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7232019 journal 2 newpdf

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RESEARCH

1

OPEN ACCESS

983089Department o ClinicalEpidemiology and BiostatisticsMcMaster University HamiltonON Canada983090Chanchlani Research CentreMcMaster University HamiltonON Canada983091Department o NutritionalSciences University o TorontoToronto ON Canada983092Clinical Nutrition and Risk FactorModification Center St MichaelrsquosHospital Toronto ON Canada983093Population Health ResearchInstitute Hamilton HealthSciences Hamilton ON Canada983094Scotiabank Health SciencesLibrary St Michaelrsquos HospitalToronto ON Canada983095Hospital Library and ArchivesHospital or Sick ChildrenToronto ON Canada983096Department o MedicineMcMaster University HamiltonON Canada

Correspondence to S AnandMcMaster University 983089983090983096983088 MainSt W MDCL-983091983090983088983092 Hamilton ONL983096N 983091Z983093 Canadaanandsmcmasterca

Additional material is publishedonline only To view please visit

the journal online (ht tpdxdoiorg983089983088983089983089983091983094bmjh983091983097983095983096)

Cite this as BMJ 983090983088983089983093983091983093983089h983091983097983095983096doi 983089983088983089983089983091983094bmjh983091983097983095983096

Accepted 983089983093 July 983090983088983089983093

Intake of saturated and trans unsaturated fatty acids and risk of

all cause mortality cardiovascular disease and type 2 diabetes

systematic review and meta-analysis of observational studies

Russell J de Souza983089 983090 983091 983092 Andrew Mente983089 983090 983093 Adriana Maroleanu983090 Adrian I Cozma983091 983092 Vanessa Ha983089 983091 983092 Teruko Kishibe983094 Elizabeth Uleryk983095 Patrick Budylowski983092 Holger Schuumlnemann983089 983096 Joseph Beyene983089 983090 Sonia S Anand983089 983090 983093 983096

ABSTRACT

OBJECTIVE

To systematically review associations between intake

of saturated fat and trans unsaturated fat and all cause

mortality cardiovascular disease (CVD) and associated

mortality coronary heart disease (CHD) and associated

mortality ischemic stroke and type 983090 diabetes

DESIGN

Systematic review and meta-analysisDATA SOURCES

Medline Embase Cochrane Central Registry of

Controlled Trials Evidence-Based Medicine Reviews

and CINAHL from inception to 983089 May 983090983088983089983093

supplemented by bibliographies of retrieved articles

and previous reviews

ELIGIBILITY CRITERIA FOR SELECTING STUDIES

Observational studies reporting associations of

saturated fat andor trans unsaturated fat (total

industrially manufactured or from ruminant animals)

with all cause mortality CHDCVD mortality total CHD

ischemic stroke or type 983090 diabetes

DATA EXTRACTION AND SYNTHESISTwo reviewers independently extracted data and

assessed study risks of bias Multivariable relative

risks were pooled Heterogeneity was assessed and

quantified Potential publication bias was assessed

and subgroup analyses were undertaken The GRADE

approach was used to evaluate quality of evidence and

certainty of conclusions

RESULTSFor saturated fat three to 983089983090 prospective cohort studies

for each association were pooled (five to 983089983095

comparisons with 983097983088 983093983088983089-983091983091983097 983088983097983088 participants)

Saturated fat intake was not associated with all cause

mortality (relative risk 983088983097983097 983097983093 confidence interval

983088983097983089 to 983089983088983097) CVD mortality (983088983097983095 983088983096983092 to 983089983089983090) total

CHD (983089983088983094 983088983097983093 to 983089983089983095) ischemic stroke (983089983088983090 983088983097983088 to

983089983089983093) or type 983090 diabetes (983088983097983093 983088983096983096 to 983089983088983091) There was

no convincing lack of association between saturatedfat and CHD mortality (983089983089983093 983088983097983095 to 983089983091983094 P=983088983089983088) For

trans fats one to six prospective cohort studies for

each association were pooled (two to seven

comparisons with 983089983090 983097983092983090-983090983091983088 983089983091983093 participants) Total

trans fat intake was associated with all cause mortality

(983089983091983092 983089983089983094 to 983089983093983094) CHD mortality (983089983090983096 983089983088983097 to 983089983093983088)

and total CHD (983089983090983089 983089983089983088 to 983089983091983091) but not ischemic

stroke (983089983088983095 983088983096983096 to 983089983090983096) or type 983090 diabetes (983089983089983088 983088983097983093

to 983089983090983095) Industrial but not ruminant trans fats were

associated with CHD mortality (983089983089983096 (983089983088983092 to 983089983091983091) v 983089983088983089

(983088983095983089 to 983089983092983091)) and CHD (983089983092983090 (983089983088983093 to 983089983097983090) v 983088983097983091 (983088983095983091

to 983089983089983096)) Ruminant trans-palmitoleic acid was inversely

associated with type 983090 diabetes (983088983093983096 983088983092983094 to 983088983095983092)The certainty of associations between saturated fat

and all outcomes was ldquovery lowrdquo The certainty of

associations of trans fat with CHD outcomes was

ldquomoderaterdquo and ldquovery lowrdquo to ldquolowrdquo for other

associations

CONCLUSIONS

Saturated fats are not associated with all cause

mortality CVD CHD ischemic stroke or type 983090

diabetes but the evidence is heterogeneous with

methodological limitations Trans fats are associated

with all cause mortality total CHD and CHD mortality

probably because of higher levels of intake of

industrial trans fats than ruminant trans fats Dietary

guidelines must carefully consider the health effects of

recommendations for alternative macronutrients to

replace trans fats and saturated fats

Introduction

Recent high profile opinion pieces informed by system-

atic reviews of randomized trials983089 983090 and prospective

cohort studies983089 983091 have called for a re-evaluation of

dietary guidelines for intake and a re-appraisal of the

effects of saturated fat on health during this time pub-

lic health efforts to remove trans fats from the food sup-

ply in several countries have intensified

Saturated fats contribute about 983089983088 of energy to theNorth American diet983092 983093 The main sources of saturated

WHAT IS ALREADY KNOWN ON THIS TOPIC

Contrary to prevailing dietary advice authors of a recent systematic review and

meta-analyses claim that there is no excess cardiovascular risk associated with

intake of saturated fat and the US has recently taken policy action to remove

partially hydrogenated vegetable oils from its food supply

Population health guidelines require a careful review and assessment of the

evidence of harms of these nutrients with a focus on replacement nutrients

WHAT THIS STUDY ADDS

This study reviewed prospective observational studies and assessed the certainty

of the associations with GRADE methods

There was no association between saturated fats and health outcomes in studies

where saturated fat generally replaced refined carbohydrates but there was a

positive association between total trans fatty acids and health outcomes

Dietary guidelines for saturated and trans fatty acids must carefully consider theeffect of replacement nutrients


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RESEARCH

2

fatty acids in the food supply are animal products such

as butter cowsrsquo milk meat salmon and egg yolks and

some plant products such as chocolate and cocoa butter

coconut and palm kernel oils Previous meta-analyses

of prospective cohort studies reported pooled relative

risk estimates comparing extremes of intake of saturated

fat of 983089983088983095 (983097983093 confidence interval 983088983097983094 to 983089983089983097 P=983088983090983090)

for coronary heart disease (CHD) 983088983096983089 (983088983094983090 to 983089983088983093

P=983088983089983089) for stroke and 983089983088983088 (983088983096983097 to 983089983089983089 P=983088983097983093) for car-

diovascular disease (CVD)983094 Intervention trials have

shown modest cardiovascular benefits of reducing

intake of saturated fat while increasing intake of polyun-

saturated fat983095 but most trials lasted only up to two years

and examined surrogate outcomes A meta-analysis of

randomized trials suggested a 983089983095 reduction in risk of

CVD in studies that reduced saturated fat intake from

about 983089983095 to about 983097 of energy (983088983096983091 983088983095983090 to 983088983097983094)983096

Trans fats contribute about 983089-983090 of energy in the

North American diet983097-983089983089 and are produced industrially

through partial hydrogenation of liquid plant oils in the

presence of a metal catalyst vacuum and high heat or

can occur naturally in meat and dairy products where

ruminant animals biohydrogenate unsaturated fatty

acids via bacterial enzymes The major industrially

produced trans fatty acids in the food supply are elaidic

acid isomers and the major ruminant derived trans

fatty acid is vaccenic acid both share the characteristic

of having at least one double bond in the ldquotrans-rdquo rather

than ldquocis-rdquo configuration A prior meta-analysis

reported pooled relative risk estimates of CHD of 983089983090983090

(983097983093 confidence interval 983089983088983096 to 983089983091983096 P=983088983088983088983090) for

extremes of total intake of trans fats 983089983091983088 (983088983096983088 to 983090983089983092

P=983088983090983097) for intake of industrially produced trans fats

and 983088983097983091 (983088983095983092 to 983089983089983096 P=983088983093983094) for intake of ruminantderived trans fats983089983090 suggesting that industrially pro-

duced trans fats might increase the risk of CHD though

this could also reflect the low levels of ruminant derived

trans fats compared with the higher doses of industri-

ally produced trans fats typically consumed in studies

and available in the food supply983089983091

Dietary guidelines recommend that saturated fats

should be limited to lt983089983088 (983093-983094 for those who would

benefit from lowering of LDL cholesterol) and trans fats

to lt983089 of energy or as low as possible983089983092-983089983097 primarily to

reduce risk of ischemic heart disease and stroke To

clarify controversies surrounding guidelines for satu-

rated and trans fats for adults we have extended andupdated previous work to synthesize prospective asso-

ciations between these fats and all cause mortality and

type 983090 diabetes (which have not been previously synthe-

sized) separate estimates for risks of cardiovascular

morbidity and mortality and assess the confidence in

the observational evidence using the Grading of Recom-

mendations Assessment Development and Evaluation

(GRADE) approach983090983088-983090983090

Methods

This review was conducted in accordance with the

WHOrsquos guideline development process983090983091 based on the

Cochrane Collaboration approach983090983092 and reportedaccording to the MOOSE checklist983090983093

Data sources

We conducted independent searches for relevant

observational studies assessing the association

between saturated andor trans fats and health out-

comes up to 983089 May 983090983088983089983093 (appendix 983089 gives full details)

This included searching Medline (from 983089983097983092983094) Embase

(from 983089983097983095983092) Cochrane Central Registry of Controlled

Trials (from 983089983097983097983094) Evidence Based Medicine Reviews

(from 983089983097983097983094) and CINAHL (from 983089983097983096983091) Reference lists of

retrieved articles and previous systematic and narra-

tive reviews983089 983089983090 983090983094-983090983097 were hand searched There were no

language restrictions

Study selection

Eligible studies included any observational study con-

ducted in humans (such as prospective cohort

case-control nested case-control or case-cohort

design) that reported a measure of association (such as

hazard ratios or incident rate ratios for prospective

studies or odds ratios for retrospective studies)

between intakes of saturated or trans fat measured by

self report or a biomarker and all cause mortality coro-

nary heart disease stroke or type 983090 diabetes measured

by self report andor confirmed by medical records or

registry linkage One reviewer assessed titles and

abstracts of all studies identified through electronic

searches Potentially eligible studies were reviewed

independently by a second reviewer with discrepan-

cies resolved by discussion and when necessary a

senior author was consulted to reach consensus

Data extraction

Pairs of authors independently extracted details of the

study design country of conduct exposure and out-come assessment participant characteristics and sta-

tistical analyses including adjustment for confounders

from included studies using pretested instruments (see

appendix 983089) with discrepancies resolved by discussion

Authors were contacted for additional data when nec-

essary We used Plot Digitizer (httpplotdigitizer

sourceforgenet) to extract numerical estimates from

graphs

Assessment of trans fats exposure methods

To assess the accuracy of measures of trans fats in stud-

ies that did not directly measure concentrations in

blood or adipose tissues we assessed the potential formisclassification The lowest risk of misclassification

was for those studies that used a food frequency ques-

tionnaire validated against multiple day prospective

diet records or 983090983092 hour recalls directly measured adi-

pose tissue trans fatty acids in a subset of the popula-

tion and analyzed dietary intake with an updated

database of foods A study was rated as at low risk of

misclassification if it accomplished all three moderate

risk of misclassification) if it accomplished two of three

high risk of misclassification if it accomplished one of

three or at very high risk of misclassification if it did

not accomplish any For assessment of ruminant trans

fats the most common approach was to use the knownnutrient composition from food tables for dairy and



RESEARCH

3

meat products to estimate ruminant trans fats and pos-

sibly supplemented by direct measurement with gas

chromatography (see eTable 983089 in appendix 983090)

Study risk of bias

We used the Newcastle-Ottawa scale983091983088 to assess the risk

of bias of the included studies on the basis of selection

of study groups comparability of groups and ascer-

tainment of exposure(s) or outcome(s)

Grading of recommendations assessment

development and evaluation (GRADE)

The GRADE approach was used to assess the confi-

dence in the effect estimates derived from the body of

evidence (quality of evidence) by outcome and pro-

duce evidence profiles983090983088-983090983090 We limited the presenta-

tions of results in the main text to the synthesis of

prospective cohort studies as these are considered the

highest level of evidence for observational studies and

thus were used for the GRADE assessments of confi-

dence Appendix 983091 provides full details of designs that

did not directly inform GRADE (that is retrospective

case-control studies and other studies not amenable

to quantitative synthesis) All investigators discussed

and reviewed evidence summaries and GRADE assess-

ments which were reviewed with the WHO Nutrition

Guidance Expert Advisory Group (NUGAG) subgroup

on diet and health as part of WHOrsquos guideline develop-

ment process Confidence in the estimate of each asso-

ciation was categorized into four levels from very low

to high

Data synthesis and analysis

Statistical synthesis o effect estimatesThe principal association measures were the risk ratios

between extreme levels of intake (highest v lowest) for

prospective studies and the odds ratio between extreme

levels of exposure (highest v lowest) for retrospective

studies For each study we calculated most adjusted

(that is the multivariable association measure with the

highest number of covariates) and least adjusted (that

is the multivariable association measure with the few-

est number of covariates) estimates and corresponding

983097983093 confidence intervals for each outcome We

extracted both estimates to assess whether relevant

confounders (such as smoking age) and intermediate

variables (such as LDL cholesterol blood pressure)were captured in the statistical models Analyses that

adjust for potential confounders and intermediate vari-

ables will generally represent conservative estimates of

the strength of the associations and analyses that do

not adjust for these will generally reflect the effect not

only of exposure to fat but of other determinants of the

health outcomes We present both models to assess the

impact of these variables on the reported association

When at least two studies provided data we performed

a DerSimonian and Laird random effects meta-analysis

which yields conservative confidence intervals around

relative risks in the presence of heterogeneity983091983089 When

three or fewer studies were combined we also consid-ered fixed effect estimates

Heterogeneity

Heterogeneity was determined with Cochranrsquos Q test

(significant at Plt983088983089983088) quantified with the I983090 statistic

(range from 983088-983089983088983088)983091983090 and used to assess inconsis-

tency as part of the GRADE assessment of evidence

quality If ge983089983088 studies were available983091983091 983091983092 and heteroge-

neity was substantial (I983090gt983094983088 or PQlt983088983089983088)983091983090 we used

meta-regression to explore heterogeneity by baseline

year of study continent of conduct length of follow-up

median age of participants proportion of smokers in

the sample amount of saturated fat in reference cate-

gory mean saturated or trans fat intake of the popula-

tion sex α-linoleic acid total polyunsaturated fat

adjustment for total energy method and frequency of

exposure assessment risk of bias score and adjust-

ment for lipids or blood pressure (that is causal inter-

mediates)

