META-ANALYSIS Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose–response meta-analysis of prospective cohort studies Jing Guo 1 • Arne Astrup 2 • Julie A. Lovegrove 3 • Lieke Gijsbers 4 • David I. Givens 1 • Sabita S. Soedamah-Muthu 4 Received: 6 October 2016 / Accepted: 27 March 2017 / Published online: 3 April 2017 Ó The Author(s) 2017. This article is an open access publication Abstract With a growing number of prospective cohort studies, an updated dose–response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose–response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associa- tions were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/ low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk prod- ucts, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97–0.99; I 2 = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97–0.99; I 2 = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95–1.00; I 2 = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods. Keywords Dairy Á Milk Á Fermented dairy Á All-cause mortality Á Cardiovascular disease Á Dose–response meta- analysis Introduction Cardiovascular disease (CVD) is the leading cause of mortality and disability worldwide [1]. Together with smoking, obesity and inactivity, diet is considered to be one of the most important prevention strategies for CVD Electronic supplementary material The online version of this article (doi:10.1007/s10654-017-0243-1) contains supplementary material, which is available to authorized users. & Jing Guo [email protected]Arne Astrup [email protected]Julie A. Lovegrove [email protected]Lieke Gijsbers [email protected]David I. Givens [email protected]Sabita S. Soedamah-Muthu [email protected]1 Institute for Food, Nutrition and Health, University of Reading, Reading RG6 6AR, UK 2 Department of Nutrition, Exercise and Sports, University of Copenhagen, 2200 Copenhagen, Denmark 3 Hugh Sinclair Unit of Human Nutrition, Institute for Cardiovascular and Metabolic Research, University of Reading, Reading RG6 6AP, UK 4 Division of Human Nutrition, Wageningen University and Research, 6708 WE Wageningen, The Netherlands 123 Eur J Epidemiol (2017) 32:269–287 DOI 10.1007/s10654-017-0243-1
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META-ANALYSIS
Milk and dairy consumption and risk of cardiovascular diseasesand all-cause mortality: dose–response meta-analysisof prospective cohort studies
Jing Guo1• Arne Astrup2
• Julie A. Lovegrove3• Lieke Gijsbers4
• David I. Givens1•
Sabita S. Soedamah-Muthu4
Received: 6 October 2016 / Accepted: 27 March 2017 / Published online: 3 April 2017
� The Author(s) 2017. This article is an open access publication
Abstract With a growing number of prospective cohort
studies, an updated dose–response meta-analysis of milk
and dairy products with all-cause mortality, coronary heart
disease (CHD) or cardiovascular disease (CVD) have been
conducted. PubMed, Embase and Scopus were searched for
articles published up to September 2016. Random-effect
meta-analyses with summarised dose–response data were
performed for total (high-fat/low-fat) dairy, milk,
fermented dairy, cheese and yogurt. Non-linear associa-
tions were investigated using the spine models and
heterogeneity by subgroup analyses. A total of 29 cohort
studies were available for meta-analysis, with 938,465
participants and 93,158 mortality, 28,419 CHD and 25,416
CVD cases. No associations were found for total (high-fat/
low-fat) dairy, and milk with the health outcomes of
mortality, CHD or CVD. Inverse associations were found
between total fermented dairy (included sour milk prod-
ucts, cheese or yogurt; per 20 g/day) with mortality (RR
0.98, 95% CI 0.97–0.99; I2 = 94.4%) and CVD risk (RR
0.98, 95% CI 0.97–0.99; I2 = 87.5%). Further analyses of
individual fermented dairy of cheese and yogurt showed
cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI
0.95–1.00; I2 = 82.6%) per 10 g/day, but not yogurt. All of
these marginally inverse associations of totally fermented
dairy and cheese were attenuated in sensitivity analyses by
removing one large Swedish study. This meta-analysis
combining data from 29 prospective cohort studies
demonstrated neutral associations between dairy products
and cardiovascular and all-cause mortality. For future
studies it is important to investigate in more detail how
Cardiovascular disease (CVD) is the leading cause of
mortality and disability worldwide [1]. Together with
smoking, obesity and inactivity, diet is considered to be
one of the most important prevention strategies for CVD
Electronic supplementary material The online version of thisarticle (doi:10.1007/s10654-017-0243-1) contains supplementarymaterial, which is available to authorized users.
