Joseph Beyene, Cyril WC Kendall and David JA Jenkins Marco Dibuono, Alexandra L. Jenkins ...

19 Pages·2012·0.85 MB·English

Effect of Fructose on Blood Pressure : A Systematic Review and Meta-Analysis
of Controlled Feeding Trials
Vanessa Ha, John L. Sievenpiper, Russell J. de Souza, Laura Chiavaroli, D. David
Wang, Adrian I. Cozma, Arash Mirrahimi, Matthew E. Yu, Amanda J. Carleton,
Marco Dibuono, Alexandra L. Jenkins, Lawrence A. Leiter, Thomas M.S. Wolever,
Joseph Beyene, Cyril W.C. Kendall and David J.A. Jenkins
Hypertension published online February 13, 2012
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Effect of Fructose on Blood Pressure
A Systematic Review and Meta-Analysis of Controlled Feeding Trials
Vanessa Ha, John L. Sievenpiper, Russell J. de Souza, Laura Chiavaroli, D. David Wang,
Adrian I. Cozma, Arash Mirrahimi, Matthew E. Yu, Amanda J. Carleton, Marco Dibuono,
Alexandra L. Jenkins, Lawrence A. Leiter, Thomas M.S. Wolever, Joseph Beyene,
Cyril W.C. Kendall, David J.A. Jenkins
Abstract—Concerns have been raised about the adverse effect of fructose on blood pressure. International dietary
guidelines,however,havenotaddressedfructoseintakedirectly.Asystematicreviewandmeta-analysiswasconducted
to assess the effect of fructose in isocaloric exchange for other carbohydrates on systolic, diastolic, and mean arterial
blood pressures. Studies were identified using Medline, Embase, and Cochrane databases (through January 9, 2012).
Humanclinicaltrialsofisocaloricoralfructoseexchangeforothercarbohydratesourcesfor(cid:1)7dayswereincludedin
the analysis. Data were pooled by the generic inverse variance method using random-effects models and expressed as
mean differences with 95% CI. Heterogeneity was assessed by the Q-statistic and quantified by I2. Study quality was
assessedusingtheHeylandMethodologicalQualityScore.Thirteenisocaloric(n(cid:1)352)and2hypercaloric(n(cid:1)24)trials
mettheeligibilitycriteria.Overall,fructoseintakeinisocaloricexchangeforothercarbohydratessignificantlydecreased
diastolic(meandifference:(cid:2)1.54[95%CI:(cid:2)2.77to(cid:2)0.32])andmeanarterialpressure(meandifference:(cid:2)1.16[95%
CI: (cid:2)2.15 to (cid:2)0.18]). There was no significant effect of fructose on systolic blood pressure (mean difference: (cid:2)1.10
[95% CI: (cid:2)2.46 to 0.44]). The hypercaloric fructose feeding trials found no significant overall mean arterial blood
pressureeffectoffructoseincomparisonwithothercarbohydrates.Toconfirmtheseresults,longerandlargertrialsare
needed.Contrarytopreviousconcerns,wefoundthatisocaloricsubstitutionoffructoseforothercarbohydratesdidnot
adversely affect blood pressure in humans. (Hypertension. 2012;59:00-00.) ● Online Data Supplement
Key Words: blood pressure (cid:2) fructose (cid:2) meta-analysis (cid:2) diabetes mellitus (cid:2) guidelines
Hypertension remains a major risk factor for stroke, has mirrored the increase in the prevalence of hypertension
cardiovascular disease, renal disease, and death. It over the last century.5 Furthermore, animal data regarding
accounts for 10% of the total annual health budget in fructose and BP are inconsistent and exhibit considerable
developed countries.1 By 2025, the number of people living interspecies variability. Dogs fed fructose show no effect on
with hypertension is expected to reach 1.56 billion people.2 BP,6whereasratstudieshaveconsistentlyshownthatchronic
Despite the complications associated with hypertension, two high fructose intake raises systolic BP (SBP).7–10 These
thirds of patients remain untreated or treated ineffectively.3 observationsledtothedevelopmentofahighlyreproducible
Dietary factors that increase blood pressure (BP) are of fructose-induced hypertensive rat model.9,11 Human studies,
interest to public health authorities, and recent attention has however, are inconsistent. Recent reports from the Harvard
focusedonfructose.4,5Theintroductionofrefinedsugarsinto Health Professionals and Nurses cohorts have shown no
thefoodsupplyandthesubsequentriseinsugarconsumption associationbetweenfructoseandhypertensionrisk.12Clinical
ReceivedSeptember2,2011;firstdecisionSeptember22,2011;revisionacceptedJanuary15,2012.
FromtheClinicalNutritionandRiskFactorModificationCentre(V.H.,J.L.S.,L.C.,R.J.d.S.,D.D.W.,A.I.C.,A.M.,M.E.Y.,A.J.C.,A.L.J.,L.A.L.,
T.M.S.W.,C.W.C.K.,D.J.A.J.)andKeenanResearchCenteroftheLiKaShingKnowledgeInstituteandDivisionofEndocrinologyandMetabolism
(L.A.L.,T.M.S.W.,D.J.A.J.),StMichael’sHospital,Toronto,Ontario,Canada;DepartmentsofNutritionalSciences(V.H.,R.J.d.S.,L.C.,D.D.W.,A.I.C.,
A.M.,M.E.Y.,L.A.L.,T.M.S.W.,C.W.C.K.,D.J.A.J.)andMedicine(L.A.L.,D.J.A.J.),FacultyofMedicine,UniversityofToronto,Toronto,Ontario,
Canada; Departments of Pathology and Molecular Medicine (J.L.S.) and Clinical Epidemiology and Biostatistics (R.J.d.S., J.B.), Faculty of Health
Sciences,McMasterUniversity,Hamilton,Ontario,Canada;DallaLanaSchoolofPublicHealth(J.B.),UniversityofToronto,Toronto,Ontario,Canada;
PopulationHealthSciencesResearchInstitute(J.B.),HospitalforSickChildren,Toronto,Ontario,Canada;HeartandStrokeFoundationofOntario
(M.D.),Toronto,Ontario,Canada;CollegeofPharmacyandNutrition(C.W.C.K.),UniversityofSaskatchewan,Saskatoon,Saskatchewan,Canada.
Thistrialhasbeenregisteredatwww.clinicaltrials.gov(identifierNCT01363791).
