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Saturated Fat and Heart Diesease

Saturated Fat and Heart Diesease

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See corresponding editorial on page 497.
Meta-analysis of prospective cohort studies evaluating the associationof saturated fat with cardiovascular disease
Patty W Siri-Tarino, Qi Sun, Frank B Hu, and Ronald M Krauss
A reduction in dietary saturated fat has generallybeen thought to improve cardiovascular health.
The objective of this meta-analysis was to summarizethe evidence related to the association of dietary saturated fat withrisk of coronary heart disease (CHD), stroke, and cardiovasculardisease (CVD; CHD inclusive of stroke) in prospective epidemio-logic studies.
Twenty-one studies identified by searching MEDLINE andEMBASE databases and secondary referencing qualified for inclu-sion in this study. A random-effects model was used to derivecomposite relative risk estimates for CHD, stroke, and CVD.
During 5–23 y of follow-up of 347,747 subjects, 11,006developed CHD or stroke. Intake of saturated fat was not associatedwith an increased risk of CHD, stroke, or CVD. The pooled relativerisk estimates that compared extreme quantiles of saturated fat in-take were 1.07 (95% CI: 0.96, 1.19;
= 0.22) for CHD, 0.81 (95%CI: 0.62, 1.05;
= 0.11) for stroke, and 1.00 (95% CI: 0.89, 1.11;
= 0.95) for CVD. Consideration of age, sex, and study quality didnot change the results.
A meta-analysis of prospective epidemiologic studiesshowed that there is no significant evidence for concluding thatdietary saturated fat is associated with an increased risk of CHDor CVD. More data are needed to elucidate whether CVD risks arelikely to be influenced by the specific nutrients used to replacesaturated fat.
Am J Clin Nutr 
Early animal studies showed that high dietary saturated fat andcholesterol intakes led to increased plasma cholesterol concen-trations as well as atherosclerotic lesions (1). These findings weresupported by associations in humans in which dietary saturatedfatcorrelated withcoronaryheartdisease(CHD) risk(2,3).Morerecent epidemiologic studies have shown positive (4–10), inverse(11,12),orno(4,13–18)associationsofdietarysaturatedfatwithCVD morbidity and/or mortality.A limited number of randomized clinical interventions havebeen conducted that have evaluated the effects of saturated fat onriskof CVD.Whereas some studieshaveshown beneficial effectsof reduced dietary saturated fat (19–21), others have shown noeffects of such diets on CVD risk (22, 23). The studies thatshowed beneficial effects of diets reduced in saturated fatreplaced saturated fat with polyunsaturated fat, with the impli-cation that the CVD benefit observed could have been due to anincrease in polyunsaturated fat or in the ratio of polyunsaturatedfat to saturated fat (P:S), a hypothesis supported by a recentpooling analysis conducted by Jakobsen et al (24).The goal of this study was to conduct a meta-analysis of well-designedprospectiveepidemiologicstudiestoestimatetheriskof CHD and stroke and a composite risk score for both CHD andstroke, or total cardiovascular disease (CVD), that was associatedwith increased dietary intakes of saturated fat. Large prospectivecohort studies can provide statistical power to adjust for cova-riates, thereby enabling the evaluation of the effects of a specificnutrient on disease risk. However, such studies have caveats,including a reliance on nutritional assessment methods whosevalidity and reliability may vary (25), the assumption that dietsremain similar over the long term (26) and variable adjustmentfor covariates by different investigators. Nonetheless, a summaryevaluation of the epidemiologic evidence to date provides im-portant information as to the basis for relating dietary saturatedfat to CVD risk.
Study selection
Two investigators (QS and PS-T) independently conductedasystematic literature search ofthe MEDLINE (http://www.ncbi.nlm.nih.gov/pubmed/) and EMBASE (http://www.embase.com)databases through 17 September 2009 by using the followingsearch terms: (“saturated fat” or “dietary fat”) and (“coronary” or“cardiovascular” or “stroke”) and (“cohortor “follow up”).