Sensitivity

We carried out four a priori sensitivity analyses We

removed each single study from the meta-analyses and

recalculated the summary association (the ldquoleave one

outrdquo approach)983091983093 removed studies with scores lt983095 on

the Newcastle-Ottawa scale and recalculated the

pooled association included unpublished data on

trans fats and CHD mortality (P Knekt personal com-

munication) and removed risk estimates imputed

because of incomplete reporting A study whose

removal either pushed the significance level of the

overall association from lt983088983088983093 to ge983088983088983093 (or vice versa)

or altered the nominal effect size by 983089983088 or more was

considered an influential outlier At the request of the

WHOrsquos Nutrition Guidelines Advisory Committee (983089983088

July 983090983088983089983093) we performed two post hoc sensitivity analyses limited to comparisons in which the estimated

dietary intake of trans fatty acids was lt983089 of energy in

the referent group and ge983089 of energy in the highest

exposure category

Publication bias

If ge983089983088 studies were available983091983094 we explored the possi-

bility of publication bias by inspecting funnel plots and

conducting Eggerrsquos and Beggrsquos tests (each significant at

Plt983088983089983088) If publication bias was suspected results are

shown without imputation and with ldquomissingrdquo studies

imputed with Duval and Tweediersquos trim and fill

method983091983095

Sofware

Primary summary analyses were carried out separately

for each outcome with Review Manager version 983093983090

(Nordic Cochrane Center Cochrane Collaboration

Copenhagen) Meta-regression and sensitivity analyses

were undertaken with Stata version 983089983090983089 (StataCorp

College Station TX)

Patient involvement

No patients were involved in setting the research ques-

tion or the outcome measures nor were they involved in

the design and implementation of the study There areno plans to involve patients in dissemination



RESEARCH

4

Results

Saturated fats and health outcomes

Literature low

We identified 983090983088 983092983089983091 potentially eligible articles After

full text review 983092983089 primary reports of associations

between saturated fats and health outcomes in prospec-

tive cohort studies (published between 983089983097983096983089 and 983090983088983089983092)

provided 983094983095 data points that contributed to the quanti-

tative synthesis Cohorts were enrolled from the United

States (983089983095 studies 983090983093 data points) the United Kingdom

(four studies six data points) Japan (four studies nine

data points) Sweden (four studies seven data points)

Israel (one study four data points) Finland (three stud-

ies four data points) Denmark (one study four data

points) Canada (one study two data points) China

(one study one data point) Greece (one study one data

point) and Australia (one study one data point) (fig 983089

appendix 983090 provides full study characteristics in

eTables 983090-983092 and scores on the Newcastle-Ottawa scale in

eTables 983093-983094) The Seven Countriesrsquo study with cohorts

enrolled from the US Finland the Netherlands Italy

the former Yugoslavia (Serbia and Croatia) Greece and

Japan is discussed separately as its design was not

appropriate for pooling Meta-regression analyses

summaries of results for case-control studies nested

case-control studies dose-responsesubstitution rela-

tions and studies that did not directly bear on the

GRADE evidence table are presented in appendix 983091 and

eTables 983095-983089983088 in appendix 983090

All cause mortality

Six prospective investigations examined the association

between intake of saturated fats and all cause mortality

The Seven Countries Study983091983096 (983089983090 983095983094983091 men) which couldnot be included in the quantitative synthesis because of

an incompatible association measure reported large

differences in intake across countries from 983091983097

(Tanushimaru Japan) to 983090983090983095 (East Finland) Over 983090983093

years of follow-up 983093983097983095983091 (983092983095) deaths were reported In

a multivariable regression model a 983093 increase in

energy from saturated fats was associated with a 983092983095

increase in age adjusted all cause mortality rate For

saturated fats and all cause mortality983091983097-983092983091 the summary

most adjusted multivariable risk ratio was 983088983097983097 (983097983093

confidence interval 983088983097983089 to 983089983088983097 P=983088983097983089 I983090=983091983091

Phet=983088983089983095) (fig 983090 appendix 983092 eFigure 983089) Subgroup analy-

ses or publication bias tests were not performed (lt983089983088

studies)

Fatal and total CHD and CVD

For saturated fats and CHD mortality983092983088 983092983089 983092983092-983093983090 the sum-

mary most adjusted multivariable risk ratio was 983089983089983093

(983097983093 confidence interval 983088983097983095 to 983089983091983094 P=983088983089983088 I983090=983095983088

Phetlt983088983088983088983089) (fig 983090 appendix 983092 eFigure 983091) The summary

least adjusted risk ratio was 983089983090983088 (983089983088983090 to 983089983092983089 P=983088983088983090

I983090=983095983092 Phetlt983088983088983088983089) (appendix 983092 eFigure 983092) As risk esti-

mates of four comparisons could not be directly

extracted983092983095 983092983096 983093983088 we used the estimates reported in a pre-

vious meta-analysis983091 Removal of these four compari-

sons resulted in a summary risk ratio of 983089983090983094 (983088983097983096 to

983089983094983090 P=983088983088983095 I983090=983095983092 Phetlt983088983088983088983089) Removal of the age

groupgt983094983088 in the study by Goldbourt and colleagues983092983095 or

the study by Pietinen and colleagues983092983097 shifted the over-

all estimate to 983089983090983088 (983089983088983089 to 983089983092983090 P=983088983088983092 I983090=983094983096

Phetlt983088983088983088983089) suggesting these two studies were influen-

tial outliers For CVD mortality the summary most

adjusted multivariable risk ratio (five compari-

sons)983091983097 983092983091 983093983091 was 983088983097983095 (983088983096983092 to 983089983089983090 P=983088983094983097 I983090=983089983097

Phet=983088983090983097) (fig 983090 appendix 983092 eFigure 983091)

For saturated fats and total CHD983092983092 983092983097-983094983090 the summary


confidence interval 983088983097983093 to 983089983089983095 P=983088983090983097 I983090=983092983095Phet=983088983088983090) (fig 983090 appendix 983092 eFigure 983093) As risk esti-

mates from three comparisons983093983092 983093983096 could not be

extracted we used estimates reported in a previous

meta-analysis983091 Removal of these three comparisons

resulted in a summary risk ratio of 983089983088983096 (983088983097983095 to 983089983090983088

P=983088983089983096 I983090=983093983089 Phet=983088983088983089) The summary least adjusted

relative risk was 983089983089983090 (983089983088983088 to 983089983090983094 P=983088983088983093 I983090=983094983091

Phetlt983088983088983088983089) (appendix 983092 eFigure 983094) No study was an

influential outlier

For saturated fats and ischemic stroke983092983095 983093983091 983093983095 983093983096 983094983089 983094983091-983095983088

the summary most adjusted multivariable risk ratio was

983089983088983090 (983097983093 confidence interval 983088983097983088 to 983089983089983093 P=983088983095983097

I983090=983093983097 Phet=983088983088983088983090) (fig 983090 appendix 983092 eFigure 983095) As riskestimates for four comparisons983092983095 983093983092 983093983096 could not be


meta-analysis983091 Removal of these four comparisons


P=983088983094983096 I983090=983094983094 Phetlt983088983088983088983089) The summary least

adjusted risk ratio was 983089983088983091 (983088983097983089 to 983089983089983094 P=983088983094983093 I983090=983094983094


influential outlier

Type 983090 diabetes

For saturated fats and type 983090 diabetes983095983089-983095983095 983095983096 the sum-


(983097983093 confidence interval 983088983096983096 to 983089983088983091 P=983088983090983088 I983090=983088Phet=983088983094983089) (fig 983090 appendix 983092 eFigure 983097) The summary

Observational evidence that did not directly inform GRADE evidence synthesis (n=) Nested case-control or case-cohort studies (n=) Prospective cohort studies (n=) Case-control studies (n=) Pooling study (n=)

Prospective cohorts used in GRADE quantitative evidence synthesis (n=) Prospective cohort studies (n= data points)

Records identified through database search (n= )

Full text articles assessed for eligibility (n=)

Included publications (n=)

κ=

Excluded on title and abstract review (including duplicates) (n= )

Excluded (n=)

Did not assess saturated fat exposure (n=) Did not measure outcome(s) of interest (n=) Duplicate data from previous publication (n=) Did not present a measure of association (n=) Inappropriate study design (abstracts cross sectional studies reviews) (n=)

Fig 983089 | PRISMA summary of evidence search and selection for saturated fat and healthoutcomes (up to 983089 May 983090983088983089983093)



RESEARCH

5


I983090=983097983089 Phetlt983088983088983088983089) (appendix 983092 eFigure 983089983088) No study

was an influential outlier

Trans fats and health outcomes

Literature low

We identified 983089983096 983096983091983093 potentially eligible articles (fig 983091 )

After full text review 983090983088 primary reports of associa-

tions between total trans fats and the health outcomes

in prospective cohort studies (published between 983089983097983097983094

and 983090983088983089983093) provided 983090983096 data points that contributed to

the quantitative synthesis Cohorts were enrolled from

the US (983089983092 studies 983089983097 data points) Finland (four stud-

ies six data points) China (one study one data point)

and the Netherlands (one study two data points)

One systematic review contributed one data point

from a previously unpublished prospective cohort

study983089983090 and one author provided updated unpub-

lished data from the Finnish Mobile Health clinics

(P Knekt personal communication) Four primary

reports of associations between industrial trans fats

and the health outcomes (published between 983089983097983097983091 and

983090983088983089983091) provided four data points that contributed to the

quantitative synthesis Cohorts were enrolled from the

US (one study one data point) Finland (one study

one data point) the Netherlands (one study one data

point) and Norway (one study one data point) Nine

primary reports of associations between ruminant

trans fats and the health outcomes (published

between 983089983097983097983091 and 983090983088983089983093) provided 983089983091 data points that

contributed to the quantitative synthesis Cohorts

came from the US (five studies five data points) Nor-

way (one study four data points) Finland (one studyone data point) Denmark (one study two data points)

and the Netherlands (one study one data point)

Appendix 983090 shows full study characteristics in eTable

983089983089 for prospective cohort studies eTable 983089983090 for retro-

spective case-control studies eTable 983089983091 for nested

case-control or case-cohort studies and eTables 983093 and

983094 for scores on the Newcastle-Ottawa scale Summaries

of results for case-control studies nested case-control

studies dose-responsesubstitution relations and

studies that did not inform the GRADE evidence table

are presented in appendix 983091 We use the term ldquototal

trans fatsrdquo to refer to the estimate of exposure to all

trans fats whether industrially produced or ruminantderived and present specific associations of industri-

ally produced and ruminant derived trans fats with

health outcomes separately when available The spec-

ificity of trans fat measurement provided by each study

is presented in appendix 983090 eTables 983089 983089983089 983089983090 and 983089983091

All cause mortality

The pooled random effects most adjusted multivariable

risk ratio of high versus low total intake of trans unsatu-

rated fatty acid estimated from two published reports983092983090 983095983097

(two comparisons) including 983090983089983092983089 deaths in 983090983088 983091983092983094

individuals was 983089983092983090 (983097983093 confidence interval 983089983088983092 to 983089983097983092

P=983088983088983091) with some evidence of heterogeneity betweenstudies (I983090=983095983088 Phet=983088983088983095) appendix 983092 eFigure 983089983089)

All cause mortality

CHD mortality

CVD mortality

CHD total

Ischemic strokeType diabetes

( to )

( to )

( to )

( to )

( to ) ( to )

Outcome

Saturated fatsprotective

Saturated fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

lt

Phet

P

No of studiescomparisons

No of eventsparticipants

Fig 983090 | Summary most adjusted relative risks for saturated fat intake and all cause mortality CHD mortality CVD mortalitytotal CHD ischemic stroke and type 983090 diabetes All effect estimates are from random effects analyses P value is for Z testof no overall association between exposure and outcome Phet is for test of no differences in association measure amongstudies I983090 is proportion of total variation in study estimates from heterogeneity rather than sampling error

Observational evidence that did not directly inform GRADE evidence synthesis (n=) Nested case-control or case-cohort studies (n=) Case-control studies (n=)

Prospective cohorts used in GRADE quantitative evidence synthesis (n=) Total trans fats Prospective cohort studies (n= data points) Industrial trans fats Prospective cohort studies (n= data points) Ruminant trans fats Prospective cohort studies (n= data points)




κ=


Previously unpublished data added during manual search (n=)

Excluded (n=) Did not assess trans fat exposure (n=) Cross sectional studies (n=) Did not allow isolation of trans fat effect (n=) Did not present a measure of association (n=) Did not measure outcome(s) of interest (n=) Could not obtain original article (n=)

Other (editorials commentaries reviews case series duplicate publications abstracts only (n=)

Fig 983091 | PRISMA summary of evidence search and selection for trans unsaturated fat andhealth outcomes (up to 983089 May 983090983088983089983093)



RESEARCH

6

Because of the small number of studies and the lower

power to estimate τ for random effects analysis we also

performed a fixed effect meta-analysis which results in

a pooled association of 983089983091983092 (983089983089983094 to 983089983093983094 Plt983088983088983088983089

I983090=983095983088 Phet=983088983088983095 (fig 983092 appendix 983092 eFigure 983089983090)

The least adjusted estimate was 983089983096983088 (983089983093983095 to 983090983088983095

Plt983088983088983088983089 I983090=983088 Phet=983088983095983089) presented in appendix 983092

eFigures 983089983091 and 983089983092


For total trans fats and CHD mortality983092983092 983092983097 983093983089 983093983090 983096983088 the

summary most adjusted multivariable risk ratio was


I983090=983088 Phet=983088983094983094 fig 983092 appendix 983092 eFigure 983089983093 the least

adjusted figure is shown in appendix 983092 eFigure 983089983094)

Removal of the study by Pietinen and colleagues983092983097

resulted in a relative risk of 983089983090983088 (983088983097983094 to 983089983092983096 P=983088983089983088

I983090=983088 Phet=983088983094983093) Addition of three unpublished

comparisons from two cohorts including updated data

from one investigator (P Knekt personal communi-

cation)983089983090 weakened the estimate (983089983090983090 983089983088983095 to 983089983091983096

P=983088983088983088983090 I983090=983088 Phet=983088983092983094) (appendix 983092 eFigure 983089983095

least adjusted eFigure 983089983096)

For total trans fats and total CHD983092983092 983092983097 983093983089 983093983093 983093983097 983096983088 the sum-


(983089983089983088 to 983089983091983091 Plt983088983088983088983089 I983090=983088 Phet=983088983092983091 fig 983092 appendix 983090

eFigure 983089983097 least adjusted in eFigure 983090983088) We included

data from one randomized trial983093983093 as the report allowed a

comparison of usual (about 983090983093) versus low (lt983089983089)

intake of trans fat at one year Its removal did not alter

the estimate of association (983089983090983090 983089983088983096 to 983089983091983096 P=983088983088983088983090

I983090=983089983093 Phet=983088983091983090)

For total trans fats and ischemic stroke983094983093 983094983097 983096983089 the sum-


(983097983093 confidence interval 983088983096983096 to 983089983090983096 P=983088983093983088) (fig 983092

appendix 983092 eFigure 983090983089 and least adjusted in eFigure 983090983090)

There was however considerable heterogeneity

between studies (I983090=983094983095 Phet=983088983088983091)


For total trans fats and type 983090 diabetes983095983090-983095983094 983096983090 the sum-



Phet=983088983088983089) (fig 983092 appendix 983092 eFigure 983090983091) Removal of one

moderate quality study983095983090 did not alter the estimate (983089983089983092