Presentedinpartatthe14thAnnualCanadianSocietyforEndocrinologyandMetabolism/CanadianDiabetesAssociationProfessionalConferenceand
AnnualMeetings,Toronto,Ontario,Canada,October26–29,2011.
Theonline-onlyDataSupplementisavailablewiththisarticleathttp://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
111.182311/-/DC1.
CorrespondencetoJohnL.Sievenpiper,RiskFactorModificationCentre,StMichael’sHospital,#6137-61QueenStEast,Toronto,OntarioM5C2T2,
[email protected]
©2012AmericanHeartAssociation,Inc.
Hypertensionisavailableathttp://hyper.ahajournals.org DOI:10.1161/HYPERTENSIONAHA.111.182311
Downloaded from http://hyper.ahajour1nals.org/ by guest on February 14, 2012
2 Hypertension April 2012
interventionstudies,however,haveshownconflictingresults: additional information. Missing SD values were imputed from the
fructose has been shown to increase and decrease BP.13–18 pooledSDfromotherpublishedreports.29
The quality of each study was assessed using the Heyland
Few nutrition guidelines address fructose directly. BP
Methodological Quality Score (MQS).30 Studies could receive a
guidelines have not addressed the effect of fructose or any maximum score of 13 points. Studies with a score of (cid:1)8 were
othersugarsonBPintheirguidelines.19,20OnlytheAmerican consideredhighquality.Pointswereawardedbasedonthequalityof
HeartAssociation,CanadianDiabetesAssociation,andAmeri- thestudymethods,sampleselectionandfollow-up,andintervention.
can Diabetes Association have addressed fructose directly but
Statistical Analyses
only based on proposed lipid effects.21–24 To assess whether
DatawereanalyzedusingReviewManager(RevMan)version5.0.25
fructosehasanadverseeffectonBPandbuildanevidencebase
(Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen,
for dietary guidelines, we conducted a systematic review and
Denmark).Pooledanalysesforisocaloricandhypercaloricfructose
meta-analysis of controlled feeding trials investigating the ef- feeding trials were conducted using the Generic Inverse Variance
fectsoffructoseonBP. method using random-effects models. Analyses were stratified by
diabetesmellitusstatus.Ouroverallanalysiscombinedthenondia-
beticwiththeprediabetic/diabeticparticipants.Meanendpointsof
Methods
SBP, DBP, and MAP were compared between fructose and its
The Cochrane Handbook for Systematic Reviews of Interventions respective CH O comparator. Data were expressed as mean differ-
wasusedasaguidelineforthismeta-analysis.25Reportingofresults ences (MD) w2ith 95% CIs. To mitigate the unit-of-analysis error
followedthePreferredReportingItemsforSystematicReviewsand fromincludingtrialswithmultipleinterventionarms,wecombined
Meta-Analysesguidelines.26 arms to create single pairwise comparisons. Because correlation
coefficients could not be derived for paired analyses of crossover
Study Strategy trials,31 we made assumptions about the degree of correlation
RelevantcontrolledfeedingtrialswereidentifiedusingMedline,Em- betweentreatmentandcontrolendvalues.Weassumedaconserva-
base,andtheCochraneCentralRegisterofControlledTrialsthrough tivedegreeofcorrelationof0.50,withsensitivityanalysesdoneat2
January 9, 2012, using the search terms and Boolean operators: additionallevels,0.25and0.75.A2-sidedPvalue(cid:5)0.05wassetas
“fructoseAND(bloodpressureORBPORSBPORDBPORmean thelevelofsignificanceforaneffect.TheQ-statisticassessedandI2
arterial pressure OR MAP).” Manual searches of references cited by quantified the interstudy heterogeneity with significance set at
publishedstudiesalsosupplementedthedatabasesearch. P(cid:5)0.10. An I2 (cid:1)50% indicated “substantial” heterogeneity, and
(cid:1)75%indicated“considerable”heterogeneity.Sourcesofheteroge-
Inclusion Criteria neity were explored using a priori subgroup analyses of CH O
2
Humantrialsthatinvestigatedtheeffectofisocaloricorhypercaloric comparator(starch,glucose,sucrose,andhigh-fructosecornsyrup),
fructosecomparedwithothercarbohydratesources(CH O)onSBP, dose(CanadianDiabetesAssociationthresholdof(cid:2)60g/dor(cid:6)60
diastolic BP (DBP), or mean arterial BP (MAP) we2re included. g/d),22 follow-up ((cid:2)4 weeks or (cid:6)4 weeks), fructose form (fluid,
Investigators must have administered fructose and control CH O mixed,orsolid),studyquality(MQS(cid:5)8or(cid:1)8),randomization(yes
orallyforaminimumof7days.Weexcludedtrialsinwhichfructo2se orno),andstudydesign(crossoverorparallel).Systematicremoval
of studies was conducted during sensitivity analyses to determine
wasadministeredexclusivelyassucroseorhigh-fructosecornsyrup,
whetheranysinglestudyexertedanundueinfluenceontheoverall
becausethisdidnotpermitustoisolatetheeffectoffructose.Studies
results. Subgroup analyses were conducted only for nondiabetic
were considered to be “isocaloric” when the fructose intervention
participants,becauseonly2trials,14,17withconflictingresults,had
was compared with its CH O comparator under iso-energetic con-
2 beenundertakeninprediabetic/diabeticparticipants.
ditions (ie, even if both arms were hypocaloric relative to weight
Metaregressions were performed to assess the significance of
maintenance requirements) and “hypercaloric” when the oral fruc-
subgroup effects (Stata 11.2, StataCorp, College Station, TX).
tose was provided as a supplement to the control diet, providing
Publicationbiaswasinvestigatedbyvisualinspectionoffunnelplots
excess energy relative to the control diet alone. No restriction was
andformallytestedusingEggerandBeggtests.
placedonlanguage.