Data were extracted from published articles by using a
structured extraction form, which included descriptive
characteristics of the study, range of intake, median intake,
number of participants, number of mortalities, CHD or
CVD cases, person-years at risk, and relative risk (RR)
with 95% CI for each unit of dairy intake. For studies that
reported results from different multivariable-adjusted
models, the model with the most confounding factors was
extracted for the meta-analysis. If dairy intake was pre-
sented in servings or times per period of time
[12–20, 22, 23, 34–36, 39], we converted the portion size
into grams per day by using standard units of 244 g for
milk (585 g for 1 pint of milk); 244 g for yoghurt and 40 g
for cheese [41, 42]. One serving of total dairy, high-fat
dairy and low-fat dairy was taken to be 200 g, similar to
our previous meta-analysis [5]. When studies reported
country specific conversion factors, these were used to
calculate intake as g/day [26, 29, 30].
In some studies the mean intakes of dairy categories
were not reported, in which case we calculated the mean
value by using the lower and upper limit. For open-ended
upper limits of intake, the same range as the lower category
was applied. The categories of dairy types were defined in
accordance with the definition in the original articles
(Supplemental Table 2).
Two independent reviewers determined the quality of
the 29 studies based on the Newcastle–Ottawa quality
assessment scale (NOS, Supplemental Methods) [43]. By
evaluation of selection, comparability and outcome, the
rating system scores studies from 0 (highest degree of bias)
to 9 (lowest degree of bias). Additionally we investigated
the funding sources of all of the eligible studies. The four
categories of funding were recorded as industry, partial
funded by industry, research institution and unknown.
Statistical analysis
Meta-analyses of each dairy type were performed if the
number of studies was three or more. Splined variables
were generated by MKSPLINE in STATA version 13.0 to
determine the most appropriate knot points of nonlinear
associations from goodness-of-fit tests and Chi square
statistics. Spine analysis and dose–response generalised
least-square trend (GLST) meta-analysis were applied for
the further analysis of linear or nonlinear associations.
Incremental dose–response RRs were derived from the
random-effects meta-regression trend estimation of sum-
marised dose–response data. Ding’s spaghetti plot was
used to present the shapes of the association within indi-
vidual studies, as described previously [44]. Forest plots
were created to assess the linear dose–response slopes and
270 J. Guo et al.
123
corresponding 95% CI across relative studies with incre-
ments of 200 g/day for total, high-fat, and low-fat dairy;
244 g/day for milk; 20 g/day for total fermented dairy
(includes cheese, yogurt and soured milk products);
10 g/day for cheese; 50 g/day for yogurt. Sensitivity
analysis was based on linear dose–response slopes by
excluding one study population at a time.
To explore heterogeneity between studies, I-squared was
calculated from Cochrane Q test [45]. In addition, sub-
group analyses were performed providing that at least 6
study populations were available by age (B50 years,
[50 years), follow-up duration (B10 years, [10 years),
gender (men, women, both men and women), continent,
confounding factors (whether analyses were or were not
adjusted for the following 7 confounders age, sex, smok-
ing, alcohol, body mass index (BMI), physical activity,
food energy intake), BMI (B25 kg/m2, [25 kg/m2) and
Newcastle–Ottawa quality score\or C7. When number of
the examined studies C10, potential publication bias was
assessed by means of the Eggers test [46] and symmetry of
the funnel plot. All of the statistical analyses were per-
formed in STATA version 13.0 (StataCorp. College Sta-
tion, Texas, USA). Two-sided P values \0.05 were
considered as statistically significant.
Results
Overviews of key characteristics of the 29 prospective
cohort studies are shown in Table 1. The included partic-
ipants of each dairy exposure data on all-cause mortality,
CHD or CVD are presented in Table 2. A total of 783,989
participants, 93,158 mortality cases, 28,419 CHD and
25,416 CVD were included in the analysis. There were 3
studies conducted in Asia (Japan and Taiwan) [28, 35, 39],
2 studies in Australia [24, 29], 7 in the United States
[12, 14–16, 19, 22, 34] and the remaining 17 studies in
Europe. A total of 6 studies presented sex-specific results, 3
studies were in men [18–20] and 3 in women [15, 16, 30].