983088983097983096 to 983089983091983090 P=983088983089983088 I983090=983094983091 Phet=983088983088983091) Pooling of min-

imally adjusted associations yielded a 983090983096 increased

risk of type 983090 diabetes (983089983090983096 983089983088983093 to 983089983093983093 P=983088983088983089 I983090=983096983095

Phetlt983088983088983088983089 appendix 983092 eFigure 983090983092)

Industrially produced trans fats

The Norwegian Countries prospective cohort study983096983091

(983095983089 983092983094983092 participants 983090983093983096 year follow-up) found no

association between industrially produced trans fats

from partially hydrogenated vegetable (PHVO) or fish

oils (PHFO) and all cause mortality (983089983089 983097983096983088 deaths) The

multivariable adjusted risk ratio was 983088983097983094 (983097983093 confi-

dence interval 983088983096983096 to 983089983088983093 P=983088983089983089 for trend) for high

(ge983089983094983093 of energy) versus low (lt983088983089983093 of energy) PHVO

and 983089983088983088 (983088983097983090 to 983089983089983088 P=983088983089983089 for trend) for high (ge983090983091983093

of energy) versus low (lt983088983096983093 of energy) PHFO (fig 983092

shows the pooled risk ratio of PHVO and PHFO I 983090=983088

Phet=983088983093983090) Two studies showed that industrially pro-

duced trans fats are associated with CHD mortality

Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Industrial trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome

Trans fatsprotective

Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P



Fig 983092 | Summary most adjusted relative risks of total trans fat industrial trans fat and ruminant trans fat and all causemortality CHD mortality total CHD ischemic stroke and type 983090 diabetes For total trans fats effect estimate for is fixedeffect analysis all others random effects analyses P value is for Z test of no overall association between exposure and

outcome Phet is for test of no differences in association measure among studies I983090 is proportion of total variation in studyestimates from heterogeneity rather than sampling error



RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092

appendix 983092 eFigures 983090983093-983090983096)983092983097 983096983091 Two other studies

showed that industrially produced trans fats are associ-

ated with total CHD (983089983092983090 983089983088983093 to 983089983097983090 P=983088983088983090 I983090=983091983092

Phet=983088983090983090)983096983088 983096983092 (fig 983092 appendix 983092 eFigures 983090983097-983091983090) We did

not find any prospective cohort studies of total intake of

industrially produced trans fats and risk of ischemic

stroke or type 983090 diabetes

Ruminant derived trans fats

In the Norwegian Countries prospective cohort study983096983091

the multivariable adjusted risk ratio for all cause mor-

tality was 983089983088983092 (983097983093 confidence interval 983088983097983090 to 983089983089983096

P=983088983093983089 I983090=983092 Phet=983088983091983089) for the highest versus lowest

categories of ruminant derived trans fats (fig 983092 appen-

dix 983092 eFigure 983091983091-983091983092) Two studies found no association

between ruminant derived trans fats and CHD mortal-

ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092

appendix 983092 eFigure 983091983093-983091983094) Three studies found no asso-

ciation between ruminant derived trans fats and total

CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)

(fig 983092 appendix 983092 eFigure 983091983095-983092983088) Removal of the study

by Jakobsen and colleagues983096983093 (in men) resulted in a

pooled risk ratio of 983088983096983091 (983088983093983097 to 983089983089983093 P=983088983090983094 I983090=983090983096

Phet=983088983090983093) which met our definition of an ldquoinfluential

outlierrdquo Five studies found an inverse association

between 983089983094983089 n-983095 trans-palmitoleic acid principally

derived from dairy and type 983090 diabetes983096983090 983096983094-983096983097 (983088983093983096 983088983092983094

to 983088983095983092 Plt983088983088983088983089 I983090=983091983088 Phet=983088983090983090 fig 983092 appendix 983092

eFigures 983092983089-983092983090) We did not find any prospective cohort

studies of ruminant derived trans fats and risk of isch-

emic stroke

GRADE confidence in estimates o associationFor the GRADE confidence in estimates of association

we considered only prospective cohort studies because

these are generally considered the highest level of

observational study design983097983088 Overall the certainty of

the estimates for the association between saturated fats

and all outcomes was very low mainly because of low

precision and high inconsistency (appendix 983093) The cer-

tainty of the estimates for the association between total

trans fats and total CHD and CHD mortality is moderate

and very low to low for all others (appendix 983094) Insuffi-

cient data were available to produce GRADE evidence

profiles for industrially produced trans fats and isch-

emic stroke and ruminant derived trans fats and totalCHD and ischemic stroke These results suggest that

further research is likely to have an important effect on

our confidence in the estimation of association and

could change the estimate

Discussion

Principal findings

In this synthesis of observational evidence we found no

clear association between higher intake of saturated

fats and all cause mortality CHD CHD mortality isch-

emic stroke or type 983090 diabetes among apparently

healthy adults Consumption of trans unsaturated fatty

acids however was associated with a 983091983092 increase inall cause mortality a 983090983096 increased risk of CHD mortal-

ity and a 983090983089 increase in the risk of CHD Further these

data suggest that industrial trans fats confer a 983091983088

increase in the risk of CHD events and an 983089983096 increase

in the risk of CHD mortality No associations were

observed for ruminant trans fat Because of inconsis-

tency in the included studies we could not confirm an

association between trans fats and type 983090 diabetes and

found no clear association between trans fats and isch-

emic stroke This is the first meta-analysis of prospec-

tive observational studies examining associations of

saturated and trans fats with all cause mortality and

confirms the findings of five previous systematic

reviews of saturated and trans fats and CHD983089 983091 983097983089-983097983091


All cause mortality

We found no association between saturated fat intake

and all cause mortality the Seven Countriesrsquo Study not-

withstanding Controlled trials have shown that when

saturated fats replaces carbohydrate in the diet total

and LDL cholesterol increase983097983092 Direct positive associa-

tions between total and LDL cholesterol concentrations

and all cause and CHD mortality have been shown pre-

viously983097983093-983097983095 We found no convincing lack of association

with CHD mortality the major contributor to total mor-

tality Studies of saturated fats and other major causes

of death such as colon983097983096 and breast983097983097 cancer also gen-

erally fail to find significant associations Foods high in

saturated fats particularly processed and red meats

however have been associated with increased mortal-

ity983089983088983088-983089983088983090 and risk of cancer983089983088983091-983089983088983093 though dairy foods are

not consistently associated with cancers983089983088983094 A small

body of evidence suggests that saturated fat increases

risk of CVD and mortality among people with diabe-tes983089983088983095 983089983088983096 This could relate to the LDL cholesterol raising

effect of saturated fat and other metabolic conse-

quences of insulin resistance among people with diabe-

tes In metabolic studies saturated fat impairs insulin

sensitivity and unsaturated fat improves glucose

metabolism983089983088983097 replacing saturated fat with monoun-

saturated fat improves lipoprotein and glycemic control

in those with type 983090 diabetes983089983089983088

CHD and CHD mortality

Saturated fats were not associated with total CHD but

we found a trend for association with CHD mortality

Risks associated with higher or lower intakes of macro-nutrients are sensitive to choice of replacement nutri-

ent(s) In a pooled analysis of 983089983089 prospective cohort

studies (not included in our quantitative syntheses to

avoid duplication of data) replacement of saturated

fats with polyunsaturated fat reduced coronary risk by

983089983091983089983089983089 consistent with results of randomized controlled

trials983089983089983090-983089983089983092 but replacement of saturated fat with mono-

unsaturated fat or carbohydrate increased the risk of

non-fatal myocardial infarction983089983089983089 In the Pooling Study

cohorts the primary sources monounsaturated fatty

acids (MUFA) was animal fat and some cohorts

included trans fats in their definition of MUFA983089983089983089 so the

effect of substitution of saturated fats with MUFA couldreflect animal or processed food components not shared



RESEARCH

8

by plant sources of MUFA (such as olive or canola oils

avocado and nuts) Carbohydrates in western diets are

typically highly processed high glycemic load foods

which could increase risk when they replace saturated

fats983089983089983093 983089983089983094 Inconsistent benefit was found for exchang-

ing one food source of saturated fats for another 983089983089983095 983089983089983096

probably because many saturated fatty acids are com-

mon across different food sources

Ischemic stroke

We found no association between saturated fats and

risk of ischemic stroke though the relative risk of stroke

in the highest compared with the lowest categories of

saturated fat exposure was reduced by 983089983096 (983088983096983090 983097983093

confidence interval 983088983094983097 to 983088983097983096) in studies conducted in

Asian countries The background saturated fat intake in

North American studies was about 983089983090 (range 983097-983089983094)

while in Asian studies it was about 983097 (range 983093-983089983092)

with Japanese cohorts consistently lt983095 suggesting

that the effect of saturated fat might not be uniform

across ethnic populations intake levels or possibly

food sources983094983089 In the multi-center KANWU trial

(n=983089983094983090) a diet high in monounsaturated fat was associ-

ated with reduced blood pressure but a diet high in sat-

urated fat was not983089983089983097


We found no association between total saturated fat

intake and incident type 983090 diabetes Though saturated

fats are believed to compromise insulin sensitivity983089983090983088

small randomized trials testing this relation yielded

inconclusive results In two larger trials replacement

of saturated fats with either MUFA or carbohydrate

improved indices of glucose homeostasis983089983090983089 983089983090983090 In theWomenrsquos Health Initiative reducing saturated fat

intake from about 983089983091 of energy to 983097983093 did not reduce

type 983090 diabetes after 983096983089 year follow-up983089983090983091 Positive

associations have been reported between major

sources of saturated fats such as red and processed

meat and development of type 983090 diabetes983089983090983092 983089983090983093 while

inverse associations have been reported for dairy

products983089983090983094

A large (983089983090 983088983092983091 cases) case-cohort study (EPIC-Inter-

Act)983089983090983095 with nearly four million person years of fol-

low-up prospectively measured individual plasma

phospholipid saturated fatty acids at a single time

point It found even-chain saturated fats were positivelyassociated with incident type 983090 diabetes (hazard ratios

were 983089983089983093 (983097983093 confidence interval 983089983088983097 to 983089983090983090) for 983089983092983088

myristic acid 983089983090983094 (983089983089983093 to 983089983091983095) for 983089983094983088 palmitic acid

and 983089983088983094 (983089983088983088 to 983089983089983091) for 983096983088 stearic acid per 983089 SD) By

contrast measured odd-chain saturated fats were

inversely associated with incident type 983090 diabetes (983088983095983097

(983088983095983091 to 983088983096983093) for 983089983093983088 pentadecanoic acid and 983088983094983095 (983088983094983091

to 983088983095983089) for 983089983095983088 heptadecanoic acid per 983089 SD)

Odd-chain saturated fats seem to be relatively accu-

rate biomarkers of dairy intake whereas even chained

saturated fats are poor markers of overall dietary

intake983089983090983096 983089983090983097 The findings for odd-chain saturated fats

are consistent with an inverse association betweendairy products and type 983090 diabetes983089983091983088 although residual

confounding by other dairy components such as vita-

min D calcium or fermentation products could explain

this finding983089983091983088 983089983091983089 Even-chain saturated fats (such as

myristic palmitic and stearic acids) originate from de

novo lipogenesis from carbohydrates and alcohol in

liver or adipose tissue983089983091983090 983089983091983091 Blood concentrations of

these saturated fats therefore might not closely match

dietary intake of saturated fats983089983091983092 The association of

even-chain fatty acids with type 983090 diabetes might reflect

the effect of these other dietary components or other

mechanisms that also upregulate de novo lipogenic

pathways Palmitic acid however might activate

inflammatory cytokines and pose specific lipotoxicity to

pancreaticβ cells983089983091983093

Trans fat and health outcomes

All cause mortality

Studies in the US and China were the first published

cohort studies to report that trans fatty acids are associ-

ated with increased all cause mortality though previ-

ous attempts had been made to model the impact of

trans fats on mortality983089983091983094 983089983091983095 In addition to CHD

deaths983092983092 983092983097 983093983089 983096983088 trans fats have been associated with

sudden cardiac death983089983091983096 and fatal colon983089983091983097 and breast

cancers983089983092983088 The World Cancer Fund panel however

found insufficient evidence to implicate trans fats spe-

cifically for any type of cancer983089983088983094 More studies are

needed to evaluate the contribution to non-cardiac

mortality which could be examined with data from

existing cohorts


We found reliable and strong positive associations

between trans fat intake and CHD and CHD mortalityconsistent with several previous systematic reviews and

meta-analyses983089983090 983090983095 983090983097 983097983091 The effects on risk of heart dis-

ease are mediated via blood lipids and pro-inflamma-

tory processes983089983092983089-983089983092983096 Our finding that a 983090 increase in

energy from trans fats is associated with a 983090983093

increased risk of CHD and 983091983089 increase in CHD mortal-

ity (appendix 983090 eTables 983089983092-983089983095) is consistent with conclu-

sions of two previous meta-analyses983090983097 983097983091

Ischemic stroke

The two prospective studies that assessed the associa-

tion between trans fats and ischemic stroke yielded

inconsistent results One study in men showed no asso-ciation with stroke983094983093 the other in women showed a

positive association in those who did not take aspirin983094983097

Further the association with trans fats was significant

only for lacunar stroke with a trend for hemorrhagic

stroke but not for stroke of cardioembolic origin

A nested case-control study conducted within the Wom-

enrsquos Health Initiative Observational Study (WHI-OS)

with 983089983088 year follow-up983089983092983097 found no association between

serum total trans 983089983094983089 983089983096983089 or 983089983096983090 and ischemic stroke

these results were not included in our quantitative syn-

thesis because the different trans fats reported could

not be classified as ldquototalrdquo or strictly ldquoindustrialrdquo or

ldquoruminantrdquo derived The association with risk of strokerequires further study



RESEARCH

9


We found no association between trans fats and type 983090

diabetes though the interpretation of this finding is

complicated by heterogeneity Inconsistency has also

been noted in randomized trials of the effects on glu-

cose homeostasis983089983093983088 Two cohort studies reporting

strong associations between trans fats and type 983090 diabe-

tes983095983091 983095983092 were generally similar to those that did not with

respect to measures of exposures outcomes and most

covariates except that the three studies that failed to

show an association adjusted for fiber and magne-

sium983095983090 983095983093 983095983094 which might protect against diabetes983089983093983089 983089983093983090

while the two studies that showed an association983095983091 983095983092 did

not Pooling estimates without adjustment for magne-

sium and fiber yields a 983089983094 increased risk of type 983090 dia-

betes with high trans fat intake (four studies risk ratio

983089983089983094 983097983093 confidence interval 983088983097983093 to 983089983092983089 I983090=983096983090

Phetlt983088983088983088983089) when we limited analysis to the three stud-

ies with no serious risks of bias983095983091 983095983092 983095983094 this became a 983090983096

increased risk (three studies 983089983090983096 983089983089983094 to 983089983092983089 Plt983088983088983088983089

I983090=983088 Phet=983088983096983095)