Results
Data Extraction
Studiesthatmettheinclusioncriteriahadtheirstudycharacteristicsand Search Results
resultsextractedby3independentreviewers(V.H.,L.C.,andD.D.W.). Figure 1 shows the flow of literature. The search identified
These data included study design, randomization, blinding, sample
319reports,303ofwhichweredeterminedtobeirrelevanton
characteristics,comparator,dose,follow-up,fructoseform,compliance
measures,andmacronutrientprofileofthebackgrounddiet.Disagree- review of the titles and abstracts. The remaining 16 reports
mentswereresolvedbyconsensusandwhennecessarywithJ.L.S.All were reviewed in full. A total of 11 reports were selected
ofthedisagreementswereconcerningtheHeylandScore.17,27,28 for analysis, providing data for 15 trials: 13 isocal-
Start and end mean(cid:3)SD for SBP, DBP, and MAP were recorded oric14,15,17,27,28,32–36 and 2 hypercaloric feeding trials,27,37
whenprovided,aswellasanyreportedPvaluesfordifferencesbetween
withamedianfollow-upof4.0weeks(range:15.5daysto10
startandendvaluesandbetweentreatments.MAPwascalculatedfor
weeks).
studiesthatreportedSBPandDBPendpointsbutnotMAPusingthe
following formula: MAP(cid:1) 2⁄3DBP(cid:4)1⁄3SBP. The SDs for these
calculatedMAPswerecalculatedusingthefollowingformula: Study Characteristics
(cid:1)(cid:2) (cid:3) (cid:2) (cid:3) The Table shows the characteristics of the 13 isocaloric
1 1 2 2 2
(cid:1)N · 3 sS2BP(cid:4) 3 sD2BP (n(cid:1)352)and2hypercaloricfeedingtrials(n(cid:1)24).Elevenof
the isocaloric trials were in nondiabetic participants, and 1
where N is the sample size, and s is the SD. All of the data were each in prediabetic and diabetic participants. Five isocaloric
entered in triplicate into a spreadsheet template (Microsoft Excel,
trials were randomly assigned and 4 have a parallel design.
MicrosoftCorp).Trialsthatdidnotreporteitherchange-from-start
SixoftheisocalorictrialsusedstarchasaCH Ocomparator,
differenceswithinorbetweentreatmentsorenddifferencesbetween 2
treatmentshadtheseimputedfromtheavailabledatausingstandard 7inglucose,1inhigh-fructosecornsyrup,and1insucrose.
formulas.25 Authors were contacted, when possible, to request Fructosewasadministeredinsolid(2trials),mixed(4trials),
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Ha et al Fructose and Blood Pressure 3
319 articles identified
37 MEDLINE (through January 9, 2012)
232 EMBASE (through January 9, 2012)
43 Cochrane Library (through January 9, 2012)
7 Manual searches
303 articles excluded on basis of title and/or abstract
60 duplicate reports
80 animal or in vitro studies
3 case studies
78 review papers (including commentaries,
editorials, and conferences)
49 studies with no fructose intervention
3 studies with intravenous administration
3 studies with unsuitable endpoints
16 observational studies
6 acute or short-term studies
4 co-interventions
Figure1.Flowoftheliteraturesearch.
1 not retrievable
16 articles reviewed in full
5 articles excluded
1 studies with no fructose intervention
1 studies with unsuitable endpoints
2 acute or short-term studies
1 not retrievable
11 articles (15 trials) included in the meta-analysis
2 isocaloric trials in DM/IGT (n= 19)
11 isocaloric trials in non-DM (n= 333)
2 hypercaloric trials in non-DM (n=24)
andfluid(7trials)formsatamediandoseof78.5g/d(range: status(Figure2).Therewassignificantevidenceofinterstudy
53–182 g/d). The background diet in the isocaloric trials heterogeneity in the prediabetes/diabetes mellitus stratum.
consisted of 43% to 55% energy (E) CH O, 13% to 20% E The use of broader correlation coefficients (0.25 and 0.75)
2
protein, and 30% to 42% E fat. Four of the isocaloric trials didnotalterthesemainfindings;however,usingcorrelation
weremetabolicallycontrolled,3werepartiallymetabolically coefficient of 0.75, interstudy heterogeneity became signifi-
controlled, and 6 were not controlled. Seven trials took BP cant in the overall analysis (data not shown). Sensitivity
measurementsusinganautomatedtechnique,2usedmanual, analyses in which each individual study was systematically
1 used continuous ambulatory measurements, and 3 did not removed, and the effect estimate recalculated without it,
specify.ThreetrialsconsideredBPasaprimaryendpoint,1 showed that the removal of Madero et al34 resulted in a
as secondary, and 9 did not specify. Median follow-up was significant SBP-lowering effect in the nondiabetic stratum
4.0 weeks (range: 15.5 days to 10.0 weeks). Eight of the 13 and the overall analysis.
isocalorictrialswerescoredashighqualitywithanMQS(cid:1)8.
To conserve power, a priori subgroup analyses were carried
There were 2 reported hypercaloric trials. Both hyperca-
outusingdataonlyfromisocalorictrialsinnondiabetestotest
loric trials used a nonrandomized, crossover design. Both
for possible fructose effect modifiers on SBP by study design
administered fructose in a fluid format at a median dose of
characteristics (Figure S1, please see the online-only Data
(cid:7)143g/d((cid:4)18%to25%E).Thebackgrounddietconsisted
Supplement).WefoundnosignificanteffectmodifiersofSBP
of55%ECH O,15%Eprotein,and30%Efatinbothtrials.
2 by metaregression analysis. There was significant evidence of
OneofthetrialsusedanautomatedtechniquetomeasureBP
interstudy heterogeneity, however, if the study had a parallel
and the other did not specify. Both trials did not specify the
studydesignoranMQSscore(cid:5)8(I2(cid:1)61%;P(cid:5)0.10).
