Evidence For A Whole Grains and Coronary Heart Disease Health Claim

ARTICLE
International Food Risk Analysis Journal
Evidence for a Whole Grains and Coronary Heart Disease Health Claim
Susan E. Sinclair1,*, Elizabeth D. Mansfield1,2 and George A. Wells3
1 Bureau of Nutritional Sciences, Food Directorate, Health Canada 2 School of Dietetics and Human Nutrition, McGill University 3 Cardiovascular Research Methods Centre, University of Ottawa, Heart Institute * Corresponding author E-mail: susan.sinclair@hc-sc.gc.ca
Received 7 September 2012; Accepted 21 January 2013 2013 Sinclair et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract A systematic review was undertaken to evaluate the evidence for a health claim about whole grain (WG) products and coronary heart disease (CHD). Studies were excluded if the American Association of Cereal Chemists International WG definition was not met or if foods with less than 51% WG ingredients were classified as WG. Seventeen of 26 clinical trials reported sufficient information to be included in the meta analysis. Overall, pooled analyses suggested that WG products have total and LDL cholesterollowering effects. No effect remained when trials that tested single grains high in glucan fibre, such as oats, and poor quality studies were removed from the analysis. The cohort studies were too heterogeneous to calculate pooled risk estimates. Four of 6 cohort studies reported at least one improved CHD outcome in individuals who consumed more WG products. Two of the positive studies were poor quality; the remaining 2 were separate analyses of the same cohort. Health Canada concluded that the evidenceto datewas not sufficientto support a health claim about WG products in general and CHD. The effect of glucan fibre cannot be generalized to other grains, including wheat, the main grain consumed in Canada. Health Canada has already accepted health claims about oat and barley products andcholesterollowering.
Keywords Whole Grain, Health Claim, Coronary Heart Disease
1.Introduction Cereal grains include the seed heads of plants in the Poaceae (or Gramineous) family and plants known as pseudocereals. Unprocessed cereal grains are comprised ofbran,endospermandgerm.Thebranandgermcontain bioactivecomponents,includingfibre,vitamins,minerals, trace elements and other plant compounds such as lignans and phytosterols. In 1999, a committee of experts from the American Association of Cereal Chemists International (AACCI) defined whole grains as the intact, ground, cracked or flaked caryopsis, whose principal anatomical components the starchy endosperm, germ and bran are present in the same relative proportions as they exist in the intact caryopsis [1]. Whole grains can be processed a number of ways (for example, soaking, rolling, cracking, toasting, puffing, popping or slow cooking) so long as the end result contains all three components in the same relative proportions.Forthepurposesofhealthclaims,theUnited States Food and Drug Administration (US FDA) has defined whole grain foods as those containing 51% or
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more whole grain ingredient(s) by weight per reference amountcustomarilyconsumed[2]. Canadian dietary guidelines encourage Canadians to make at least half of your grain products whole grain each day [3]. Higher intakes of whole grains have been consistently associated with lower CHD risk in epidemiological studies. In a metaanalysis of 12 prospectivecohortstudies,regularconsumptionofwhole grains was associated with a 26% reduction in CHD risk [4]. In a more recent metaanalysis of 7 cohort studies, higher whole grain intake was associated with a 21% lower risk of CVD events [5]. The majority of studies includedinthesemetaanalysesdidnotapplytheAACCI definition for whole grain or the US FDA definition for whole grain foods; therefore, the risk estimates for whole grain may be biased by misclassification of added bran, orothertypesofcerealfibre,aswholegrain. EvidencefrominterventionstudiesthatappliedtheAACI definition for whole grain or the US FDA definition for whole grain foods to evaluate biological markers of CHD is not consistent. Some trials show a benefit with increased whole grain intake [68] while others do not [9 11]. A 2007 systematic review limited to studies done in individuals with previously diagnosed risk factors for CHD found beneficial lowering of lipid levels; however, only studies that tested oats met the criteria for inclusion [12]. A second review published in 2009 excluded studies that did not meet the AACCI definition for whole grains; however theapplication ofthis criterion wasso strictthat only two observational studies and two intervention studieswereeligibleforinclusion[13]. Health claims on food labels and in advertising can convey information about potential health benefits consistent with national recommendations. As such, health claims can contribute to improved eating patterns and ultimately to improved public health. Health claims must therefore be generalizable to the target population and substantiated in an evidencebased, systematic manner to ensure that they are accurate and reliable. The objective of this systematic review was to determine whether or not the evidence from intervention and prospective cohort studies supports a health claim about whole grains and CHD risk in generally healthy populations. 2.Methods 2.1EligibilityCriteria Peerreviewed intervention and prospective cohort studies were included. Intervention studies without a control arm or period were excluded. Casecontrol studies were excluded to minimize the risk of recall bias. Because they measured biomarkers rather than the
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clinically meaningful outcome (CHD) and because, similar to prospective cohort studies, they are susceptible to confounding bias if investigators failed to account for all confounding variables, crosssectional studies were also excluded. Articles published in languages other than English or French were excluded at the fulltext filtering stage because funding for translation was not available. Nopublicationdaterestrictionswereimposed. Studies in generally healthy, noninstitutionalized adults (18 years) were included. Participants with risk factors for CHD, such as mild to moderately elevated serum lipids, hypertension, overweight, obesity, and metabolic syndrome were included. Participants with a diagnosed disease such as diabetes mellitus or coronary artery diseasewereexcluded. Studies were included if they assessed the effect of whole grain foods, or diets high in whole grain foods, with control foods or diets low in whole grains. Eligible grains included those considered a true cereal or pseudocereal by AACCI (Table 1). To be considered whole, the grain(s) had to meet the criteria in the AACCI definition. Whole grain foods had to contain51% whole grain ingredients by wet weight. Studies that described the intervention or exposure using the term whole meal or whole grain and were intended to evaluate the health benefits of whole grains rather than cereal fibre, for example, were included.
Truecereals Wheat(spelt,emmer,faro,einkorn,kamut,durums) Rice,Africanrice Barley Corn(maize,popcorn) Rye Oats Millets Sorghum Teff(tef) Triticale CanarySeed JobsTears Fonio,BlackFonio,AsianMillet Wildrice Pseudocereals Amaranth Buckwheat,TartarBuckwheat Quinoa Table1.Truecerealandpseudocerealgrains
Intervention studies where the whole grain was in capsule or mealreplacement format were excluded. Also excluded were multicomponent intervention studies wheretheeffectofwholegraincouldnotbeisolatedfrom theeffectofothercomponentsoftheintervention,suchas added fibre or weight loss. Cohort studies that included added bran or other grain components in their
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measurement of whole grain intake or that classified foods such as breakfast cereals as whole grain if they contained 25% instead of 51% whole grain by weight wereexcluded. The outcomes of interest included CHD mortality and incidence and changes in CHD risk biomarkers. Three risk biomarkersarecurrentlyaccepted asvalid predictors of CHD risk for food health claims [14] and therefore servedastheprimarybiomarkeroutcomesinthisreview. These were blood pressure, total blood cholesterol, and blood LDL cholesterol. Biomarkers such as highdensity lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins, Creactive protein and plasma fibrinogen were examined on an exploratory basis. Intervention studies where the treatment period was less than 3 weeks in duration were excluded, since 3 weeks is considered the minimum duration for evaluation of the effectofaninterventiononlowdensitylipoprotein(LDL) cholesterolconcentrations[15]. 2.2InformationSources Electronic databases searched included MEDLINE (1966 to January 10, 2012), EMBASE (1980 to January 10, 2012), CINAHL (1982 to January 10, 2012), and Global Health (1973 to January 10, 2012). The searches were limited to studies in humans. The reference lists of all included studies were handsearched to identify other potentially relevant studies. Published reviews in the area of whole grains and CHD were identified and similarly hand searchedtoidentifypotentiallyrelevantstudies. 2.3LiteratureSearch A Health Canada reference librarian was consulted to develop and execute the electronic database search. The MEDLINE search strategy is described in Table 2. This strategy was translated by the librarian into the other electronicdatabases. 2.4StudySelection Studies identified by the literature searches were screened by one reviewer (SS). Article titles were screened followed by abstracts; when a study could not be excluded with certainty based on the title or abstract, the full text article was retrieved for evaluation. Potentially relevant articles identified during hand searchingwerefilteredinthesamemanner. 2.5DataExtraction Data were extracted from the studies by one reviewer (SS). A research assistant checked the study reports and the information in the data tables to identify any errors thatmighthaveoccurredduringextraction,conversionor imputation. General information on study characteristics such as study aim, objective, study population,
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interventions or comparisons, outcomes and funding sourcewasextractedintosummarytables.Atthispointit becameclearthattheoutcomesinthecohortstudieswere too heterogeneous to pool so metaanalysis of this data was not pursued. For example, in the studies selected for inclusion,primaryoutcomeswerestandardizedmortality ratio, CHD hazard ratio, CHD odds risk ratio, or hypertensionhazardratio. Tofacilitateconversionandtransformationpriortometa analysis, results from the intervention studies were extracted into a detailed Excel spreadsheet. Items in the spreadsheet included mean baseline, end and change measurementsaswellasstandarddeviationanderrorfor eachmeasurement. Once conversion and imputation of the data were complete, data from the spreadsheet was entered into RevMan [16]. Summary measures were mean endof treatment values and their standard deviation. Endof treatment values were selected over mean change values because thedataforendoftreatmentwasmore complete (i.e.lessimputationwasrequired).Toensurethattheend and change summary measures were consistent, mean change values and their standard deviation were pooled fortotalcholesterolandLDLcholesterolandcomparedto themeanendoftreatmentvalues.
