Health Benefits of the Mediterranean Diet: An Update of Research Over the Last 5 Years

Abstract

The Mediterranean Diet (MedDiet) has been reported to be protective against the occurrence of several diseases. Increasing evidence suggests that the MedDiet could counter diseases associated with chronic inflammation, including metabolic syndrome, atherosclerosis, cancer, diabetes, obesity, pulmonary diseases, and cognition disorders. Adoption of a MedDiet was associated with beneficial effects on the secretion of anti-inflammatory cytokines, antioxidant cellular and circulating biomarkers as well as with regulation of gene polymorphisms involved in the atherosclerotic process. The MedDiet has been considered for the prevention of cardiovascular and other chronic degenerative diseases focusing on the impact of a holistic dietary approach rather than on single nutrients. Epidemiological dietary scores measuring adherence to a MedDiet have been developed. This narrative review considers the results of up-to-date clinical studies (with a focus on the last 5 years) that evaluated the effectiveness of the MedDiet in reducing the prevalence of chronic and degenerative diseases.

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Name: Efthymios Surname:
Gotsis
Name: Panagiotis Surname:
Anagnostis
Name: Anargyros Surname:
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Name: Athanasia Surname:
Vlachou
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Katsiki
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Karagiannis
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Degrees: Efthymios Gotsis
MD,MSc, Panagiotis
Anagnostis MD, PhD,
Anargyros Mariolis MD, PhD,
Athanasia Vlachou, Niki
Katsiki MD MSc PhD,
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Correct ref 16: Freedland SJ, Aronson WJ. Words of wisdom.
Re: Weight loss with a low-carbohydrate, Mediterranean, or low-
fat diet. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow
S, Greenberg I, Golan R, Fraser D, Bolotin A, Vardi H, Tangi-
Rozental O, Zuk-Ramot R, Sarusi B, Brickner D, Schwartz Z,
Sheiner E, Marko R, Katorza E, Thiery J, Fiedler GM, Blüher M,
Stumvoll M, Stampfer MJ. Dietary Intervention Randomized
Controlled Trial (DIRECT) Group. N Engl J Med
2008;359:229-41. Eur Urol. 2009;55(1):249-50.

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Article
Health Benefits of the Mediterranean
Diet: An Update of Research Over
the Last 5 Years
Efthymios Gotsis
1
, Panagiotis Anagnostis
1
, Anargyros Mariolis
2
,
Athanasia
AQ 1
Vlachou
1
, Niki Katsiki
1
, and Asterios Karagiannis
1
Abstract
The Mediterranean
AQ 2
Diet (MedDiet) has been reported to be protective against the occurrence of several diseases. Increasing
evidence suggests that the MedDiet could counter diseases associated with chronic inflammation, including metabolic syndrome,
atherosclerosis, cancer, diabetes, obesity, pulmonary diseases, and cognition disorders. Adoption of a MedDiet was associated
with beneficial effects on the secretion of anti-inflammatory cytokines, antioxidant cellular and circulating biomarkers as well as
with regulation of gene polymorphisms involved in the atherosclerotic process. The MedDiet has been considered for the pre-
vention of cardiovascular and other chronic degenerative diseases focusing on the impact of a holistic dietary approach rather
than on single nutrients. Epidemiological dietary scores measuring adherence to a MedDiet have been developed. This narrative
review considers the results of up-to-date clinical studies (with a focus on the last 5 years) that evaluated the effectiveness of the
MedDiet in reducing the prevalence of chronic and degenerative diseases.
Keywords
Mediterranean diet, inflammation, atherosclerosis, metabolic syndrome, carotid intima–media thickness, cardiovascular disease,
cancer
Introduction
The impact of nutrition on human health has been evaluated
by several case–control, prospective cohorts and randomized
clinical trials which provide evidence that diet may affect the
health status of a population.
1
Nowadays, the World Health
Organization as well as all the major scientific associations
recognize that diet plays an important role in preventing
noncommunicable diseases.
2-4
Several studies evaluated the
associations between diets, foods or nutrients, and chronic dis-
eases, leading to general agreement about the effect of nutri-
tional factors on the etiology of common diseases, such as
cardiovascular disease (CVD), neoplastic diseases, and meta-
bolic syndrome (MetS).
