The Effect of Mediterranean Diet on
Metabolic Syndrome and its Components
A Meta-Analysis of 50 Studies and 534,906 Individuals
Christina-Maria Kastorini, MSC,*† Haralampos J. Milionis, MD, PHD,†
Katherine Esposito, MD, PHD,‡ Dario Giugliano, MD, PHD,‡ John A. Goudevenos, MD, PHD,†
Demosthenes B. Panagiotakos, PHD*
Athens and Ioannina, Greece; and Naples, Italy
The aim of this study was to meta-analyze epidemiological studies and clinical trials that have assessed the ef-
fect of a Mediterranean diet on metabolic syndrome (MS) as well as its components.
The Mediterranean diet has long been associated with low cardiovascular disease risk in adult population.
The authors conducted a systematic review and random effects meta-analysis of epidemiological studies and
randomized controlled trials, including English-language publications in PubMed, Embase, Web of Science, and
the Cochrane Central Register of Controlled Trials until April 30, 2010; 50 original research studies (35 clinical
trials, 2 prospective and 13 cross-sectional), with 534,906 participants, were included in the analysis.
The combined effect of prospective studies and clinical trials showed that adherence to the Mediterranean diet
was associated with reduced risk of MS (log hazard ratio: ?0.69, 95% confidence interval [CI]: ?1.24 to ?1.16).
Additionally, results from clinical studies (mean difference, 95% CI) revealed the protective role of the Mediterra-
nean diet on components of MS, like waist circumference (?0.42 cm, 95% CI: ?0.82 to ?0.02), high-density
lipoprotein cholesterol (1.17 mg/dl, 95% CI: 0.38 to 1.96), triglycerides (?6.14 mg/dl, 95% CI: ?10.35 to
?1.93), systolic (?2.35 mm Hg, 95% CI: ?3.51 to ?1.18) and diastolic blood pressure (?1.58 mm Hg, 95% CI:
?2.02 to ?1.13), and glucose (?3.89 mg/dl, 95% CI:?5.84 to ?1.95), whereas results from epidemiological
studies also confirmed those of clinical trials.
These results are of considerable public health importance, because this dietary pattern can be easily adopted
by all population groups and various cultures and cost-effectively serve for primary and secondary prevention of
the MS and its individual components.(J Am Coll Cardiol 2011;57:1299–313) © 2011 by the American
College of Cardiology Foundation
The prevalence of the metabolic syndrome (MS) is increas-
ing rapidly throughout the world, in parallel with the
increasing prevalence of diabetes and obesity; thus, it is now
considered as a major public health problem (1). With the
National Cholesterol Education Program Adult Treatment
Panel III (NCEP ATP III) definition, prevalence of the MS
in Europe, Asia, Australia, and North and South America
ranges between 9.6% and 55.7%; with the World Health
Organization (WHO) definition, prevalence ranges be-
tween 13.4% and 70.0%; and with the International Diabe-
tes Federation definition, prevalence ranges between 7.4%
and 50% (2–4).
Regardless of the true actual figures, there is undoubtedly
a dramatic increase of this condition, and therefore, emerg-
ing action should be taken to prevent and control its
development. Lifestyle interventions, including dietary
changes and physical activity, play a crucial role in the
prevention of this condition (5). In fact, the NCEP ATP III
has already suggested dietary intervention to prevent this
epidemic. Diets rich in whole grain cereals, fruits, and
vegetables, with low animal-fat consumption, seem to
confer the prevention of cardiovascular disease risk factors,
like hypertension, hypercholesterolemia, and obesity (6).
The Mediterranean diet (MD) is a dietary pattern that has
already shown its cardioprotective effects. The MD was first
presented by Ancel Keys in the 1960s (7), and it is
characterized by high consumption of monounsaturated
From the *Department of Nutrition Science-Dietetics, Harokopio University, Ath-
ens, Greece; †School of Medicine, University of Ioannina, Ioannina, Greece; and the
‡Department of Geriatrics and Metabolic Diseases, Second University of Naples,
Naples, Italy. All authors have reported that they have no relationships to disclose.