There was one study [12] with missing data on age and 4
studies with missing BMI data [12, 21, 33, 36]. The esti-
mated mean age was 57 years (range 34–80 years) and
mean value of BMI was 25.4 kg/m2 (range 22.3–27.1 kg/
m2). The duration of follow-up ranged from 5 to 25 years,
with a mean follow-up of 13 years. Study characteristics of
each dairy intake category by outcomes are shown in
Table 2. Results of quality assessment are shown in the
Supplemental Table 1, with 18 studies scoring C7. All of
the studies were funded by a research institute except one
study [13] without funding information, thus sub-group
analysis was not conducted by funding source. There was
no evidence of publication bias in the meta-analyses of
milk or dairy consumption with different health outcomes
(Supplemental Figs. 19–27).
Total, high-fat, and low-fat dairy
Total dairy intake (per 200 g/day) was not associated with
the risk of all-cause mortality (Supplemental Figure 1; RR
0.99, 95% CI 0.96–1.03, 10 populations), CHD (Supple-
mental Figure 2; RR 0.99, 95% CI 0.96–1.02, 12 popu-
lations) or CVD (Supplemental Figure 3; RR 0.97, 95%
CI 0.91–1.02). Considerable heterogeneity was observed
in the meta-analyses of mortality (I2 = 62.2%,
PubMed 5248
Embase6182
Title selectionExclusion criteria(manual):- Animal studies- Children (age≤18)- Prior CVD, diabetes, or other chronic diseases
Abstract selectionInclusion criteria (manual):- prospective cohort study- general population- men or women- original article- determinants dairy/milk - CVD outcomes/mortality
Title and abstract selection
57 articles (undoubled)
Extra references through hand search3 articles
Available for meta-analyses
29 articles
Full-text selection:data available to conduct pooled analyses (RR, OR)
60 articles full articles
Scopus9179
Fig. 1 Flowchart of meta-analysis on dairy consumption and incident CVD, CVD mortality and all-cause mortality
Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose… 271
123
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Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose… 273
123
Ta
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f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
En
gb
erin
k
etal
.[4
0]
Th
eR
ott
edam
Stu
dy
,
Net
her
lan
ds
38
66
.92
6.2
11
.21
11
1
dea
th
(30
7
fro
m
CV
D)
39
71
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Ch
eese
FF
Q(v
alid
ated
)A
ll-c
ause
mo
rtal
ity
,C
VD
mo
rtal
ity
;m
edic
al
reco
rdan
dd
igit
al
reco
rdli
nk
age
Ag
e,se
x,
BM
I,S
BP
,to
tal
cho
lest
ero
l,fa
mil
y
his
tory
of
MI,
use
of
oes
tro
gen
,sm
ok
ing
,
edu
cati
on
alle
vel
,
alco
ho
lco
nsu
mp
tio
n,
tota
len
erg
y,
satu
rate
d
fat,
inta
ke
of
fru
it,
veg
etab
les,
mea
t,fi
sh,
coff
ee,
and
tea
Pan
agio
tak
os
etal
.[2
3]
AT
TIC
AS
tud
y;
Gre
ece
50
53
27
53
0C
VD
(fat
al
and
no
n-
fata
l)
68
6T
ota
ld
airy
,
Ch
eese
,
Yo
gu
rt,
Mil
k
FF
Q(v
alid
ated
)C
VD
(fat
alan
dn
on
-
fata
l);
med
ical
reco
rds
Ag
e,se
x,
BM
I,
hy
per
ten
sio
n,
dia
bet
es,
hy
per
cho
lest
ero
lem
ia,
curr
ent
smo
kin
g,
ph
ysi
cal
acti
vit
y
Bo
nth
uis
etal
.[2
4]
Co
mm
un
ity
-
bas
edsa
mp
le,
Au
stra
lia
43
49
.82
6.2
14
.41
77
dea
th
(61
fro
m
CV
D)
15
29
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Mil
k,
Yo
gu
rt,
Fu
ll-f
at
chee
se
FF
Q(v
alid
ated
)A
ll-c
ause
mo
rtal
ity
,C
VD
mo
rtal
ity
;N
atio
nal
Dea
thIn
dex
of
Au
stra
lia
Ag
e,se
x,
tota
len
erg
y
inta
ke,
bo
dy
mas
s
ind
ex,
alco
ho
lin
tak
e,
sch
oo
lle
avin
gag
e,
ph
ysi
cal
acti
vit
yle
vel
,
pac
ky
ears
of
smo
kin
g,
die
tary
sup
ple
men
tu
se,
b-c
aro
ten
etr
eatm
ent
du
rin
gtr
ial,
pre
sen
ceo
f
any
med
ical
con
dit
ion
,
and
die
tary
calc
ium
inta
ke.
