Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study
Despite convincing evidence in
the Mediterranean region, the cardiovascular benefit of the
Mediterranean diet is not well established in non-Mediterranean
countries and the optimal criteria for defining adherence are unclear.
The population attributable fraction (PAF) of adherence to this diet is
also unknown.
Methods
In the UK-based EPIC-Norfolk
prospective cohort, we evaluated habitual diets assessed at baseline
(1993–1997) and during follow-up (1998–2000) using food-frequency
questionnaires (n = 23,902). We estimated a Mediterranean diet score
(MDS) using cut-points projected from the Mediterranean dietary pyramid,
and also three other pre-existing MDSs. Using multivariable-adjusted
Cox regression with repeated measures of MDS and covariates, we examined
prospective associations between each MDS with incident cardiovascular
diseases (CVD) by 2009 and mortality by 2013, and estimated PAF for each
outcome attributable to low MDS.
Results
We observed 7606 incident CVD
events (2818/100,000 person-years) and 1714 CVD deaths (448/100,000).
The MDS based on the Mediterranean dietary pyramid was significantly
associated with lower incidence of the cardiovascular outcomes, with
hazard ratios (95 % confidence intervals) of 0.95 (0.92–0.97) per one
standard deviation for incident CVD and 0.91 (0.87–0.96) for CVD
mortality. Associations were similar for composite incident ischaemic
heart disease and all-cause mortality. Other pre-existing MDSs showed
similar, but more modest associations. PAF due to low dietary pyramid
based MDS (<95th percentile) was 3.9 % (1.3–6.5 %) for total incident
CVD and 12.5 % (4.5–20.6 %) for CVD mortality.
Conclusions
Greater adherence to the
Mediterranean diet was associated with lower CVD incidence and mortality
in the UK. This diet has an important population health impact for the
prevention of CVD.
Background
The
Mediterranean diet describes the traditional diet of Mediterranean
regions such as Crete, other parts of Greece and Southern Italy [1, 2, 3].
The diet is typically high in the consumption of cereals, fruits,
vegetables, legumes and olive oil, low in red meats, and moderate in the
consumption of fermented dairy products, fish, poultry and wine [2, 4].
Since its recognition, adherence to the Mediterranean diet has been
reported to be associated with lower incidence of non-communicable
diseases, including cardiovascular diseases (CVD), cancer,
neurodegenerative diseases and mortality [5, 6, 7, 8, 9].
Results from two randomised controlled trials also demonstrated the
causal protective role of the diet in high-risk populations [8, 9, 10, 11].
Although
studies on the potential cardiovascular benefits of the Mediterranean
diet have been published in both Mediterranean and non-Mediterranean
cohorts, evidence from non-Mediterranean regions is less consistent. A
Swedish cohort, for example, observed that high adherence to the
Mediterranean diet was associated with lower cardiovascular mortality
only among women [12], while in an Australian cohort, the association was observed only among men [13].
An Eastern European study also showed that high adherence to a
Mediterranean diet was associated with lower all cause and CVD
mortality, but not with ischaemic heart disease (IHD) or stroke
mortality [14].
In the United Kingdom (UK), although the UK National Institute for
Health and Care Excellence recommends a Mediterranean style diet for the
secondary prevention of CVD, no study in the country has examined the
association of adherence to the Mediterranean diet with incident CVD [15].
Moreover,
in assessing adherence to the Mediterranean diet, published studies
evaluated different Mediterranean diet scores (MDSs) [16, 17, 18, 19, 20, 21],
but there is sparse evidence on whether or not each algorithm would be
useful in non-Mediterranean countries. In addition, most published MDSs
did not take into account the current recommendations for adopting the
Mediterranean diet [22].
Finally, the population impact of a cardiovascular benefit from
adhering to the Mediterranean diet at the general population level also
remains unknown, partly because the previous trials may have limited
generalisability by recruiting highly selected adults only.
Therefore,
we aimed to assess the association of the Mediterranean diet as defined
by different MDSs with incident CVD, CVD mortality and all-cause
mortality in a UK-based cohort, and to estimate the population
attributable fraction (PAF) for cardiovascular and mortality outcomes
for low adherence to the Mediterranean diet.
Methods
Study population and design
European
Prospective Investigation of Cancer (EPIC)-Norfolk is an ongoing
UK-based prospective cohort and part of the Europe-wide multi-centre
EPIC study. Details of the study design were described previously [23].