type of end point for BP. Median follow-up was 7 weeks
(range: 4–10 weeks). Both hypercaloric trials scored as low Diastolic BP
quality with an MQS (cid:5)8. IsocaloricexchangeoffructoseforotherCH Ohadasignif-
2
icant DBP-reducing effect in the overall analysis and in the
Isocaloric Feeding Trials nondiabetesstratumbutnosignificanteffectintheprediabe-
Systolic BP tes/diabetesmellitusstratum(Figure3).Onlytheprediabetes/
IsocaloricexchangeoffructoseforotherCH Ohadnoeffecton diabetes mellitus stratum showed no significant evidence of
2
SBPintheoverallanalysisorinanalysesstratifiedbydiabetes interstudy heterogeneity. The use of broader correlation
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4 Hypertension April 2012
Table. Characteristicsofthe13Isocaloric(n(cid:1)352)and2HypercaloricFeedingTrials(n(cid:1)24)
BloodPressure
StudyIdentification Subjects,n(M:F)† Age,y Design‡ MethodofBloodPressureMeasurement EndPoint Setting
Isocalorictrials
Nodiabetesmellitus
Aeberlietal32 29N(29:0) 26.3(cid:3)6.6 C Automatedsphygmomanometerafter15-min Neither Outpatient,Zurich,Switzerland
restinsupineposition,measurementswere
madeatbaselineandendofintervention
Aeberlietal32 29N(29:0) 26.3(cid:3)6.6 C Automatedsphygmomanometerafter15-min Neither Outpatient,Zurich,Switzerland
restinsupineposition,measurementswere
madeatbaselineandendofintervention
Brymoraetal33 28CKD(17:11) 59(cid:3)15 C 24-Hambulatorybloodpressuremonitoring Primary Outpatient,Torun´,Poland
measurementsweremadeatbaseline,wk6,
andwk12
Hallfrischetal15 12N(12:0) 39.8(cid:3)8.3 C Automatatedsphygmomanometerafter5-min Neither Metabolicward/outpatient,Maryland
restinsittingposition,measurementswere
madeweekly
Hallfrischetal15 12HI(12:0) 39.5(cid:3)7.3 C Automatatedsphygmomanometerafter5-min Neither Outpatient,Oklahoma
restinsittingposition,measurementswere
madeweekly
Kohetal17 9N(3:6) 50(cid:3)15 C Automatatedsphygmomanometerafter5-min Primary Outpatient,Oklahoma
restinsittingposition2measurementswere
made5minsapart,measurementsweremade
atbeginningandendofintervention
Maderoetal34 107OW/OB 38.8(cid:3)8.8 P Manualsphygmomanometerafter10-minrestin Secondary Outpatient,MexicoCity,Mexico
sittingposition,3measurementsweremadeat
5-minintervals,measurementsweremadeweekly
Sibernegaletal35 20N(12:8) (cid:8)30.5(cid:3)8.9 P N/A Neither Outpatient,Tu¨bingen,Germany
Stanhopeetal27(cid:1) 32OW(16:16) 53.75(cid:3)7.8 P Automatedsphygmomanometermeasurements Neither Outpatient(8wk),clinicalresearch
weremadetwicedailyduringinpatientperiods centerinpatient(2wk),California
Stanhopeetal36 48N(27:21) 27.6(cid:3)7.1 P N/A Neither Outpatient(12d),clinicalresearch
centreinpatient(3.5d),California
Swarbricketal28 7OW/OB(0:7F,PM) 50–72 C N/A Neither Residentialfacilityinpatient,
California
Prediabetes
Kohetal17 9IGT(3:6) 54(cid:3)18 C Automatatedsphygmomanometerafter5-min Primary Outpatient,Oklahoma
restinsittingposition2measurementswere
made5minsapart,measurementsweremade
atbeginningandendofintervention
Type2diabetesmellitus
Koivistoetal14 10DM2(4:6) 61(cid:3)9.5 C Manualsphygmomanometerafter5-minrestin Neither Inpatient,hospital,Helsinki,Finland
sittingposition
Hypercalorictrials
Nodiabetesmellitus
Lêetal37 7N(7:0) 24.7(cid:3)3.5 C Measurementtaken3timesover20-minperiod Neither OutpatientLausanne,Switzerland
Stanhopeetal27(cid:1) 17OW/OB(9:8) 52.5(cid:3)13.2 C Automatedsphygmomanometermeasurements Neither Clinicalresearchcenterinpatient
weremadetwicedailyduringinpatientperiods (2wk),outpatient(8wk),California
(cid:1)
Stanhopeetal27includeda2-wkbaselineisocaloricperiodfollowedby8wkofhypercaloricfeedingandfinallyfollowedby2wkofisocaloricfeeding,foratotal
studydurationof10wk.Thus,weconsideredthecomparisonbetweenglucoseandfructosearmsatweek10astheisocalorictrialandthecomparisonoffructose
atweek8withthecontroldietatweek0asthehypercalorictrial.
†Nindicatesnormal;CKD,chronickidneydisease;HI,hyperinsulinemic;OW,overweight;OB,obese;IGT,impairedglucose-tolerant;DM2,type2diabetesmellitus;
PM,postmenopausal.
‡CindicatescrossoverandPindicatesparallel.
§Yesindicatesthatallfoodwaspreparedandprovidedbyametabolickichenattheresearchinstitution;partialindicatesthatsomefoodwaspreparedandprovided
byinvestigators;noindicatessupplementsoffructoseandothercarbohydrateontopofanadlibitumdiet.
(cid:4)Dosesprecededby“(cid:7)”representaveragedoses;%Eindicatespercentageoftotaldailycaloricintake.
¶Fructosewasprovidedoneof3forms:(1)liquid,whereallormostofthefructosewasprovidedasabeverageorcrystallinefructosetobeaddedtoliquidfor
consumption;(2)solid,whereallormostofthefructosewasprovidedinpreparedfood;or(3)mixed,acombinatonofliquidandsolidformsoffructose.
#Comparatorreferstothereferencecarbohydrate(starch,glucose,sucrose,orhigh-fructosecornsyrup).
**StudyqualitywasassessedbytheHeylandMethodologicalQualityScore(MQS).
coefficients(0.25and0.75)didnotalterthesemainfindings; was systematically removed showed that the removal of Stan-
however,usingcorrelationcoefficientof0.25,theinterstudy hopeetal27orBrymoraetal33resultedinalossofsignificance
heterogeneity in the overall analysis became nonsignificant, intheoverallanalysisandinthenondiabeticstratum.