Go
ldb
oh
m
etal
.[2
5]
Net
her
lan
d
Co
ho
rtS
tud
y
48
61
.62
4.4
10
16
,13
6
dea
th
(26
89
fro
m
IHD
)
12
0,8
52
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Hig
h-f
at
ferm
ente
d
dai
ry,
Lo
w-
fat
ferm
ente
d
dai
ry,
Ch
eese
15
0it
emF
FQ
(val
idat
ed)
All
-cau
sem
ort
alit
y,
IHD
mo
rtal
ity
;D
utc
h
Cen
tral
Bu
reau
of
Gen
ealo
gy
and
the
Du
tch
Cen
tral
Bu
reau
of
Sta
tist
ics
Ag
e,ed
uca
tio
n,
cig
aret
te,
cig
ar,
and
pip
e
smo
kin
g,
no
no
ccu
pat
ion
al
ph
ysi
cal
acti
vit
y,
occ
up
atio
nal
ph
ysi
cal
acti
vit
y,
BM
I,
mu
ltiv
itam
inu
se,
alco
ho
l,en
erg
y,
ener
gy
-
adju
sted
mo
no
-an
d
po
lyu
nsa
tura
ted
fat
inta
kes
,an
d
veg
etab
lean
dfr
uit
con
sum
pti
on
274 J. Guo et al.
123
Ta
ble
1co
nti
nu
ed
Ref
eren
ces
Stu
dy
,co
un
try
Men
(%)
Mea
n
age,
yea
r
Mea
n
BM
I,k
g/
m2
Fo
llo
w-
up
tim
e
No
.o
f
case
s
No
.o
f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
So
nes
ted
t
etal
.[2
6]
Th
eM
alm
od
iet
and
can
cer
coh
ort
,S
wed
en
38
57
.32
5.2
12
25
20
CV
D2
6,4
45
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Fer
men
ted
dai
ry,
Mil
k,
Ch
eese
Die
tary
asse
ssm
ent
met
ho
d
CV
D(f
atal
and
no
n-f
atal
)S
ex,
seas
on
,m
eth
od
,
ener
gy
inta
ke,
BM
I,
smo
kin
g,
alco
ho
l
con
sum
pti
on
,le
isu
re-
tim
ep
hy
sica
lac
tiv
ity
,
and
edu
cati
on
Dal
mei
jer
etal
.[2
7]
EP
IC-N
L;
Net
her
lan
ds
25
.54
8.7
25
.61
01
18
4
dea
th,
18
07
tota
l
CV
D,
13
09
tota
l
CH
D,
33
,62
5T
ota
ld
airy
,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Fer
men
ted
dai
ry,
Ch
eese
79
-ite
mF
FQ
(val
idat
ed)
All
-cau
sem
ort
alit
y,
CV
D
(fat
alan
dn
on
fata
l),
CH
D(f
atal
and
no
nfa
tal)
;R
egis
ter
of
ho
spit
ald
isch
arg
e
dia
gn
ose
s
Gen
der
,ag
e,to
tal
ener
gy
inta
ke,
ph
ysi
cal
acti
vit
y,
smo
kin
g,
edu
cati
on
,B
MI,
eth
ano
l,co
ffee
,fr
uit
,
veg
etab
les,
fish
,m
eat
and
bre
ad
Ko
nd
oet
al.
[28
]
Nat
ion
al
Inte
gra
ted
Pro
ject
for
Pro
spec
tiv
e
Ob
serv
atio
no
f
No
n-
com
mu
nic
able
Dis
ease
An
dit
s
Tre
nd
sin
the
Ag
ed,
Jap
an
44
50
.32
2.7
24
89
3C
VD
dea
th,
17
4
CH
D
dea
th;
92
43
Mil
kW
eig
hed
die
t
reco
rds
and
die
tary
inte
rvie
ws
CV
Dm
ort
alit
y,
CH
D
mo
rtal
ity
;fo
llo
w-u
p
surv
eys
Ag
e,b
od
ym
ass
ind
ex,
smo
kin
gst
atu
s,al
coh
ol
dri
nk
ing
hab
it,
his
tory
of
dia
bet
es,
use
of
anti
hy
per
ten
siv
e,w
ork
cate
go
ry,
and
tota
l
ener
gy
inta
ke
So
edam
ah-
Mu
thu
etal
.