Briefly, 25,639 men and women aged 40–79 in eastern England were
recruited through general practice registers and underwent baseline
assessment between 1993 and 1997. Participants were further invited to
the follow-up assessment (1998 to 2000), and were followed up by 2009
for incident outcomes and by 2013 for mortality. At the baseline and
follow-up visits, the participants were asked to complete a health and
lifestyle questionnaire and a food frequency questionnaire (FFQ). We
excluded 644 participants who did not complete any FFQs. In the analysis
for incident CVD, we additionally excluded 1093 participants who
reported myocardial infarction (n = 790) or stroke (n = 303) at
baseline. This study thus evaluated 23,902 participants (n = 11,258 with
dietary data at both baseline and follow-up, and n = 208 with dietary
data at follow-up only). Ethical approval for the study was obtained
from the Norwich District Ethics Committee and participants gave
informed consent.
Dietary assessment and Mediterranean diet scores (MDSs)
Habitual
diet was assessed using a 130-item semi-quantitative FFQ which asked
about participants’ average intake of the food items over the past year.
Validity of this FFQ for major foods and nutrients was previously
assessed against 16-day weighted dietary records, 24-hour recall and
selected biomarkers in the sub-sample of EPIC-Norfolk [24, 25, 26].
Reproducibility of the assessment of dietary components typical of the
Mediterranean diet and the MDSs were evaluated in this study. For MDS
calculation, we evaluated dietary intakes adjusted to a 2000 kcal/day
(8.37 MJ/day) diet using the residual method to assess diet quality
independent of diet quantity, and to partly reduce measurement errors
because energy intake is partly related to under- or over-reporting of
dietary consumption [27].
In
this study, we evaluated four MDSs as measures of adherence to the
Mediterranean diet. The algorithm for each is summarised in Additional
file 1:
Text S1 and Table S1. As the primary exposure, we evaluated a MDS based
on the Mediterranean diet pyramid (pyramid-based MDS, PyrMDS). The
pyramid was recently proposed by the Mediterranean Diet Foundation [4]
to be applied to both Mediterranean and non-Mediterranean regions, with
dietary guidelines accounting for the traditional Mediterranean diet
and also the contemporary food environment [4]. We newly developed the algorithm to calculate the PyrMDS (Additional file 1:
Table S2). The other three MDSs were identified through our systematic
search for quantitative review articles published by January 12, 2016,
on the Mediterranean diet and non-communicable diseases. We identified
254 unique records and retrieved 31 full-text articles. An algorithm for
one MDS was recently developed by Sofi et al. [5]
from their review of published literature on the Mediterranean diet
(literature-based MDS, LitMDS). Whereas PyrMDS and LitMDS account for
absolute levels of dietary consumption, the other two MDSs [17, 28],
the most commonly used MDSs in the literature, assigned component
scores based on cohort medians (mMDS) or tertiles of dietary consumption
(tMDS) (Additional file 1: Text S1 and Table S1).
Outcome ascertainment
The
primary outcome was incident CVD, which included any first ever case of
both non-fatal or fatal events due to IHD, ischaemic stroke,
haemorrhagic stroke, heart failure, peripheral vascular disease, or
other cardiovascular outcomes described by the relevant ICD codes (ICD9
401–448 or ICD10 I10–I79) [29]. Cause-specific hospital admission was determined using East Norfolk Commission Record of the National Health Service [29, 30].
Incident CVD was ascertained until March 31, 2009. CVD mortality and
all-cause mortality, treated as a secondary outcome in this study, was
confirmed via death certificates with ICD codes held at the UK Office
for National Statistics and ascertained until June 30, 2013 [29, 30].
Assessment of other covariates
Demographic,
lifestyle and health characteristics were assessed at baseline and
follow-up using a self-administered questionnaire. Physical activity
levels were self-reported and characterised as a validated 4-point index
[31].
Trained nurses measured each participant’s weight, height, waist
circumference and blood pressure (systolic and diastolic) at each visit,
and took non-fasting bloods from which blood lipids were assayed.
Statistical analyses
Linear
regression was used for descriptive analyses of associations between
the MDSs and cohort baseline characteristics. Spearman’s rank
correlation coefficients were assessed to examine reproducibility over
time for MDSs and relevant dietary factors. In longitudinal analysis,
repeated measures of diet and covariates were used, wherever possible,
through the cumulative-average method [27].