The role of trans-palmitoleic acid in prevention of type

983090 diabetes could represent an important new direction

for fatty acid research It is important to note however

that the exposure levels to this nutrient are typically low

In the three included studies trans-palmitoleic acid rep-

resented lt983089 of total fatty acid intake with the mean

reported exposure level varying about eightfold across

cohorts (mean 983088983088983094 to 983088983092983097 of plasma phospholipid

fatty acids) with considerable variability within the

cohort (SD ranging from 983088983088983091 to 983088983090983088) Nevertheless

the protective associations with type 983090 diabetes are quite

consistent (I983090=983091983088) and compatible with a 983090983094-983093983092

reduction in risk across an estimated threefold intakerange The biology of a potential protective effect of

trans-palmitoleic acid against type 983090 diabetes could

relate to its ability to mimic the role of cis-palmitoleic

acid which is protective against diabetes in animals983089983093983091

Industrially produced v ruminant derived trans fats

Consistent with the findings of a previous meta-analysis of

observational studies983089983090 our study which included recent

data from a large Norwegian study983096983091 found that industri-

ally produced but not ruminant derived trans fats are

associated with risk of CHD This might reflect a true differ-

ence between sources or might be a function of consump-

tion levels Ruminant derived trans fats are consumed atrelatively low levels in most populations in the studies

included in our present analysis the average intake of

industrially produced trans fats was about 983090983093-fold that of

ruminant derived trans fats (mean energy intakes of about

983089983096 (range about 983088983091-983091983095) and 983088983095 (983088983094-983088983096) respec-

tively) The greater range of intake of industrially produced

trans fats in cohort studies provides greater statistical

power for detection of associations

Two quantitative syntheses of randomized controlled

trials of ruminant derived trans fats and biomarkers of

cardiovascular risk arrived at opposite conclusions

Brouwer and colleagues pooled six randomized

controlled trials of ruminant derived trans fats and 983090983097 ofindustrially produced trans fats and found that both had

similar impacts on LDLHDL cholesterol when they were

consumed across an equivalent intake range (983088983095-983094983094 of

energy)983089983091 which supports the notion that the lack of

association of ruminant derived trans fats with cardio-

vascular outcomes in the present and previous analy-

ses983089983090 is related to their lower intake levels Gayet-Boyer

and colleagues however pooled 983089983091 randomized con-

trolled trials (including all of those included by Brouwer

and colleagues) and found no linear association

between ruminant derived trans fats and LDLHDL cho-

lesterol or totalHDL cholesterol across a dose range of

983088983089-983092983090 of energy983089983093983092 The reasons for this discrepancy

are unclear but could relate to differences in the

approaches taken to the quantitative synthesis (such as

study weighting regression modeling) or inclusion

criteria (such as minimum duration of studies accept-

able choice of comparison arms) Further research is

required to assess the impact of ruminant derived versus

industrially produced trans fats on health outcomes but

the best available observational evidence suggests that

at the reported intake levels in the included studies

ruminant trans fats do not increase the risk of develop-

ing the health outcomes reviewed here

In support of the importance of exposure levels

case-control studies in Costa Rica and Australia found

that the association between total trans fats and CHD

was attenuated after removal of industrially produced

trans fats from the food supply983089983093983093 983089983093983094 which resulted in

lower levels of consumption of total trans fats primarily

consisting of ruminant derived trans fats Case-control

studies have shown a strong association between trans-

983089983096983090 isomers983089983093983093 983089983093983095-983089983094983089 abundant in partially hydrogenated

oils and CHD (six studies seven comparisons multi-

variable odds ratio 983089983096983090 983097983093 confidence interval 983089983089983092 to983090983097983088 P=983088983088983089 I983090=983095983095 Phetlt983088983088983088983089 appendix 983092 eFigure 983092983091)

but no significant association between trans-983089983096983089 iso-

mers983089983093983093 983089983093983095-983089983094983090mdashderived principally from partially hydro-

genated oils but also found in ruminant foodsmdashand

CHD (seven studies eight comparisons 983089983089983097 983088983097983091 to 983089983093983089

P=983088983089983094 I983090=983093983097 Phet=983088983088983090 appendix 983092 eFigure 983092983092)

A community based 983089983088 year prospective cohort study

of older adults (the Cardiovascular Health Study US)983089983092983097

measured the association between phospholipid con-

centrations of specific trans fatty acids found chiefly in

prepared foods983089983094983091 (trans-983089983094983089n983097 trans-983089983096983090 (transcis-983089983096983090

cistrans-983089983096983090 and transtrans-983089983096983090) and trans-983089983096983089) and

all cause death and deaths from CHD and CVD Circulat-ing transtrans- and transcis-983089983096983090 were generally harm-

ful but variation existed across classes with a

noteworthy lack of association for trans-983089983096983089 the major

component of partially hydrogenated vegetable oils Of

public health importance is that commercially produced

trans fatty acids other than trans-983089983096983089 can remain in the

food supply even after removal of partially hydroge-

nated oils via vegetable oil deodorization and high tem-

perature frying983089983094983092-983089983094983094 Future work is needed to assess the

public health importance of this residual risk

Methodological issues related to measuring intake of

a nutrient at such low levels (lt983089 of energy) and the

complexity of parsing specific trans fatty acids intoldquoindustrialrdquo or ldquoruminantrdquo sources also decreases our



RESEARCH

10

confidence in the results for ruminant derived trans

fats With the phasing out of industrially produced par-

tially hydrogenated oils in several countries future pro-

spective studies might be better positioned to assess the

effects of ruminant derived trans fats on health Based

on currently available data from prospective cohort

studies ruminant derived trans fats are not associated

with risk of CHD though it is uncertain whether this a

true biological difference or a function of their lower

levels of intake during the periods of study

In a post hoc sensitivity analysis we estimated the

effect of total trans fats on CHD mortality and total CHD

at levels similar to those reported in the studies of rumi-

nant trans fats included in the analysis to help to assess

whether the generally low exposure levels to ruminant

trans fatty acids were driving the lack of association

observed for these outcomes in the ruminant trans fat

analysis To do so we pooled the multivariable relative

risks for quantiles that most closely approximated a

983088983096 of energy increase from the referent category for

total trans fat and CHD mortality and a 983089983090 of energy

increase from the referent category for total trans fat and

CHD In this sensitivity analysis for total trans fats and

CHD mortality the risk ratio was 983089983088983090 (five studies six

comparisons 983097983093 confidence interval 983088983097983088 to 983089983089983094

P=983088983095983091 Phet=983088983090983093 I983090=983090983092 appendix 983092 eFigure 983092983093 expo-

sure estimates in appendix 983090 eTable 983090983088) or 983089983088983091 when we

added unpublished studies (seven studies nine com-

parisons 983088983097983093 to 983089983089983090 P=983088983092983093 Phet=983088983091983094 I983090=983097 appendix 983092

eFigure 983092983094) For total trans fats and CHD the risk ratio

was 983089983089983095 (six studies seven comparisons 983089983088983095 to 983089983090983097

Plt983088983088983088983089 Phet=983088983092983089 I983090=983089 appendix 983092 eFigure 983092983095)

Consistency across observational designsFindings in prospective cohorts were generally consis-

tent with those from case-control studies which found

that higher exposure to trans fats (whether measured by

food frequency questionnaire or biomarker) was associ-

ated with a 983093983089 increased odds of CHD (odds ratio 983089983093983089

983097983093 confidence interval 983089983088983096 to 983090983088983097 P=983088983088983089 I983090=983095983093

Phetlt983088983088983088983089) This was attenuated and no longer signifi-

cant when we restricted the synthesis to high quality

studies (983089983091983095 983088983095983096 to 983090983092983089 P=983088983090983096 I983090=983095983096 Phetlt983088983088983088983089)

(appendix 983092 eFigures 983092983093-983092983095) Inclusion of nested

case-control studies983089983094983095-983089983095983090 in meta-analyses of prospec-

tive studies of total trans fats and CHD mortality (appen-

dix 983092 eFigure 983092983096) CHD (appendix 983092 eFigure 983092983097) type 983090diabetes (appendix 983092 eFigure 983093983088) did not substantively

alter the pooled association from the association derived

from prospective cohort studies Nested case-control

studies with biomarkers of saturated fat intake (such as

erythrocyte or adipose tissue) collected before occur-

rence of disease though few in number consistently

found that people with highest levels of exposure to sat-

urated fat were at increased risk of CHD mortality total

CHD and type 983090 diabetes and these methods of expo-

sure measurement are less subject to bias Pooling of

prospective cohorts with nested case-control studies

of saturated fats resulted in a borderline significant

association with CHD mortality but not total CHD ortype 983090 diabetes (appendix 983092 eFigures 983093983089-983093983091) Prospective

studies with repeated biomarker assessments will

advance knowledge in this area

Strengths and weaknesses of the study

This study has several strengths First we assessed con-

fidence in the estimates with GRADE to facilitate guide-

line development Second studies were identified

through a systematic search of the literature aug-

mented with manual searches of reference lists of pub-

lished papers and systematic reviews Third the

quantitative synthesis focused on studies measuring

comparable outcomes with similar designs reducing

methodological heterogeneity

There were however important limitations related to

evidence synthesis and quality First meta-analytic tech-

niques depend on the availability of conceptually similar

and combinable effect estimates across studies If such

estimates are not available the ability to pool all available

and relevant data in a meaningful way is compromised

and the pooled estimate of effect might be suboptimal

Notably in our evidence synthesis the positive associa-

tion between saturated fat and total mortality observed in

the Seven Countriesrsquo Study983091983096 could not be combined with

other association estimates because theβ coefficient could

not be directly converted into an estimate of relative risk

The GRADE approach offers a methodological advance in

evaluating the quality of the body of evidence in a trans-

parent fashion and thus a ldquonon-combinablerdquo estimate

can still inform our judgment of the presence strength

and direction of an effect Therefore because of this incon-

sistency we document the inconsistency between this

finding (positive) and that of the pooled prospective

cohort studies (null) and rate the confidence we have in a

true quantitative ldquonullrdquo association as ldquovery lowrdquoSecond observational studies cannot provide causal

evidence of an effect of saturated or trans fatty acids on

the development of health outcomes examined they can

describe only associations Measurement error is often

serious in epidemiologic studies of diet and disease

which can bias such associations towards the null Major

limitations of the included studies are described in

appendix 983090 eTables 983091a and 983091b (Newcastle-Ottawa evalua-

tions) and in the footnotes to the GRADE tables (appendi-

ces 983093 and 983094) These include unrepresentative cohorts or a

vaguely defined cohort sampling frame misclassifica-

tion of exposure from inaccurate measurement tools

(selection and exposure measurement biases) failure toaccount for major confounders such as age socioeco-

nomic status smoking total energy or family history

(non-comparability biases) and lack of validated out-

come measures or insufficient study duration to observe

a high number of events (outcome assessment biases)

Additionally random error can attenuate the observed

associations between trans fats and health outcomes and

also explain the lack of association between saturated fat

and health outcomes This error can arise from several

sources including residual confounding recall bias and

exposure misclassification

The reviewed studies typically relied on food fre-

quency questionnaires 983090983092 hour recalls or seven dayfood records each of which has serious limitations in



RESEARCH

11

their ability to accurately capture long term dietary fat

intake Tissue levels of saturated fat are not always valid

measures of dietary saturated fat and associations

based on these exposure measures are difficult to inter-

pret because of shared endogenous and exogenous

sources Exposure measurement error is potentially

more serious with trans fatty acids though analytical

methods for determining trans fatty acid content of

foods and tissues and differentiating ruminant derived

from industrially produced trans fatty acids has evolved

considerably since 983089983097983096983088983089983095983091 It is difficult to classify trans

fat isomers as ruminant or industrial because of shared

food sources and self reported intakes can be incorrect

because of outdated food databases and the rapidly

changing trans fat content of foods These limitations

are especially important given that during the timeframe

of the studies reviewed most countries were making

major efforts to remove trans fats from the food supply

Third several investigators adjusted for changes in risk

factors on the causal pathway between diet and disease

serum lipids and blood pressure which attenuates rela-

tions between saturated or trans fats and the outcomes

The validity of use of ldquomost adjustedrdquo models which

account both for potential confounders and causal inter-

mediates has been debated983089983095983092 983089983095983093 Models adjusted for

potential confounders and intermediate variables under-

estimate associations because of over-controlling for the

effect of causal intermediates unadjusted models overes-

timate associations because estimates reflect other deter-

minants of the health outcomes Comparability across

studies is compromised when different studies include

different sets of confounders To assess the potential

impact of over-adjustment we assessed ldquointermediately

adjusted modelsrdquomdashthat is those that adjusted for themost relevant confounders (smoking age sex and total

energy) but not potential causal intermediates (blood

pressure or anti-hypertensive drugs serum lipids or lipid

lowering drugs)mdashfor associations for which we had a high

number of studies saturated fat and cardiovascular out-

comes In these sensitivity analyses the adjusted risk

ratio was 983089983090983089 (983097983093 confidence interval 983088983097983091 to 983089983093983096 eight

studies) for saturated fat and CHD mortality 983089983088983093 (983088983097983091 to

983089983089983097 983089983089 studies) for saturated fat and total CHD and 983088983096983095

(983088983095983094 to 983089983088983088 two studies) for saturated fat and ischemic

stroke These figures would not meaningfully change our

conclusions based on the fully adjusted models

Fourth although we carried out extensive subgroupanalyses with meta-regression the substantial hetero-

geneity present in most analyses for saturated fats

remains unexplained

Fifth because of a small number of cohorts dose-re-

sponse relations or differences between specific sources

of saturated or trans fatty acids on health outcomes were

not robustly quantified We had insufficient data to per-

form robust subgroup analyses for trans fatty acids asso-

ciations In post hoc sensitivity analyses presenting

highest versus lowest intakes only in those studies where

the referent group had an estimated trans fat intake lt983089

of energy or a highest intake ge983089 of energy provided

results consistent with the main analyses (appendix 983090eTables 983089983096 and 983089983097 appendix 983092 eFigures 983093983092-983094983090)

Strengths and weaknesses in relation to other

studies

This is the seventh systematic review and meta-analy-

sis of observational studies of saturated andor trans

fats and health outcomes in the past 983089983088

years983089 983091 983089983090 983097983089 983097983091 983089983092983089 983089983095983094 Our work updates and corroborates

previous systematic reviews and meta-analyses of

observational studies that have also failed to find asso-

ciations between saturated fat and CVD983089 total

CHD983089 983091 983097983089 983097983091 fatal CHD983089 983097983091 and stroke983091 positive associa-

tions between trans fat and total CHD983089 983089983090 983097983089 983097983091 983089983092983089 and fatal

CHD983089983090 983097983091 and no association with type 983090 diabetes983089983095983094

A Cochrane review of randomized trials of reduced sat-

urated fats and cardiovascular events found a 983089983095

reduced risk with lower saturated fat intake (risk ratio

983088983096983091 983097983093 confidence interval 983088983095983090 to 983088983097983094 983089983091 studies

with 983093983091 983091983088983088 participants moderate GRADE)983096 Method-

ological advantages of randomized controlled trials

over prospective cohort studies include the balancing

of known and unknown confounders and better mea-

surement and finer control of dietary fat levels

Limitations of comparison of extremes

Our a priori research question was to examine the effect

on the health outcomes of higher compared with lower

saturated fat which we did by comparing highest and

lowest intake estimates Such a comparison however

obscures the importance of reciprocal and possibly het-

erogeneous decreases in other macronutrients that

accompany high saturated or trans fat intakes Thus an

overarching consideration is that the effect estimate of

higher intakes of saturated or trans fats on health out-

comes is linked to the nutrient that it replaces Most

studies in the present review did not explicitly modelthe effects of nutrient substitution but when total

energy protein and alcohol are covariates in the multi-

variable model coefficients for fat reflect substitution

of saturated or trans fat for carbohydrate Indeed car-

bohydrate energy was typically lowest in those in the

highest intakes of saturated and trans fat Common

sources of carbohydrate in typically studied popula-

tions were highly processed high glycemic load foods983089983089983093

which can increase risk of CHD independently of satu-

rated and trans fats through different metabolic path-

ways likely attenuating the observed associations

between these fats and outcomes983089983095983095

Replacement of saturated fats by high quality

carbohydrate

The analysis of data from the largest prospective study

to examine carbohydrate quality as measured by glyce-

mic index suggests that replacement of saturated fat

with high glycemic index carbohydrate increased the

risk of CVD but replacement with low glycemic index

carbohydrate (such as whole fruits vegetables pulses

and grains) decreased risk983089983089983094

Replacement of saturated fats by unsaturated fats

In cohort studies that have directly modeled substitution

effects replacement of saturated fat by polyunsaturatedfat (with a corresponding increase in polyunsaturated