[31
]
Wh
iteh
all
II
Stu
dy
,U
nit
ed
Kin
gd
om
72
56
25
.91
03
23
CH
D;
23
7al
l-
cau
se
mo
rtal
ity
45
26
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Mil
k,
Fer
men
ted
dai
ry,
Ch
eese
,
Yo
gu
rt
11
4it
emF
FQ
(val
idat
ed)
All
-cau
sem
ort
alit
y,
CH
D
(fat
alan
dn
on
-fat
al);
Dea
thw
asco
llec
ted
fro
mN
HS
Cen
tral
Reg
istr
y,
case
so
fM
I
wer
eid
enti
fied
fro
m
twel
ve-
lead
elec
tro
card
iog
ram
s
Ag
e,et
hn
icit
yan
d
emp
loy
men
tg
rad
e,
smo
kin
g,
alco
ho
l
inta
ke,
BM
I,p
hy
sica
l
acti
vit
yan
dfa
mil
y
his
tory
of
CH
D/
hy
per
ten
sio
n,
fru
itan
d
veg
etab
les,
bre
ad,
mea
t,
fish
,co
ffee
,te
aan
d
tota
len
erg
yin
tak
e
Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose… 275
123
Ta
ble
1co
nti
nu
ed
Ref
eren
ces
Stu
dy
,co
un
try
Men
(%)
Mea
n
age,
yea
r
Mea
n
BM
I,k
g/
m2
Fo
llo
w-
up
tim
e
No
.o
f
case
s
No
.o
f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
Lo
uie
etal
.
[29
]
Th
eB
lue
Mo
un
tain
Ey
e
44
65
.42
6.2
15
10
48
dea
th
29
00
To
tal
dai
ry,
14
5-i
tem
FF
1
(val
idat
ed)
CV
Dm
ort
alit
y,
CH
D
mo
rtal
ity
;
Ag
e,se
x,
tota
len
erg
y,
bas
elin
e
Stu
dy
,A
ust
rali
a(5
48
fro
m
CV
D,
43
2fr
om
CH
D)
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry
Au
stra
lian
Nat
ion
al
Dea
thIn
dex
BM
I,ch
ang
ein
wei
gh
t
du
rin
gfo
llo
wu
p,
ph
ysi
cal
acti
vit
yle
vel
(ME
Ts)
,p
rev
iou
sac
ute
my
oca
rdia
lin
farc
tio
n,
pre
vio
us
stro
ke,
smo
kin
gst
atu
s,st
age
II
hy
per
ten
sio
n,
typ
e2
dia
bet
esst
atu
s,u
seo
f
anti
hy
per
ten
siv
e
med
icat
ion
,u
seo
f
stat
ins
and
chan
ge
in
dai
ryin
tak
e
Ru
este
net
al.
[33
]
EP
IC-P
ots
dam
Stu
dy
;G
erm
an
39
50
–8
36
3C
VD
23
,53
1H
igh
-fat
dai
ry,
Lo
w-
fat
dai
ry,
Hig
h-f
at
chee
se,
Lo
w-f
at
chee
se
FF
Q(v
alid
ated
)C
VD
(fat
alan
dn
on
-
fata
l);
self
-ad
min
iste
red
foll
ow
-up
qu
esti
on
nai
res
and
med
ical
lyv
erifi
ed
Ag
e,se
x,
smo
kin
gst
atu
s,
pac
k-y
ears
of
smo
kin
g,
alco
ho
lco
nsu
mp
tio
n,
leis
ure
-tim
ep
hy
sica
l
acti
vit
y,
BM
I,w
aist
-to
-
hip
rati
o,
pre
val
ent
hy
per
ten
sio
nat
bas
elin
e,h
isto
ryo
fh
igh
blo
od
lip
idle
vel
sat
bas
elin
e,ed
uca
tio
n,
vit
amin
sup
ple
men
tati
on
and
tota
len
erg
yin
tak
e
Van
Aer
de
etal
.[3
2]
Th
eH
oo
rnS
tud
y;
43
.86
1.1
26
.51
2.4
40
31
95
6T
ota
l9
2-i
tem
FF
QA
ll-c
ause
Ag
e,se
x,
BM
I,
Net
her
lan
ds
dea
th(1
16
fro
m
CV
D,
50
fro
m
CH
D)
Dai
ry,
Hig
h-
fat
dai
ry,
Lo
w-f
at
dai
ry,
Mil
k,
Fer
men
ted
dai
ry,
Ch
eese
(val
idat
ed)