We modelled Cox proportional-hazards regression to estimate hazard
ratio (HR) and 95 % confidence interval (CI) for each of the selected
outcomes. The underlying time variable was age from the first available
FFQ to age at diagnosis of CVD (or death for mortality outcomes), or the
date of administrative censoring, whichever occurred first. Each of the
four MDSs was modelled continuously per standard deviation (SD) and
categorically (three groups: low, medium or high adherence) with
approximately equal numbers of participants in each group. Analyses were
adjusted for potential confounders, and additionally for potential
physiological mediators. Variables considered as potential confounders
were age, sex, education level, social class, marital status, smoking,
physical activity, season of FFQ assessment, body mass index (BMI),
waist circumference, prevalent diabetes, medication use
(anti-hypertensive drugs, lipid-lowering drugs, and hormone replacement
therapy for women), and family history of diseases (diabetes, myocardial
infarction and stroke). Potential mediators included total cholesterol,
high-density lipoprotein cholesterol, low-density lipoprotein
cholesterol, log triglycerides, and systolic and diastolic blood
pressure. The proportional hazard assumption for MDSs was not rejected
on the basis of Schoenfeld residuals in multivariable-adjusted Cox
model. We performed additional analyses modelling two MDSs
simultaneously to test if one of the MDSs was more strongly associated
with CVD than the other. Missing covariates were observed in ≤ 3.9 % of
participants for socioeconomic and lifestyle variables (3.9 % for social
class and < 1.4 % for the others), and in ≤ 9.6 % of participants
for physiological markers (9.6 % for blood lipids, 0.2 % for blood
pressure or anthropometry). The missing information was imputed
simultaneously by conducting regression-based multiple imputation
(n = 10). In all analyses unless specified, estimates from 10 datasets
were pooled under Rubin’s rules [32].
We
estimated PAFs for each outcome attributable to low Mediterranean diet
adherence, for which we assumed the observed associations were causal.
Results based on PyrMDS are presented in this report accounting for its
strongest public-health importance based on the longitudinal analyses.
We calculated PAF based on the formula of rate difference [33]: PAF = (I0 − Ii)/I0, equivalent to I0 − HR × dMDS/I0, where HR was estimated continuously with adjustment for potential confounders as aforementioned, I0 is observed incidence per 10,000 person-years, and Ii represents a hypothetical, ideal incidence if the population achieved high MDS (95th percentile) (dMDS = MDSideal – MDSobserved). The CI of the PAF was derived from bootstrapping [34]
to estimate HR and PAF iteratively (n resampling = 100, after
confirming no difference in results between n = 100 and 1000). In
addition, we repeated estimation of PAFs in a high-risk population only.
A high risk was defined as having a 10-year CVD risk of 10 % or higher
based on QRISK2 [35], by which a clinical intervention is recommended in the UK [36].
In
analysis of any dietary scores, an observed association with a health
outcome can be driven by one component of the score. To rule out this
possibility and assess importance of combining multiple dietary
components, we repeated the primary analysis for each MDS after
sequentially excluding each Mediterranean diet component from the total
score. Other sensitivity analyses include using FFQ assessed at baseline
only without use of repeated measures of diet; including only
participants who completed both FFQs and using repeated measures only;
excluding participants with potential implausible energy intakes
(extreme 1st or 5th percentile); and adjusting for censoring due to
competing risks of non-CVD mortality [37].
We also repeated analyses by re-constructing MDSs by grouping food
items differently to consider variations of the Mediterranean diet [2, 4],
for example by including only wine in the alcohol component. To assess
whether the association of MDSs with outcomes was independent of
baseline risk of CVDs, we also additionally adjusted for QRISK2 as a
covariate. All analyses were performed using Stata version 13.1 (Stata
Corp, Texas, United States) and P values of < 0.05 were considered significant.
Results
Cohort characteristics
Associations
of adherence to the Mediterranean diet as defined by the four MDSs with
baseline characteristics (sociodemographic, anthropometric, health and
lifestyle) were similar across the scores (Table 1).
Participants with high adherence were less likely to be current
smokers, and more likely to be physically active and have a college
education and higher social status compared to participants with low
adherence. The primary MDS, PyrMDS, was moderately reproducible over
3.7 years (Spearman’s ρ = 0.60) (Additional file 1: Table S3) and correlated with the other MDSs (ρ = 0.53 with mMDS to ρ = 0.81 with tMDS). The Mediterranean diet components showed moderate reproducibility (ρ = 0.47 to 0.85 over).