andusingacorrelationcoefficientof0.75,interstudyheteroge- A priori subgroup analyses were carried out using data
neitybecamesignificantintheprediabetic/diabeticstratum(data only from isocaloric trials in nondiabetes to test for possible
notshown).Sensitivityanalysesinwhicheachindividualstudy fructose effect modifiers on DBP by study design character-
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Ha et al Fructose and Blood Pressure 5
Table. Continued
Fructose Carbohydrate MacronutrientProfile, Energy
Metabolic§ Randomization FructoseDose,g/d(cid:4) Form Comparator Carbohydrate:Protein:Fat%E Balance Follow-Up MQS** Funding
No Yes 85.0((cid:7)14%E) Fluid Glucose 52:14:33 Neutral 3wk 9 SwissNationalScienceFoundation,Vontobel
Foundation
No Yes 115.9((cid:7)19%E) Fluid Glucose,sucrose 55:13:31 Neutral 3wk 9 SwissNationalScienceFoundation,Vontobel
Foundation
No No 53((cid:7)9%E) Mixed Starch 55:15:30 Neutral 6wk 8 NicolausCopernicusUniversity,NationalInstitutes
ofHealth
Yes No (cid:7)74.2(7–15%E) Solid Starch 43:15:42 Neutral 5wk 8 N/A
Yes No (cid:7)74.2(7–15%E) Solid Starch 43:15:42 Neutral 5wk 8 N/A
Partial No (cid:7)78.5(15%E) Mixed Glucose 50–55:15–20:30–35 Neutral 4wk 8 N/A
No Yes (cid:7)60g/d((cid:7)13%E) Mixed Starch 55:15:30 Negative 6wk 7 ConsejoNacionaldeCienciayTecnologiagrant,
NationalInstitutesofHealth
No Yes 150((cid:7)21%E) Fluid Glucose 50:15:35 Positive 4wk 7 GermanResearchFoundation,Zentrum
ErnährungsmedizinTu¨bingen-Hohenheim
No No (cid:7)182(25%E) Fluid Glucose 55:15:30 Positive 10wk 6 NationalInstitutesofHealth,NationalCenterfor
ResearchResources,NationalInstitutesofHealth
RoadmapforMedicalResearch,American
DiabetesAssociation
Partial No 168(25%E) Fluid Glucose,HighFructose 55:15:30 Positive 15.5d 6 NationalInstitutesofHealth/NationalHeart,Lung,
CornSyrup andBloodInstitute,NationalCenterforResearch
Resources
Yes No (cid:7)125(25%E) Fluid Starch 55:15:30 Neutral 10wk 7 NationalResearchInitiativeCompetitiveGrant,
Co-operativeAgreementwithWesternHuman
NutritionResearchCenter,Clinicaland
TranslationalScienceCenter’sClinicalReearch
Center,UniversityofCalifornia,NationalInstitutes
ofHealth,AmericanDiabetesAssociation
Partial No (cid:7)64(15%E) Mixed Glucose 50–55:15–20:30–35 Neutral 4wk 8 N/A
Yes Yes (cid:7)55(20%E) Fluid Starch 50:20:30 Neutral 4wk 9 FinnishAcademyofScience,NordiskInsulinfod,
ElseandWilhelmStockmann’sFoundation
No No (cid:7)103.5((cid:4)18%E) Fluid Starch 55:15:30 Positive 4wk 7 SwissNationalScienceFoudnation,Novartis
ConsumerHealthFoundation
No No (cid:7)182((cid:4)25%E) Fluid Starch 55:15:30 Positive 10wk 6 NationalInstitutesofHealth,NationalCenterfor
ResearchResources,NationalInstitutesofHealth
RoadmapforMedicalResearch,American
DiabetesAssociation
istics(FigureS2).Wefoundnosignificanteffectmodifiersof whicheachindividualstudywassystematicallyremovedshowed
DBP by metaregression analysis. Unexplained interstudy thattheremovalofMaderoetal,34Silbernageletal,35orKohetal17
heterogeneity was seen in studies that used glucose as a resultedinthelossofsignificanceintheoverallanalysis.
CH O comparator, have a follow-up period (cid:6)4 weeks, A priori subgroup analyses were carried out using data
2
administeredfructoseineitherafluidormixedformat,have from only isocaloric trials in nondiabetes to explore effect
eitheracrossoveroraparallelstudydesign,orhaveanMQS modifiers of fructose on MAP (Figure S3). We found no
score (cid:1)8 (I2(cid:1)50%; P(cid:2)0.10). significant effect modifiers of MAP by metaregression anal-
ysis.Unexplainedinterstudyheterogeneityremainedinthese
Mean Arterial Pressure analyses (I2(cid:1)53%; P(cid:2)0.01).
IsocaloricexchangeoffructoseforotherCH Ohadasignificant
2
MAP-reducingeffectintheoverallanalysisandinthenondia- Hypercaloric Feeding Trials
betesstratumbutnosignificanteffectintheprediabetes/diabetes The 2 trials that reported hypercaloric fructose feeding
mellitusstratum(Figure4).Significantevidenceofinterstudy showed conflicting MAP results, with no significant overall
heterogeneity was seen across all 3 of the strata (I2(cid:1)97%; effect and evidence of interstudy heterogeneity. Sensitivity
P(cid:2)0.10). The use of broader correlation coefficients (0.25 analysis using a correlation coefficient of 0.25 showed the
and 0.75) did not alter these findings. Sensitivity analysis in summary effect to be significant (P(cid:1)0.03).
Downloaded from http://hyper.ahajournals.org/ by guest on February 14, 2012
6 Hypertension April 2012
Mean Difference Mean Difference
Study or Subgroup Weight IV, Random, 95% CI IV, Random, 95% CI
1.1.1 Non-Diabetics
Aeberli (COM-H)[32] 13.0% -0.35[-3.47,2.77]
Aeberli (MOD) [32] 13.0% -1.00 [-4.12, 2.12]
Brymora (COM) [33] 8.9% 1.00 [-3.27, 5.27]
Hallfrisch (COM-HI) [15] 4.5% -1.00 [-7.66, 5.66]
Hallfrisch (COM-N) [15] 4.5% -1.50 [-8.16, 5.16]
Koh (NGT) [17] 1.2% -2.00 [-15.72, 11.72]
Madero [34] 17.7% 1.61 [-0.60, 3.82]
Sibernegal [35] 5.5% -5.00[ -10.88, 0.88]
Stanhope (COM) [36] 9.6% -4.00 [-8.04, 0.04]
Stanhope [27] 9.9% -3.00 [-6.92, 0.92]
Swarbrick [28] 0.3% 3.00 [-24.44, 30.44]
Subtotal (95% CI) 88.2% -0.74 [-2.07, 0.59]
Heterogeneity: Tau² = 0.45; Chi² = 10.96, df = 10 (P = 0.36); I² = 9%
Test for overall effect: Z = 1.10 (P = 0.27)
1.1.2 Pre-diabetics/Diabetics
Koh (IGT) [17] 9.9% -4.00 [-7.92, -0.08]
Koivisto [14] 1.9% 10.00 [-0.92, 20.92]
Subtotal (95% CI) 11.8% 2.03 [-11.55, 15.62]
Heterogeneity: Tau² = 80.49; Chi² = 5.60, df = 1 (P = 0.02); I² = 82%
Test for overall effect: Z = 0.29 (P = 0.77)
Total (95% Cl) 100.0% -1.10 [-2.64, 0.44]
Heterogeneity: Tau² = 2.19; Chi² = 17 .38, df = 12 (P = 0.14); I² = 31%
-20 -10 0 10 20
Test for overall effect: Z = 1.40 (P = 0.16)
Favors Fructose Favors Any CHO
Test for subgroup differences: Chi² = 0.16 , df = 1 (P = 0.69), I² = 0%
Figure2.Forestplotsoffeedingtrialsinvestigatingtheeffectofisocaloricexchangeoffructoseforcarbohydratesonsystolicblood
pressure(SBP)indiabetic,prediabetic,andnondiabeticparticipants.Threepooledeffectestimates(diamonds)areshown:1eachfor
trialsindiabetesmellitus/prediabetes,nondiabetes,andtheircombination.Pairedanalyseswereappliedtoallofthecrossovertrials.