From the Children’s Hospital Oakland Research Institute, Oakland, CA(PWS-T and RMK), and the Departments of Nutrition (QS and FBH) andEpidemiology (FBH), Harvard School of Public Health, Boston, MA.
PWS-T and QS contributed equally to this work.
The contents of this article are solely the responsibility of the authorsand do not necessarily represent the official view of the National Center forResearch Resources (http://www.ncrr.nih.gov) or the National Institutes of Health.
Supported by the National Dairy Council (PWS-T and RMK) and madepossible by grant UL1 RR024131-01 from the National Center for ResearchResources, a component of the National Institutes of Health (NIH), and NIHRoadmap for Medical Research (PWS-T and RMK). QS was supported bya Postdoctoral Fellowship from Unilever Corporate Research. FBH wassupported by NIH grant HL60712.
Address correspondence to RM Krauss, Children’s Hospital OaklandResearch Institute, 5700 Martin Luther King Junior Way, Oakland, CA94609. E-mail: rkrauss@chori.org.Received March 6, 2009. Accepted for publication November 25, 2009.First published online January 13, 2010; doi: 10.3945/ajcn.2009.27725.
 Am J Clin Nutr 
2010;91:535–46. Printed in USA.
2010 American Society for Nutrition
Studies were eligible if 
) data related to dietary consumption of saturated fat were available;
) the endpoints were nonfatal orfatal CVD events, but not CVD risk factors;
) the association of saturated fat with CVD was specifically evaluated;
) the studydesign was a prospective cohort study; and
) study participantswere generally healthy adults at study baseline. The initialsearch yielded 661 unique citations, of which 19 studies met theinclusion criteria and were selected as appropriate for inclusionin this meta-analysis (
Figure 1
) (4–6, 8–11, 14–16, 18, 27–34).All 4 investigators participated in the selection process (PS-T,QS, FBH, and RMK). Additional reference searches were per-formed by conducting a hand review of references from re-trieved articles, and 3 more studies were identified (13, 17, 35).Of the 22 identified studies, 10 studies provided data appropriateto the constraints of this meta-analysis, specifically, relative risk (RR) estimates for CVD as a function of saturated fat intake (10,14–16, 28, 30–34). Where such data were not provided (
= 12),data requests were made to investigators. Investigators from 6 of the studies (4, 5, 8, 18, 29, 35) responded with the requesteddata. A data set of the Honolulu Heart Study (9), obtained fromthe National Heart, Lung, and Blood Institute (36), was used toderive the RR estimates for this study. Investigators from 5 studieseither did not respond or could no longer access data sets (6, 11,13, 17, 27). However, 4 of 5 of these studies provided data forsaturated fat intake as a continuous variable (6, 11, 13, 17). Forthese studies, we derived RR estimates (
Statistical analysis)for categorical saturated fat intake and CHD and/or stroke. Thestudy by Boden-Albala et al (27) was excluded because the RRestimate published did not correspond to the values given for theupper and lower bounds of the CI, ie, using these values toderive the SE resulted in different estimates, and the authors didnot respond to our attempts to obtain the correct data.Altogether, this meta-analysis included data from 21 uniquestudies, with 16 studies providing risk estimates for CHD and8 studies providing data for stroke as an endpoint. Data were de-rivedfrom347,747participants,ofwhom11,006developedCVD.