Table 1
Cohort characteristics according to adherence to the Mediterranean diet at baseline of the EPIC-Norfolk Study (n = 23,902)
Characteristics
Mediterranean diet score (MDS), basis of scoringa
The Mediterranean diet pyramid (PyrMDS)
Published literature (LitMDS)
Medians of dietary intake (mMDS)
Tertiles of dietary intake (tMDS)
Low
High
Low
High
Low
High
Low
High
n = 7898
n = 7898
n = 7730
n = 8351
n = 7903
n = 6266
n = 8927
n = 8574
Age (years)
59.4 (9.4)
58.2 (9.0)c
58.8 (9.4)
58.6 (9.1)
59.2 (9.3)
58.4 (9.1)c
59.1 (9.3)
58.7 (9.1)c
Sex, men (%)
56
32c
58
32c
44
45
46
42c
Education level (%)
School until age 16 years
10
11
10
10
11
11
10
10
School until age 18 years
38
42
40
42
38
43
38
43
Bachelor’s degree or above
8
19c
10
16c
10
17c
10
17c
Marital status, married (%)
84
79c
83
80c
80
83
81
82
Smoking status (%)
Current
16
8
17
8
16
7
15
8
Former
42
41c
42
41c
38
45c
38
45c
Physical activity level (%)
Moderately inactive
26
31
27
30
28
29
28
30
Moderately active
23
24
23
24
22
24
22
24
Active
19
19c
19
19c
17
22c
17
20c
Occupational status (%)
Unskilled worker
6
3
5
4
6
3
6
3
Skilled worker
63
52
60
54
61
53
61
51
Manager or equivalent
28
39
30
38
29
38
28
39
Professional
4
5c
4
5c
4
5c
4
5c
Family history of diabetes (%)
13
13
13
13
13
14
13
13
Family history of MI (%)
34
39c
34
38c
34
39c
35
38c
Family history of stroke (%)
24
25
24
25
24
24
24
24
Season of FFQ administered (%)
Spring
27
27
26
28
26
27
27
27
Summer
24
26
24
26
25
26
25
25
Autumn
25
25b
26
25
25
25
25
25
Prevalent diabetes (%)
3
3
2
4c
3
3b
2
3c
Use of anti-hypertensive drug (%)
16
16
15
17c
16
17
16
17b
Use of lipid-lowering drug (%)
1
1c
1
2c
1
2c
1
2c
Use of HRT among women (%)
31
43c
29
43c
38
35c
37
37c
Body mass index, kg/m2
26.4 (3.8)
26.1 (3.9)
26.3 (3.7)
26.2 (4.0)
26.3 (4.0)
26.3 (3.8)
26.2 (3.9)
26.2 (3.9)
Waist circumference, cm
90 (12)
86 (12)c
90 (12)
86 (12)c
88 (12)
88 (12)c
88 (12)
87 (13)c
Systolic BP, mmHg
137 (18)
133 (18)c
136 (18)
134 (19)c
136 (18)
135 (18)c
136 (18)
135 (19)c
Diastolic BP, mmHg
83 (11)
81 (11)c
83 (11)
82 (11)c
83 (11)
82 (11)c
83 (11)
82 (11)c
Total cholesterol, mmol/L
6.2 (1.2)
6.2 (1.2)
6.2 (1.2)
6.2 (1.2)
6.2 (1.2)
6.1 (1.1)c
6.2 (1.2)
6.2 (1.2)
HDL cholesterol, mmol/L
1.4 (0.4)
1.5 (0.5)c
1.4 (0.4)
1.5 (0.4)c
1.4 (0.4)
1.5 (0.5)c
1.4 (0.4)
1.5 (0.5)c
LDL cholesterol, mmol/L
4.0 (1.0)
3.9 (1.1)c
4.0 (1.0)
3.9 (1.1)
4.0 (1.0)
3.9 (1.0)c
4.0 (1.0)
3.9 (1.0)b
Triglycerides, mmol/L
1.9 (1.2)
1.7 (1.0)c
1.9 (1.1)
1.7 (1.0)c
1.8 (1.1)
1.8 (1.1)c
1.9 (1.1)
1.7 (1.1)c
QRISK2 score, %d
19.4 (13.3)
16.5 (12.4)c
18.7 (13.1)
17.3 (12.7)c
18.8 (13.3)
17.3 (12.7)c
18.6 (13.1)
17.6 (12.9)c
EPIC, European
Prospective Investigation of Cancer; FFQ, food frequency questionnaire;
BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density
lipoprotein; HRT, hormone replacement therapy; MI, myocardial infarction
aSummary
statistics in mean (SD) or percentages for extreme groups of thirds
(assigned ensuring approximately equal numbers of observations per
group) of each Mediterranean diet scores based on 23,694 participants
with baseline FFQ. For each of the Mediterranean diet scores, ordinal
scores were assigned to participants (see methods, Additional file 1: Table S1 and S2 for details)
bP < 0.05 and cP < 0.01 for an association between a Mediterranean diet score and each row variable
dPredicts 10 year risk (%) of cardiovascular diseases
Association of adherence to the Mediterranean diet with incident CVD and mortality
Of
23,902 participants, 7606 developed primary incident CVD (non-fatal or
fatal) over 269,935 person-years (12.2 years of follow-up on average). A
total of 5660 participants died over 382,765 person-years (17.0 years
of follow-up on average), among whom 1714 deaths were due to CVD.
Greater adherence to the Mediterranean diet was significantly associated
with lower incidence of CVD in different multivariable-adjusted models
(Table 2).
For example, after adjustment for potential confounders, the HR per SD
difference in PyrMDS was 0.95 (95 % CI, 0.93–0.97). The LitMDS and tMDS
showed similar results, with an HR of 0.96 (95 % CI, 0.94–0.97) and 0.97
(95 % CI, 0.94–0.99), respectively, whereas mMDS was not significantly
associated with incident CVD in any models (P
trend > 0.05). Similar trends were observed when we additionally
examined the HRs for quintiles of each MDS (Additional file 1:
Table S4). In exploratory analyses comparing the four MDSs for
prediction of CVD, PyrMDS, LitMDS and tMDS appeared similarly predictive
of CVD, but superior to mMDS (Additional file 1: Table S5).