Dataaremeandifferences(MD)with95%CIs,whereMDisinterpretedasfollows.Pvaluesareforgenericinversevariancerandom-
effectsmodels.InterstudyheterogeneitywastestedbyCochrane’sQ(I2)atasignificancelevelofP(cid:5)0.10andquantifiedbyI2,where
I2(cid:1)50%isconsideredtobeevidenceofsubstantialheterogeneityand(cid:1)75%considerableheterogeneity.
Publication Bias may be beneficial for future studies to collect ambulatory BP
Neither visual inspection of funnel plots nor Egger or Begg measurementstobetterelucidatetheeffectoffructoseonBP.
testsprovidedsufficientevidenceofpublicationbiasforSBP Fructose is proposed to raise BP via increasing uric acid
(Egger test P(cid:1)0.683; Begg test P(cid:1)0.854), DBP (Egger production, which exerts hemodynamic effects, such as in-
test: P(cid:1)0.943; Begg test P(cid:1)1.000), or MAP (Egger test: creasedoxidativestress,endothelialdysfunction,andactivation
P(cid:1)0.260; Begg test: P(cid:1)0.807; Figures S4 through S6). of the renin-angiotensin-aldosterone system.4,5 As a proof of
concept, this mechanism was investigated directly in humans.
Discussion Perez-Pozoetal38reportedarandomized,2-weekcrossovertrial
This meta-analysis of 13 isocaloric controlled feeding trials in which participants were fed 200 g/d of fructose and then
(n(cid:1)352)withamedianfollow-upof4weeksfoundasignificant randomized to either allopurinol, a xanthine oxidase inhibitor
DBP-andMAP-loweringeffectwhenfructosewassubstituted thatinhibitstheproductionofuricacid,orplacebofor2weeks.
for other carbohydrates but no effect on SBP. Hypercaloric Allopurinolwasshowntopreventthefructose-inducedpheno-
fructosefeedingdidnotsignificantlyaffectMAP. type of raised uric acid and BP. Theauthorsconcludedthatthe
The present study is in agreement with prospective cohort excessive fructose intake induced hypertension via elevated uric
studies12infailingtodemonstrateanadverseeffectoffructose acid. However, 200 g of fructose is more than twice the 95th
onBPbutatoddswithacuteclinicalstudiesandanimalmodels. percentileofintakeintheUnitedStates,39andthetreatmenteffect
Acute clinical studies have reported an increase in BP after offructosewasnotcomparedwithanothersourceofcarbohydrate
fructose intake,13,16,18 and rat studies have consistently shown underisocaloricconditions.Wedidnotseesuchaneffectinthe
that chronic high fructose intake raises SBP.7–10 This discrep- presentanalysis.Fiveoftheisocalorictrialsthatareincludedinour
ancybetweentheresultsofourstudyandthoseofobservational analysis that measured uric acid showed no significant
and intervention studies may be explained by heterogeneous change15,17,33–35; however, the fructose dose in these studies was
conditionsofBPmeasurement.Studiesincludedinoursystem- (cid:5)200gandwhencomparedwithothersourcesofcarbohydrates.
aticreviewdidnotspecificallymeasurepostprandialBP,16,18at Whether these mechanisms are sufficient to exert chronic and
whichtimetheadverseeffectsoffructoseonBPhavebeenmost clinicallysignificanteffectsonBPinhumansisuncertain.
consistentlyshowninhumans16,18andlaboratoryrats.7–10Fur- Doseremainsanimportantconsiderationintheinterpreta-
thermore, although our analysis suggests that casual BP is not tionofouranalyses.Thediscrepancybetweenourresultsand
elevatedinresponsetolonger-termfructoseconsumption,most those of Perez-Pozo et al38 and animal models7–10 may be
of these studies investigated BP after an overnight fast when explained by differences in fructose dose. Whereas the
fructosemayhavebeencompletelymetabolized.Becauseintermit- median fructose dose in the available isocaloric trials in-
tentelevationsofBPareariskfactorforpermanenthypertension,it cluded in our meta-analysis was (cid:7)78.5 g/d (range: 53–182
Downloaded from http://hyper.ahajournals.org/ by guest on February 14, 2012
Ha et al Fructose and Blood Pressure 7
Mean Difference Mean Difference
Study or Subgroup Weight IV, Random, 95% CI IV, Random, 95% CI
1.2.1 Non-Diabetics
Aeberli (COM-H)[32] 94% 210[-0.84,5.04]
Aeberli (MOD) [32] 11.9% 0.00 [-2.27, 2.27]
Brymora (COM) [33] 10.6% -4.00 [-6.59, -1.41]
Hallfrisch (COM-HI) [15] 5.0% 1.00 [-3.76, 5.76]
Hallfrisch (COM-N) [15] 5.0% -2.00 [-6.76, 2.76]
Koh (NGT) [17] 3.6% -4.00 [-9.88, 1.88]
Madero [34] 16.2% -0.87 [-2.22, 0.48]
Sibernegal [35] 3.3% -300[9.19,3.19]
Stanhope (COM) [36] 12.6% -1.00 [-3.12, 1.12]
Stanhope [27] 13.3% -4.00 [-5.96, -2.04]
Swarbrick [28] 0.3% -1.00 [-24.52, 22.52]
Subtotal (95% CI) 91.2% -1.45 [-2.75, -0.15]
Heterogeneity: Tau² = 2.02; Chi² = 20 .31, df = 10 (P = 0.03); I² = 51%
Test for overall effect: Z = 2.19 (P = 0.03)
1.2.2 Pre-diabetics/Diabetics
Koh (IGT) [17] 6.6% -4.00 [-7.92, -0.08]
Koivisto [14] 2.2% 2.00 [-5.84, 9.84]
Subtotal (95% CI) 8.8% -2.00 [-7.54, 3.54]
Heterogeneity: Tau² = 8.00; Chi² = 1.80, df = 1 (P = 0.18); I² = 44%
Test for overall effect: Z = 0.71 (P = 0.48)
Total(95%CI) 100.0% -154[-2.77, -0.32]
Heterogeneity: Tau² = 1.95; Chi² = 22 .67, df = 12 (P = 0.03); I² = 47%
-20 -10 0 10 20
Test for overall effect: Z = 2.46 (P = 0.01)
Favors Fructose Favors Any CHO
Test for subgroup differences: Chi² = 0.04 , df = 1 (P = 0.85), I² = 0%
Figure3.Forestplotsoffeedingtrialsinvestigatingtheeffectofisocaloricexchangeoffructoseforcarbohydratesondiastolicblood
pressure(DBP)indiabetic,prediabetic,andnondiabeticparticipants.Threepooledeffectestimates(diamonds)areshown:1eachfor
trialsindiabetesmellitus/prediabetes,nondiabetes,andtheircombination.Pairedanalyseswereappliedtoallofthecrossovertrials.