Manuscript received May 24, 2010; revised manuscript received August 12, 2010,
accepted September 6, 2010.
Journal of the American College of Cardiology
© 2011 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 57, No. 11, 2011
fatty acids, primarily from olives
and olive oil, and encourages
daily consumption of fruits, veg-
etables, whole grain cereals, and
low-fat dairy products; weekly
consumption of fish, poultry, tree
nuts, and legumes; a relatively
low consumption of red meat,
approximately twice/month; as
well as a moderate daily con-
sumption of alcohol, normally
with meals. The beneficial role of
the MD with regard to mortality
from all causes, cardiovascular
disease (CVD) and cancer (8), as
well as obesity and type 2 diabe-
tes (9,10) has already been reported from the results of many
epidemiological studies and clinical trials. Major bio-
pathophysiological mechanisms include antioxidant and
anti-inflammatory effects of the foods included in the
Mediterranean dietary pattern (9,11–17). However, the
influence of the MD on the development of the MS has
never been extensively studied. Thus, the aim of this work
was to perform a systematic review and a meta-analysis of
the findings of published original research articles in which
the investigators have assessed the effect of a Mediterranean
type of diet on the development of the MS as well as on its
Data sources. Original research studies that were pub-
lished in English until April 30, 2010 were selected through
a computer-assisted published data search (i.e., PubMed,
Embase, Scopus, and the Cochrane Central Register of
Controlled Trials databases). Computer searches used com-
binations of Medical Subject Headings or other key words
relating to the aim of the study (i.e., MD, moderate fat diet,
monounsaturated fat diet, MS, syndrome X). Also, specific
searches were included: MD and high-density lipoprotein
(HDL)-cholesterol, MD and triglycerides, MD and blood
pressure, MD and glucose, MD and waist circumference. In
addition, the reference list of the retrieved articles was in
some cases used to find other articles relevant to the present
articles that were not allocated through the searching
procedure. The initial search resulted in 48 entries in
PubMed on MD and MS, 31 entries on MD and syndrome
X, 94 entries on MD and HDL cholesterol, 77 entries on
MD and triglycerides, 106 entries on MD and blood
pressure, 26 entries on MD and waist circumference, and 92
entries on MD and glucose. The relevance of studies was
assessed with a hierarchical approach on the basis of title,
abstract, and the full manuscript. For the reports that were
not fully available, a copy of the article was requested from
Study selection. In total, 474 studies that evaluated the
effect of an MD on MS and its components were identified.
Exclusion criteria with regard to clinical trials included
studies that reported lack of randomization, lack of a control
diet group, comparison of the MD against the MD plus an
additional intervention or intervention without inclusion of
all the components of an MD and especially olive oil.
Observational studies and clinical trials not published in
English and studies that performed a post hoc analysis of
previously published studies—already selected for this
review—were also excluded. Thus, of the initial 474 studies
that were extracted from the search machines, 398 were
excluded on the basis of the title or abstract (i.e., irrelevant
research hypothesis studied). Of the remaining 76 studies,
24 were excluded for the following reasons: lacking a control
group (n ? 7), intervention of Mediterranean versus a
Mediterranean plus diet (n ? 5), not clear MD (n ? 6),
written in a language other than English (n ? 5), and
post-hoc analysis (n ? 1). Therefore, 52 studies were
eligible for inclusion in the meta-analysis. Studies included
in the meta-analysis were those that had available results in
a form that could be used for the present analysis. When it
was necessary, data in the required form were requested
from the authors. Overall, 50 studies with a total of 534,906
participants were finally included in this meta-analysis; of
these, 2 were prospective, 13 were cross-sectional, and 35
were clinical trials. In addition, for the meta-analysis of the
selected studies, the MOOSE (Meta-analysis Of Observa-
tional Studies in Epidemiology) and QUOROM (Quality
of Reporting of Meta-analyses) guidelines have been fol-
lowed (18,19) (Fig. 1).