Table 2
Prospective
association between adherence to the Mediterranean diet and incident
cardiovascular diseases in EPIC-Norfolk (n = 23,902, 7606 cases, 269,935
person-years)
Mediterranean diet scorea
Hazard ratios (95 % confidence intervals)
Adjusted for age and sex
Further adjusted for potential confoundersb
Further adjusted for potential mediatorsb
PyrMDS, based on dietary pyramid (0–15)
Low (3.2–8.0)
Reference
Reference
Reference
Medium (8.0–9.1)
0.95 (0.90–1.00)
0.96 (0.91–1.02)
0.97 (0.92–1.02)
High (9.1–13.1)
0.85 (0.80–0.90)
0.89 (0.84–0.94)
0.91 (0.85–0.96)
P trend
<0.001
<0.001
0.001
Per SD difference
0.93 (0.91–0.95)
0.95 (0.92–0.97)
0.95 (0.93–0.97)
LitMDS, based on literature (0–18)
Low (0–8)
Reference
Reference
Reference
Medium (9–10)
0.96 (0.90–1.01)
0.95 (0.90–1.01)
0.95 (0.90–1.01)
High (11–18)
0.91 (0.86–0.97)
0.92 (0.87–0.97)
0.92 (0.87–0.98)
P trend
0.002
0.005
0.005
Per SD difference
0.96 (0.93–0.98)
0.96 (0.94–0.99)
0.96 (0.94–0.98)
mMDS, based on medians (0–9)
Low (0–3)
Reference
Reference
Reference
Medium (4–5)
0.94 (0.89–0.99)
0.96 (0.91–1.01)
0.95 (0.90–1.00)
High (6–9)
0.95 (0.89–1.00)
0.97 (0.92–1.03)
0.97 (0.91–1.03)
P trend
0.053
0.295
0.21
Per SD difference
0.97 (0.95–1.00)
0.98 (0.96–1.01)
0.98 (0.96–1.00)
tMDS, based on tertiles (0–18)
Low (0–7)
Reference
Reference
Reference
Medium (8–9)
0.97 (0.92–1.03)
0.98 (0.93–1.04)
0.97 (0.92–1.03)
High (10–18)
0.93 (0.88–0.98)
0.94 (0.89–0.99)
0.93 (0.88–0.98)
P trend
0.008
0.024
0.011
Per SD difference
0.96 (0.94–0.98)
0.97 (0.94–0.99)
0.96 (0.94–0.99)
aFor
each Mediterranean diet score, three groups (low, medium and high
adherence) were assigned to ensure approximately equal numbers of
observations per group. Ordinal scores were assigned to participants,
according to four different pre-specified algorithms (see methods, Additional file 1: Table S1 and S2 for details)
bSee methods for list of confounders and mediators
When
we examined the association of adherence to the Mediterranean diet with
subtypes of primary CVD events (i.e. IHD and stroke separately) and
cause-specific and all-cause mortality (Fig. 1),
the trends in magnitude of associations were similar to that for all
incident CVD. Overall, PyrMDS was associated with lower hazard of most
outcomes examined. Per SD difference in PyrMDS, we observed a lower
incidence of all-cause mortality (HR adjusted for potential confounders
0.95; 95 % CI, 0.93–0.98), CVD mortality (0.91; 0.87–0.96), incident IHD
(0.94; 0.90–0.98), incident stroke (0.93; 0.87–0.99), incident
composite IHD or stroke (0.93; 0.90–0.97), IHD mortality (0.90;
0.83–0.97), and composite IHD or stroke mortality (0.92; 0.87–0.97), but
no significant association for stroke mortality (0.96; 0.87–1.05).
Fig. 1
Prospective
associations of Mediterranean diet adherence with cardiovascular
diseases and all-cause mortality in EPIC-Norfolk (n = 23,902). CVD,
cardiovascular diseases; IHD, ischaemic heart disease. Hazard ratio (HR)
and 95 % confidence interval (CI) were estimated per one standard
deviation of each of the four Mediterranean diet scores (MDSs). All
estimates were estimated with adjustment for confounders
Population attributable fraction
In
the EPIC-Norfolk population, 3.9 % (95 % CI, 1.3–6.5 %) of total CVD
was estimated to be attributable to low Mediterranean diet adherence
(PyrMDS lower than its 95th percentile, 10.7 of 15 points) (Table 3).