Interventions/exposures 1. ((whole*orintact*orin?tact*)adj2grain*).ti,ab. 2. expdietaryfibre/orexpdietarycarbohydrates/ 3. exppoaceae/orexpchenopodiumquinoa/orexp fagopyrum/orexpamaranthus/orexpcereals/ Outcomes 4. cardiovasculardiseases/orexpheartdiseases/orexp vasculardiseases/orexpdyslipidemias/orexpcholesterol/ orexpcholesterol,ldl/orexpcholesterol,hdl/orexp triglycerides/orexplipoproteins/orexpbloodpressure/or expbloodcoagulationfactors/orexpmetabolicsyndrome x/orexpcreactiveprotein/orexpinsulinresistance/ Studytypes 5. (clinicaltrialorclinicaltrialphaseiorclinicaltrialphaseii orclinicaltrialphaseiiiorclinicaltrialphaseivor controlledclinicaltrialormulticenterstudyorrandomized controlledtrial).pt.orexpepidemiologicstudy characteristicsastopic/orexpresearchdesign/or(clin*adj5 trial*).ti,ab.or((singl*ordoubl*ortreb*ortrip*)adj5 (blind*ormask*)).ti,ab.or(placebo*orrandom*).ti,ab.or expnutritionsurveys/ Combination 6. ((1and2)or3)and4and5 Limits 7. Limit6tohumans Table2.MEDLINEsearchstrategy
2.6QualityAppraisalofIndividualStudies The quality assessment of individual studies was independently performed by two reviewers (SS and EM). Differences in quality ratings were settled by consensus.
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The methodology checklists developed by the Scottish Intercollegiate Guidelines Network (SIGN) for controlled trials and for cohort studies [17] were modified to evaluate the quality of the studies selected for inclusion. Sensitivity analysis was used to take into account the influenceofstudiesjudgedtobelowerquality. 2.6.1InterventionStudies Thefollowing SIGNcriteriawereusedtoidentifysources of potential bias that could affect the results of the intervention studies: randomization; allocation concealment; blinding; and attrition less than or equal to 20%.Whetherornotthetreatmentgroupsweresimilarat the start of the trial was also examined; if the overall risk ofbiaswasdifficulttojudgebasedonthefirstfouritems, this fifth item was used to help make a decision. Table 3 includes descriptions of the methods used to judge each of the key items used to determine the risk of bias rating. If a study was rated wellcovered or adequately addressedforanitemonthechecklist,thestudymetthe criterion. If it scored poorly addressed, not addressed, or not reported, it did not meet the criterion. An overall quality judgment was reached based onhowmanyofthequalitycriteriaweremet.
Description Ifthestudydidnotreportrandomizing participantstotreatmentgroups,the methodofrandomizationwasnot reported,orthemethodof randomizationwaspoor,thestudywas givenalowerrating. Allocation Ifthestudydidnotreportconcealing concealment allocationfromresearchers,themethod ofconcealmentwasnotreported,orthe methodofconcealmentwaspoor,the studywasgivenalowerrating. Blinding Ifthestudydidnotreportblinding,the studywasgivenalowerrating.Studies thatblindedparticipants,researchers,or outcomeassessorsweregivenahigher ratingaccordingtothelevelofblinding. Attrition Ifthedropoutratewasnotreportedorit wasgreaterthan20%,thestudywas givenalowerrating. Ifbetweengroupbaselinevalueswere Comparabilityof treatmentgroupsat notreportedornotequivalentandthe riskofbiasjudgementwasundecided, baseline thestudywasgivenalowerrating.
measurement; validated and reliable outcome assessment; and adjustment for potential confounding (Table 4). The same rating system described above for interventionstudieswasapplied.
Description Ifthestudygroupswerenotassimilaras possibleinallcharacteristics(exceptfor exposurestatus)thestudywasgivena lowerrating. Outcomeattime Ifthestudydidnotprovideevidencethat ofenrolmentis themethodofoutcomeassessmentis reliableandvalid,orifthestudydidnot assessed usemultiplemethodstoverifytheoutcome, itwasgivenalowerrating. Reliableexposure Studiesthatdidnotuseareliablemethodto measurewholegrainintakeweregivena assessment lowerrating. method Studiesthatdidnotprovideevidencethat Validatedand reliableoutcome themethodofoutcomeassessmentis reliableandvalid,orifmultiplemethods assessment werenotusedtoverifytheoutcome,the studywasgivenalowerrating. Adjustmentfor Ifthestudydidnotreportwhichpotential potential confounderswereconsidered,orthestudy confounding didnotcontrolforapotentialconfounder, suchastotalenergyintakeorfruitsand vegetablesintake,itwasgivenalower rating.
Adaptedfrom[17].
Criterion Comparable source populations
Criterion Randomization
Table4.Keycriteriausedtodeterminethequalityofindividual prospectivecohortstudies
2.7DataConversionandImputation(InterventionStudies) Cholesterol and triglyceride measurements reported as milligrams per decilitre (mg/dL) were converted to millimoles per litre (mmol/L). Apolipoprotein measurements reported as mg/dL were converted to grams per litre (g/L). Creactive protein and fibrinogen were consistently measured in mg/L and g/L, respectively, so no conversion was required. When dispersion was reported as standard error (SE), it was converted to standard deviation (SD). If confidence intervalswereprovided,theywereconvertedtostandard deviations. If mean endoftreatment values were not provided but baseline and change values were, end values were calculated by adding the baseline and change. Similarly, if mean change values were not provided but baseline and end values were, change values were calculated by subtracting baseline from end. Formulae for calculating thestandarddeviationofthemeanwithingroupendand changevalueswere,respectively:
1. 2. SDend=SDbaseline+((SDbaseline)2(SDbaseline2SDchange2)) SDchange=(SDbaseline2+SDend22SDbaselineSDend)
Adaptedfrom[17].
Table3.Keycriteriausedtodeterminetheriskofbiasin individualinterventionstudies
2.6.2ProspectiveCohortStudies The following SIGN criteria for cohort studies were used to identify key sources of potential bias that could affect studyresults: comparablesource populations; outcome at time of enrolment is assessed; reliable exposure
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The mean correlation () was calculated for study arms that reported the standard deviation for all three mean total cholesterol values (baseline, end and change) (n=9). The mean correlation was strongly positive (=0.86). Therefore a of 0.8 was selected for use in the above formulae; if 0.8 resulted in a negative number under the squarerootsign,thenumberclosestto0.8thatresultedin apositivenumberunderthesquarerootsignwasused. 2.8DataSynthesis(InterventionStudies) When two or more intervention studies reported data for an outcome of interest and they were sufficiently similar, statistical analyses were performed using the RevMan software. Weighted mean differences between treatment and control groups (in the case of the parallel studies) or between treatment and control periods (in the case of crossover studies) were computed using the random effectsmodel. Three parallel studies investigated the effects of more than one whole grain treatment arm [6,11,18]. The data forthesestudieswereenteredintoRevManasifeacharm was a separate study. The mean value for the control group was used as the comparator for each arm and the number of participants in the control group was divided by the numberofwholegraintreatmentgroupstoensure that the weight attributed to each arm was appropriate. The crossover studies reported means and standard deviations(orstandarderrors)formeanendoftreatment values separately so a paired analysis was not possible. Allofthemeanendoftreatmentvalueswereanalysedas if the study was a parallel design. Two crossover studies reported results for participant subgroups separately [19,20]. Results for the subgroups were not combined; rather they were entered into RevMan as if they were separate studies. To avoid unit of analysis error, parallel studies and crossover studies were analyzed as separate subgroups and overall summary means were not calculated. Descriptive synthesis was used to analyze the data from the intervention studies that did not provide sufficientdataforinclusioninthemetaanalysis. Heterogeneity between trial results was assessed using the I2 statistic [21]. The following criteria for heterogeneity were established. I2 values over 50% indicate substantial heterogeneity. If heterogeneity was greater than 50% the data would not be pooled. If heterogeneity was moderate (I2 between 25% and 50%), potential reasons for the variation would be identified by examining the study characteristics. If one study seemed to be the source of the heterogeneity, sensitivity analysis would be used to determine the influence of the study on the pooled mean difference. If removing the study made little difference to the summary mean difference, the studywouldbeleftinthepooledanalysis.Thesymmetry of funnel plots was examined for evidence of potential biasduetoheterogeneityorselectivereporting.
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Sensitivity analysis was used to evaluate the influence of the following factors: study quality (poor vs. acceptable), population health status (elevated lipids or blood pressure vs. normal levels), and source of funding (commercialornot reportedvs.other), andtype ofwhole graintested(grainshighinglucanvs.grainswithout glucan). Since it has already been established that grains high in glucan (i.e. oats and barley) have cholesterol lowering effects [22,23], it was important to distinguish between the effects of whole grains high in glucan, whole grains with relatively low levels of glucan (e.g. wheat, rye), and whole grains in general. In order to support a health claim about whole grains in general and coronary heart disease, there must be evidence for an effect in whole grains with relatively low levels of glucan,sincewheat,themaingrainconsumedinCanada, islowinglucan. 3.Results 3.1DescriptionofStudies Theliteraturesearch andfilteringresultsaresummarized in Figure 1. Eightythree publications were excluded at the fulltext filtering stage. The number of publications and reasons for their exclusion are summarized in Table5. In total, 32 studies met the criteria for inclusion (Table 6). Of 26 intervention studies (from 27 papers) 17 were parallel [6,8,9,11,18,2435] and 9 were crossover design [7,10,19,20,3641]. Six prospective cohort studies were selected for inclusion [4247]. Characteristics of the intervention and observational studies selected for inclusionaresummarizedintheAppendix. 3.1.1InterventionStudies Intervention Twelve parallel studies examined the effects of whole grain oats [6,8,2527,2935]. Four oat studies tested a readytoeat breakfast cereal that meets the criteria for classification as whole grain [8,25,27,30]. Five parallel studies investigated the effects of a mix of whole grain foods[9,11,18,24,28].Testfoodswereprovidedinallbut1 parallel study [9]. None of the crossover studies tested oats alone; however, one tested the effects of barley [41]. The remaining crossover studies tested the effects of whole grain rye bread [20,40], whole grain wheat bread [19,36,39], whole grain wheat cereal [37] or a mix of whole grain foods [7,10,43]. Test foods were provided in allofthecrossoverstudies. Funding Twelve parallel studies [6,8,9,25,27,29,3135] and 4 crossoverstudies[7,20,36,40,41]reportedreceiving
Susan E. Sinclair, Elizabeth D. Mansfield and George A. Wells: Evidence for a Whole Grains and Coronary Heart Disease Health Claim