Mo
rtal
ity
,fa
tal
CV
D,
fata
lC
HD
;G
ener
al
pra
ctit
ion
ers
and
the
loca
lh
osp
ital
Sm
ok
ing
,ed
uca
tio
nal
lev
el,
tota
len
erg
y
inta
ke,
alco
ho
l
con
sum
pti
on
,p
hy
sica
l
acti
vit
yan
din
tak
eo
f
mea
t,fi
sh,
bre
ad,
veg
etab
les,
fru
it,
coff
ee,
and
tea
276 J. Guo et al.
123
Ta
ble
1co
nti
nu
ed
Ref
eren
ces
Stu
dy
,co
un
try
Men
(%)
Mea
n
age,
yea
r
Mea
n
BM
I,k
g/
m2
Fo
llo
w-
up
tim
e
No
.o
f
case
s
No
.o
f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
Pat
ters
on
etal
.[3
0]
Sw
edis
h
Mam
mo
gra
ph
y
coh
ort
,S
wed
en
06
1.2
24
.91
1.6
13
92
MI
33
,63
6T
ota
ld
airy
,
Mil
k,
Fer
men
ted
dai
ry,
Lo
w-
fat
ferm
ente
d
dai
ry,
Hig
h-
fat
ferm
ente
d
dai
ry,
Ch
eese
96
-ite
mse
mi
qu
anti
tati
ve
FF
Q
(val
idat
ed)
Inci
den
tca
ses
of
MI
(fat
alan
dn
on
fata
l);
Reg
istr
yan
dre
cord
lin
kag
e
Sm
ok
ing
stat
us,
ph
ysi
cal
acti
vit
y,
wai
st-t
o-h
ip
rati
o,
alco
ho
l
con
sum
pti
on
,d
iag
no
sis
of
hy
per
ten
sio
n,
dia
gn
osi
so
fh
igh
cho
lest
ero
l,fa
mil
y
his
tory
of
my
oca
rdia
l
infa
rcti
on
,ed
uca
tio
n,
asp
irin
usa
ge,
ho
rmo
ne
ther
apy
usa
ge,
ener
gy
inta
ke,
all
oth
erd
airy
foo
dg
rou
ps,
fru
itan
d
veg
etab
les
and
wh
ole
-
gra
info
od
s,u
seo
fo
ils
inco
ok
ing
,an
du
seo
f
low
-fat
mar
gar
ine
on
bre
ad
Hu
ang
etal
.
[35
]
Nu
trit
ion
and
Hea
lth
Su
rvey
inT
aiw
an,
Tai
wan
–3
5.6
22
.91
3.7
44
4d
eath
(87
fro
m
CV
D)
38
10
To
tal
dai
ryF
FQ
(val
idat
ed)
All
-cau
sem
ort
alit
y,
CV
D
mo
rtal
ity
;N
atio
nal
dea
thre
gis
trat
ion
Ag
e,g
end
er,
BM
I,
reg
ion
,et
hn
icit
y,
edu
cati
on
lev
el,
mar
riag
e,h
isto
ryo
f
dis
ease
(car
dio
vas
cula
r
dis
ease
and
/or
can
cer)
,
smo
kin
g,
dri
nk
ing
,
chew
bet
eln
ut,
and
sup
ple
men
tu
se,
ov
eral
l
Die
tary
Ind
ex–
Rev
ised
(dai
rysc
ore
excl
ud
ed),
Cal
ciu
min
tak
e,v
itam
in
Din
tak
e
Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose… 277
123
Ta
ble
1co
nti
nu
ed
Ref
eren
ces
Stu
dy
,co
un
try
Men
(%)
Mea
n
age,
yea
r
Mea
n
BM
I,k
g/
m2
Fo
llo
w-
up
tim
e
No
.o
f
case
s
No
.o
f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
Har
ing
etal
.