Dataaremeandifferences(MD)with95%CIs,whereMDisinterpretedasfollows.Pvaluesareforgenericinversevariancerandom-
effectsmodels.InterstudyheterogeneitywastestedbyCochrane’sQ(I2)atasignificancelevelofP(cid:5)0.10andquantifiedbyI2,where
I2(cid:1)50%isconsideredtobeevidenceofsubstantialheterogeneityand(cid:1)75%considerableheterogeneity.
g/d),or(cid:7)20.5%ofenergy(range:(cid:7)9%to25%),itwaswell groups.42,43 Because of insufficient variability, we could not
below that used to induce BP increases in the Perez-Pozo et formallytestforheterogeneityinthesedomains.
al38 study (200 g) and animal models ((cid:7)60% E).7–10 This There are several limitations to our work. First, the external
evidence for a BP-raising effect is derived from trials of validity of the BP effects remains a concern given that the
fructose doses that are well above the (cid:6)95th percentile of participantpoolwassmalland,ofthetotal352participants,only
intake(87g/d)intheUnitedStates,accordingtotheNational 19 were classified as having diabetes mellitus or prediabetes;
andHealthandNutritionExaminationSurveyIII.39Evenfor therefore, our conclusions may not be generalizable to the
the group with the highest level of exposure, males and populationofthoselivingwiththeseconditions.Second,only2
femalesaged19to22years,ofwhom(cid:2)10%consume(cid:1)100 hypercaloricstudiesassessedMAP,andonly1ofthehyperca-
g/d,39 it is difficult to make generalizations. There is a clear loricstudiesreportedSBPandDBP.Third,thedataprovidedby
need for larger and longer trials of fructose feeding at Maderoetal34mustbeinterpretedcarefully.Althoughthisstudy
generalizable doses ((cid:5)87 g/d) to confirm whether “real- met all of our specified inclusion criteria, they used fruits as a
world”fructoseexposurecontributestotheburdenofhyper- vehicle for fructose administration. Fruits contain compounds
tension and by association vascular and renal disease. suchasvitaminC,quercetin,andresveratrolthatmayalterthe
We found no significant effect modifiers of fructose on metabolic effects of fructose. Fourth, the lack of reporting of
SBP,DBP,orMAP.Inapreviousmeta-analysisontheeffect baselinevaluesandteststatisticsinsomeoftheincludedtrials
of fructose on triglycerides in type 2 diabetes mellitus, we necessitatedimputationofseveraldatapoints.Weovercamethis
reported significant effect modification by dose ((cid:6)60 g/d), problembyselectingaconservativecorrelation(r(cid:1)0.5)between
follow-up ((cid:6)4 weeks), and comparator (starch).40 Livesey treatment and control end values, according to the methods
and Taylor,41 in their meta-analysis on the effect of fructose proposed by Elbourne et al,31 and then performed sensitivity
ontriglycerides,glycatedhemoglobin,andbodyweight,also analyses at 2 other levels (0.25 and 0.75). Lastly, subgroup
reportedsignificanteffectmodificationbydose((cid:6)50g/dand analysis at 0.25 and 0.75 changed some subgroups from non-
(cid:6)100 g/d for postprandial and fasting triglycerides, respec- significant to significant. This finding may suggest a lack of
tively).Wedidnotseesimilarsourcesofeffectmodification robustnessinthedata.
in our meta-analysis. Substantial interstudy heterogeneity re-
mainedunexplainedinouranalysis.Otherunmeasuredsources Perspectives
ofheterogeneityacrosstheavailabletrialsneedtobeconsidered, MostconcernsregardingtheadverseeffectsoffructoseonBP
includingdifferencesintechniquesofBPmeasurement,whether are based on results of studies using rat models7–10 and acute
BP was obtained as a primary or secondary end point, and human studies.13,16,18 The present meta-analysis, however,
differentefficienciesoffructoseabsorptionacrossdifferentage showsasignificantDBP-andMAP-loweringeffectandatrend
Downloaded from http://hyper.ahajournals.org/ by guest on February 14, 2012
8 Hypertension April 2012
Mean Difference Mean Difference
Study or Subgroup Weight IV, Random, 95% CI IV, Random, 95% CI
1.3.1 Non-Diabetics
Aeberli(COM-H)[32] 9.5% 1.28[0.81,1.75]
Aeberli (MOD) [32] 9.6% -0.33 [-0.66, 0.00]
Brymora (COM) [33] 5.4% -1.00 [-3.80, 1.80]
Hallfrisch (COM-HI) [15] 7.2% 0.33 [-1.53, 2.19]
Hallfrisch (COM-N) [15] 7.2% -1.83 [-3.67, 0.01]
Koh (NGT) [17] 7.0% -3.33 [-5.31, -1.35]
Madero [34] 9.7% -0.04 [-0.18, 0.10]
Sibernegal[35] 8.0% -3.67 [-5.12,-2.22]
Stanhope (COM) [36] 9.4% -2.00 [-2.57, -1.43]
Stanhope [27] 9.5% -3.67 [-4.14, -3.20]
Swarbrick [28] 1.7% 0.33 [-6.53, 7.19]
Subtotal (95% CI) 84.2% -1.34 [-2.34, -0.34]
Heterogeneity: Tau² = 2.21; Chi² = 321.48, df = 10 (P < 0.00001); I² = 97%
Test for overall effect: Z = 2.63 (P = 0.009)
1.3.2 Pre-diabetics/Diabetics
Koh (IGT) [17] 8.9% -4.00 [-4.98, -3.02]
Koivisto [14] 6.9% 4.67 [2.67, 6.67]
Subtotal (95% CI) 15.8% 0.29 [-8.21, 8.79]
Heterogeneity: Tau² = 36.94; Chi² = 58.25, df = 1 (P < 0.00001); I² = 98%
Test for overall effect: Z = 0.07 (P = 0.95)
Total(95%CI) 100.0% -1.16[-2.15, -0.18]
Heterogeneity: Tau² = 2.61; Chi² = 398.98, df = 12 (P < 0.00001); I² = 97%
-10 -5 0 5 10
Test for overall effect: Z = 2.32 (P = 0.02)
Favors Fructose Favors Any CHO
Test for subgroup differences: Chi² = 0.14, df = 1 (P = 0.71), I² = 0%
Figure4.Forestplotsoffeedingtrialsinvestigatingtheeffectofisocaloricexchangeoffructoseforcarbohydratesonmeanarterial
pressure(MAP)indiabetic,prediabetic,andnondiabeticparticipants.Threepooledeffectestimates(diamonds)areshown:1eachfor
trialsindiabetesmellitus/prediabetes,nondiabetes,andtheircombination.Pairedanalyseswereappliedtoallofthecrossovertrials.