Potentiallyrelevant publicationsidentifiedusing electronicdatabases:732 Potentiallyrelevant publicationsremainingafter titlefiltering:293 Potentiallyrelevant publicationsremainingafter abstractfiltering:109 Publicationsidentifiedusing electronicdatabasesthat mettheinclusioncriteria:26 Totalnumberofpublications identifiedforinclusioninthe review:33
Excludedbecausetitle didnotmeetinclusion criteria:439
calculations; however two studies calculated the number neededtodetectdifferencesinoutcomesotherthanlipids or blood pressure [9,29]. In several studies that did not reportpowercalculations,thesamplesizewasverysmall (thatis,N<20)[36,38,39,41]. 3.1.2ProspectiveCohortStudies
Excludedbecause abstractdidnotmeet inclusioncriteria:184 Excludedbecausefull textdidnotmeet inclusioncriteria:83
PopulationandSetting Threeoftheprospectivecohortstudieswereconductedin the U.S. [43,46,47], 1 in the U.K. [42], 1 in Norway [44] and 1 in rural Sweden [45]. One of the U.S. studies was done in a Seventh Day Adventist population [43]. Three of the prospective cohort studies enrolled only male participants[4547]. Exposure Two prospective cohort studies looked at the intake of all whole grain foods using food frequency questionnaires [46,47]. Grams of whole grain were calculated from all sources using food composition databases. Total whole grainintakeingramswasusedtorankparticipantswhole grain intake into quartiles [47] or quintiles [46]. Four of the cohort studies measured the intake of whole grain or wholemeal bread consumption. One examined whole wheat bread consumption [43], 1 examined whole grain rye and crisp/hard bread [45] and 2 measured intake of all types of whole grain bread[42,44]. Thewhole wheat bread study used a FFQ to categorize participants into white, mixed or whole wheat groups [43]. In the whole grain rye and crisp/hard bread study, a FFQ was used to categorize participants into wholemeal or white or rye breadconsumers[45].Inthestudiesthatlookedatalltypes of whole grain bread, bread consumption data obtained using FFQs was used to categorize participants into daily orlessthandailyconsumptionofwholegrainbread[42]or intoquartilesofwholegrainintake[44].
StudyType Interventionstudies Parallel Crossover Totalnumberofinterventionstudies Observationalstudies Prospectivecohort Totalnumberofincludedstudies #Studies 17 9* 26 6 32
Relevantpublications identifiedusinghand searching:7
Reason
Figure1.Flowdiagramofliteraturesearchandfilteringresults Refs. [4867] [6885] [8698] #
Interventiondidnotmeetthecriteriafor 21 wholegrain 18 Effectofwholegraincouldnotbeisolated fromothercomponentsoftheintervention
Measurementofwholegrainsexposure 13 includednonwholegrainsorwholegrain components,suchasaddedbranandgerm Participantshadadiagnoseddisease,suchas diabetesmellitus Designwasnotinterventionorprospective cohort Insufficientdatawasprovidedtoconfirmthat theinterventionwaswholegrain Interventionwasintheformofameal replacement
[99108] 10 [109114] 6
[115120] 6 Outcomesofinterestwerenotmeasured [121123] 3 [124,125] 2 [128] [129]
[126,127] 2 Interventionwaslessthan3weeks 1 Nonewdatawasreported 1 ArticlewaspublishedinGerman(resources werenotavailablefortranslation)
Table5.Studiesexcludedatthefulltextfilteringstageincluding reasonforexclusion
*Theresultsofonestudywerereportedintwopublications[20,40]
funding from sources with commercial interests in cereal products. Three parallel studies [11,18,24] and four crossover studies [18,19,38,39] were funded by non commercial sources. Two parallel studies [28,30] and one crossoverstudydidnotreportsourceoffunding[37]. Power Eight parallel [6,8,9,11,18,29,30,32] and four crossover [7,10,19,20] studies reported conducting power
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Table6.Numberofstudiesselectedforinclusionaccordingto studydesign
Funding One of the prospective cohort studies reported receiving support from both industry and government sources. Government sources were the sole funding source reported for 3 prospective cohort studies ([43,45,47]. Two prospective cohort studies did not report their source of funding[42,44].
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3.2QualityAppraisalofIndividualStudies 3.2.1InterventionStudies All but one parallel study [28] and 2 crossover studies [38,39]reportedrandomizingparticipants;however,none described the method used. No studies reported concealment of allocation. Six parallel studies [6,18,24,26,29,30] and 1 crossover study [37] reported keeping investigators or outcome assessors blind to the treatment allocation. One parallel study [30] and 1 crossover study [37] also blinded participants. Two parallelstudies[28,31]and4crossoverstudies[7,38,39,41] did not report the number of dropouts and the rate could not be calculated from the information provided. Of the remaining studies, 3 reported a dropout rate greater than 20% [8,30,34]. Four studies did not report sufficient data to assess baseline differences in outcomes of interest between treatment groups [7,28,35,38]. In 6 studies, the baseline differences between groups in 1 or more outcome measures seemed appreciable [9,18,27,30,31,34]. Overall,2parallel[28,31]and3crossoverstudies[7,38,39] received poor overall quality judgements, meaning they were not designed particularly well to minimize the risk ofbias. 3.2.2ProspectiveCohortStudies None of the included cohort studies compared groups from different subsets of the target population (i.e. differentsourcepopulations).Twostudiesfailedtoreport whether the likelihood that participants might have the outcome at the time of enrolment was assessed [42,43]. All of the studies reported using a reliable method to measure whole grain intake. Only 1 study cited evidence from other sources to demonstrate that the method of outcome assessment was valid and reliable [47]. Three studies measured and adjusted for known sources of potential confounding [4547]. One study failed to report adjustment for potential confounders [42] and 2 studies were not able to adjust for fruit and vegetable intake becausethedietassessmentquestionnairedidnotinclude questions on fruit and vegetable intake [43,44]. Overall, four prospective cohort studies received poor overall qualityjudgements[4245]. 3.3EffectsofWholeGrains 3.3.1InterventionStudies TotalCholesterol Only 1 [24] parallel study and 1 [36] crossover study did not report total cholesterol as an outcome; however, 3 parallel studies [8,28,35] and 2 crossover studies [37,38] didnot reportsufficient datato beincludedinthe pooled analysis. Four of these studies reported that total
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cholesterollevelsweresignificantlyimprovedwithwhole grain versus control foods [8,28,35,38], one of which received a poor overall quality judgement [28]. The pooled analysis of the remaining studies suggest that overall, whole grain foods lower total cholesterol comparedtocontrolfoods(Figure2).Theweightedmean endoftreatment differences for the parallel and crossover studies were 0.16 and 0.18 mmol/L, respectively. There was no evidence of statistical heterogeneity according to the I2 statistics in either subgroup analysis. The funnel plots were symmetrical. The pooled analyses of the change in total cholesterol measurements were consistent with the endoftreatment analyses.Sensitivityanalyseswereundertakentoidentify the influence of various factors on the relationship between whole grains and total cholesterol (Table 7). The parallel studies pooled mean difference was no longer statistically significant when 1) the studies that tested glucancontainingwholegrainswereremovedfromthe analysisor2)studiesthatreceivedcommercialfundingor did not report funding source were removed from the analysis. The crossover studies pooled mean difference was no longer statistically significant when the studies judged to be of poor quality [7,39] were removed from theanalysis. LDLCholesterol Fifteen parallel studies [6,8,9,11,18,2531,3335] and 8 crossover studies [7,10,19,20,37,3941,43] reported LDL cholesterol outcomes. Four parallel studies [8,28,33,35] and 2 crossover studies [37,38] did not report sufficient data to be included in the pooled analysis. One of the parallelstudiesreceivedapooroverallqualityjudgement [28]. Among the studies that did not report sufficient data, two parallel [28,35] and both crossover studies [37,38]reportedimprovedLDLcholesterollevelswiththe whole grain treatment. Moderate heterogeneity was observed in one pooled analysis; the I2 statistic for the LDL cholesterol crossover studies subgroup analysis was 48%. Further investigation revealed that the heterogeneity occurred because 2 mean differences favoured (although not significantly so) the control groups [10,19] and 2 favoured the whole grains groups [39,41]. When either pair of studies was removed from the analysis the heterogeneity diminished. The funnel plot for each subgroup analysis was symmetrical. The pooled analysis of the endoftreatment LDL cholesterol results in the remaining parallel and crossover studies suggest that whole grain foods lower LDL cholesterol comparedtocontrolfoods(Figure3).Theweightedmean differences for the parallel and crossover studies were 0.12and0.20 mmol/L,respectively. Thepooledanalyses of the change in LDL cholesterol measurements were consistentwiththeendoftreatmentanalyses.
Figure2.Pooledanalysisofendoftreatmenttotalcholesterolresults
Figure3.PooledanalysisofendoftreatmentLDLcholesterolresults