RESEARCH

12

saturated (PS) ratio conferred the greatest reduction in

risk of CVD983089983089983089 though these studies did not distinguish

between n-983091 and n-983094 fatty acids as the replacement choice

Several intervention studies that have replaced saturated

fat with polyunsaturated fats achieved relatively high PS

ratios (gt983089983088 to about 983090983093) through replacement of saturated

fat with predominantly soybean (n-983094 linoleic) and marine

oils (n-983091 eicosapentaenoic and docosahexaenoic acids

from sardines) At these levels significant CHD benefits

were seen983089983089983090-983089983089983092 consistent with the finding that favorable

effects of diets with reduced saturated fat on cardiovascu-

lar risk might depend on a significant reciprocal increase

in polyunsaturated fat983097983090 or high quality carbohydrate from

whole fruits vegetables pulses and grains which tend to

have a lower glycaemic index983089983089983094 In a meta-analysis of

cohort studies replacement of 983093 of energy from satu-

rated fat with linoleic acid (n-983094 PUFA) was associated with

a 983097 lower risk of CHD events (risk ratio 983088983097983089 983097983093 confi-

dence interval 983088983096983095 to 983088983097983094 983089983091 studies with 983091983089983088 983094983088983090 partici-

pants) and a 983089983091 lower risk of CHD deaths (983088983096983095 983088983096983090 to

983088983097983092)983089983095983096 A re-analysis of the Sydney Diet Heart Study and

updated meta-analysis however found no benefit and

possible harm associated with replacement of saturated

fat by linoleic acid (hazard ratio 983089983091983091 (983097983093 confidence

interval 983088983097983097 to 983089983095983097) for CHD death and 983089983090983095 (983088983097983096 to 983089983094983093)

for CVD) in secondary prevention trials983089983095983097 Replacement of

saturated fat with monounsaturated fat or carbohydrate

was not associated with significant reduction in CHD risk

but was associated with a small increase in risk of non-fa-

tal myocardial infarction983089983089983093 The relative risks associated

with different saturated fats or their food sources were not

importantly different with the exception of a single study

that noted replacement of saturated fat from meat with

saturated fat from dairy decreased risk of CVD983089983089983096 Othercomponents of these foods however could also be

responsible for these effects

Replacement of trans fats by carbohydrate

In the two studies that directly assessed the impact on

type 983090 diabetes of replacement of carbohydrate with

trans fat replacement of 983089 of energy from carbohy-

drate with trans fatty acids was associated with a 983090983091

increased risk (hazard ratio 983089983090983091 983097983093 confidence inter-

val 983089983088983090 to 983089983092983096)983095983091 and replacement of 983090 of energy from

carbohydrate with trans fatty acids was associated with

a 983091983097 increased risk (983089983091983097 983089983089983093 to 983089983094983095)983095983090 In the two stud-

ies that directly assessed the impact of replacement ofcarbohydrate with trans fats983094983092 983094983096 replacement was asso-

ciated with either no increased risk of stroke in men (risk

ratio 983088983096983094 983088983093983093 to 983089983091983090 per 983090 of energy)983094983092 or a small but

significant increase risk of stroke in older post-meno-

pausal women (983089983088983096 983089983088983088983092 to 983089983089983094 per 983090 g of intake)983094983096

Replacement of trans fat by unsaturated fats

Using data from two of the largest prospective cohort

studies Mozaffarian and Clarke983090983096 reported the adjusted

risk ratio of CHD for isocaloric replacement of 983090 of

energy from trans unsaturated fatty acids with saturated

fatty acids monounsaturated fatty acids or polyunsat-

urated fatty acids They found that replacement of 983090 ofenergy from trans fats with saturated fat would reduce

risk by 983089983095 (risk ratio 983088983096983091 983097983093 confidence interval 983088983095983093

to 983088983097983091) The reductions in risk were 983090983089 (983088983095983097 983088983095983088 to

983088983096983096) for replacement with monounsaturated fat and

983090983092 (983088983095983094 983088983094983095 to 983088983096983093) for replacement with polyunsat-

urated fat In the present analysis we found no new evi-

dence that would substantially alter these risks

Meaning of the study

This systematic review and meta-analysis of evidence

from large generally well designed observational stud-

ies does not support a robust association of saturated

fats with all cause mortality CHD CHD mortality isch-

emic stroke or diabetes in healthy individuals but the

choice of comparison nutrient (n-983094 andor n-983091 PUFA

MUFA refined or high quality carbohydrate) must be

carefully considered Few observational studies how-

ever modeled the effect of replacing saturated or trans

fats with other nutrients In large prospective studies

when polyunsaturated fats replace saturated fats risk

of CHD is reduced but not when MUFA or carbohydrate

is the replacement choice Higher compared with

lower intakes of trans fats are associated with a 983090983088-983091983088

increased risk of all cause mortality CHD and CHD mor-

tality regardless of choice of replacement nutrient but

associations with type 983090 diabetes and stroke are unclear

The association seems to be most consistently driven by

industrially produced trans fats probably because of

their higher intakes among participants during the fol-

low-up periods of the included studies Dietary guide-

lines for saturated and trans fatty acids must carefully

consider the effect of replacement nutrients

Unanswered questions and future research

Several questions could not be answered by our reviewFirst do different sources (for example animal v plant)

and chain lengths (odd v even) of saturated fat have dif-

ferent effects on health particularly with respect to risk

of diabetes The current evidence reviewed suggests

that dairy fats specifically odd chained saturated fatty

acids might be protective against type 983090 diabetes but

apart from recommendations for broad sources of fatty

acids (such as dairy v plant v animal flesh) it is not fea-

sible to separate different types of saturated fats with

respect to food choices because the foods contain a

combination of several saturated fats Second what is

the impact of saturated fats consumed in the context of

diverse background diets on health Notably the asso-ciation between certain foods and CHD cannot be pre-

dicted solely by their content of total saturated fats

because individual saturated fats might have different

cardiovascular effects and major food sources of satu-

rated fat contain other constituents that could influence

risk of CHD Third are there meaningful differences in

the choice of polyunsaturated fatmdashfor instance n-983091 or

n-983094mdashthat replaces saturated (or trans) fats in the diet

Current evidence suggests that either group of polyun-

saturated fats provide similar benefit Fourth is the

reported protective effect of trans-palmitoleic acid for

type 983090 diabetes robust and if so does the apparent

benefit extend to cardiovascular disease outcomesFifth do threshold levels of ruminant trans fatty acid



RESEARCH

13

intakes exist above which cardiovascular risk increases

in a similar fashion to that seen with industrial trans

fatty acids Finally what should be the ldquogoldrdquo standard

for measurement of fatty acid intake Development of

reliable and valid methods of assessing fatty acid

intakes in large longitudinal cohort studies with suffi-

cient follow-up to observe clinical events and deaths

must remain a priority to improve the quality of the evi-

dence on which dietary advice is based

We are grateul to Viranda Jayalath (University o Toronto) or hisassistance developing the data abstraction orms We thank PaulKnekt Anthony Hanley and Ingrid Santaren or providing data andHannia Campos and Kay-tee Khaw or clariying aspects o theirstudies Christine Neilson and Natalie Campbell or their assistancewith the literature search Michael Zulyniak or assistance withpreparing the manuscript or publication and the members o theWHO Nutrition Guidance Advisory Group (NUGAG) Subgroup on Dietand Health or their helpul comments on the dra results WHOagreed to the publication o this systematic review in a scientificjournal because it serves as the background evidence review orupdating WHO guidelines on saturated and trans atty acids andshould thereore be available widely We appreciate the helpulcomments o peer reviewers Arne Atrup Ronald Krauss JM Chardigny

and Evangeline Mantzioris which have greatly improved the quality othe manuscript

Contributors Study concept and design RJdeS SSA JB AMeDevelopment and implementation o literature search strategy EU TKAcquisition o data including review o literature search results anddata abstraction RJdeS EU TK AMe AMa AIC VH PB Analysis andinterpretation o data RJdeS AMe SSA JB HS Draing o themanuscript RJdeS AMe VH AIC Critical revision o the manuscript orimportant intellectual content all authors Statistical analysis RJdeS

JB Administrative technical and material support EU TK AM Studysupervision SSA JB RJdeS is guarantor

Funding This study was unded by WHO which derayed costsassociated with preparing the dra manuscript including inormationspecialist and technical support and article retrieval costs Thissystematic review was presented by RJdeS at the 983093th NutritionGuidelines Advisory Group (NUGAG) meeting in Hangzhou China (983092-983095March 983090983088983089983091) the 983094th NUGAG meeting in Copenhagen Denmark (983090983089-983090983092

Oct 983090983088983089983091) and the 983095th NUGAG meeting in Geneva Switzerland (983097-983089983090Sept 983090983088983089983092) and via skype during the 983096th NUGAG meeting in Fukuoka

Japan (983097-983089983090 June 983090983088983089983093) WHO covered travel and accommodation costsor RJdeS to attend these meetings The research questions or thereview were discussed and developed by the WHO Nutrition GuidanceExpert Advisory Group (NUGAG) Subgroup on Diet and Health and theprotocol was agreed by the WHO NUGAG Subgroup on Diet and Healthhowever neither WHO nor the WHO NUGAG Subgroup on Diet andHealth had any role in data collection or analysis

Competing interests All authors have completed the UnifiedCompeting Interest orm at wwwicmjeorgcoi_disclosurepd(available on request rom the corresponding author) and declareRJdeS has received a Canadian Institutes or Health Research (CIHR)postdoctoral ellowship VH has received a Province o Ontariograduate scholarship and research support rom the CanadianInstitutes o Health Research (CIHR) AIC has received a Province oOntario graduate scholarship

Ethical approval Not required

Transparency statement RJdeS affirms that the manuscript is anhonest accurate and transparent account o the study being reportedthat no important aspects o the study have been omitted and thatany discrepancies are disclosed

Data sharing The ull dataset and statistical code are available romthe corresponding author

This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 983092983088) licensewhich permits others to distribute remix adapt build upon this worknon-commercially and license their derivative works on differentterms provided the original work is properly cited and the use isnon-commercial See httpcreativecommonsorglicensesby-nc983092983088

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Atheroscler Rep 983090983088983089983088983089983090983091983096983092-983097983088983095 Mozaffarian D Micha R Wallace S Effects on coronary heart disease

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Anal Control Expo Risk Assess 983090983088983089983090983090983097983096983094983089-983095983092983089983088 Kris-Etherton PM Leevre M Mensink RP Petersen B Fleming J

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J Clin Nutr 983090983088983089983089983094983093983095983095983091-983096983091983089983091 Brouwer IA Wanders AJ Katan MB Effect o animal and industrial

trans atty acids on HDL and LDL cholesterol levels in humansmdashaquantitative review PLoS One 983090983088983089983088983093e983097983092983091983092

983089983092 Eckel RH Jakicic JM Ard JD et al 983090983088983089983091 AHAACC guideline on liestylemanagement to reduce cardiovascular risk a report o the AmericanCollege o CardiologyAmerican Heart Association Task Force onPractice Guidelines J Am Coll Cardiol 983090983088983089983092983094983091983090983097983094983088-983096983092

983089983093 FAOWHO Fats and atty acids in human nutrition report o an expertconsultation FAO 983090983088983089983088

983089983094 Lichtenstein AH Appel LJ Brands M et al Diet and liestyle

recommendations revision 983090983088983088983094 a scientific statement rom the AmericanHeart Association Nutrition Committee Circulation 983090983088983088983094983089983089983092983096983090-983097983094983089983095 US Department o Agriculture and US Department o Health and

Human Services Dietary Guidelines or Americans 983090983088983089983088 983095th ed USGovernment Printing Office 983090983088983089983088

983089983096 EFSA Panel on Dietetic Products NaA Scientific opinion on dietaryreerence values or ats including saturated atty acidspolyunsaturated atty acids monounsaturated atty acids trans attyacids and cholesterol EFSA J 983090983088983089983088983096983089983092983094983089

983089983097 Food Standards Australia New Zealand Trans atty acids wwwoodstandardsgovauconsumernutritiontransatPagesdeaultaspx

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983090983090 Guyatt GH Oxman AD Schunemann HJ Tugwell P Knottnerus AGRADE guidelines a new series o articles in the Journal o Clinical

Epidemiology J Clin Epidemiol 983090983088983089983089983094983092983091983096983088-983090983090983091 World Health Organization WHO handbook or guideline

development httpappswhointirisbitstream983089983088983094983094983093983095983093983089983092983094983089983097983095983096983097983090983092983089983093983092983096983092983092983089_engpd

983090983092 Higgins JPT Green S Cochrane handbook or systematic reviews ointerventions wwwcochrane-handbookorg

983090983093 Stroup DF Berlin JA Morton SC et al Meta-analysis o observationalstudies in epidemiology a proposal or reporting Meta-analysis OObservational Studies in Epidemiology (MOOSE) group JAMA 983090983088983088983088983090983096983091983090983088983088983096-983089983090

983090983094 Gebauer SK Chardigny JM Jakobsen MU et al Effects o ruminanttrans atty acids on cardiovascular disease and cancer acomprehensive review o epidemiological clinical and mechanisticstudies Adv Nutr 983090983088983089983089983090983091983091983090-983093983092

983090983095 Wang T Cai MQ Meta-analysis o risk o trans atty acids on coronaryheart diseases Shanghai Jiao Tong Da Xue Xue Bao Yi Xue Ban 983090983088983089983089983091983089983089983089983094983092-983094983097

983090983096 Mozaffarian D Clarke R Quantitative effects on cardiovascular riskactors and coronary heart disease risk o replacing partiallyhydrogenated vegetable oils with other ats and oils Eur J Clin Nutr 983090983088983088983097983094983091S983090983090-S983091983091



RESEARCH

14

983090983097 Mozaffarian D Aro A Willett WC Health effects o trans-atty acidsExperimental and observational evidence Eur J Clin Nutr 983090983088983088983097983094983091S983093-S983090983089

983091983088 Wells GA Shea B OrsquoConnell D et al The Newcastle-Ottawa Scale(NOS) or assessing the quality o nonrandomised studies inmeta-analyses wwwohricaprogramsclinical_epidemiologyoxordasp

983091983089 DerSimonian R Laird N Meta-analysis in clinical trials Control ClinTrials 983089983097983096983094983095983089983095983095-983096983096

983091983090 Higgins JP Thompson SG Deeks JJ Altman DG Measuringinconsistency in meta-analyses BMJ 983090983088983088983091983091983090983095983093983093983095-983094983088983091983091 Borenstein M Hedges LV Higgins JPT Rothstein HR Introduction to

meta-analysis John Wiley 983090983088983088983096983091983092 Thompson SG Higgins JP How should meta-regression analyses be

undertaken and interpreted Stat Med 983090983088983088983090983090983089983089983093983093983097-983095983091983091983093 Greenhouse JB Iyengar S Sensitivity analysis and diagnostics In