5
Conversely, poor-quality diets may
favor the development of pathological health outcomes and
chronic diseases such as diabetes mellitus (DM), coronary artery
disease (CAD), cancer, and neurodegenerative disorders.
6,7
In order to explore the multiple associations between Med-
iterranean Diet (MedDiet) and chronic diseases, dietary scores
have been developed.
8
Furthermore, these scores are used to
evaluate food consumption trends and to develop public health
nutrition recommendations.
9
Unfortunately, despite the recog-
nition of the multiple benefits of the MedDiet, there has been a
gradual abandonment of this dietary pattern by the inhabitants
of the Mediterranean basin (especially among the young) in the
recent years.
10
In comparison with 45 years ago, population
adherence to MedDiet nowadays is diminished,
11
and this is
further enhanced by the observation that currently farmers from
Crete are likely to be at a higher risk of developing CVD com-
pared to earlier generations.
12
These findings were confirmed
recently in 12 Mediterranean Islands (the Mediterranean Island
Study), which showed that these populations gradually move
away from the protective traditional dietary pattern.
13
How-
ever, the MedDiet still remains a prevalent nutritional option
with multiple health profits.
The aim of this narrative review was to consider the cur-
rent evidence about the protective role of the MedDiet in
various chronic diseases and to elucidate potential underly-
ing mechanisms.
1
Second Propedeutic Department of Internal Medicine, Medical School, Aristotle
University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
2
Health Center, Areopoli, Greece
AQ 3
Corresponding Author:
Efthymios Gotsis, Second Propedeutic Department of Internal Medicine,
Medical School, Aristotle University of Thessaloniki, Hippokration Hospital,
Thessaloniki, 70 Leonidou Str, Sparta, 23100, Greece.
Email: thymiosgotsis@yahoo.gr
Angiology
1-15
ªThe Author(s) 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0003319714532169
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The MedDiet: Elemental and Holistic Approach
For decades, several studies attempted to evaluate the signifi-
cance of single dietary components of the MedDiet on health
outcomes. However, several recent clinical trials of single-
nutrient supplementation, such as vitamins A, C, and E, failed
to show any benefit regarding primary CVD prevention.
14,15
People usually consume a complex of nutrients and do not gen-
erally focus on specific foods; this approach has several con-
founders and methodological limitations, as the components
of a diet may participate in multiple synergistic and antagonist
interactions.
16
Therefore, several epidemiological studies, dur-
ing the last 5 years, evaluated the adherence of a population to
the MedDiet pattern using diet indices based on a traditional
MedDiet reference pattern.
17
The MedDiet indices summarize
the diet by means of a single score that is affected by different
components, such as foods, food groups, or a combination of
foods and nutrients. Furthermore, dietary scores have been
used to explore the associations between the MedDiet, as an
integral entity, and health parameters such as life expectancy
or the incidence of obesity, CVD, and some types of cancers.
These indices are also useful tools to estimate food con-
sumption trends and to identify the factors involved, thus con-
tributing to the establishment of effective public health
nutrition recommendations.
18
In this context, a recent large
study reported that a greater adherence to MedDiet was associ-
ated with higher intake of total vegetal protein, polyunsaturated
fatty acids (PUFAs), mainly n-6 PUFAs, and lower intake of
total saturated fat.
19
Moreover, the PREvencion con DIeta
MEDiterranea (PREDIMED) trial, including 7305 participants,
aged 55 to 80 years, at high risk of CVD, showed that those
with little education, a larger waist to height ratio, or DM as
well as those who were less physically active, single, divorced,
separated, or smokers were less likely to adhere to the
MedDiet.
20
Therefore, the beneficial impact of MedDiet on
general health, despite differences in populations or research
practices, remains important.
Mediterranean Diet and Cancer
Ongoing findings from the European Prospective Study into
Cancer and Nutrition (EPIC) study (Greek cohort: n ¼23
349 men and women, not previously diagnosed with cancer,
CAD, or DM, with a mean follow-up time of 8.5 years) showed
that a greater adherence to a MedDiet was related to a signifi-
cant reduction in total mortality.
21,22
Alternate MedDiet
(aMED) score was recently shown to correlate inversely with
the risk of head and neck cancer.