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Analysisdescription Overall Poorquality removed Elevatedlipidsremoved glucangrainsremoved Commercialfunding removed Subgroup Parallel Crossover Parallel Crossover Parallel Crossover Parallel Crossover Parallel Crossover #studiesin analysis 13 6 12 4 6 5 3 5 3 3 #trial arms 17 8 16 6 9 6 5 7 4 4 #participants 1517 285 1494 215 1129 205 518 265 471 155 Meandifferencemmol/L (95%CI) 0.16(0.24,0.07) 0.18(0.32,0.07) 0.16(0.32,0.11) 0.13(0.33,0.08) 0.16(0.28,0.03) 0.17(0.30,0.04) 0.11(0.28,0.07) 0.16(0.29,0.03 0.11(0.29,0.03) 0.14(0.28,0.00) pvalue 0.0004 0.005 0.0004 0.22 0.01 0.01 0.23 0.02 0.24 0.06
Table7.Overallpooledmetaanalysisandsensitivityanalysisresultsfortotalcholesterol Analysisdescription Overall Subgroup #studiesin analysis 11 6 10 4 5 5 3 5 2 3 #trial arms 15 8 14 6 7 6 5 7 4 4 #participants 1142 285 1099 215 754 205 518 265 471 155 Meandifferencemmol/L (95%CI) 0.12(0.20,0.03) 0.20(0.36,0.04) 0.11(0.20,0.01) 0.13(0.31,0.06) 0.05(0.18,0.09) 0.18(0.38,0.01) 0.05(0.11,0.21) 0.14(0.37,0.08) 0.05(0.11,0.22) 0.09(0.46,0.28) pvalue 0.008 0.02 0.03 0.17 0.52 0.07 0.55 0.22 0.52 0.64
Parallel Crossover Parallel Lowerqualityremoved Crossover Parallel Elevatedlipidsremoved Crossover Parallel glucangrainsremoved Crossover Commercial/ NR funding Parallel removed Crossover
Table8.OverallpooledmetaanalysisandsensitivityanalysisresultsforLDLcholesterol
Sensitivity analyses were undertaken to evaluate the influence of various factors on the effect of whole grains on LDL cholesterol (Table 8). The parallel studies pooled mean difference was no longer statistically significant when 1) the studies that recruited participants with elevated lipids or blood pressure, 2) the studies that testedglucan containing whole grains or 3) studies that received commercial funding or did not report funding source were removed from the analysis. The crossover studiespooledmeandifferencewasnolongerstatistically significantineachofthesescenariosaswellaswhenpoor qualitystudieswereremoved. BloodPressure Nine parallel studies [8,9,11,18,26,2931,34] and 4 crossover studies [7,10,19,36] reported systolic and diastolic blood pressure results. Three parallel studies [8,18,30] and 2 crossover studies [19,36] did not report adequatedatatobeincludedinapooledanalysis.Twoof the studies not included in the pooled analyses reported statistically significant reductions in systolic blood pressurewiththewholegrainintervention[18,36]. The pooled analysis of the endoftreatment systolic and diastolic blood pressure results in the remaining parallel and crossover studies were not statistically significant (Figures 4 and 5, respectively). Sensitivity analyses did not reveal any important changes based on type of whole grain, participant blood pressure status, study quality or sourceoffundingforeitheroutcome.
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ExploratoryOutcomes Only one parallel study [31] and one crossover study [7] reported sufficient VLDL cholesterol data for meta analysis, so pooled analysis for this outcome was not performed. Similarly, only one crossover fibrinogen comparison [40] and one crossover Creactive protein [7], were reported so pooled analyses for theseoutcome were notperformed.Pooledmeanendoftreatmentdifferences between whole grain and control groups were very small (Table9). 3.3.2ProspectiveCohortStudies Two of the six cohort studies selected for inclusion did not observe significantly lower risk of CHD outcomes in individuals who reported consuming more whole grain foods [42,45]. Both studies were assigned a poor overall quality. The first reported an ischemic heart disease standardized morality ratio of 44.5 in participants who reported eating whole meal bread daily compared with 41.4 in participants who did not report weekly or less than weekly consumption. Among the participants, 62% of reported daily consumption. Adjustment for potential confounders was not reported [42]. The second reported an odds risk ratio for CHD death or hospitalization of 0.87 (95% CI 0.57, 1.33) in participants who reported consuming wholemeal bread compared with those who reported consuming white or rye bread. 71% of participantsreportedconsumingwholemealbread.
Figure4.Pooledanalysisofendoftreatmentsystolicbloodpressureresults
Figure5.Pooledanalysisofendoftreatmentdiastolicbloodpressureresults Outcome HDLcholesterol(mmol/L) Triglycerides (mmol/L) ApolipoproteinA1 (g/L) ApolipoproteinB (g/L) Fibrinogen(mg/L) Subgroup Parallel Crossover Parallel Crossover Parallel Crossover Parallel Crossover Parallel #studiesin analysis 11 6 11 6 4 1 4 1 1 3 #trial arms 15 8 15 8 5 2 5 2 2 5 #participants 1142 308 1142 292 524 55 524 55 266 381 Meandifference mmHg(95%CI) 0.01(0.05,0.02) 0.02(0.07,0.03) 0.04(0.13,0.04) 0.05(0.12,0.02) 0.02(0.03,0.06) 0.03(0.15,0.09) 0.04(0.08,0.00) 0.03(0.15,0.09) 0.10(0.06,0.26) 0.01(0.65,0.63) pvalue 0.52 0.53 0.33 0.18 0.47 0.65 0.03 0.65 0.23 0.98
CReactiveProtein(mg/L) Parallel
Table9.Summaryofexploratoryoutcomepooledmeandifferences(wholegrainsversuscontrol)
Relevant sources of potential confounding were controlledforinthisstudy[45]. Four studies reported statistically significant associations between whole grain foods and cardiovascular disease outcomes[43,44,46,47].Twowereassignedagoodoverall quality judgement [46,47]. One observed lower incidence of hypertension among Health Professional Followup
Studyparticipantsinthehighestversuslowestquintileof whole grain intake after adjustment for potential confounding (HR 0.81; 95% CI 0.75, 0.87; P for trend <0.0001). Median whole grain intake was 3.3 and 46.0 grams per day in the lowest and the highest quintiles, respectively [47]. The second observed lower risk of incident CHD in individuals with the highest versus lowest intake of whole grains after adjustment for
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potential confounding, including added bran and germ (HR 0.82; 95% CI 0.70, 0.96; P for trend=0.01). Interestingly,furtheradjustmentfortheeffectoffibreand other whole grain constituents did not alter the results appreciably (HR 0.85; 95% CI 0.71, 1.02; P for trend=0.06). Median intake of whole grains in the lowest quintile was 3.5 grams per day compared with 42.4 grams per day in thehighest[46].Twostudieswereassignedapooroverall quality judgment [43,44]. The first observed a lower risk of nonfatal myocardial infarction in individuals who reported consuming whole grain bread compared with those who reported consuming white bread (HR 0.56; 95% CI 0.35, 0.89, P for trend<0.01). Risk of definite fatal CHD was not significantly lower (HR 0.89; 95% CI 0.60, 1.33) but risk of fatal CHD as determined by death certificate was (HR 0.74; 95% CI 0.56, 0.99; P for trend<0.0001). While several potential confounders were adjusted for in the analyses, fruit and vegetable intake was not [43]. Similarly, the second reported lower risk of CHD death (HR 0.76; 95% CI 0.56, 1.02; P for trend=0.04) and CVD (HR 0.77; 95% CI 0.60, 0.98; P for trend=0.16) in individuals who consumed the most whole grain bread compared with individuals who reported consuming the least [44]. Fruit and vegetable intake was also not adjustedforintheseeffectestimates. 4.Discussion Among the intervention studies selected for inclusion, there was evidence for an overall effect of whole grains on total and LDL cholesterol, but not on blood pressure or exploratory biomarker outcomes such as HDL cholesterol, VLDL cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B, Creactive protein and fibrinogen. No evidence for an effect remained after studies that tested grains high inglucan and studies that were judged to be lower quality were removed, leaving only 3 parallel and 3 crossover studies in the analyses. It is interesting to note that all three parallel studies that remained [9,11,18] reported conducting power calculations, so the false negativescenarioisunlikely. Two studies that did not report sufficient data to be included in the pooled blood pressure analyses reported statisticallysignificantreductionswithwheatbasedgrain interventions [18,36]. One was a pilot crossover study withaverysmallsamplesize[36],howevertheotherwas arelativelylargerandomizedcontrolledtrial[18].Further researchisneededtoconfirmtheseresults. Among 6 prospective cohort studies selected for inclusion, 4 observed significant associations favouring whole over refined grains. Two of the 4 favourable studies added little strength to the body of evidence for whole grains and CHD risk, since fruit and vegetable intake could not be adjusted for in the analyses. The remaining2favourablestudieswereabletoadjustforthe appropriate confounding variables; however, the results are not entirely generalizable to the entire target population (generally healthy adults) since the study population was a cohort of male health professionals [46,47]. Overall, the evidence from prospective studies, while mostly favourable, is limited by potential bias due to confounding factors and poor generalizability. It should be noted that several prospective cohort studies were excluded at the fulltext filtering stage (Table 5) because the measurement of whole grains included non wholegrainsorgraincomponents,suchasaddedbranand germ [8691,9396,98]. Reanalysis of these studies, using the newer quantitative methods forestimating dailyintake ofwholegrains(ingrams)fromallfoods[46,47,130]should be explored. If this was possible, the evidence from these studies could improve the generalizability of the evidence for an association between whole grains and CHD from observationalstudies. Based on the results of