Dataaremeandifferences(MD)with95%CIs,whereMDisinterpretedasfollows.Pvaluesareforgenericinversevariancerandom-
effectsmodels.InterstudyheterogeneitywastestedbyCochrane’sQ(I2)atasignificancelevelofP(cid:5)0.10andquantifiedbyI2,where
I2(cid:1)50%isconsideredtobeevidenceofsubstantialheterogeneityand(cid:1)75%considerableheterogeneity.
favoring SBP in the overall analysis and in the nondiabetic Almond Board of California, the International Nut Council, Para-
stratum when fructose was exchanged isocalorically for other mount Farms, the California Strawberry Commission, the Canola
and Flax Councils of Canada, and Saskatchewan Pulse Growers.
carbohydrates.Giventhesmallparticipantpoolinouranalyses,
C.W.C.K. also receives partial salary funding from research grants
larger and longer human trials are needed to gain a better
provided by Unilever, Loblaws Supermarkets, and the Almond
assessmentoftheeffectoffructoseonBP.Becauseelevateduric Board of California. D.J.A.J. holds an unrestricted grant from the
acidhasbeenproposedasamediatoroftheeffectsoffructoseon Coca-ColaCompanyandhasservedonthescientificadvisoryboard
BP, future meta-analyses of human trials should also consider fororreceivedresearchsupport,consultantfees,orhonorariafrom
Barilla, Solae, Unilever, Hain Celestial, Loblaws Supermarkets,
thisendpoint.Thesetrialswillhelpresolvewhetherthepotential
SanitariumCompany,HerbalifeInternational,PacificHealthLabo-
roleoffructoseinthedevelopmentofthehypertensionepidemic
ratories Inc, Metagenics/MetaProteomics, Bayer Consumer Care,
shouldbereconsidered. Oldways Preservation Trust, The International Tree Nut Council
Nutrition Research & Education, The Peanut Institute, Procter and
Sources of Funding GambleTechnicalCentreLimited,GriffinHospitalforthedevelop-
SupportforthisarticlewasprovidedbyaCanadianInstitutesofHealth mentoftheNuValSystem,PepsiCompany,SoyAdvisoryBoardof
ResearchKnowledgeSynthesisGranttoJ.L.S.,R.J.d.S.,A.M.,A.J.C., Dean Foods, Alpro Soy Foundation, Nutritional Fundamentals for
J.B., M.D., A.L.J., L.A.L., T.M.S.W., C.W.C.K., and D.J.A.J. and a Health, Pacific Health Laboratories, Kellogg’s, Quaker Oats, The
Calorie Control Council unrestricted research grant to J.L.S., R.J.D., Coca-ColaSugarAdvisoryBoard,AgrifoodsandAgricultureCanad
J.B.,C.W.C.K.,andD.J.A.J.R.J.d.S.wasfundedbyaCIHRPostdoc- (AAFC), Canadian Agriculture Policy Institute (CAPI), Abbott
toral Fellowship Award, and A.M. was funded by a CIHR Canada Laboratories,theAlmondBoardofCalifornia,theCaliforniaStraw-
GraduateScholarshipMaster’saward.D.J.A.J.wasfundedbytheGovern- berryCommission,Orafti,theCanolaandFlaxCouncilsofCanada,
mentofCanadathroughtheCanadaResearchChairEndowment. Pulse Canada, and the Saskatchewan Pulse Growers. D.J.A.J. also
holdsadditionalgrantsupportfromtheCanadianInstitutesofHealth
Disclosures Research, Canadian Foundation for Innovation, Ontario Research
Fund,andAdvancedFoodsandMaterialNetwork.T.M.S.W.isthe
J.L.S. has received several unrestricted travel grants from the
president,A.L.J.avicepresidentanddirectorofresearch,andL.C.,
Coca-Cola Company to present research at meetings and is a
aclinicalresearchcoordinatoratGILaboratories(Toronto,Ontario,
coinvestigatoronanunrestrictedresearchgrantfromtheCoca-Cola
Canada). V.H., A.I.C., D.D.W., M.E.Y., A.M., A.J.C., M.D., and
Company.J.L.S.hasalsoreceivedtravelfundingandhonorariafrom
L.A.L.havenodeclaredconflictsofinterestrelatedtothisarticle.
AbbottLaboratories,ArcherDanielsMidland,andtheInternational
LifeSciencesInstituteNorthAmerica,aswellasresearchsupport,
consultantfees,andtravelfundingfromPulseCanada.R.J.d.S,J.B., References
andC.W.C.K.arecoinvestigatorsonanunrestrictedgrantfromthe 1. LawesCM,VanderHoornS,LawMR,ElliottP,MacMahonS,Rodgers
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Celestial, Loblaws Supermarkets, Oldways Preservation Trust, the burdenofhypertension:analysisofworldwidedata.Lancet.2005;365:217–223.
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