23
Furthermore, data from the
Italian segment, including over 31 000 women, aged 36 to
64 years, who were followed up for 11.25 years, supported a
clear protective role of fruit and vegetable consumption in
breast cancer risk.
24
Another Italian study
25
reported that a
greater adherence to a MedDiet significantly improved CVD
risk as well as markers of oxidative stress and inflammation,
which are molecular pathways potentially involved in carcino-
genesis.
26,27
The entire EPIC study (142 605 men and 335 873
women) demonstrated that 4.7%of cancers among men and
2.4%among women might have been avoided if patients had
a greater adherence to the MedDiet pattern.
28
Animal studies of induced breast cancer have shown that
diets rich in extra virgin olive oil (such as the MedDiet) exert
a negative modulatory effect on tumors, particularly affecting
cell membranes composition, signaling proteins activity, and
gene expression. These influences may inhibit proliferation,
induce apoptosis, and minimize DNA damage, thus supporting
a potential benefit for olive oil on breast cancer risk.
29
Several dietary factors have been associated with the occur-
rence of cancers of the upper aerodigestive tract (UADT).
A recent case–control study in Greece showed that adherence
to the traditional MedDiet was related to a reduced risk of
UADT cancers.
30
This finding is in agreement with the lower
incidence of such cancers in Greece, despite the increased pre-
valence of smoking and drinking habits.
31
Similarly, prostatic
cancer risk was reduced in individuals following MedDiet
compared with those adopting a Western diet.
32
The increased
quantity and quality of phytochemicals that MedDiet contains
may contribute to these beneficial effects due to their antioxi-
dant and anti-inflammatory properties.
A dietetic approach to the anti-inflammatory action of food
lipids (PUFAs, monounsaturated fatty acids [MUFAs]
and saturated fatty acids [SFAs]) showed that dietary fatty acid
(FA) may affect FA availability to produce prostaglandins and
leukotrienes.
33
Intake of fat from a Greek-style MedDiet
(mostly MUFA from olive oil consumption) can be expected
to influence FA-metabolizing proteins, with an emphasis on the
metabolic pathways leading to the diminished formation of
proinflammatory eicosanoids.
34
Judging from the increasing
evidence for the anti-inflammatory effects of the MedDiet,
we can assume such a protective role in cancer pathophysiol-
ogy, but up to date, no direct correlation exists between diet,
or its components, and carcinogenic cell proliferation.
Mediterranean Diet and Neurodegenerative Diseases
A higher adherence to a MedDiet has been associated with
reduced cognitive decline.
35
Similarly, the foods, micro-, and
macronutrients that MedDiet contains have been separately
reported to protect against dementia and predementia syn-
dromes.
36
A recent meta-analysis examined the association
between adherence to a MedDiet and cognitive impairment, Par-
kinson disease, and depression.
37
Partial analyses showed that a
high adherence to the MedDiet significantly reduced the risk of
ischemic stroke, cognitive impairment, dementia, and Alzheimer
disease. A high adherence to the MedDiet also protected against
depression independent of age, but the benefits of moderate
adherence tended to diminish with advancing age.
37
These find-
ings for cognitive function were in agreement with the results of
the PREDIMED-NAVARRA randomized trial.
38
This may be of
special significance, given the ongoing aging of Western societ-
ies. Previous data also reported a lower risk of Alzheimer disease
following adherence to MedDiet as well as the Japanese diet.
39
A 9-year follow-up study in Tuscany, Italy (CHIANTI:
Invecchiare in CHIANTI), including 935 women and men, aged
2Angiology

65 years and older, showed that adherence to a Mediterranean-
style diet was related to a slower decline in mobility.
40
The
beneficial effect of this dietary pattern may be attributed to the
protective properties of 2 components of olive oil, that is, tyr-
osol (Tyr) and hydroxytyrosol (OH-Tyr), against b-amyloid
(Ab)-induced toxicity. Based on these findings, these 2 food
components of the MedDiet have been suggested as neuropro-
tective agents against Abtoxicity and may at least partly
explain the benefits of the MedDiet on prevention of Alzheimer
disease.
41
Several studies reported that adherence to a MedDiet
is associated with a reduction in the incidence of dementia, but
conflicting results exist.
42,43
Therefore, a clear correlation of
MedDiet with dementia and cognition mechanisms remains
to be established in future studies.