this systematic review, Health Canada concluded that the evidence to date from intervention and cohort studies is not sufficient to support a health claim about whole grains and CHD risk reduction. Cholesterollowering caused by oats and barley cannot be generalized to wheat, the predominant whole grain that would carry a health claim about whole grainsinCanadaifitwerepermitted.Canadahasalready accepted a disease risk reduction claim about oats products and cholesterol lowering [22] and barley productsand cholesterollowering[23].This conclusionis consistent with other systematic reviews with similar inclusion criteria. In a systematic review of intervention studies done in individuals with existing risk factors for CHD there was insufficient evidence available to make conclusionsaboutwholegrainsingeneralandriskfactors for CHD, except for whole grain oats [12]. A second systematic review also concluded that there was not enough evidence to draw a conclusion about the effect of wholegrainintakeontheriskofCVD[13]. Health Canadas conclusion is also consistent with recent decisions from other scientific or regulatory authorities. In 2007, Food Standards Australia New Zealand concluded that the relationship between a higher intake ofwholegrainsand areduction in coronaryheartdisease was not convincing [131]. Similarly, in 2010 the European Food Safety Authority concluded that a cause and effect relationship could not be established between the consumption of whole grain and several claimed effects, including blood cholesterol and cardiovascular health [132]. 4.1FutureData HealthCanadaisawareof3inprogresstrialsdesignedto testwholegraininterventions(Table10).
Susan E. Sinclair, Elizabeth D. Mansfield and George A. Wells: Evidence for a Whole Grains and Coronary Heart Disease Health Claim 11
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Ref. [133] Study Population Healthy; 2570years Intervention Wholegrain barley;whole grainoats Outcomes
Biomarkersof CHDrisk (primary) Femaleonly; Biomarkersof Wholegrain [134] overweight;40 CHDrisk wheatproducts 70years (secondary) Metabolic Biomarkersof [135] syndrome;2065 Wholegrainfoods CHDrisk years (secondary) Table10.Inprogressclinicaltrialstestingwholegrains
and other grains with relatively low levels of glucan andCHDriskreduction. 4.2DietaryGuidelines While the evidence to date is not sufficient to support a health claim about whole grains and CHD, there is little doubt that whole grains offer bioactive components including fibre, vitamins, minerals, trace elements, lignans and phytosterols. To obtain these substances, Canadians are encouraged to eat a diet rich in whole grain foods by consuming at least half of their grain productsaswholegrain[3].
Theresultsofongoingtrialsmayshedfurtherlightonthe relationship between whole grains, particularly wheat
5.Appendix:CharacteristicsofIncludedStudies ParallelInterventionStudies
Interventions/Comparisons Study Brownlee 2010[11] Design,N Randomized; parallel;known asthe WHOLEheart trial;N=266(of 316). Population Treatments,Duration BackgroundDiet, Method Participantswere 120g/dor60g/d. providedwitharange WGintakein1st ofWGfoodsand armwas74g/d averagedforwks8 askedtosubstitute theseforrefinedgrain and16(no foodsintheirdiettoa differenceb/w8 prescribedamount. and16wks).WG Dietmeasuredusing intakeinthe2nd was83g/datwk8 FFQ. and115g/datwk 16.WGintakein thecontrolarm averaged19g/d. 28,56,and84g/d Backgrounddietwas dosesofoatmeal NCEPstep1diet. andoatbranand Cerealsupplements 28g/ddoseof werepackagedin1oz farina(betaglucan packetsandprovided control). toparticipants. Patientscompleted4d recordsfourtimes duringthetrial; recordswereanalyzed usingnutrition software. Backgroundwas Participants usualdiet. recordedamean Participantswere intakeof7.9and instructedtoreplace 6.8portionsper dayintheWGand usualcerealproducts withproducts controlgroups, respectively.Mean containingatleast dailyintakeofthe 50%oftheir WGoatsnackbar compositionfromWG source.Cereal was13gperday. products(bread, pasta,snackbars) wereprovided. Participantskept4d dietrecordduring runinandagainat weeks4,8,and12. AmountofWG Relevant Outcomes Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides;C reactiveprotein; fibrinogen; systolicblood pressure;diastolic bloodpressure.
Davidson 1991[6]
Randomized; parallel;single blinded;N=140 (of156).
UK;healthy,overweight; 3treatmentarms:1)60g/d maleandfemale; WGfor8wksfollowedby 1825y. 120g/dfor8wks(WG foodsincludeWWbread, Cheerios,brownbasmati rice);2)60g/dWGfor16 wks;3)Control(no dietarychange). Treatmentwasdivided into28wkperiodsinthe 1starm;in2ndand3rdarms thetreatmentlasted16 wks. USA;hyper 7treatmentarms:1)28g/d, cholesterolemic;male 2)56g/d,3)84g/doatmeal; andfemale; 4)28g/d,5)56g/d,or6) 3065y. 84g/doatbran;7)28g/d farina(control). RuninonNCEPstep1 dietlasted8wks,followed by6wktreatmentphase withthecereal supplement,followedbya 6wkwashout. Finland;metabolic syndrome;maleand female;4070y. 3treatmentarms:1) healthydiet(fattyfish, bilberriesandWGcereal productsincludingrye breads,wholemealpasta); 2)WGproducts(sameas (1)plusawholegrainoat snack);3)refinedgrain products.Treatments lasted12weeks.
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides.
DeMello 2011[24]
Randomized; parallel;single blind(outcome assessors); N=104(of131)
Highsensitivity Creactive protein.
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Interventions/Comparisons Study Johnston 1998[25] BackgroundDiet, Method BackgroundofAHA Randomized; USA;mildmoderate 2treatmentarms:1)AHA 2x42.5g(1.5oz) portionperday. StepOnefatmodified parallel;N=135 hypercholesterolemia; StepOnedietplusoat dietplustreatment (of185). maleandfemale;4070y. basedbreakfastcereal cereal(cereal (Cheerios);2)AHAStep provided). Onedietplusbreakfast Patientscompleted3d cereal(Cornflakes). recordsthreetimes 6wkruninonStepOne duringthetrial; dietfollowedby6wkon recordswereanalyzed StepOneplustreatment usingnutrition cereal. software. 2x45gportionsper Backgrounddietwas Randomized; USA;healthy;Hispanic; 2treatmentarms:1)Oat NCEPSTEP1for parallel;N=152; maleandfemale;3070y. basedWGbreakfastcereal day. weightmaintenance; 2065y. (Cheerios);2)Cornbased mealpatternprovided breakfastcerealwithout andparticipantsself solublefibre(preparedby selectedfoods. GeneralMills).5wkrun Packagesoftreatment inonNCEPStepOnediet cerealwereprovided. followedby6wkon Compliancewithdiet treatmentcereal. wasassessedusing3d foodrecordsand unannounced24h recalls;recordsand recallswereanalyzed usingnutrition software Backgrounddietwas 47servingsper Randomized, USA;Metabolic 2treatmentarms:1) daydependingon 500kcal/ddeficitto parallel;N=47 Syndrome;maleand Dietaryadvicetoobtain achieveweightloss. 2005Dietary (of50). female;2065y. allgrainservingsfrom Dietbasedon2005 WGfoods(WGbreadand Guidelinesfor dietaryguidelinesfor Americans rolls,RTEcereal,brown Americans. rice,oatmeal,pasta,salty recommendation forageandgender. Participantsself snacks,andsnackbars) selectedWGsorRGs andhypocaloricdiet;2) (dietitiantrainingand RGandhypocaloricdiet. listofWGswith Treatmentslasted12wks. descriptionprovided). Atbaselineandevery 4wk,participants completeda3ddiet record.Dietrecords analysedusing nutritionsoftware. USA;hypertensiveand 2treatmentarms:1)Oats 137goatcereal Backgrounddietnot Randomized; hyperinsulinemic;male cereal;2)Lowfibrecereal. (5.52gbetaglucan reported.Participants parallel; andfemale;2759y. Treatmentlasted6wks. perday). wereinstructedto physician consumealltheir blinded;pilot cerealdailybutwere study;N=18(of allowedtoprepare 22). andconsumethe cerealhoweverand wheneverthey wished(cereal provided).Cereal intakerecordeddaily usingcalendars.Total dietaryintake reviewedusing3d records. Treatments,Duration AmountofWG Design,N Population Relevant Outcomes Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; apolipoprotein A1; apolipoproteinB.
Karmally 2005[27]
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; apolipoprotein A1; apolipoproteinB.
Katcher 2008[9]
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; apolipoprotein A1; apolipoproteinB; Creactive protein;systolic bloodpressure; diastolicblood pressure.
Keenan 2002[26]
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.
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Interventions/Comparisons Study Maki2010 [8] Design,N Randomized; parallel;N=144 (of204). Population USA;overweight,obese andhyper cholesterolemic;male andfemale;2065y. Treatments,Duration 2treatmentarms:1)WG RTEoatcereal+ hypocaloricdiet;2)Low fibrebreakfast/snack foodswithsimilarenergy andmacronutrient content.Eachtreatment lasted12wks. BackgroundDiet, Method 2portions(approx Backgrounddietwas hypocaloric(target 3cperday)WG energydeficitwas readytoeatoat cerealproviding3g 500kcal/d)plus interventionfood.WG betaglucanper cerealwasprepared, day. packagedand providedbythe manufacturer.3ddiet recordsatbaseline andatweeks4and12 analyzedusing NutritionSoftware. 50gWGcerealat Backgroundwas breakfastand2 usualdiet. WGchapattisper day. AmountofWG Relevant Outcomes Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides;C reactiveprotein; systolicblood pressure;diastolic bloodpressure.
Mushtaq 2009[28]
Parallel;N=64.
Pakistan;obese;female only.
Pins2002 [29]
Randomized; parallel; physician blinded;N=88.
USA;historyofmildor moderateessentialHT; undergoingtreatment forHTwithnomore than1drug;maleand female;3367y.
2treatmentarms:1)WG cerealatbreakfast,WG chapattiswithlunchand dinner;2)conventionally availablecarbohydratesin meals. Treatmentlasted4weeks 2treatmentarms:1)Oats 60goatmealper cereal(QuakerOatmeal day;77goatsquare andQuakerOatSquares); perday. 2)Lowfibrecereal(Malt OMealHotwheatcereal andKelloggsCrispix). Treatmentlasted12wks.