This was equivalent to 9.7 cases of total CVD preventable per 1000
population over 10 years. If considering incident IHD or stroke events,
the PAF estimate was 8.5 % (3.1, 13.9 %), equivalent to 10.2 IHD or
stroke cases preventable per 1000 population. For CVD mortality and
all-cause mortality, PAFs in the whole cohort were 12.5 % (4.5, 20.6 %)
and 5.4 % (1.3, 9.5 %), equivalent to 5.5 and 7.5 cases per 1000
population over 10 years, respectively. Amongst a high-risk population
(QRISK2 score ≥ 10 %) (n = 15767), the corresponding PAF (95 % CI) for
total incident CVD was 3.9 % (1.1, 6.7 %), equivalent to 13.0 cases
preventable per 1000 population over 10 years. Estimates for adherence
to PyrMDS lower than the top third, or 67th percentile (scoring 9.1
points out of 15) among the EPIC-Norfolk population were of a comparable
magnitude (Additional file 1: Table S6).
Table 3
Cardiovascular
diseases and all-cause mortality, the number of cases and proportion
potentially preventable by increasing adherence to the Mediterranean
diet: the EPIC-Norfolk studya
The whole cohort (n = 23,902)
High risk population (n = 15,767)b
Incidencec
Cases preventablec
PAF% (95 % CI)c
Incidencec
Cases preventablec
PAF% (95 % CI)c
Incident CVD events
All incident CVD
248.6
9.7
3.9 (1.3–6.5)
334.4
13.0
3.9 (1.1–6.7)
Incident IHD
98.2
8.4
8.5 (1.9–15.2)
138.3
10.8
7.8 (1.3–14.3)
Incident stroke
33.8
3.7
10.8 (−1.5 to 23.1)
48.1
4.9
10.2 (−2.1 to 22.6)
Incident IHD or stroke
120.3
10.2
8.5 (3.1–13.9)
168.9
13.1
7.7 (2.3–13.2)
Mortality events
All-cause mortality
138.4
7.5
5.4 (1.3–9.5)
191.3
10.9
5.7 (1.6–9.8)
CVD mortality
43.9
5.5
12.5 (4.5–20.6)
65.0
7.4
11.4 (3.3–19.6)
IHD mortality
21.1
3.5
16.6 (1.9–31.2)
31.3
4.8
15.4 (0.5–30.3)
Stroke mortality
13.2
0.7
5.3 (−12.0 to 22.7)
19.6
0.9
4.6 (−13.0 to 22.2)
IHD or stroke mortality
34.1
4.1
11.9 (1.75–22.0)
50.3
5.4
10.7 (0.48–20.9)
aIncreasing
adherence to the top 5 % (95th percentile, or 10.7 out of possible 15
points) of the Mediterranean dietary score based on the dietary pyramid
(PyrMDS). See Additional file 1: Table S2 for further details on the scoring criteria for PyrMDS
bHigh
risk defined as a QRISK2 score of 10 % or above for 10 year risk of
CVD, for whom a pharmacological intervention (statin treatment) is
advised in the United Kingdom
cPer
1000 population over 10 years. PAF, indicating proportion of cases
attributable to the exposure of interest (low adherence to the
Mediterranean diet)
In
analyses using MDSs in which each Mediterranean diet component was
sequentially excluded, significant inverse associations remained
reasonably stable regardless of the excluded component, especially when
adherence was assessed using either PyrMDS or LitMDS (Additional file 1:
Figure S1). Results were also similar in analyses using baseline FFQ
only, using averages of the two FFQs from follow-up onwards only,
excluding outliers of total energy intake, or controlling for competing
risks due to non-CVD mortality (Additional file 1:
Table S7). The association was also unchanged when we modified food
groupings, excluding non-fermented dairy products, processed fish,
refined cereal products, and alcohol other than wine, or when we
additionally adjusted for QRISK2.
Discussion
Our
study is the first report on the association of predefined
Mediterranean diet adherence with CVD in a UK general population
setting. In this UK cohort, overall, we observed an inverse association
of adherence to the Mediterranean diet with incident CVD and all-cause
mortality. Our findings suggest that the MDS based on the Mediterranean
dietary pyramid had the strongest associations with cardiovascular
outcomes. Moreover, we report that other scoring algorithms of the
Mediterranean diet that are based on dietary cut-offs in prior
literature and on cohort tertiles may also be useful in the UK
population. We further estimated that 3.9 % of total CVD incidence,
8.5 % of IHD or stroke incidence, and 12.5 % of CVD mortality in the
EPIC-Norfolk cohort could have been avoided by increasing adherence to
the Mediterranean diet. The findings indicate that adherence to the
Mediterranean diet may contribute to a strategy for the primary
prevention of CVD in the UK.
Comparison with other studies
The
modest degree of inverse association between adherence to the
Mediterranean diet and incidence of CVD, CVD mortality, and all-cause
mortality observed in EPIC-Norfolk is broadly in line with other
published studies on the Mediterranean diet and CVD [11, 14, 38, 39, 40, 41, 42, 43, 44].