Cooper HM Hedges LV Valentine JC eds The handbook o researchsynthesis and meta-analysis 983090nd ed Russell Sage Foundation983090983088983088983097983092983090983091-983090983092

983091983094 Sterne JA Gavaghan D Egger M Publication and related bias inmeta-analysis power o statistical tests and prevalence in theliterature J Clin Epidemiol 983090983088983088983088983093983091983089983089983089983097-983090983097

983091983095 Duval S Tweedie R Trim and fill a simple unnel-plot-based methodo testing and adjusting or publication bias in meta-analysisBiometrics 983090983088983088983088983093983094983092983093983093-983094983091

983091983096 Kromhout D Bloemberg B Feskens E Menotti A Nissinen ASaturated at vitamin C and smoking predict long-term populationall-cause mortality rates in the Seven Countries Study Int J Epidemiol

983090983088983088983088983090983097983090983094983088-983093983091983097 Leosdottir M Nilsson PM Nilsson JA Mansson H Berglund G Dietary

at intake and early mortality patternsmdashdata rom The Malmo Diet andCancer Study J Intern Med 983090983088983088983093983090983093983096983089983093983091-983094983093

983092983088 Mann JI Appleby PN Key TJ Thorogood M Dietary determinants oischaemic heart disease in health conscious individuals Heart 983089983097983097983095983095983096983092983093983088-983093

983092983089 Tucker KL Hallrisch J Qiao N Muller D Andres R Fleg JL Thecombination o high ruit and vegetable and low saturated at intakesis more protective against mortality in aging men than is either alonethe Baltimore Longitudinal Study o Aging J Nutr 983090983088983088983093983089983091983093983093983093983094-983094983089

983092983090 Chien KL Lin HJ Hsu HC et al Comparison o predictive perormanceo various atty acids or the risk o cardiovascular disease events andall-cause deaths in a community-based cohort Atherosclerosis 983090983088983089983091983090983091983088983089983092983088-983095

983092983091 Wakai K Naito M Date C Iso H Tamakoshi A Group JS Dietaryintakes o at and total mortality among Japanese populations with alow at intake the Japan Collaborative Cohort (JACC) Study Nutr

Metab (Lond) 983090983088983089983092983089983089983089983090983092983092 Ascherio A Rimm EB Giovannucci EL Spiegelman D Stamper MWillett WC Dietary at and risk o coronary heart disease in mencohort ollow up study in the United States BMJ 983089983097983097983094983091983089983091983096983092-983097983088

983092983093 Boniace DR Tef ME Dietary ats and 983089983094-year coronary heart diseasemortality in a cohort o men and women in Great Britain Eur J ClinNutr 983090983088983088983090983093983094983095983096983094-983097983090

983092983094 Esrey KL Joseph L Grover SA Relationship between dietary intakeand coronary heart disease mortality lipid research clinics prevalenceollow-up study J Clin Epidemiol 983089983097983097983094983092983097983090983089983089-983094

983092983095 Goldbourt U Yaari S Medalie JH Factors predictive o long-termcoronary heart disease mortality among 983089983088983088983093983097 male Israeli civilservants and municipal employees A 983090983091-year mortality ollow-up inthe Israeli Ischemic Heart Disease Study Cardiology 983089983097983097983091983096983090983089983088983088-983090983089

983092983096 Kushi LH Lew RA Stare FJ et al Diet and 983090983088-year mortality romcoronary heart disease The Ireland-Boston Diet-Heart Study N Engl JMed 983089983097983096983093983091983089983090983096983089983089-983096

983092983097 Pietinen P Ascherio A Korhonen P et al Intake o atty acids and risko coronary heart disease in a cohort o Finnish men The Alpha-

Tocopherol Beta-Carotene Cancer Prevention Study Am J Epidemiol 983089983097983097983095983089983092983093983096983095983094-983096983095

983093983088 Shekelle RB Shryock AM Paul O et al Diet serum cholesterol anddeath rom coronary heart disease The Western Electric study N Engl

J Med 983089983097983096983089983091983088983092983094983093-983095983088983093983089 Xu J Eilat-Adar S Loria C et al Dietary at intake and risk o coronary

heart disease the Strong Heart Study Am J Clin Nutr 983090983088983088983094983096983092983096983097983092-983097983088983090

983093983090 Virtanen JK Mursu J Tuomainen TP Voutilainen S Dietary atty acidsand risk o coronary heart disease in men the Kuopio ischemic heartdisease risk actor study Arterioscler Thromb Vasc Biol 983090983088983089983092983091983092983090983094983095983097-983096983095

983093983091 Sauvaget C Nagano J Hayashi M Yamada M Animal protein animalat and cholesterol intakes and risk o cerebral inarction mortality inthe adult health study Stroke 983090983088983088983092983091983093983089983093983091983089-983095

983093983092 Fehily AM Yarnell JW Sweetnam PM Elwood PC Diet and incidentischaemic heart disease the Caerphilly Study Br J Nutr 983089983097983097983091983094983097983091983088983091-983089983092

983093983093 Howard BV Van Horn L Hsia J et al Low-at dietary pattern and risk ocardiovascular disease the Womenrsquos Health Initiative RandomizedControlled Dietary Modification Trial JAMA 983090983088983088983094983090983097983093983094983093983093-983094983094

983093983094 Jakobsen MU Overvad K Dyerberg J Schroll M Heitmann BL Dietaryat and risk o coronary heart disease possible effect modification bygender and age Am J Epidemiol 983090983088983088983092983089983094983088983089983092983089-983097

983093983095 Leosdottir M Nilsson PM Nilsson JA Berglund G Cardiovascularevent risk in relation to dietary at intake in middle-aged individualsdata rom The Malmo Diet and Cancer Study Eur J Cardiovasc PrevRehabil 983090983088983088983095983089983092983095983088983089-983094

983093983096 McGee D Reed D Stemmerman G Rhoads G Yano K Feinleib M Therelationship o dietary at and cholesterol to mortality in 983089983088 years the

Honolulu Heart Program Int J Epidemiol 983089983097983096983093983089983092983097983095-983089983088983093983093983097 Oh K Hu FB Manson JE Stamper MJ Willett WC Dietary at intakeand risk o coronary heart disease in women 983090983088 years o ollow-up othe nursesrsquo health study Am J Epidemiol 983090983088983088983093983089983094983089983094983095983090-983097

983094983088 Posner BM Cobb JL Belanger AJ Cupples LA DrsquoAgostino RB Stokes J983091rd Dietary lipid predictors o coronary heart disease in men TheFramingham Study Arch Intern Med 983089983097983097983089983089983093983089983089983089983096983089-983095

983094983089 Yamagishi K Iso H Kokubo Y et al Dietary intake o saturated attyacids and incident stroke and coronary heart disease in Japanesecommunities the JPHC Study Eur Heart J 983090983088983089983091983091983092983089983090983090983093-983091983090

983094983090 De Goede J Soedamah-Muthu SS Trichia E Geleijnse JM Kromhout DDietary intake o saturated at by ood source and incident coronaryheart disease The zutphen elderly study Circulation 983090983088983089983093983089983091983089

983094983091 Atkinson C Whitley E Ness A Baker I Associations between types odietary at and fish intake and risk o stroke in the CaerphillyProspective Study (CaPS) Public Health 983090983088983089983089983089983090983093983091983092983093-983096

983094983092 Gillman MW Cupples LA Millen BE Ellison RC Wol PA Inverseassociation o dietary at with development o ischemic stroke in men

JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088

983094983093 He K Merchant A Rimm EB et al Dietary at intake and risk o strokein male US healthcare proessionals 983089983092 year prospective cohortstudy BMJ 983090983088983088983091983091983090983095983095983095983095-983096983090

983094983094 Misirli G Benetou V Lagiou P Bamia C Trichopoulos D TrichopoulouA Relation o the traditional Mediterranean diet to cerebrovasculardisease in a Mediterranean population Am J Epidemiol 983090983088983089983090983089983095983094983089983089983096983093-983097983090

983094983095 Seino F Date C Nakayama T et al Dietary lipids and incidence ocerebral inarction in a Japanese rural community J Nutr Sci Vitaminol(Tokyo) 983089983097983097983095983092983091983096983091-983097983097

983094983096 Wiberg B Sundstrom J Arnlov J et al Metabolic risk actors or strokeand transient ischemic attacks in middle-aged men a community-based study with long-term ollow-up Stroke 983090983088983088983094983091983095983090983096983097983096-983097983088983091

983094983097 Yaemsiri S Sen S Tinker L Rosamond W Wassertheil-Smoller S He KTrans at aspirin and ischemic stroke in postmenopausal women

Ann Neurol 983090983088983089983090983095983090983095983088983092-983089983093983095983088 Yamagishi K Folsom AR Steffen LM ARIC Study Investigators Plasma

atty acid composition and incidence ischemic stroke in middle-aged

adults the atherosclerosis risk in communities (ARIC) studyCerebrovasc Dis 983090983088983089983091983091983094983091983096-983092983094983095983089 Alhazmi A Stojanovski E McEvoy M Garg ML Macronutrient intake

and type 983090 diabetes risk in middle-aged Australian women Resultsrom the Australian Longitudinal Study on Womenrsquos Health PublicHealth Nutr 983090983088983089983092983089983095983089983093983096983095-983097983092

983095983090 Meyer KA Kushi LH Jacobs Jr DR Folsom AR Dietary at and incidenceo type 983090 diabetes in older Iowa women Diabetes Care 983090983088983088983089983090983092983089983093983090983096-983091983093

983095983091 Salmeroacuten J Hu FB Manson JE et al Dietary at intake and risk o type983090 diabetes in women Am J Clin Nutr 983090983088983088983089983095983091983089983088983089983097-983090983094

983095983092 Simila ME Kontto JP Valsta LM Mannisto S Albanes D Virtamo JCarbohydrate substitution or at or protein and risk o type 983090 diabetesin male smokers Eur J Clin Nutr 983090983088983089983090983094983094983095983089983094-983090983089

983095983093 Song Y Manson JE Buring JE Liu S A prospective study o red meatconsumption and type 983090 diabetes in middle-aged and elderly womenThe Womenrsquos Health study Diabetes Care 983090983088983088983092983090983095983090983089983088983096-983089983093

983095983094 Van Dam RM Willett WC Rimm EB Stamper MJ Hu FB Dietary at andmeat intake in relation to risk o type 983090 diabetes in men Diabetes Care

983090983088983088983090983090983093983092983089983095-983090983092983095983095 Lindstrom J Peltonen M Eriksson JG et al High-fibre low-at diet

predicts long-term weight loss and decreased type 983090 diabetes riskthe Finnish Diabetes Prevention Study Diabetologia 983090983088983088983094983092983097983097983089983090-983090983088

983095983096 Mahendran Y Agren J Uusitupa M et al Association o erythrocytemembrane atty acids with changes in glycemia and risk o type 983090diabetes Am J Clin Nutr 983090983088983089983092983097983097983095983097-983096983093

983095983097 Kiage JN Merrill PD Robinson CJ et al Intake o trans at and all-causemortality in the Reasons or Geographical and Racial Differences inStroke (REGARDS) cohort Am J Clin Nutr 983090983088983089983091983097983095983089983089983090983089-983090983096

983096983088 Oomen CM Ocke MC Feskens EJ van Erp-Baart MA Kok FJ KromhoutD Association between trans atty acid intake and 983089983088-year risk ocoronary heart disease in the Zutphen Elderly Study a prospectivepopulation-based study Lancet 983090983088983088983089983091983093983095983095983092983094-983093983089

983096983089 Kiage JN Merrill PD Judd SE et al Intake o trans at and incidence ostroke in the REasons or Geographic And Racial Differences in Stroke(REGARDS) cohort Am J Clin Nutr 983090983088983089983092983097983097983089983088983095983089-983094

983096983090 Wang Q Imamura F Ma W et al Circulating and dietary trans-attyacids and incident type-983090 diabetes mellitus in older adults Thecardiovascular health study Circulation 983090983088983089983092983089983090983097983089983088983097983097-983089983088983095



RESEARCH

15

983096983091 Laake I Pedersen JI Selmer R et al A prospective study o intake otrans-atty acids rom ruminant at partially hydrogenated vegetableoils and marine oils and mortality rom CVD Br J Nutr 983090983088983089983090983089983088983096983095983092983091-983093983092

983096983092 Willett WC Stamper MJ Manson JE et al Intake o trans atty acidsand risk o coronary heart disease among women Lancet 983089983097983097983091983091983092983089983093983096983089-983093

983096983093 Jakobsen MU Overvad K Dyerberg J Heitmann BL Intake o ruminanttrans atty acids and risk o coronary heart disease Int J Epidemiol

983090983088983088983096983091983095983089983095983091-983096983090983096983094 Mozaffarian D Cao H King IB et al Trans-palmitoleic acid metabolicrisk actors and new-onset diabetes in US adults a cohort study

Ann Intern Med 983090983088983089983088983089983093983091983095983097983088-983097983096983095 Mozaffarian D de Oliveira Otto MC Lemaitre RN et al trans-

Palmitoleic acid other dairy at biomarkers and incident diabetesthe Multi-Ethnic Study o Atherosclerosis (MESA) Am J Clin Nutr 983090983088983089983091983097983095983096983093983092-983094983089

983096983096 Yakoob MY Shi P Hu FB et al Circulating biomarkers o dairy at andincident type 983090 diabetes in two US prospective cohort studiesCirculation 983090983088983089983092983089983090983097

983096983097 Santaren ID Watkins SM Liese AD et al Serum pentadecanoic acid(983089983093983088) a short-term marker o dairy ood intake is inverselyassociated with incident type 983090 diabetes and its underlying disorders

Am J Clin Nutr 983090983088983089983092983089983088983088983089983093983091983090-983092983088983097983088 Centre or Evidence-Based Medicine Levels o evidence March 983090983088983088983097

wwwcebmnetoxord-centre-evidence-based-medicine-levels-evidence-march-983090983088983088983097

983097983089 Mente A de Koning L Shannon HS Anand SS A systematic review o

the evidence supporting a causal link between dietary actors andcoronary heart disease Arch Intern Med 983090983088983088983097983089983094983097983094983093983097-983094983097

983097983090 Micha R Mozaffarian D Saturated at and cardiometabolic riskactors coronary heart disease stroke and diabetes a resh look atthe evidence Lipids 983090983088983089983088983092983093983096983097983091-983097983088983093

983097983091 Skeaff CM Miller J Dietary at and coronary heart disease summary oevidence rom prospective cohort and randomised controlled trials

Ann Nutr Metab 983090983088983088983097983093983093983089983095983091-983090983088983089983097983092 Mensink RP Zock PL Kester ADM Katan MB Effects o dietary atty

acids and carbohydrates on the ratio o serum total to HDL cholesteroland on serum lipids and apolipoproteins a meta-analysis o 983094983088controlled trials Am J Clin Nutr 983090983088983088983091983095983095983089983089983092983094-983093983093

983097983093 Stamler J Wentworth D Neaton JD Is relationship between serumcholesterol and risk o premature death rom coronary heart diseasecontinuous and graded Findings in 983091983093983094983090983090983090 primary screenees o theMultiple Risk Factor Intervention Trial (MRFIT) JAMA 983089983097983096983094983090983093983094983090983096983090983091-983096

983097983094 Kannel WB Neaton JD Wentworth D et al Overall and coronary heart

disease mortality rates in relation to major risk actors in 983091983090983093983091983092983096 menscreened or the MRFIT Multiple Risk Factor Intervention Trial AmHeart J 983089983097983096983094983089983089983090983096983090983093-983091983094