Data extraction
Two authors (PS-T and QS) independently extracted and tab-ulated data from each study using a standard extraction form.Discrepancieswereresolvedviareviewoftheoriginalarticlesandgroup discussion. From each study, we extracted information onfirst author, publication year, disease outcome, country of origin,method of outcome ascertainment, sample size, age, sex, averagestudyfollow-uptime,numberofcases,dietaryassessmentmethodand the validity of the method, number of dietary assessments,covariates adjusted, unit of measurement, RR of CVD comparingextremequantilesofsaturatedfatintakeorperunitofsaturatedfatintake, and corresponding 95% CIs, SEs, or exact
Statistical analysis
RRs and 95% CIs were log transformed to derive corre-sponding SEs for
-coefficients by using Greenland’s formula(37). Otherwise, we used exact
values to derive SEs wherepossible. To minimize the possibility that the association forsaturated fat intake may be influenced by extreme values, wecontacted the authors of studies in which RRs were presented asper-unit increments of saturated fat intake and requested RRscomparing extreme quantiles. For studies for which we did notreceive responses, we used the published trend RRs comparingthe 25th and 75th percentiles to estimate RRs comparing highwith low dichotomized saturated fat intakes (38).Meta-analyses were performed by using STATA 10.0 (Stata-Corp, College Station TX) and Review Manager 5.0 (The NordicCochrane Centre, The Cochrane Collaboration, Copenhagen,Denmark; http://www.cc-ims.net/RevMan).
0.05 was con-sidered statistically significant. Random-effects models takinginto account both within-study and between-study variabilitywere used to estimate pooled RRs for associations of dietarysaturated fat with CHD risk. Relative to fixed-effects models,random-effects models were more appropriate for the currentstudy because test statistics showed evidence of heterogeneityamong these studies. When several RRs were given for subgroupanalyses within a single study, random-effects models were usedto pool the RRs into one composite estimate.We used the STATA METAINF module to examine the in-fluence of an individual study on the pooled estimate of RR byexcluding each study in turn. We used the STATA METAREGmodule to examine whether the effect size of these studiesdepended on certain characteristics of each study, including age,sex, sample size, duration of follow-up, whether disease out-comes were confirmed by medical record review, and a scoreevaluating overall study quality. This quality score was derivedfrom the following information: dietary assessment method(where 5 points were given for diet records, 4 for validated FFQs,3forFFQsthatwerenotformallyvalidated,2fordiethistory,and1 for 24-h recall), number of dietary assessments, and number of adjusted established risk factors for CVD. Points were totaled toconstruct a composite quality score for each study.We further conducted secondary analyses to examine age- andsex-specific effects (ie, age
60 y compared with
60 y and
Study selection process. CHD, coronary heart disease; CVD,cardiovascular disease; RR, relative risk.
Three studies provided outcomedata for both CHD and stroke.
     T      A     B     L     E      1
    S   t   u    d   y    d   e   s    i   g   n   c    h   a   r   a   c   t   e   r    i   s   t    i   c   s   o    f    2    1   u   n    i   q   u   e   p   r   o   s   p   e   c   t    i   v   e   e   p    i    d   e   m    i   o    l   o   g    i   c   s   t   u    d    i   e   s   o    f   s   a   t   u   r   a   t   e    d    f   a   t    i   n   t   a    k   e   a   n    d   r    i   s    k   o    f   c   o   r   o   n   a   r   y    h   e   a   r   t    d    i   s   e   a   s   e    (    C    H    D    )   o   r   s   t   r   o    k   e
    S   t   u    d   y    D    i   s   e   a   s   e   o   u   t   c   o   m   e    D    i   e   t   a   r   y   a   s   s   e   s   s   m   e   n   t   m   e   t    h   o    d    F    F    Q    i   t   e   m   s    V   a    l    i    d   a   t    i   o   n   o    f   n   u   t   r    i   e   n   t   s    C   o   r   r   e    l   a   t    i   o   n   w    i   t    h    d    i   e   t   r   e   c   o   r    d
