDs are only intended for 64 bs_bs_query bs_bs_query 11 suppressionduringbothVLEDsandKLCDsistheobser- short-term(severalmonths)use,andtheweightregainseen 65 bs_bs_query bs_bs_query 12 vation that changes in perceived appetite and circulating withKLCDscouldberelatedtotheunsustainablyrestric- 66 bs_bs_query bs_bs_query 13 concentrationsofhormonalregulatorsofappetitecoincide tivenatureofthediet,asindicatedbystudiesshowingpoor 67 bs_bs_query bs_bs_query 14 with increased or decreased concentrations of circulating long-term adherence (76). However, whether treatment 68 bs_bs_query bs_bs_query 15 ketones.Forinstance,appetiteisincreasedduringthefirst withexogenousketonespersecouldsuppressanyincrease 69 bs_bs_query bs_bs_query 16 couple of days on VLED (or on a fasting regime), before inappetiteorcorrespondingchangesinappetite-regulating 70 bs_bs_query bs_bs_query 17 marked increases in circulating ketone concentrations hormones remains to be seen, there are a multitude of 71 bs_bs_query bs_bs_query 18 would be expected to occur (13,15,25,58). However, metabolic and hormonal changes associated with ketosis 72 bs_bs_query bs_bs_query 19 after the time when elevated circulating ketone levels are thatcouldbehavinganeffectonappetite. 73 bs_bs_query bs_bs_query 20 observed, perceived appetite (10,29,55) and circulating A limitation of this work is that we only evaluated 74 bs_bs_query bs_bs_query 21 concentrationsofhormonalregulatorsofappetite,namely, studies by comparing ‘pre-test’ and ‘post-test’ data as we 75 bs_bs_query bs_bs_query 22 ghrelin(29,55)andCCK(10,14,29),havebeenshownto only identified two studies that used a within-subject 76 bs_bs_query bs_bs_query 23 be no different from pre-VLED and/or pre-KLCD levels. comparison that compared a ketogenic diet with a non- 77 bs_bs_query bs_bs_query 24 Further,astudyofpeopleonVLEDshowedthatcirculating ketogenic diet (20,54). Further, we only identified three 78 bs_bs_query bs_bs_query 25 concentrations of the hunger-promoting hormone ghrelin KLCD studies that compared subjective appetite ratings 79 bs_bs_query bs_bs_query 26 weresuppressedrelativetobaselineconcentrationsonlyin with VAS despite a plethora of studies comparing weight 80 bs_bs_query bs_bs_query 27 those participants who were in ketosis (defined as blood lossoutcomesbetweenketogenicandnon-ketogenicdiets. 81 bs_bs_query bs_bs_query 28 β-hydroxybutyratelevels≥0.3mM),withthosewhowere Anotherlimitationofthisworkisthatsubjectiveappetite 82 bs_bs_query bs_bs_query 29 not in ketosis showing an increase in circulating ghrelin assessed with VAS is not necessarily synonymous with 83 bs_bs_query bs_bs_query 30 levels relative to baseline (29). Consistent with the above energy intake. However, the fact that people can actually 84 bs_bs_query bs_bs_query 31 observationsisthefindingthatafteraperiodofre-feeding adheretoVLEDsforseveralweekstomonthsatatime,as 85 bs_bs_query bs_bs_query 32 that abolishes ketosis post-VLED, perceived appetite and evidenced by the rapid and large weight losses achieved 86 bs_bs_query bs_bs_query 33 circulatinglevelsofghrelinincreased,whereasthatofthe (12),suggeststhattheydoindeedsuppressanycompensa- 87 bs_bs_query bs_bs_query 34 appetite-suppressing hormone CCK decreased, compared toryincreaseinappetite. 88 bs_bs_query bs_bs_query 3356bs_bs_query w(1i0th,29th).eTlheevealbsofvoeusntdudaietsbparsoevliindeesaunpdpoinrtefonrertghyehbyaplaonthce- 89bs_bs_query bs_bs_query Conclusion 90 37 esis that the now well-established changes in appetite, as bs_bs_query bs_bs_query 38 wellastheeffectofchangesincirculatinglevelsofappetite- Thissystematicreviewandmeta-analysisprovidesevidence 91 bs_bs_query bs_bs_query 39 regulatinghormonesthathavebeenshowntoaccompany that VLEDs significantly reduce appetite during weight 92 bs_bs_query bs_bs_query 40 diet-induced weight loss (1–4,8,9,42,64), appear to be loss.KLCDalsoshowpromise,butonlyalimitednumber 93 bs_bs_query bs_bs_query 41 ‘blocked’duringketosis.Theremaybeotherfactors(such ofstudieshaveaddressedthisquestionwithinthescopeof 94 bs_bs_query bs_bs_query 42 as the protein, fat or carbohydrate content of the diet ourreview.Thefindingsofthisstudyhaveimportantimpli- 95 bs_bs_query bs_bs_query 43 per se) contributing to the suppression of appetite during cationsforthecommunicationofinformationbyclinicians 96 bs_bs_query bs_bs_query 44 VLEDorKLCD,butnoneofthesedietaryfactorsprovides to patients. Based on this meta-analysis, clinicians can 97 bs_bs_query bs_bs_query 45 as consistent an explanation as ketosis for the appetite advisepatientsthatalthoughtheymayindeedfeelslightly 98 bs_bs_query bs_bs_query 46 suppressioninbothdiets. lesshungry(ormorefullorsatisfied)whileonVLED,the 99 bs_bs_query bs_bs_query 47 Another line of evidence that ketosis is associated with truebenefitofVLEDisinpreventinganincreaseinappe- 100 bs_bs_query bs_bs_query 48 appetite suppression (inferred from a reduction in energy tite, and that this can help them to comply with a severe 101 bs_bs_query bs_bs_query 49 intake and/or subjective appetite ratings) is that studies restrictionofenergyintakeinordertoachievesubstantial 102 bs_bs_query bs_bs_query 50 have shown elevations in circulating ketones and/or free weightlosses,ratherthantheabsenceofhungeraltogether. 103 bs_bs_query bs_bs_query 51 fatty acids (two metabolites that are characteristically Although other contributory factors cannot be ruled out, 104 bs_bs_query bs_bs_query 52 increasedduringfastingandthereforeketosis)affectappe- ketosisappearstoprovideaplausibleexplanationforthe 105 bs_bs_query bs_bs_query 53 titeinhumans(65,66)andanimals(67–71).Recentstudies suppression of appetite during adherence to a ketogenic 106 bs_bs_query bs_bs_query 54 have investigated the safety and tolerability of synthetic diet.Futurestudiesshouldinvestigatetheminimumlevelof 107 bs_bs_query bs_bs_query ©2014InternationalAssociationfortheStudyofObesity(IASO)
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