Reynolds 2000[30]
USA;Mildmoderate Randomized; hypercholesterolemic; parallel; doubleblinded; maleandfemale;2768y. N=43(of46).
Saltzman 2001[31]
Randomized; parallel;N=43 (of52).
USA;healthy;maleand female;1878y.
2treatmentarms:1)AHA StepOnedietplusoat basedbreakfastcereal (Cheerios);2)AHAStep Onedietplusbreakfast cereal(Country Cornflakes).6wkbaseline periodfollowedby4wks ontreatment. 2treatmentarms:1) hypocaloricdietplus rolledoats(Quakerquick oats);2)hypocaloric controldiet.Treatment lasted6wks.
2x42.5g(1.5oz) portionperday.
Cerealswere provided.Remaining cerealwasreturned andweighed. Participantskepta dailycerealcalendar tohelpdetermine compliance. 3dfoodrecordswere keptatbaselineand endof12wksthen analyzedwith nutritionsoftware. Basedietoffat modifiedStepOne plustreatmentcereal (cerealprovided).4d foodrecords, analyzedusing nutritionsoftware.
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.
Tighe2010 [18]
Randomized; parallel;single blinded;N=206 (of233).
UK;healthymaleand 2treatmentarms:1)WG female;middleaged(age wheatfood(1serving)+ rangenotreported). oatfoods(2servings) (W+O)2)WGwheatfood (3servings)(W)3) refinedgraincontrol(R). Eachtreatmentlasted12 weeksfollowinga4wk runinwiththerefined graincontroldiet.
Backgrounddietwas NCEPStepI hypocaloricdiet(800 1000kcal/ddeficit includingtreatment food).Allfoodand beveragesprovided. Dietaryintake measuredusing3d foodrecordsand analyzedusing nutritionsoftware. 3servingsperday Treatmentfoodswere WGfoods;7080g providedand wholemealbread+ participantswere 3040gWGcereals. askedtosubstitute refineditemswith WGitems. Dietintakeassessed using7dfooddiaries beforeandduringthe runinandduringthe intervention.
45gperdayrolled oats(1.5servings perday)
Totalcholesterol; LDLcholesterol; HDLcholesterol; VLDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.
Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides;C reactiveprotein; systolicblood pressure;diastolic bloodpressure.
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Interventions/Comparisons Study VanHorn 1986[32] Design,N Population Treatments,Duration 3treatmentarms:1)oat bran(2oz/d)+AHAfat modifieddiet;2)oatmeal (2oz/d)+AHAfat modifieddiet;3)control (AHAfatmodifieddiet alone). 6wkruninonAHAfat modifieddietfollowedby 6wksontreatment. AmountofWG 2ozoatmealoroat bran;half consumedashot cereal,half consumedas oatmealproducts (forexample, cerealsand muffins). BackgroundDiet, Method Oatproductswere serveddailyina companycafeteria. Backgrounddietwas AHAisocaloric reductionintotalfat tonotmorethan30% totalcalories,with equaldistribution amongSFA,MUFA andPUFA.Dietary cholesterolintakewas limitedto250mg/d. 3dayfoodrecords werecollectedat baselineandduring weeks6and12and analyzedwith nutritionsoftware. Backgrounddietwas AHAisocaloric reductionintotalfat tonotmorethan30% totalcalories,with equaldistribution amongSFA,MUFA andPUFA.Dietary cholesterolintakewas limitedto250mg/d. 3dayfoodrecords werecollectedateach visitandanalyzed withnutrition software Backgrounddietwas usualintake.Instant oatswereprovidedto participantsin packets. Participants completed3drecords beforetheirbaseline andat2subsequent visits;records analyzedusing nutritionsoftware. NCEPStepIdietplus treatmentfoods.3d foodrecords, analyzedusing nutritionsoftware. Relevant Outcomes Totalcholesterol.
Randomized; USA;normolipidemic; parallel;N=208. maleandfemale;3065y; recruitedfrom2work forceslocatedinthe Merchandisemartin Chicago.
VanHorn 1988[33]
Randomized; USA;normolipidemic; parallel;N=236. maleandfemale;3065y; recruitedfromNational BankofChicagostaff.
2treatmentarms:1) oatmeal(2ozor56g/)+ AHAfatmodifieddiet,2) control(AHAfat modifieddietalone). 4wkruninonAHAfat modifieddietfollowedby 4wksontreatment.
2packetsof oatmealperday (57.6gdryweight). Oatmealrecipes andasupplyof oatmealwere providedforhome use.Oatmealcereal andmuffinswere servedinthe employeecafeteria.
VanHorn 1991[34]
Randomized; parallel;N=80.
2treatmentarms:1) USA;serum TC>5.2mmol/L;maleand instantoatsinplaceof othercarbohydratefoods; female;2276y. 2)usualintake. Treatmentslasted8wks.
2packetsofinstant oatsperday(57.6g dryweight).
Totalcholesterol; LDLcholesterol; HDLcholesterol; VLDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.
VanHorn 2001[35]
USA;moderate Randomized; parallel;N=127. hypercholesterolemia; postmenopausal;female only;mean66y.
4treatmentarms:1)oats andmilk;2)wheatand soy;3)oatsandsoy;4) wheatandmilk. Treatmentlasted6wks followinga3wk runin.
2servings/dof cookedoatmealor RTEoatbran cereal(provided byQuakerOats).
Totalcholesterol; LDLcholesterol; HDLcholesterol.
Abbreviations: AHA=American Heart Association; b/w=between; c=cup(s); d=day; e.g.=for example; FFQ=Food Frequency Questionnaire; g=gram(s); HDL=highdensity lipoprotein; h=hour(s); kcal=kilocalories; LDL=lowdensity lipoprotein; l=litre(s); mg=milligrams; mmol=millimoles; MUFA=Monounsaturated fatty acids; N=sample size; NCEP=National Cholesterol Education Program; oz=ounces; PUFA=polyunsaturated fatty acids; RG=refined grain; RTE=readytoeat; SFA=saturated fatty acids; UK=United Kingdom; USA=United States of America; VLDL=very lowdensity lipoprotein; WG=whole grain; wk(s)=weeks(s); WW=whole wheat; y=year(s).
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CrossoverInterventionStudies
Interventions/Comparisons Study Design,N Population Sweden;healthy, moderately overweight;male andfemale;3570y. BackgroundDiet, Method Participantsfollowed 2treatmentperiods:1) 7servingsor112g/d: usualdietbutincluded WGproducts(WG 3breadslices,2crisp bread,WGcrispbread, breadslices,1portion fixedamountofWGor WGmuseli,WG muesli,1portionpasta. RGproducts. WGproductswere pasta);refinedgrain ProductswereWGif provided.Diet products.Treatments 50%WGdry measuredusing3d lasted6wkswitha68 substance.Wheat recordsbeforeand wkwashoutbetween. dominatedbutrye, oatsandWGricewere duringeachtestperiod. Dietanalysedusing included. nutritionsoftware. 2treatmentperiods:1) 48g/d Usualdietplustestrolls 2wholegrainwheat (rollswereprovided). rolls;2)2controlrolls. Participantswereable Eachtreatmentperiod toconsumetherollsat was3wkswitha3wk anytimeofthedayand washoutbetween. withanyfillingoftheir choice. Usualdietplus 2treatmentperiods:1) 48g/d packagesoftreatment wholegrainwheat cerealsprovided. cereal;2)wheatbran cereal.Eachtreatment periodlasted3wkwith a2wkruninand2wk washoutbetween. Commonbasedietof 4treatmentperiods:1) Wheat(shredded) 40g/d;corn(mealwith 2800kcal/dwasused; WGproducts treatmentsweregiven germorpopcorn) (shreddedwheat, asasupplementtothe cornmealwithgermor 38g/d; popcorn,oatmeal);2) oats(asoatmeal)30g/d. basediet. Foodwaspreparedand Total400kcalfrom leafyvegetables;3) servedinasmalldining WG/d vegetableroots;4) roomwithinalabor sucrose(control).Each providedintakeaway treatmentperiodlasted bags. 3wks. Backgrounddietwas 2treatmentperiods:1) fixedamount habitualintake.Alltest WGwheatbread, foodswereprovided. pasta,rusksand Energyandnutrient crackers(provided);2) compositionofthe RGbread,pasta,rusks interventionfoodswere andcrackers measureddirectlyby (provided).Each themanufacturer. treatmentlasted3wks Complianceassessed following2wkrunin. using7dfoodrecords. 2treatmentperiods:1) 20%dailyenergyfrom Usualdiet,butreplace variousWGrye treatmentbread usualbreadandbaked breads,2)various (minimum45 productswithprovided whitewheatbreads. portions/d). testbreads. Eachtreatmentperiod 4dfoodrecords, lasted4wkswith4wk analyzedwithnutrition washoutbetween. software. Nutrientcompositionof thetestbreadswas analyzedandaddedto thedatabase. 3meals/dweresupplied 2treatmentperiods:1) 60%oftotalenergy wasfromcarbohydrate everydayinpackages barleydiet(70/30% andconsumedathome. barley/rice;barleywas treatment. WGthatmaintained 45%barleybran); standarddiet(100% rice).Treatment periodslasted4wks witha4wkwashout between. Treatments,Duration AmountofWG Outcomes Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides;C reactiveprotein; systolicblood pressure;diastolic bloodpressure.
Andersson2007 Randomized; [10] crossover;N=30(of 34).
Bodinham2011 [36]
Randomized; crossover;N=14.
UK;healthy;mean age:26y.
Systolicanddiastolic bloodpressure.
Costabile2008 [37]
Randomized; crossover;double blinded;N=31(of 32).
UK;healthy;men andwomen;20 42y.
Totalcholesterol;HDL cholesterol; triglycerides.
Fraser1981[38]
Latinsquare;N=16.
USA;healthy; universitystudents; maleonly.
Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides.
Giacco2010 [7]
Italy;healthy;male andfemale;mean 54.5y.
Totalcholesterol;LDL cholesterol;HDL cholesterol;VLDL cholesterol; triglycerides; apolipoproteinA1; apolipoproteinB.
Leinonen2000; Turpeinen2000 [20,40]
Randomized; crossover;N=40(of 43).
Finland;healthy withslightly elevated cholesterol;male andfemale;age rangenot provided.
Li2003[41]
Japan;healthy; universitystudents; femaleonly;mean 20.4y.
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Interventions/Comparisons Study Sofi2010[39] Design,N Randomized; crossover;N=20. Population Treatments,Duration AmountofWG 150gbreadperday BackgroundDiet, Method Testandcontrolbread wasprovidedto participantsinweighted portionsize. Outcomes Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides.
Tucker2010[19] Randomized; crossover;N=27(of 28).