Specifically in the UK context, the Whitehall II study (n = 7731)
concluded potential cardio-metabolic benefits of a Mediterranean-like
diet for British adults, but did not find any significant associations
after adjustment for confounders and did not assess the Mediterranean
diet per se, by inferring the diet based on data-driven cluster analysis
[45]. A few other studies in non-Mediterranean countries examined the association of pre-defined Mediterranean diet with CVD [12, 13, 14, 41, 42, 43, 46].
While their findings were broadly consistent with our findings,
estimates of associations were often imprecise with wide confidence
intervals or were non-significant. Exceptionally, one recent US study
based on a large multi-ethnic cohort (n = 215,782) found that mMDS was
associated with 11 to 28 % lower CVD mortality [43].
Based on our findings evaluating different MDSs, the inverse
association could be stronger, if the study evaluated the other MDSs
better suited to a non-Mediterranean population than mMDS. However,
compared to studies conducted in Mediterranean cohorts [40, 47, 48],
our estimates appear modest, which could be reflective of the fact that
high adherence to a Mediterranean diet in this UK cohort might still
not be fully representative of a traditional Mediterranean diet, as
might be observed in the Mediterranean regions.
PAF
was not estimated from any prior prospective studies, but can be
manually calculated in the PREDIMED trial for incidence of either IHD or
stroke [11].
The control group of this high-risk trial in Spain had an incidence of
the composite outcome of 11.2 per 1000 person-years, similar to the
incidence of our overall cohort (12.0 per 1000 person-years). According
to effect estimates reported in the publication, the PAF for the outcome
for no intervention in the PREDIMED trial was estimated to be 27.8 %,
whereas PAF in the EPIC-Norfolk cohort for suboptimal adherence to
PyrMDS was 8.5 %. The corresponding number of cases preventable and the
number needed to treat over 10 years of follow-up were estimated to be
28.5 per 1000 population and 35.1, respectively, in PREDIMED and 9.2 per
1000 and 108.9, respectively, in EPIC-Norfolk.
One
possible explanation for this discrepancy in these measures between
PREDIMED and EPIC-Norfolk could be bias toward the null in the
EPIC-Norfolk cohort, because of measurement errors and temporal changes
in diet. Moreover, despite the inverse association with CVD incidence,
the variability of adherence to the Mediterranean diet might not fully
capture a high-quality diet in the UK. Indeed, none of the participants
recorded the optimal score of PyrMDS (the observed highest = 13.1; the
possible highest = 15.0). Alternatively, as mentioned above, the
difference could reflect that the PREDIMED trial compared the
Mediterranean diet against a non-Mediterranean diet, whereas
EPIC-Norfolk tested a diet not fully in line with the Mediterranean
diet.
Interpretation of results and implications
Evidence
from the Lyon Diet Heart Study in France and the more recent PREDIMED
trial in Spain supports the causal effect of adherence to the
Mediterranean diet on CVD outcomes [10, 11, 49, 50].
The PAF estimates in EPIC-Norfolk suggest that 1 to 6 % of all CVD, and
2 to 14 % of IHD or stroke incidence could be avoided by adhering to
the Mediterranean diet in both a general population and a high-risk
population, defined by QRISK2, for whom statin prescription would be
recommended in the UK [36]. Of note, statin treatment could prevent 24 % of new-onset CVD, according to trials in the UK [51]. However, while statins do not influence other outcomes or may even increase risk of diabetes [52],
greater adherence to the Mediterranean diet by contrast may have
benefits beyond prevention of CVD. Our estimates are comparable to the
corresponding PAF estimates for physical inactivity, which were 5.8 %
for IHD mortality and 9.4 % for all-cause mortality [53].
While
an alternative healthy dietary pattern beyond the Mediterranean diet
may exist due to cultural differences, our PAF estimates indicate that
the Mediterranean diet should be one option for a healthy diet in the
UK, where CVD accounts for approximately 155,000 deaths, or more than a
quarter of all deaths each year, and associated healthcare costs are
estimated to be £11 billion per year and increasing [54].
If we assume causality and generalizability of our findings to the
general UK population, a PAF of 12.5 % would have equated to 19,375
cases of CVD deaths preventable each year. Further investigation is
warranted to explore the effectiveness of a population-level
recommendation and cost-effectiveness of the Mediterranean diet in the
UK and other non-Mediterranean countries, as a component of lifestyle
recommendations for both the general and high CVD risk populations.
The
use of FFQ as the dietary assessment instrument in our study limits the
ability to precisely measure adherence to the Mediterranean diet, as it
did not differentiate between extra virgin olive oil and other olive
oils or between tree nuts (legumes) and peanuts, as evaluated in the
PREDIMED trial [4].