    V   a    l    i    d   a   t    i   o   n    i   n   s   t   u    d   y   p   o   p   u    l   a   t    i   o   n    M   u    l   t    i   p    l   e   a   s   s   e   s   s   m   e   n   t   o    f    d    i   e   t    A   s   s   e   s   s   m   e   n   t    i   n   t   e   r   v   a    l    A   v   e   r   a   g   e    d   u   r   a   t    i   o   n   o    f    f   o    l    l   o   w  -   u   p
    y    y
    C    H    D    S    h   e    k   e    l    l   e   e   t   a    l ,    1    9    8    1    (    1    7    )    F   a   t   a    l    C    H    D    I   n   t   e   r   v    i   e   w    (    2    8    d    )    1    9    5    N   o   t   v   a    l    i    d   a   t   e    d  —  —    B   a   s   e    l    i   n   e  —    2    0    M   c    G   e   e   e   t   a    l ,    1    9    8    4    (    9    )
    T   o   t   a    l    C    H    D    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    0    K   u   s    h    i   e   t   a    l ,    1    9    8    5    (    1    3    )    F   a   t   a    l    C    H    D    D    i   e   t  -    h    i   s   t   o   r   y    (   t    i   m   e    f   r   a   m   e   u   n    k   n   o   w   n    )  —    N   o   t   v   a    l    i    d   a   t   e    d  —  —    B   a   s   e    l    i   n   e  —    2    0    P   o   s   n   e   r   e   t   a    l ,    1    9    9    1    (    1    6    )    T   o   t   a    l    C    H    D    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    6    F   e    h    i    l   y   e   t   a    l ,    1    9    9    3    (    2    8    )    T   o   t   a    l    C    H    D    7  -    d    d    i   e   t   r   e   c   o   r    d   s  —    N    A  —  —    B   a   s   e    l    i   n   e  —    5    G   o    l    d    b   o   u   r   t   e   t   a    l ,    1    9    9    3    (    3    5    )
    F   a   t   a    l    C    H    D    F    F    Q    (   t    i   m   e    f   r   a   m   e   u   n    k   n   o   w   n    )    N    R    N   o   t   v   a    l    i    d   a   t   e    d  —  —    B   a   s   e    l    i   n   e  —    2    3    A   s   c    h   e   r    i   o   e   t   a    l ,    1    9    9    6    (    4    )    T   o   t   a    l    C    H    D    F    F    Q    (    1   y    )    1    3    1    V   a    l    i    d   a   t   e    d    0 .    7    5    Y   e   s    T   w    i   c   e    4    1    4    E   s   r   e   y   e   t   a    l ,    1    9    9    6    (    6    )    F   a   t   a    l    C    H    D    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    2    M   a   n   n   e   t   a    l ,    1    9    9    7    (    3    2    )    F   a   t   a    l    C    H    D    F    F    Q    (   t    i   m   e    i   n   t   e   r   v   a    l   u   n    k   n   o   w   n    )    N    R    N   o   t   v   a    l    i    d   a   t   e    d  —  —    B   a   s   e    l    i   n   e  —    1    3    P    i   e   t    i   n   e   n   e   t   a    l ,    1    9    9    7    (    1    5    )    T   o   t   a    l    C    H    D    F    F    Q    (    1   y    )    2    7    6    V   a    l    i    d   a   t   e    d    0 .    7    0    Y   e   s    B   a   s   e    l    i   n   e  —    6    B   o   n    i    f   a   c   e   a   n    d    T   e    f    f   t ,    2    0    0    2    (    5    )    F   a   t   a    l    C    H    D    F    F    Q    (   t    i   m   e    f   r   a   m   e   u   n    k   n   o   w   n    )    3    0    V   a    l    i    d   a   t   e    d    0 .    3    4    Y   e   s    B   a   s   e    l    i   n   e  —    1    6    J   a    k   o    b   s   e   n   e   t   a    l ,    2    0    0    4    (    8    )    T   o   t   a    l    C    H    D    7  -    d    d    i   e   t   r   e   c   o   r    d   s  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    6    L   e   o   s    d   o   t   t    i   r   e   t   a    l ,    2    0    0    7    (    1    4    )