Italy;healthy;male 2treatmentperiods:1) andfemale;2161y. WGwheatbread2) refinedwheatbread. Treatmentperiods lasted10wkwitha10 wkwashoutbetween. Canada;normal 2treatmentperiods:1) (NGI)and WGwheatsourdough hyperglycaemic bread(predominately (HGI);maleand WGwheatflourbut postmenopausal alsoincludedother female;4370y. nonwheatgrains)2) whiterefinedwheat bread.Eachtreatment periodlasted6wks witha45wkwashout between.
Women6slicesWG bread;men7slices WGbread. Women4sliceswhite bread;men5slices whitebread.
Backgrounddietwas usualdiet. Interventionbreads werepackaged,frozen anddistributedin2wk suppliesthroughout study.Participants maintainedadaily diarytorecordhowand whenbreadwas consumed. Dietmeasuredusing3d recordsandanalyzed usingnutrition software.
Totalcholesterol;LDL cholesterol;HDL cholesterol;VLDL cholesterol; triglycerides; apolipoproteinA1; apolipoproteinB.
Abbreviations: d=day; g=gram(s); HDL=highdensity lipoprotein; kcal=kilocalories; LDL=lowdensity lipoprotein; N=sample size; RG=refined grain; UK=United Kingdom; USA=United States of America; VLDL=very lowdensity lipoprotein; WG=whole grain; wk(s)=weeks(s);y=year(s).
ProspectiveCohortStudies
Study Burr1982 [42] N,Cohort N=10,943 Population Intervention/Comparisons Exposure DietMethod Dailyvs.notdailywholemeal FFQ,validatedforwholemeal breadconsumption.7yfollow breadintake. up. Outcomes
Fraser1992 [43]
UK;maleand female;special interestinhealth foods. N=26,473; USA;maleand AdventistHealth female;>25yat Study. baseline(meanage 51yformenand 53yforwomen).
Jacobs2001 [44]
N=33,848;CVD Studyin Norwegian Countries.
Holmberg 2009[45]
N=1,752
IHDstandardizedmortalityratio, cerebrovasculardisease standardizedmortalityratio. Definitenonfatalmyocardial FFQquestionreadWhatone Wholegrainwheatbread typeofbreaddoyouusemost infarctionhazardratio,Definite consumption.9%reported ofthetime?withoptionsbeing fatalCHDHR,FatalCHDas consumingwhitebread,14% determinedbydeathcertificate consumedbothwhiteandWW white,100%WWorWG, sproutedwheatorwheatberry HR. bread,77%consumedWW andother(rye,crackedwheat, Adjustedfornondietaryrisk bread. factorsandconsumptionofother pumpernickel,soy,etc. 6yfollowup. FFQvalidatedforbreadintake foods. using24hrrecalls. Coronaryheartdiseasedeath Norway;healthy; WGbreadintakerangedfrom 66itemFFQ. maleandfemale; 0.050.60to2.255.40servings/d 4questionsaboutbreadintake, hazardratio,cardiovascular 3556yatbaseline. acrossquintiles. WGbreadscoreformedbased diseasedeathhazardratio. Adjustedforage,energyintake, Studycarriedoutduring1977 ontheanswers. 1983thenfollowedtoDec31, WGbreadscorewasvalidated. sex,currentsmoking,past smoking,physicalactivityduring 1994. leisure,physicalactivityduring work,customaryuseofcodliver oil,customaryuseofmulti vitamins,saturatedfatintake,SBP, TC,BMI. 15itemFFQ CHDdeathorhospitalizationodds RuralSweden; Themostcommontypeof riskratio. maleonly. breadconsumedwasasked Adjustedforage,BMI,LDL,SBP, aboutinonequestionwithfour physicalworkload,smoking,food alternatives(whitebread,rye choices(fish,dairyfat,cream, bread,WGryebreadand sandwichspread,milk,fruitand crisp/hardbreadthelatter vegetables). twowerechosentoindicate intakeofwholemealbread). 12yfollowup.
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Study Jensen2004 [46] N,Cohort Population Intervention/Comparisons Exposure DietMethod WWandWWflour,wholeoats FFQvalidatedforWGintake. WGintakeestimates: andwholeoatflour,whole cornmealandwholecornflour, fromallfoodswithgramsof WGperfoodcalculateddirectly brownriceandbrownrice flour,wholebarley,wholerye fromafoodcomposition database;51%WGcontent; andryeflour,bulgur, 25%WGcontent. buckwheat,popcorn, amaranth,andpsyllium. Addedwheatbran,cornbran, oatbran,ricebranandwheat germthatwereconsidered added. MeanintakeofWGranged from3.3g/dto49.6g/dacross quintiles. 14yfollowup. MedianWGintakeranged FFQ;WGintakeestimatedona from3.346.0g/dacross gramweightbasis(g/d). quartiles.18yfollowup. Outcomes Coronaryheartdiseasehazard ratio.Onemodeladjustedfor addedbranintake,addedgerm intake,age,energyintake, smoking,alcoholintake,physical activity,familyhistoryofMI,useof vitaminEsupplement,intakesof SFA,PUFAandTFA,fruit, vegetablesandfish. Anothermodeladditionally adjustedforIncludesdietaryfibre, folate,glycemicload,dietary vitaminB6,vitaminE, magnesium,andmanganese.
N=42,850;Health USA;healthy; Professionals maleonly;4075y FollowUpStudy. atbaseline.
Flint2009[47]
N=31,684;Health USA;healthy; Professionals maleonly;4075y FollowUpStudy. atbaseline.
Incidenthypertensionhazardratio. Adjustedforage,energy,family historyofCHD,familyhistoryof HT,smoking,alcohol,marital status,profession,height,fruitand vegetableintakes,sodiumintake, physicalactivity,multivitaminuse, andcholesterolscreening.
Abbreviations: BMI=body mass index; CVD=cardiovascular disease; CHD=coronary heart disease; d=day; FFQ=Food Frequency Questionnaire; g=gram; HR=hazard ratio; hr=hour; HT=hypertension; IHD=ischemic heart disease; LDL=lowdensity lipoprotein; N=sample size; PUFA=polyunsaturated fatty acids; RG=refined grain; SBP=systolic blood pressure; SFA=saturated fatty acids; TC=total cholesterol; TFA=trans fatty acids; UK=United Kingdom; USA=United States of America; WG=whole grain; WW=whole wheat; y=year(s).
6.Acknowledgements Melanie Weger, for developing the literature search strategy and executing the search. Edith Bennett, for verifying the accuracy of data extraction, conversion and imputationtables. 7.References [1]American Association of Cereal Chemists International, Press Release: AACC Members Agree on Definition of Whole Grain, [accessed on: 2012 Jan 19]. Availablefrom: http://www.aaccnet.org/news/pdfs/wgPR.pdf,(1999). [2]Food and Drug Administration, Health Claim Notification for Whole Grain Foods, [accessed on: 2012 Jun19].Availablefrom: http://www.fda.gov/Food/LabelingNutrition/LabelCl aims/FDAModernizationActFDAMAClaims/ucm073 639.htm,(1999). [3]Health Canada, Eating Well with Canadas Food Guide, [accessed on: 2012 Jan 19]. Available from: http://www.hcsc.gc.ca/fnan/foodguide aliment/order commander/eating_well_bien_mangereng.php, (2011). [4] J.W.Anderson,T.J.Hanna,X. Peng and R. J. Kryscio, Whole grain foods and heart disease risk. Journal of theAmericanCollege of Nutrition, vol. 19, no. 3 SUPPL, pp.291S299S,(2000).
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[103] A. Lammert, J. Kratzsch, J. Selhorst, P. M. Humpert, A.Bierhaus,R.Birck,K.KustererandH.P.Hammes, Clinical benefit of a short term dietary oatmeal intervention in patients with type 2 diabetes and severe insulin resistance: a pilot study. Experimental &ClinicalEndocrinology&Diabetes,vol.116,no.2,pp. 132134,(2008). [104] L. Qi, R. M. van Dam, S. Liu, M. Franz, C. Mantzoros and F. B. Hu, Wholegrain, bran, and cereal fiber intakes and markers of systemic inflammation in diabetic women. Diabetes Care, vol. 29,no.2,pp.207211,(2006). [105]E.B.Tsihlias,A.L.Gibbs,M.I.McBurneyandT.M. Wolever, Comparison of high and lowglycemic index breakfast cereals with monounsaturated fat in the longterm dietary management of type 2 diabetes. American Journal of Clinical Nutrition, vol. 72,no.2,pp.439449,(2000). [106] V. Vuksan, D. Whitham, J. L. Sievenpiper, A. L. Jenkins, A. L. Rogovik, R. P. Bazinet, E. Vidgen and A.Hanna,Supplementationofconventionaltherapy with the novel grain Salba (Salvia hispanica L.) improves major and emerging cardiovascular risk factors in type 2 diabetes: results of a randomized controlled trial. Diabetes Care, vol. 30, no. 11, pp. 28042810,(2007). [107] A. T. Erkkila, D. M. Herrington, D. Mozaffarian and A. H. Lichtenstein, Cereal fiber and wholegrain
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American Journal of ClinicalNutrition,vol.83,no.1,pp.124131,(2006). [114] H. W. Zhang, Y. H. Zhang, M. J. Lu, W. J. Tong and G. W. Cao, Comparison of hypertension, dyslipidaemia and hyperglycaemia between buckwheat seedconsuming and nonconsuming MongolianChinese populations in Inner Mongolia, China. Clinical & Experimental Pharmacology & Physiology,vol.34,no.9,pp.838844,(2007). [115] D. R. Jacobs Jr, L. F. Andersen and R. Blomhoff, Wholegrain consumption is associated with a reduced risk of noncardiovascular, noncancer death attributed to inflammatory diseases in the Iowa Womens Health Study. American Journal of Clinical Nutrition,vol.85,no.6,pp.16061614,(2007). [116] M. A. Pereira, D. R. Jacobs Jr, J. J. Pins, S. K. Raatz, M. D. Gross, J. L. Slavin and E. R. Seaquist,Effect of whole grains on insulin sensitivity in overweight hyperinsulinemic adults. American Journal of Clinical Nutrition,vol.75,no.5,pp.848855,(2002). [117] K. S. Juntunen, D. E. Laaksonen, K. S. Poutanen, L. K. Niskanen and H. M. Mykkanen, Highfiber rye bread and insulin secretion and sensitivity in healthy postmenopausal women. American Journal of Clinical Nutrition,vol.77,no.2,pp.385391,(2003). [118] D. L. Katz, H. Nawaz, J. Boukhalil, W. Chan, R. Ahmadi, V. Giannamore and P. M. Sarrel,Effects of oat and wheat cereals on endothelial responses. PreventiveMedicine,vol.33,no.5,pp.476484,(2001). [119] D. L. Katz, M. A. Evans, W. Chan, H. Nawaz, B. P. Comerford, M. L. Hoxley, V. Y. Njike and P. M. Sarrel, Oats, antioxidants and endothelial function in overweight,dyslipidemicadults.JournaloftheAmerican CollegeofNutrition,vol.23,no.5,pp.397403,(2004). [120] M. Lankinen, U. Schwab, M. Kolehmainen, J. Paananen, K. Poutanen, H. Mykkanen, T. Seppanen Laakso, H. Gylling, M. Uusitupa and M. Oresic, Whole grain products, fish and bilberries alter glucose and lipid metabolism in a randomized, controlledtrial:TheSysdimetStudy.PLoSONE,vol. 6(8),pp.e22646,(2011). [121] Booyens, V. M. de Waal and L. J. 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Evidence For A Whole Grains and Coronary Heart Disease Health Claim