983097983095 Gordon T Kannel WB Castelli WP Dawber TR Lipoproteinscardiovascular disease and death The Framingham study Arch InternMed 983089983097983096983089983089983092983089983089983089983090983096-983091983089

983097983096 Giovannucci E Rimm EB Stamper MJ Colditz GA Ascherio A WillettWC Intake o at meat and fiber in relation to risk o colon cancer inmen Cancer Res 983089983097983097983092983093983092983090983091983097983088-983095

983097983097 Smith-Warner SA Spiegelman D Adami HO et al Types o dietary atand breast cancer a pooled analysis o cohort studies Int J Cancer 983090983088983088983089983097983090983095983094983095-983095983092

983089983088983088 Larsson SC Orsini N Red meat and processed meat consumption andall-cause mortality a meta-analysis Am J Epidemiol 983090983088983089983091

983089983088983089 OrsquoSullivan TA Haekost K Mitrou F Lawrence D Food sources osaturated at and the association with mortality a meta-analysis Am JPublic Health 983090983088983089983091983089983088983091e983091983089-983092983090

983089983088983090 Rohrmann S Overvad K Bueno-de-Mesquita HB et al Meatconsumption and mortalitymdashresults rom the European Prospective

Investigation into Cancer and Nutrition BMC Med 983090983088983089983091983089983089983094983091983089983088983091 Zhu H Yang X Zhang C et al Red and processed meat intake is

associated with higher gastric cancer risk a meta-analysis oepidemiological observational studies PLoS One 983090983088983089983091983096e983095983088983097983093983093

983089983088983092 Choi Y Song S Song Y Lee JE Consumption o red and processedmeat and esophageal cancer risk meta-analysis World JGastroenterol 983090983088983089983091983089983097983089983088983090983088-983097

983089983088983093 Aune D Chan DS Vieira AR et al Red and processed meat intake andrisk o colorectal adenomas a systematic review and meta-analysis oepidemiological studies Cancer Causes Control 983090983088983089983091983090983092983094983089983089-983090983095

983089983088983094 World Cancer Research FundAmerican Institute or Cancer ResearchFood nutrition physical activity and the prevention o cancer aglobal Perspective World Cancer Research FundAmerican Instituteor Cancer Research 983090983088983088983095

983089983088983095 Tanasescu M Cho E Manson JE Hu FB Dietary at and cholesteroland the risk o cardiovascular disease among women with type 983090diabetes Am J Clin Nutr 983090983088983088983092983095983097983097983097983097-983089983088983088983093

983089983088983096 Trichopoulou A Psaltopoulou T Oranos P Trichopoulos D Diet andphysical activity in relation to overall mortality amongst adultdiabetics in a general population cohort J Intern Med 983090983088983088983094983090983093983097983093983096983091-983097983089

983089983088983097 Lichtenstein AH Schwab US Relationship o dietary at to glucosemetabolism Atherosclerosis 983090983088983088983088983089983093983088983090983090983095-983092983091

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983089983089983089 Jakobsen MU OrsquoReilly EJ Heitmann BL et al Major types o dietary atand risk o coronary heart disease a pooled analysis o 983089983089 cohortstudies Am J Clin Nutr 983090983088983088983097983096983097983089983092983090983093-983091983090

983089983089983090 Dayton S Pearce ML Hashimoto S Dixon WJ Tomiyasu U A controlledclinical trial o a diet high in unsaturated at in preventingcomplications o atherosclerosis Circulation 983089983097983094983097983092983088II-983089-II-983094983091

983089983089983091 Leren P The Oslo diet-heart study Eleven-year report Circulation 983089983097983095983088983092983090983097983091983093-983092983090

983089983089983092 Turpeinen O Karvonen MJ Pekkarinen M Miettinen M Elosuo RPaavilainen E Dietary prevention o coronary heart disease theFinnish Mental Hospital Study Int J Epidemiol 983089983097983095983097983096983097983097-983089983089983096

983089983089983093 Liu S Willett WC Stamper MJ et al A prospective study o dietaryglycemic load carbohydrate intake and risk o coronary heart diseasein US women Am J Clin Nutr 983090983088983088983088983095983089983089983092983093983093-983094983089

983089983089983094 Jakobsen MU Dethlesen C Joensen AM et al Intake o carbohydratescompared with intake o saturated atty acids and risk o myocardialinarction importance o the glycemic index Am J Clin Nutr 983090983088983089983088983097983089983089983095983094983092-983096

983089983089983095 Hu FB Stamper MJ Manson JE et al Dietary saturated ats and theirood sources in relation to the risk o coronary heart disease inwomen Am J Clin Nutr 983089983097983097983097983095983088983089983088983088983089-983096

983089983089983096 De Oliveira Otto MC Mozaffarian D et al Dietary intake o saturated

at by ood source and incident cardiovascular disease theMulti-Ethnic Study o Atherosclerosis Am J Clin Nutr 983090983088983089983090983097983094983091983097983095-983092983088983092

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983089983090983088 Riserus U Fatty acids and insulin sensitivity Curr Opin Clin NutrMetab Care 983090983088983088983096983089983089983089983088983088-983093

983089983090983089 Perez-Jimenez F Lopez-Miranda J Pinillos MD et al A Mediterraneanand a high-carbohydrate diet improve glucose metabolism in healthyyoung persons Diabetologia 983090983088983088983089983092983092983090983088983091983096-983092983091

983089983090983090 Vessby B Uusitupa M Hermansen K et al Substituting dietarysaturated or monounsaturated at impairs insulin sensitivity inhealthy men and women The KANWU Study Diabetologia 983090983088983088983089983092983092983091983089983090-983097

983089983090983091 Tinker LF Bonds DE Margolis KL et al Low-at dietary pattern and risko treated diabetes mellitus in postmenopausal women the WomenrsquosHealth Initiative randomized controlled dietary modification trial Arch

Intern Med 983090983088983088983096983089983094983096983089983093983088983088-983089983089983089983090983092 Pan A Sun Q Bernstein AM Manson JE Willett WC Hu FB Changes inred meat consumption and subsequent risk o type 983090 diabetesmellitus three cohorts o US men and women JAMA Intern Med 983090983088983089983091983089983095983091983089983091983090983096-983091983093

983089983090983093 Micha R Michas G Mozaffarian D Unprocessed red and processedmeats and risk o coronary artery disease and type 983090 diabetesmdashanupdated review o the evidence Curr Atheroscler Rep 983090983088983089983090983089983092983093983089983093-983090983092

983089983090983094 Lee JE McLerran DF Rolland B et al Meat intake and cause-specificmortality a pooled analysis o Asian prospective cohort studies Am JClin Nutr 983090983088983089983091983097983096983089983088983091983090-983092983089

983089983090983095 Forouhi NG Koulman A Sharp SJ et al Differences in the prospectiveassociation between individual plasma phospholipid saturated attyacids and incident type 983090 diabetes the EPIC-InterAct case-cohortstudy Lancet Diabetes Endocrinol 983090983088983089983092983090983096983089983088-983096

983089983090983096 Turcot V Brunet J Daneault C Tardi JC Des Rosiers C Lettre GValidation o atty acid intakes estimated by a ood requencyquestionnaire using erythrocyte atty acid profiling in the MontrealHeart Institute Biobank J Hum Nutr Diet 983090983088983089983092 wwwncbinlmnihgov

pubmed983090983093983090983088983096983094983091983088983089983090983097 Wennberg M Vessby B Johansson I Evaluation o relative intake o

atty acids according to the Northern Sweden FFQ with atty acidlevels in erythrocyte membranes as biomarkers Public Health Nutr 983090983088983088983097983089983090983089983092983095983095-983096983092

983089983091983088 Sluijs I Forouhi NG Beulens JW et al The amount and type o dairyproduct intake and incident type 983090 diabetes results rom theEPIC-InterAct Study Am J Clin Nutr 983090983088983089983090983097983094983091983096983090-983097983088

983089983091983089 OrsquoConnor LM Lentjes MA Luben RN Khaw KT Wareham NJ ForouhiNG Dietary dairy product intake and incident type 983090 diabetes aprospective study using dietary data rom a 983095-day ood diaryDiabetologia 983090983088983089983092983093983095983097983088983097-983089983095

983089983091983090 Hudgins LC Hellerstein M Seidman C Neese R Diakun J Hirsch JHuman atty acid synthesis is stimulated by a eucaloric low at highcarbohydrate diet J Clin Invest 983089983097983097983094983097983095983090983088983096983089-983097983089

983089983091983091 Siler SQ Neese RA Hellerstein MK De novo lipogenesis lipid kineticsand whole-body lipid balances in humans aer acute alcoholconsumption Am J Clin Nutr 983089983097983097983097983095983088983097983090983096-983091983094

983089983091983092 Hodson L Skeaff CM Fielding BA Fatty acid composition o adiposetissue and blood in humans and its use as a biomarker o dietaryintake Prog Lipid Res 983090983088983088983096983092983095983091983092983096-983096983088


httpslidepdfcomreaderfulljournal-2-newpdf 1616

RESEARCH

983089983091983093 Sharma RB Alonso LC Lipotoxicity in the pancreatic beta cell not justsurvival and unction but prolieration as well Curr Diab Rep 983090983088983089983092983089983092983092983097983090

983089983091983094 Willett WC Ascherio A Trans atty acids are the effects only marginal Am J Public Health 983089983097983097983092983096983092983095983090983090-983092

983089983091983095 Danaei G Ding EL Mozaffarian D et al The preventable causes odeath in the United States comparative risk assessment o dietaryliestyle and metabolic risk actors PLoS Med 983090983088983088983097983094e983089983088983088983088983088983093983096

983089983091983096 Chiuve SE Rimm EB Manson JE et al Intake o total trans trans-983089983096983089

and trans-983089983096983090 atty acids and risk o sudden cardiac death in women Am Heart J 983090983088983088983097983089983093983096983095983094983089-983095983089983091983097 Vinikoor LC Millikan RC Satia JA et al trans-Fatty acid consumption

and its association with distal colorectal cancer in the North CarolinaColon Cancer Study II Cancer Causes Control 983090983088983089983088983090983089983089983095983089-983096983088

983089983092983088 Chajes V Thiebaut AC Rotival M et al Association between serumtrans-monounsaturated atty acids and breast cancer risk in theE983091N-EPIC Study Am J Epidemiol 983090983088983088983096983089983094983095983089983091983089983090-983090983088

983089983092983089 Mozaffarian D Katan MB Ascherio A Stamper MJ Willett WC Transatty acids and cardiovascular disease N Engl J Med 983090983088983088983094983091983093983092983089983094983088983089-983089983091

983089983092983090 Abbey M Nestel PJ Plasma cholesteryl ester transer protein activity isincreased when trans-elaidic acid is substituted or cis-oleic acid inthe diet Atherosclerosis 983089983097983097983092983089983088983094983097983097-983089983088983095

983089983092983091 Mensink RP Zock PL Kester ADM Katan MB Effects o dietary attyacids and carbohydrates on the ratio o serum total to HDL cholesteroland on serum lipids and apolipoproteins a meta-analysis o 983094983088controlled trials Am J Clin Nutr 983090983088983088983091983095983095983089983089983092983094-983093983093

983089983092983092 Katan MB Zock PL Mensink RP Trans atty acids and their effects onlipoproteins in humans Annu Rev Nutr 983089983097983097983093983089983093983092983095983091-983097983091

983089983092983093 Mauger JF Lichtenstein AH Ausman LM et al Effect o different ormso dietary hydrogenated ats on LDL particle s ize Am J Clin Nutr 983090983088983088983091983095983096983091983095983088-983093

983089983092983094 Baer DJ Judd JT Clevidence BA Tracy RP Dietary atty acids affectplasma markers o inlammation in healthy men ed controlled dietsa randomized crossover study Am J Clin Nutr 983090983088983088983092983095983097983097983094983097-983095983091

983089983092983095 Libby P Ridker PM Hansson GK Leducq Transatlantic Network onAtherothrombosis Inlammation in atherosclerosis rompathophysiology to practice J Am Coll Cardiol 983090983088983088983097983093983092983090983089983090983097-983091983096

983089983092983096 Mozaffarian D Rimm EB King IB Lawler RL McDonald GB Levy WCTrans atty acids and systemic inlammation in heart ailure Am J ClinNutr 983090983088983088983092983096983088983089983093983090983089-983093

983089983092983097 Wang Q Imamura F Lemaitre RN et al Plasma phospholipidtrans-atty acids levels cardiovascular diseases and total mortalitythe cardiovascular health study J Am Heart Assoc 983090983088983089983092983091piie983088983088983088983097983089983092

983089983093983088 Aronis KN Khan SM Mantzoros CS Effects o trans atty acids onglucose homeostasis a meta-analysis o randomized placebo-

controlled clinical trials Am J Clin Nutr 983090983088983089983090983097983094983089983088983097983091-983097983089983093983089 Dong JY Xun P He K Qin LQ Magnesium intake and risk o type 983090diabetes meta-analysis o prospective cohort studies Diabetes Care 983090983088983089983089983091983092983090983089983089983094-983090983090

983089983093983090 Schulze MB Schulz M Heidemann C Schienkiewitz A Hoffmann KBoeing H Fiber and magnesium intake and incidence o type 983090diabetes a prospective study and meta-analysis Arch Intern Med 983090983088983088983095983089983094983095983097983093983094-983094983093

983089983093983091 Cao H Gerhold K Mayers JR Wiest MM Watkins SM Hotamisligil GSIdentification o a lipokine a lipid hormone linking adipose tissue tosystemic metabolism Cell 983090983088983088983096983089983091983092983097983091983091-983092983092

983089983093983092 Gayet-Boyer C Tenenhaus-Aziza F Prunet C et al Is there a linearrelationship between the dose o ruminant trans-atty acids andcardiovascular risk markers in healthy subjects results rom asystematic review and meta-regression o randomised clinical trialsBr J Nutr 983090983088983089983092983089983089983090983089983097983089983092-983090983090

983089983093983093 Colon-Ramos U Baylin A Campos H The relation between trans attyacid levels and increased risk o myocardial inarction does not holdat lower levels o trans atty acids in the Costa Rican ood supply J

Nutr 983090983088983088983094983089983091983094983090983096983096983095-983097983090983089983093983094 Clion PM Keogh JB Noakes M Trans atty acids in adipose tissue

and the ood supply are associated with myocardial inarction[erratum appears in J Nutr 983090983088983088983092 Jul983089983091983092983089983096983092983096] J Nutr 983090983088983088983092983089983091983092983096983095983092-983097

983089983093983095 Baylin A Kabagambe EK Ascherio A Spiegelman D Campos H High983089983096983090 trans-atty acids in adipose tissue are associated with increasedrisk o nonatal acute myocardial inarction in costa rican adults J Nutr 983090983088983088983091983089983091983091983089983089983096983094-983097983089

983089983093983096 Block RC Harris WS Reid KJ Spertus JA Omega-983094 and trans atty acidsin blood cell membranes a risk actor or acute coronary syndromes

Am Heart J 983090983088983088983096983089983093983094983089983089983089983095-983090983091983089983093983097 Ghahremanpour F Firoozrai M Darabi M Zavarei A Mohebbi A

Adipose tissue trans atty acids and risk o coronary artery disease acase-control study Ann Nutr Metab 983090983088983088983096983093983090983090983092-983096

983089983094983088 Park Y Lim J Lee J Kim S-G Erythrocyte atty acid profiles can predictacute non-atal myocardial inarction Br J Nutr 983090983088983088983097983089983088983090983089983091983093983093-983094983089