    F   a   t   a    l    C    H    D    F    F    Q    (    1   y    )   a   n    d    7  -    d   m   e   n   u  -    d    i   a   r   y    1    6    8    V   a    l    i    d   a   t   e    d    0 .    5    0    Y   e   s    B   a   s   e    l    i   n   e  —    8    O    h   e   t   a    l ,    2    0    0    5    (    3    3    )    T   o   t   a    l    C    H    D    F    F    Q    (    1   y    )    1    1    6    V   a    l    i    d   a   t   e    d    0 .    6    8    Y   e   s    6   t    i   m   e   s    2  –    4    2    0    T   u   c    k   e   r   e   t   a    l ,    2    0    0    5    (    1    8    )    F   a   t   a    l    C    H    D    7  -    d    d    i   e   t   r   e   c   o   r    d   s  —    N    A  —  —    4   t    i   m   e   s    3  –    9    1    8    X   u   e   t   a    l ,    2    0    0    6    (    1    0    )    T   o   t   a    l    C    H    D    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    7    S   t   r   o    k   e    M   c    G   e   e   e   t   a    l ,    1    9    8    4    (    9    )
    T   o   t   a    l   s   t   r   o    k   e    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    0    G   o    l    d    b   o   u   r   t   e   t   a    l ,    1    9    9    3    (    3    5    )
    F   a   t   a    l   s   t   r   o    k   e    F    F    Q    (   t    i   m   e    f   r   a   m   e   u   n    k   n   o   w   n    )    N    R    N   o   t   v   a    l    i    d   a   t   e    d  —  —    B   a   s   e    l    i   n   e  —    2    3    G    i    l    l   m   a   n   e   t   a    l ,    1    9    9    7    (    1    1    )    I   s   c    h   e   m    i   c   s   t   r   o    k   e    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    2    0    I   s   o   e   t   a    l ,    2    0    0    1    (    3    1    )    H   e   m   o   r   r    h   a   g    i   c   s   t   r   o    k   e    F    F    Q    (    1   y    )    1    1    6    V   a    l    i    d   a   t   e    d    0 .    6    8    Y   e   s    4   t    i   m   e   s    2  –    4    1    4    H   e   e   t   a    l ,    2    0    0    3    (    2    9    )    T   o   t   a    l   s   t   r   o    k   e    F    F    Q    (    1   y    )    1    3    1    V   a    l    i    d   a   t   e    d    0 .    7    5    Y   e   s    3   t    i   m   e   s    4    1    4    I   s   o   e   t   a    l ,    2    0    0    3    (    3    0    )    H   e   m   o   r   r    h   a   g    i   c   s   t   r   o    k   e    2    4  -    h   r   e   c   a    l    l    (    1    d    )  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    4    S   a   u   v   a   g   e   t   e   t   a    l ,    2    0    0    4    (    3    4    )    F   a   t   a    l   s   t   r   o    k   e    1  -    d    d    i   e   t   r   e   c   o   r    d  —    N    A  —  —    B   a   s   e    l    i   n   e  —    1    4    L   e   o   s    d   o   t   t    i   r   e   t   a    l ,    2    0    0    7    (    1    4    )
    I   s   c    h   e   m    i   c   s   t   r   o    k   e    F    F    Q    (    1   y    )   a   n    d    7  -    d   m   e   n   u  -    d    i   a   r   y    1    6    8    V   a    l    i    d   a   t   e    d    0 .    5    0    Y   e   s    B   a   s   e    l    i   n   e  —    8
    F    F    Q ,    f   o   o    d  -    f   r   e   q   u   e   n   c   y   q   u   e   s   t    i   o   n   n   a    i   r   e   ;    N    R ,   n   o   t   r   e   p   o   r   t   e    d   ;    N    A ,   n   o   t   a   p   p    l    i   c   a    b    l   e .
    O   n    l   y   p   e   r   t   a    i   n   s   t   o   s   t   u    d    i   e   s   t    h   a   t   u   s   e    d   a   n    F    F    Q   t   o   m   e   a   s   u   r   e   s   a   t   u   r   a   t   e    d    f   a   t    i   n   t   a    k   e .
    T    h   e   s   e   s   t   u    d    i   e   s   p   r   o   v    i    d   e    d    b   o   t    h    C    H    D   a   n    d   s   t   r   o    k   e   o   u   t   c   o   m   e    d   a   t   a .

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