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Evidence For A Whole Grains and Coronary Heart Disease Health Claim

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ARTICLE

International Food Risk Analysis Journal

Keywords Whole Grain, Health Claim, Coronary Heart Disease

Criterion Comparable source populations

Excludedbecausetitle didnotmeetinclusion criteria:439

Excludedbecause abstractdidnotmeet inclusioncriteria:184 Excludedbecausefull textdidnotmeet inclusioncriteria:83

Relevantpublications identifiedusinghand searching:7

Figure1.Flowdiagramofliteraturesearchandfilteringresults Refs. [4867] [6885] [8698] #

Interventiondidnotmeetthecriteriafor 21 wholegrain 18 Effectofwholegraincouldnotbeisolated fromothercomponentsoftheintervention

[115120] 6 Outcomesofinterestwerenotmeasured [121123] 3 [124,125] 2 [128] [129]

[126,127] 2 Interventionwaslessthan3weeks 1 Nonewdatawasreported 1 ArticlewaspublishedinGerman(resources werenotavailablefortranslation)

Int. food risk anal. j., 2013, Vol. 3, 1:2013

Theresultsofongoingtrialsmayshedfurtherlightonthe relationship between whole grains, particularly wheat

Randomized; parallel;single blinded;N=140 (of156).

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides.

Randomized; parallel;single blind(outcome assessors); N=104(of131)

Highsensitivity Creactive protein.

12 Int. food risk anal. j., 2013, Vol. 3, 1:2013

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; apolipoprotein A1; apolipoproteinB.

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.

Randomized; parallel; physician blinded;N=88.

USA;historyofmildor moderateessentialHT; undergoingtreatment forHTwithnomore than1drug;maleand female;3367y.

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides.

USA;Mildmoderate Randomized; hypercholesterolemic; parallel; doubleblinded; maleandfemale;2768y. N=43(of46).

Randomized; parallel;N=43 (of52).

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides.

Randomized; parallel;single blinded;N=206 (of233).

45gperdayrolled oats(1.5servings perday)

Totalcholesterol; LDLcholesterol; HDLcholesterol; VLDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides;C reactiveprotein; systolicblood pressure;diastolic bloodpressure.

14 Int. food risk anal. j., 2013, Vol. 3, 1:2013

Randomized; USA;normolipidemic; parallel;N=208. maleandfemale;3065y; recruitedfrom2work forceslocatedinthe Merchandisemartin Chicago.

Randomized; USA;normolipidemic; parallel;N=236. maleandfemale;3065y; recruitedfromNational BankofChicagostaff.

2treatmentarms:1) oatmeal(2ozor56g/)+ AHAfatmodifieddiet,2) control(AHAfat modifieddietalone). 4wkruninonAHAfat modifieddietfollowedby 4wksontreatment.

Totalcholesterol; LDLcholesterol; HDLcholesterol; triglycerides.

2treatmentarms:1) USA;serum TC>5.2mmol/L;maleand instantoatsinplaceof othercarbohydratefoods; female;2276y. 2)usualintake. Treatmentslasted8wks.

2packetsofinstant oatsperday(57.6g dryweight).

Totalcholesterol; LDLcholesterol; HDLcholesterol; VLDLcholesterol; triglycerides; systolicblood pressure;diastolic bloodpressure.

USA;moderate Randomized; parallel;N=127. hypercholesterolemia; postmenopausal;female only;mean66y.

4treatmentarms:1)oats andmilk;2)wheatand soy;3)oatsandsoy;4) wheatandmilk. Treatmentlasted6wks followinga3wk runin.

2servings/dof cookedoatmealor RTEoatbran cereal(provided byQuakerOats).

Totalcholesterol; LDLcholesterol; HDLcholesterol.

Andersson2007 Randomized; [10] crossover;N=30(of 34).

Randomized; crossover;double blinded;N=31(of 32).

UK;healthy;men andwomen;20 42y.

Totalcholesterol;HDL cholesterol; triglycerides.

USA;healthy; universitystudents; maleonly.

Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides.

Italy;healthy;male andfemale;mean 54.5y.

Totalcholesterol;LDL cholesterol;HDL cholesterol;VLDL cholesterol; triglycerides; apolipoproteinA1; apolipoproteinB.

Leinonen2000; Turpeinen2000 [20,40]

Randomized; crossover;N=40(of 43).

Finland;healthy withslightly elevated cholesterol;male andfemale;age rangenot provided.

Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides.

Japan;healthy; universitystudents; femaleonly;mean 20.4y.

Totalcholesterol;LDL cholesterol;HDL cholesterol; triglycerides.

16 Int. food risk anal. j., 2013, Vol. 3, 1:2013

Tucker2010[19] Randomized; crossover;N=27(of 28).

Women6slicesWG bread;men7slices WGbread. Women4sliceswhite bread;men5slices whitebread.

Totalcholesterol;LDL cholesterol;HDL cholesterol;VLDL cholesterol; triglycerides; apolipoproteinA1; apolipoproteinB.

N=33,848;CVD Studyin Norwegian Countries.

N=42,850;Health USA;healthy; Professionals maleonly;4075y FollowUpStudy. atbaseline.