Data extraction. The following characteristics were ex-
tracted from the original reports with a standardized data
extraction form and included in the meta-analysis: design of
the study (clinical-trial, cross-sectional, or prospective co-
hort), lead author, year of publication, country of origin,
sample size, mean age and gender of participants, health
status, follow-up duration, effect size measurements (i.e.,
relative risk, odds ratio), and variables that entered into the
multivariable model as potential confounding factors.
Two investigators (C.M.K., D.B.P.) collected the rele-
vant reports, whereas 2 other authors independently re-
viewed the published data (H.M., J.G.), and disagreements
were solved by consensus and by the opinion of a fifth
author, if necessary. Outcomes of interest were development
or progression of the MS and changes in the levels of the
main components of the MS: waist circumference (in cm),
HDL cholesterol (in mg/dl), triglycerides (in mg/dl), sys-
tolic and diastolic blood pressure (in mm Hg), as well as
glucose (in mg/dl). When the data were provided in other
units (i.e., mmol/l), they were transformed into mg/dl for
consistency of the results. Quality of studies was assessed
according to the number of participants, the duration of
follow-up, and adjustment for potential confounders.
Studies with a high number of participants (i.e., ?30/
group for trials or ?1,000 for observational), long dura-
CVD ? cardiovascular
HDL ? high-density
HOMA-IR ? Homeostatic
Model Assessment insulin
MD ? Mediterranean diet
MS ? metabolic syndrome
NCEP ATP III ? National
Program Adult Treatment
1300 Kastorini et al.
Mediterranean Diet and Metabolic Syndrome
JACC Vol. 57, No. 11, 2011
March 15, 2011:1299–313
tion of follow-up (?3 months for trials or ?1 year for
observational), and adjustment for confounding factors
(including demographic, anthropometric, and traditional
risk factors) were considered to be of high quality. The
characteristics of the studies and the diet regimens are
shown in Tables 1 and 2.
Statistical analysis. Random effects meta-analysis of the
selected studies was applied on the basis of within-study
comparisons, thereby avoiding any biases being caused by
methodological differences between studies. Each study was
represented by a dummy variable, and the use of a random-
effects model was possible, because standard errors of the
point estimates within studies were provided by the inves-
tigators. With regard to the analysis for the MS, each data
point consisted of adherence to the MD and the odds ratio
or the relative risk (hazard ratio) of having the MS. The
estimated models used as dependent variables the (eventual)
presence or absence of MS. With regard to the analysis for
the components of the syndrome, each data point consisted
of adherence to the MD and the difference in mean values
and SD, of the group closer to the MD and the group away
from the diet for epidemiological studies, while for clinical
trials of the difference in mean values and SD after the
intervention and at baseline, in the intervention and the
control group. The validity of the models was examined
with the influence of each separate data point (i.e., study) on
the estimated regression coefficients. The latter was assessed
with the use of Cook’s distance to detect possible outliers.
Heterogeneity was assessed with Cochran’s Q and I2
(I2ranges between 0% and 100%, with lower values repre-
senting less heterogeneity) and evaluated with the chi-
square test. To examine the source of heterogeneity, sensi-
tivity analyses were performed according to some
characteristics of the studies, such as: country of origin
(Mediterranean or not), follow-up time (below or above the
median of the clinical trials [i.e., 3 months]), number of
participants in clinical trials (below or above the median size
[i.e., 66 participants]), recommendation regarding physical
activity (yes or no), and quality of intervention (i.e., clinical
trials with ?30 participants and duration of follow-up ?3
months or not). To assess the presence of publication bias,
the “funnel plot” was tested. All statistical calculations were
performed in NCSS 2004 software (Number Cruncher
Statistical Systems, Kaysville, Utah).