983089983094983089 Van de Vijver LP van Poppel G van Houwelingen A Kruyssen DAHornstra G Trans unsaturated atty acids in plasma phospholipidsand coronary heart disease a case-control study Atherosclerosis 983089983097983097983094983089983090983094983089983093983093-983094983089

983089983094983090 Aro A Kardinaal AF Salminen I et al Adipose tissue isomeric transatty acids and risk o myocardial inarction in nine countries theEURAMIC study Lancet 983089983097983097983093983091983092983093983090983095983091-983096

983089983094983091 Micha R King IB Lemaitre RN et al Food sources o individual plasmaphospholipid trans atty acid isomers the Cardiovascular Health

Study Am J Clin Nutr 983090983088983089983088983097983089983096983096983091-983097983091983089983094983092 Allison DB Egan SK Barraj LM Caughman C Inante M Heimbach JTEstimated intakes o trans atty and other atty acids in the USpopulation J Am Diet Assoc 983089983097983097983097983097983097983089983094983094-983095983092983094

983089983094983093 Mozaffarian D Abdollahi M Campos H Houshiarrad A Willett WCConsumption o trans ats and estimated effects on coronary heartdisease in Iran Eur J Clin Nutr 983090983088983088983095983094983089983089983088983088983092-983089983088

983089983094983094 Kemeny ZRK Henon G Kovari K Zwobada F Deodorization ovegetable oils prediction o trans polyunsaturated atty acid content J

Am Oil Chem Soc 983090983088983088983089983095983096983097983095983091-983095983097983089983094983095 Sun Q Ma J Campos H Hu FB Plasma and erythrocyte biomarkers o

dairy at intake and risk o ischemic heart disease Am J Clin Nutr 983090983088983088983095983096983094983097983090983097-983091983095

983089983094983096 Khaw KT Friesen MD Riboli E Luben R Wareham N Plasmaphospholipid atty acid concentration and incident coronary heartdisease in men and women The EPIC-Norolk prospective study PLoSMed 983090983088983089983090983097

983089983094983097 Lemaitre RN King IB Mozaffarian D et al Plasma phospholipid transatty acids atal ischemic heart disease and sudden cardiac death in

older adults the cardiovascular health study Circulation 983090983088983088983094983089983089983092983090983088983097-983089983093

983089983095983088 Hodge AM English DR OrsquoDea K et al Plasma phospholipid anddietary atty acids as predictors o type 983090 diabetes interpreting therole o linoleic acid Am J Clin Nutr 983090983088983088983095983096983094983089983096983097-983097983095

983089983095983089 Kroger J Zietemann V Enzenbach C et al Erythrocyte membranephospholipid atty acids desaturase activity and dietary atty acids inrelation to risk o type 983090 diabetes in the European ProspectiveInvestigation into Cancer and Nutrition (EPIC)-Potsdam Study Am JClin Nutr 983090983088983089983089983097983091983089983090983095-983092983090

983089983095983090 Patel PS Sharp SJ Jansen E et al Fatty acids measured in plasma anderythrocyte-membrane phospholipids and derived by ood-requencyquestionnaire and the risk o new-onset type 983090 diabetes a pilot studyin the European Prospective Investigation into Cancer and Nutrition(EPIC)-Norolk cohort Am J Clin Nutr 983090983088983089983088983097983090983089983090983089983092-983090983090

983089983095983091 Svensson L Sisontes L Nyborg G Blomstrand R High perormanceliquid chromatography and glass capillary gas chromatography ogeometric and positional isomers o long chain monounsaturated

atty acids Lipids 983089983097983096983089983089983095983093983088-983097983089983095983092 Stamler J Diet-heart a problematic revisit Am J Clin Nutr 983090983088983089983088983097983089983092983097983095-983097983089983095983093 Scarborough P Rayner M van Dis I Norum K Meta-analysis o effect

o saturated at intake on cardiovascular disease overadjustmentobscures true associations Am J Clin Nutr 983090983088983089983088983097983090983092983093983096-983097

983089983095983094 Alhazmi A Stojanovski E McEvoy M Garg ML Macronutrient intakes anddevelopment o type 983090 diabetes a systematic review and meta-analysiso cohort studies J Am Coll Nutr 983090983088983089983090983091983089983090983092983091-983093983096

983089983095983095 Hu FB Are refined carbohydrates worse than saturated at Am J Clin Nutr 983090983088983089983088983097983089983089983093983092983089-983090

983089983095983096 Farvid MS Ding M Pan A et al Dietary linoleic acid and risko coronary heart disease a systematic review and meta-analysis o prospective cohort studies Circulation 983090983088983089983092983089983091983088983089983093983094983096-983095983096

983089983095983097 Ramsden CE Zamora D Leelarthaepin B et al Use o dietary linoleicacid or secondary prevention o coronary heart disease and deathevaluation o recovered data rom the Sydney Diet Heart Study andupdated meta-analysis BMJ 983090983088983089983091983091983092983094e983096983095983088983095

copy BMJ Publishing Group Ltd 983090983088983089983093

Appendix 983089 Search strategies and data extractions

forms

Appendix 983090 Supplementary tables (eTables 983089-983090983088)

Appendix 983091 Evidence reviewed but did not inform

GRADE evidence summary

Appendix 983092 Supplementary figures (eFigures 983089-983094983096)

Appendix 983093 GRADE evidence profile for prospective

cohort studies of saturated fatty acids and health

outcomes


cohort studies of trans fatty acids and health outcomes



RESEARCH

2

fatty acids in the food supply are animal products such

as butter cowsrsquo milk meat salmon and egg yolks and

some plant products such as chocolate and cocoa butter

coconut and palm kernel oils Previous meta-analyses

of prospective cohort studies reported pooled relative

risk estimates comparing extremes of intake of saturated

fat of 983089983088983095 (983097983093 confidence interval 983088983097983094 to 983089983089983097 P=983088983090983090)

for coronary heart disease (CHD) 983088983096983089 (983088983094983090 to 983089983088983093

P=983088983089983089) for stroke and 983089983088983088 (983088983096983097 to 983089983089983089 P=983088983097983093) for car-

diovascular disease (CVD)983094 Intervention trials have

shown modest cardiovascular benefits of reducing

intake of saturated fat while increasing intake of polyun-

saturated fat983095 but most trials lasted only up to two years

and examined surrogate outcomes A meta-analysis of

randomized trials suggested a 983089983095 reduction in risk of

CVD in studies that reduced saturated fat intake from

about 983089983095 to about 983097 of energy (983088983096983091 983088983095983090 to 983088983097983094)983096

Trans fats contribute about 983089-983090 of energy in the

North American diet983097-983089983089 and are produced industrially

through partial hydrogenation of liquid plant oils in the

presence of a metal catalyst vacuum and high heat or

can occur naturally in meat and dairy products where

ruminant animals biohydrogenate unsaturated fatty

acids via bacterial enzymes The major industrially

produced trans fatty acids in the food supply are elaidic

acid isomers and the major ruminant derived trans

fatty acid is vaccenic acid both share the characteristic

of having at least one double bond in the ldquotrans-rdquo rather

than ldquocis-rdquo configuration A prior meta-analysis

reported pooled relative risk estimates of CHD of 983089983090983090

(983097983093 confidence interval 983089983088983096 to 983089983091983096 P=983088983088983088983090) for

extremes of total intake of trans fats 983089983091983088 (983088983096983088 to 983090983089983092

P=983088983090983097) for intake of industrially produced trans fats

and 983088983097983091 (983088983095983092 to 983089983089983096 P=983088983093983094) for intake of ruminantderived trans fats983089983090 suggesting that industrially pro-

duced trans fats might increase the risk of CHD though

this could also reflect the low levels of ruminant derived

trans fats compared with the higher doses of industri-

ally produced trans fats typically consumed in studies

and available in the food supply983089983091

Dietary guidelines recommend that saturated fats

should be limited to lt983089983088 (983093-983094 for those who would

benefit from lowering of LDL cholesterol) and trans fats

to lt983089 of energy or as low as possible983089983092-983089983097 primarily to

reduce risk of ischemic heart disease and stroke To

clarify controversies surrounding guidelines for satu-

rated and trans fats for adults we have extended andupdated previous work to synthesize prospective asso-

ciations between these fats and all cause mortality and

type 983090 diabetes (which have not been previously synthe-

sized) separate estimates for risks of cardiovascular

morbidity and mortality and assess the confidence in

the observational evidence using the Grading of Recom-

mendations Assessment Development and Evaluation

(GRADE) approach983090983088-983090983090

Methods

This review was conducted in accordance with the

WHOrsquos guideline development process983090983091 based on the

Cochrane Collaboration approach983090983092 and reportedaccording to the MOOSE checklist983090983093

Data sources

We conducted independent searches for relevant

observational studies assessing the association

between saturated andor trans fats and health out-

comes up to 983089 May 983090983088983089983093 (appendix 983089 gives full details)

This included searching Medline (from 983089983097983092983094) Embase

(from 983089983097983095983092) Cochrane Central Registry of Controlled

Trials (from 983089983097983097983094) Evidence Based Medicine Reviews

(from 983089983097983097983094) and CINAHL (from 983089983097983096983091) Reference lists of

retrieved articles and previous systematic and narra-

tive reviews983089 983089983090 983090983094-983090983097 were hand searched There were no

language restrictions

Study selection

Eligible studies included any observational study con-

ducted in humans (such as prospective cohort

case-control nested case-control or case-cohort

design) that reported a measure of association (such as

hazard ratios or incident rate ratios for prospective

studies or odds ratios for retrospective studies)

between intakes of saturated or trans fat measured by

self report or a biomarker and all cause mortality coro-

nary heart disease stroke or type 983090 diabetes measured

by self report andor confirmed by medical records or

registry linkage One reviewer assessed titles and

abstracts of all studies identified through electronic

searches Potentially eligible studies were reviewed

independently by a second reviewer with discrepan-

cies resolved by discussion and when necessary a

senior author was consulted to reach consensus

Data extraction

Pairs of authors independently extracted details of the

study design country of conduct exposure and out-come assessment participant characteristics and sta-

tistical analyses including adjustment for confounders

from included studies using pretested instruments (see

appendix 983089) with discrepancies resolved by discussion

Authors were contacted for additional data when nec-

essary We used Plot Digitizer (httpplotdigitizer

sourceforgenet) to extract numerical estimates from

graphs

Assessment of trans fats exposure methods

To assess the accuracy of measures of trans fats in stud-

ies that did not directly measure concentrations in

blood or adipose tissues we assessed the potential formisclassification The lowest risk of misclassification

was for those studies that used a food frequency ques-

tionnaire validated against multiple day prospective

diet records or 983090983092 hour recalls directly measured adi-

pose tissue trans fatty acids in a subset of the popula-

tion and analyzed dietary intake with an updated

database of foods A study was rated as at low risk of

misclassification if it accomplished all three moderate

risk of misclassification) if it accomplished two of three

high risk of misclassification if it accomplished one of

three or at very high risk of misclassification if it did

not accomplish any For assessment of ruminant trans

fats the most common approach was to use the knownnutrient composition from food tables for dairy and



RESEARCH

3




Study risk of bias

























to high



























Heterogeneity
















mediates)

Sensitivity


















exposure category

Publication bias







method983091983095

Sofware






College Station TX)

Patient involvement






RESEARCH

4

Results


Literature low



























All cause mortality
















studies)



















sons)983091983097 983092983091 983093983091 was 983088983097983095 (983088983096983092 to 983089983089983090 P=983088983094983097 I983090=983089983097












influential outlier











influential outlier










κ=


Excluded (n=)





RESEARCH

5





Literature low












































All cause mortality







All cause mortality

CHD mortality

CVD mortality

CHD total


( to )

( to )

( to )

( to )

( to ) ( to )

Outcome



Relative risk ( CI)

Risk ratio( CI)

I

()

lt

Phet

P









κ=








RESEARCH

6








eFigures 983089983091 and 983089983092























I983090=983089983093 Phet=983088983091983090)































Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes


All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome


Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P







RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

3




Study risk of bias

























to high



























Heterogeneity
















mediates)

Sensitivity


















exposure category

Publication bias







method983091983095

Sofware






College Station TX)

Patient involvement






RESEARCH

4

Results


Literature low



























All cause mortality
















studies)



















sons)983091983097 983092983091 983093983091 was 983088983097983095 (983088983096983092 to 983089983089983090 P=983088983094983097 I983090=983089983097












influential outlier











influential outlier










κ=


Excluded (n=)





RESEARCH

5





Literature low












































All cause mortality







All cause mortality

CHD mortality

CVD mortality

CHD total


( to )

( to )

( to )

( to )

( to ) ( to )

Outcome



Relative risk ( CI)

Risk ratio( CI)

I

()

lt

Phet

P









κ=








RESEARCH

6








eFigures 983089983091 and 983089983092























I983090=983089983093 Phet=983088983091983090)































Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes


All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome


Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P







RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

4

Results


Literature low



























All cause mortality
















studies)



















sons)983091983097 983092983091 983093983091 was 983088983097983095 (983088983096983092 to 983089983089983090 P=983088983094983097 I983090=983089983097












influential outlier











influential outlier










κ=


Excluded (n=)





RESEARCH

5





Literature low












































All cause mortality







All cause mortality

CHD mortality

CVD mortality

CHD total


( to )

( to )

( to )

( to )

( to ) ( to )

Outcome



Relative risk ( CI)

Risk ratio( CI)

I

()

lt

Phet

P









κ=








RESEARCH

6








eFigures 983089983091 and 983089983092























I983090=983089983093 Phet=983088983091983090)































Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes


All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome


Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P







RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

5





Literature low












































All cause mortality







All cause mortality

CHD mortality

CVD mortality

CHD total


( to )

( to )

( to )

( to )

( to ) ( to )

Outcome



Relative risk ( CI)

Risk ratio( CI)

I

()

lt

Phet

P









κ=








RESEARCH

6








eFigures 983089983091 and 983089983092























I983090=983089983093 Phet=983088983091983090)































Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes


All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome


Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P







RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

6








eFigures 983089983091 and 983089983092























I983090=983089983093 Phet=983088983091983090)































Total trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes


All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

Ruminant trans fats

All cause mortality

CHD mortality

CHD total

Ischemic stroke

Type diabetes

( to )

( to )

( to )

( to )

( to )

( to )

( to )

( to )

-

-

( to )

( to )

( to )

-

( to )

-

-

-

Outcome


Trans fatsharmful

Relative risk ( CI)

Risk ratio( CI)

I

()

-

-

-

Phet

lt

lt

-

-

-

lt

P







RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

7

(983089983089983096 983089983088983092 to 983089983091983091 P=983088983088983088983097 I983090=983088 Phet=983088983094983096 fig 983092
















ity983092983097 983096983091 (983089983088983089 983088983095983089 to 983089983092983091 P=983088983097983093 I983090=983095983097 Phet=983088983088983089) (fig 983092



CHD983096983088 983096983092 983096983093 (983088983097983091 983088983095983091 to 983089983089983096 P=983088983093983093 I983090=983092983094 Phet=983088983089983091)











emic stroke

















Discussion

Principal findings





















All cause mortality












































RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

8









Ischemic stroke






























products983089983090983094

































All cause mortality













existing cohorts











Ischemic stroke


















RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

9





















I983090=983088 Phet=983088983096983095)

































































































RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

10





















































































































RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

11
















































remains unexplained












studies












































carbohydrate













RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

12



















































































































RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

13


























































RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

14








































JAMA 983089983097983097983095983090983095983096983090983089983092983093-983093983088
























RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH

15































































RESEARCH





















































forms







outcomes





RESEARCH





















































forms







outcomes



Documents

journal 2 new.pdf