[34
]
Ath
ero
scle
rosi
s
Ris
kin
Co
mm
un
itie
s
Stu
dy
;U
SA
44
.25
3.8
27
.12
21
14
7C
HD
12
,06
6T
ota
ld
airy
,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry
FF
Q (un
val
idat
ed)
CH
D(f
atal
and
no
n-
fata
l);
stu
dy
vis
its,
yea
rly
tele
ph
on
e
foll
ow
-up
call
s,re
vie
w
of
ho
spit
ald
isch
arg
e
list
san
dm
edic
alch
arts
,
dea
thce
rtifi
cate
s,n
ext-
of-
kin
inte
rvie
ws,
and
ph
ysi
cian
-co
mp
lete
d
qu
esti
on
nai
res
Ag
e,se
x,
race
,st
ud
y
cen
tre,
tota
len
erg
y
inta
ke,
smo
kin
g,
edu
cati
on
,sy
sto
lic
blo
od
pre
ssu
re,
use
of
anti
hy
per
ten
siv
e
med
icat
ion
,H
DL
-
cho
lest
ero
l,to
tal
cho
lest
ero
l,u
seo
fli
pid
low
erin
gm
edic
atio
n,
bo
dy
mas
sin
dex
,w
aist
-
to-h
ipra
tio
,al
coh
ol
inta
ke,
spo
rts-
rela
ted
ph
ysi
cal
acti
vit
y,
leis
ure
-rel
ated
ph
ysi
cal
acti
vit
y,
carb
oh
yd
rate
inta
ke,
fib
rein
tak
e,an
d
mag
nes
ium
inta
ke
Mic
hae
lsso
n
etal
.[6
]
Sw
edis
h
Mam
mo
gra
ph
y
Co
ho
rt,
Sw
eden
/Co
ho
rt
of
Sw
edis
h
Men
,S
wed
en
0/ 1
00
53
.7/
60
.3
24
.7/2
5.8
20
.1/
11
.2
15
,54
1
dea
th
(52
78
dea
th
fro
m
CV
D)/
10
,11
2
dea
th
(45
68
dea
th
fro
m
CV
D)
61
,43
3/
45
,33
9
Mil
k,
Ch
eese
,
Fer
men
ted
dai
ry
FF
Q(v
alid
ated
)A
ll-c
ause
mo
rtal
ity
and
CV
Dm
ort
alit
y;
Sw
edis
hca
use
of
dea
th
reg
istr
ies
Ag
e,b
od
ym
ass
ind
ex,
hei
gh
t,to
tal
ener
gy
inta
ke,
tota
lal
coh
ol
inta
ke,
hea
lth
yd
ieta
ry
pat
tern
,ca
lciu
man
d
vit
amin
D
sup
ple
men
tati
on
,ev
er
use
of
cort
iso
ne,
edu
cati
on
alle
vel
,li
vin
g
alo
ne,
ph
ysi
cal
acti
vit
y
lev
eles
tim
ated
as
met
abo
lic
equ
ival
ents
,
smo
kin
gst
atu
s,an
d
Ch
arls
on
’sco
mo
rbid
ity
ind
ex;
and
inw
om
en
add
itio
nal
lyfo
ru
seo
f
oes
tro
gen
rep
lace
men
t
ther
apy
and
nu
llip
arit
y
278 J. Guo et al.
123
Ta
ble
1co
nti
nu
ed
Ref
eren
ces
Stu
dy
,co
un
try
Men
(%)
Mea
n
age,
yea
r
Mea
n
BM
I,k
g/
m2
Fo
llo
w-
up
tim
e
No
.o
f
case
s
No
.o
f
sub
ject
s
Dai
ryty
pes
incl
ud
edin
met
a-an
aly
sis
Die
tary
asse
ssm
ent
Ou
tco
me;
asce
rtai
nm
ent
Mai
nco
nfo
un
der
s
Ber
gh
old
t
etal
.[3
6]
Co
pen
hag
en
Gen
eral
Po
pu
lati
on
Stu
dy
;
Den
mar
k
12
56
.7–
5.4
27
77
IHD
74
,96
5M
ilk
Sel
f-re
po
rted
qu
esti
on
nai
re
IHD
(fat
alan
dn
on
fata
l);
Nat
ion
alD
AN
ISH
Pat
ien
tR
egis
try
Ag
e,se
x,
ph
ysi
cal
acti
vit
yin
leis
ure
tim
e
and
atw
ork
,sm
ok
ing
,
alco
ho
lin
tak
e,u
seo
f
lip
id-l
ow
erin
gth
erap
y,
fru
it,
veg
etab
les,
fish
,
fast
foo
d,
and
sod
a
dri
nk
s
Pra
agm
an
etal
.[3
7]
the
Ro
tter
dam
Stu
dy
,
Net
her
lan