Sample sizes of the 15 observational studies that were
included in the meta-analysis varied between 328 and
497,308 and, for the 35 clinical trials, varied between 8 and
1,224 participants; 35 of the selected studies were conducted
in Mediterranean populations, 6 were performed in U.S.
populations (20–25), 7 were performed in northern Euro-
pean populations (26–32), 1 was performed in a European
population (Mediterranean and non-Mediterranean) (33),
and 1 was performed in an Australian population (34).
MD and MS. Eight studies with 10,399 subjects evaluated
the role of the MD on the development or progression of
the MS. Five of these 8 studies (35–39) reported a beneficial
effect of compliance with the MD, as compared with the
control diet (i.e., low-fat diet or usual care) or with low
adherence to the Mediterranean dietary pattern. Overall,
adherence to the MD was associated with a beneficial effect
with regard to the MS in 2 of 2 clinical trials, in 1 of 2
prospective studies, and in 2 of 4 cross-sectional studies, as
compared with lower compliance with this pattern or with a
control diet (i.e., low-fat diet or usual care) (Fig. 2). The
combined effect of both clinical trials and prospective
studies was highly protective (log-hazard ratio ? ?0.69,
95% CI: ?1.24 to ?1.16), whereas the combined effect of
cross-sectional studies was not significant (log-odds ratio ?
?0.16, 95% CI: ?0.49 to 0.17). No publication bias was
observed as indicated by the funnel plot (not presented
MD and MS components. WAIST CIRCUMFERENCE LEVELS.
Three cross-sectional studies (20,33,40) reported a benefi-
cial effect of close adherence to the MD, as compared with
low adherence (Table 3). Heterogeneity of the effect measures
regarding waist circumference was observed [Cochran’s Q ?
628.32(4), p ? 0.001, I2? 99.4%]. Moreover, 11 clinical trials
with 1,646 subjects (997 assigned to an MD, and 669 assigned
to a control diet) evaluated the role of adherence to the MD on
waist circumference. Overall, adherence to the MD was
associated with a beneficial effect with regard to waist circum-
ference as compared with the control diet (Table 4); but, it
to 1 study (21) that found a beneficial effect of the MD, as
the effect measures regarding waist circumference [Cochran’s
Q ? 8.23(13), p ? 0.83, I2? ? 0%] was observed.
LIPIDS LEVELS. Three studies (14,20,40) reported a bene-
ficial effect of close adherence to the MD on HDL cholesterol
levels, as compared with low adherence. Overall, adherence
to the MD was associated with higher HDL-cholesterol
levels as compared with the control diet (Table 3). Heter-
ogeneity of the effect measures was observed [Cochran’s Q
? 52.78(6), p ? 0.001, I2? 88.6%]. Moreover, 29 clinical
trials with 3,822 subjects (2,202 assigned to an MD, and
1,903 assigned to a control diet) examined the effect of
adherence to the MD on HDL-cholesterol. Seven studies
(31,39,41–45) reported a beneficial effect of an MD, as
compared with the control diet, whereas 2 studies reported
a beneficial effect of a high saturated fat diet as compared
with the MD (46,47). Overall, adherence to the MD was
associated with higher HDL-cholesterol levels as compared
with the control diet (Table 4). Heterogeneity of the effect
measures was observed [Cochran’s Q ? 109.99(40), p ?
0.001, I2? 63.6%].
Concerning triglycerides, 3 observational studies (14,40,48)
reported a beneficial effect of MD, as compared with low
adherence to this traditional pattern. Overall, adherence to the
JACC Vol. 57, No. 11, 2011
March 15, 2011:1299–313
Kastorini et al.
Mediterranean Diet and Metabolic Syndrome
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Key Words: blood pressure y lipids y Mediterranean diet y meta-
analysis y metabolic syndrome (MS) y waist circumference.
JACC Vol. 57, No. 11, 2011
March 15, 2011:1299–313
Kastorini et al.
Mediterranean Diet and Metabolic Syndrome