Nonetheless, this study indicates utility of three scoring algorithms
for the MDS: PyrMDS, LitMDS and tMDS, to represent adherence to a
Mediterranean-style dietary pattern in epidemiological settings. Of
note, findings are similar upon alternative categorisations of food
groups for the MDSs, and upon other sensitivity analyses (Additional
file 1:
Table S7). Our findings indicate that using sex-specific medians (mMDS)
in a given population would be too crude and not sensitive enough to
assess adherence to the diet in a non-Mediterranean country. On the
other hand, PyrMDS and LitMDS may deserve future investigation for
clinical application, as they allowed calculation of MDS without use of
reference population levels (e.g. medians or tertiles) [5].
PyrMDS is likely to be better than the others because the scoring
accounts for the continuous property of dietary consumption, for the
contemporary food environment distinguishing between processed and
unprocessed meat, and for available evidence from epidemiological
studies by encouraging moderate consumption of fermented dairy products,
as originally characterised by the Mediterranean diet [2, 55, 56];
of note, dairy consumption was considered as an adverse component in
mMDS and tMDS. Our findings guide further studies to investigate the
utility of the Mediterranean dietary pyramid (and PyrMDS) for clinical
practice and public health promotion in both Mediterranean and
non-Mediterranean populations.
Strengths and limitations
These
results are of interest as the first to extensively examine the
association of the Mediterranean diet with CVD in the UK and estimate
the population impact of increasing adherence. Evaluation of four
different MDSs clarified the difference between their characteristics
and their utility in a non-Mediterranean context. A strength of this
study is that it included a large sample size with long follow-up time.
Because outcome ascertainment in this cohort was externally linked to
medical records, it also minimised bias that could arise during
follow-up. As limitations, measurement errors were present in our
self-reported dietary and covariate measurements, and we could not fully
account for changes in diet throughout the study period, although the
errors were reduced by using repeated measures of diet, as well as
time-varying covariates [27, 46].
We considered BMI as a confounder in our analyses, although recent
evidence suggests potential mediating effects of BMI in the diet CVD
association [57],
and this could lead to underestimation of our effect estimates.
However, this is unlikely given the consistency of our estimates across
the levels of adjustment. Residual confounding is possible, because of
unmeasured confounders and imprecise measurement of potential
confounders. Generalisability is limited because of potential healthy
cohort bias [23], dietary measures collected more than 15 years ago, and inclusion of largely white European individuals in the UK.
Conclusions
We
observed a lower incidence of CVD with higher adherence to the
Mediterranean diet in this UK cohort. Our study also informs potential
population impact of increasing adherence to the Mediterranean diet in a
UK population. These results add to the pool of evidence on the health
benefits of the Mediterranean diet, even in a non-Mediterranean country
where an optimal dietary pattern is unknown. Our findings stimulate
future population-based and clinical investigations into the efficacy
and effectiveness of adhering to the Mediterranean diet in contemporary,
non-Mediterranean populations.
Abbreviations
BMI:
Body mass index
CI:
Confidence interval
CVD:
Cardiovascular diseases
EPIC:
European Prospective Investigation of Cancer
FFQ:
Food frequency questionnaire
HR:
Hazard ratio
IHD:
Ischaemic heart disease
LitMDS:
Literature based MDS
MDS:
Mediterranean diet score
PyrMDS:
Pyramid based MDS
mMDS:
median based MDS
PAF:
Population attributable fraction
PREDIMED:
Prevención con Dieta Mediterránea
SD:
Standard deviation
tMDS:
tertile based MDS
UK:
United Kingdom
Declarations
Acknowledgements
The
authors thank the participants, General Practitioners and staff of the
EPIC-Norfolk study team, in particular Mr Robert Luben for information
management and data release, and Ms Marleen Lentjes and Ms Angela
Mulligan for their assistance with the dietary data. We acknowledge MRC
Epidemiology Unit support through Programmes MC_UU_12015/1 and
MC_UU_12015/5.
Funding
The EPIC-Norfolk study was
supported by grants from the Medical Research Council and Cancer
Research UK. Funders had no role in study design or interpretation of
the findings.
Availability of data and materials
Data are available from the EPIC-Norfolk Committee for researchers who meet the criteria for access to confidential data.
Authors’ contributions
KTK and NJW conducted the
study and acquired the data. NGF and KTK conceived and designed the
research question. TYNT and FI analyzed the data. TYNT, FI and NGF wrote
the first draft of the manuscript. TYNT, FI, NGF, KTK and NJW agree
with the manuscript’s results and conclusions. All authors read and
approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Informed consent was obtained
from all study participants, and ethical approval was granted by the
Norwich District Ethics Committee.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original author(s)
and the source, provide a link to the Creative Commons license, and
indicate if changes were made. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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