ds
38
66
.92
6.2
17
.35
67
CH
D
(35
0
fata
l)
42
35
To
tal
dai
ry,
Hig
h-f
at
dai
ry,
Lo
w-
fat
dai
ry,
Fer
men
ted
dai
ry,
Ch
eese
,
Yo
gu
rt
FF
Q(v
alid
ated
)T
ota
lC
HD
and
fata
l
CH
D;
med
ical
reco
rd
and
dig
ital
reco
rd
lin
kag
e
Ag
e,g
end
er,
and
tota
l
ener
gy
inta
ke,
BM
I,
smo
kin
g,
edu
cati
on
lev
el,
and
alco
ho
l
inta
ke,
inta
kes
of
veg
etab
les,
fru
it,
mea
t,
bre
ad,
fish
coff
ee,
and
tea
Pra
agm
an
etal
.[3
8]
EP
IC-
Net
her
lan
ds
coh
ort
57
48
.92
5.6
15
24
36
dea
th
(72
7
fro
m
CV
D,
25
3fr
om
CH
D)
34
,40
9F
erm
ente
d
dai
ry,
Yo
gu
rt,
Ch
eese
FF
Q(v
alid
ated
)A
ll-c
ause
mo
rtal
ity
,C
VD
mo
rtal
ity
,C
HD
mo
rtal
ity
;R
eco
rd
lin
kag
ean
dC
entr
al
Ag
ency
for
stat
isti
cs
Ag
e,se
x,
tota
len
erg
y
inta
ke,
smo
kin
gh
abit
,
BM
I,p
hy
sica
lac
tiv
ity
,
edu
cati
on
lev
el,
hy
per
ten
sio
nat
bas
elin
e,in
tak
eso
f
alco
ho
lan
den
erg
y-
adju
sted
inta
kes
of
fru
it
and
veg
etab
les
Wan
get
al.
[39
]
Jap
an
Co
llab
ora
tiv
e
Co
ho
rtS
tud
y,
Jap
an
42
56
.82
2.7 (m
en);
22
.9
(wo
men
)
19
21
,77
5
dea
th
(62
71
dea
th
fro
m
CV
D)
94
,98
0M
ilk
Sel
f-
adm
inis
tere
d
qu
esti
on
nai
res
All
-cau
sem
ort
alit
yan
d
CV
Dm
ort
alit
y;
Th
e
dat
ean
dca
use
of
dea
th
wer
eco
nfi
rmed
wit
hth
e
per
mis
sio
no
fth
e
Dir
ecto
r-G
ener
alo
fth
e
Pri
me
Min
iste
r’s
Offi
ce
Ag
eca
teg
ori
es,
smo
kin
g
stat
us,
dri
nk
ing
stat
us,
ph
ysi
cal
acti
vit
y,
slee
pin
gd
ura
tio
n,
bo
dy
mas
sin
dex
,ed
uca
tio
n
lev
el,
par
tici
pat
ion
in
hea
lth
chec
k-u
ps,
gre
en-l
eafy
veg
etab
lein
tak
e,an
d
his
tory
of
hy
per
ten
sio
n,
dia
bet
es,
and
liv
er
dis
ease
BMI
bo
dy
mas
sin
dex
,CVD
card
iov
ascu
lar
dis
ease
,CHD
coro
nar
yh
eart
dis
ease
,FFQ
foo
dfr
equ
ency
qu
esti
on
nai
re
Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose… 279
123
P = 0.005) and CVD (I2 = 59.9%, P = 0.015) but not
CHD (I2 = 38.9%, P = 0.081). In sensitivity analyses,
heterogeneity among studies of the mortality could be
reduced to 50% (P = 0.042) with a RR of 1.00 (95% CI
0.97–1.04) by excluding the study of Soedamah-Muthu
et al. [31]; the heterogeneity among studies of CVD was
reduced (I2 = 11.2, P = 0.338) after removing the study
of Hu et al. [16] with a resulting RR of 0.98 (95% CI
0.96–1.00). Sub-group analyses of CHD (Supplemental
Table 4) indicated inverse associations for study popula-
tions with a mean age [50 years (RR 0.97, 95% CI
0.94–1.00, 8 populations) and also for studies which did
not adjust for 7 major confounders defined in methods as