Mediterranean Diet and Respiratory Disease
A previous cross-sectional study including 174 asthmatics,
40 years of age, found that those with a high adherence to the
traditional MedDiet were more likely to achieve asthma control
as assessed by lung function, symptoms, and exhaled nitric
oxide. Higher fresh fruit intake reduced the risk of uncontrolled
disease, whereas higher ethanol intake increased this risk.
44
A recent meta-analysis supported the beneficial effect of adher-
ence to a MedDiet on asthma prevalence in children.
45
Further-
more, obese adults with moderate to severe obstructive sleep
apnea syndrome significantly decreased their apnea-hypopnea
index (AHI) after a 6-month consumption of a MedDiet.
46
There is evidence that a partial interaction exists between
adherence to MedDiet and adverse health consequences of
smoking.
47
Two cohort studies, INfancia y Medio Ambiente
(INMA; Spain) and a prospective mother–child cohort (Rhea
Study in Greece), showed that a higher MedDiet adherence
decreased the risk of a fetal growth-restricted infant delivery
in smoking mothers, an association that was not observed in
nonsmoking mothers.
48
Further research is needed to elucidate
the mechanisms through which nutritional components protect
the respiratory tract.
Mediterranean Diet and Kidney Disease
Improvements in kidney function were previously reported in
patients with chronic kidney disease (CKD) after adhering to
a MedDiet.
49
Epidemiological data from 3044 healthy men and
women showed that a greater adherence to MedDiet was inde-
pendently correlated with decreased urea and creatinine levels
and raised creatinine clearance rates.
50
In a report from the
PREDIMED study, 785 participants were randomly assigned
to 3 dietary approaches: a MedDiet supplemented with virgin
olive oil (MedDiet þolive oil), a MedDiet supplemented with
mixed nuts (MedDiet þnuts), and a control low-fat diet for
1 year.
51
All these approaches significantly improved kidney
function, with similar mean increases in estimated glomerular
filtration rate but unchanged urinary albumin–creatinine ratio
(ACR). The results do not support that MedDiet is more bene-
ficial than a low-fat diet with regard to renal function in such
patients at high CVD risk.
51
In contrast, in the 3 L (Leontio
Lyceum ALbuminuria) study,
52
a Greek cohort study on ado-
lescents, those who adhered to a MedDiet, had reduced levels
of albuminuria, independent of demographic and hemody-
namic cofactors compared with those who adhered less.
Furthermore, KIDMED score (an index that includes 16 com-
ponents and summarizes the principles of the MedDiet by an
arithmetic score ranging from 0 to 12) was inversely associ-
ated with ACR.
52
Obviously, more targeted research is
needed in order to clarify the relationship between MedDiet
and CKD.
Mediterranean Diet and Obesity
The Dietary Intervention Randomized Controlled Trial
(DIRECT), a 2-year randomized study including 322 moder-
ately obese patients, showed that good adherence to a MedDiet
resulted in a more favorable health status as reflected by
improved CVD risk factors, such as lipid profile, blood pres-
sure (BP), and glucose, especially in persons with diabetes and
compared with a low-carbohydrate diet.
53
Another interven-
tional study showed a significant association between interleu-
kin 6 (IL-6) gene-174G/C polymorphism, (C) being the minor
allele frequency and (G) the major, and nutritional pattern; CC
patients following the MedDiet enriched with virgin olive oil
had the greatest weight decrease compared with those on a
low-fat diet and with GG þGC polymorphisms.
54
Researchers from 10 European countries assessed the
cross-sectional association between adherence to a modified
MedDiet (rich in foods of vegetable origin and unsaturated
FAs) and obesity markers (ie, body mass index [BMI] and
waist circumference [WC]) in 497 308 individuals, aged 25
to 70 years.
55
Waist circumference was significantly lower
in men and women with a higher adherence to modified
MedDiet for a given BMI, the association being greater in
Northern European regions.
55
Similarly, a MedDiet score
(ie, REGICOR-Mediterranean diet score [R-MDS]) was
inversely correlated with WC increase in a Spanish popula-
tion.
56
Furthermore, recent studies concluded that adipokines
are involved in the regulation of BP, coagulation, food intake
and energy balance, insulin resistance, lipid and glucose
metabolism, angiogenesis, and vascular remodeling.
57
Among them, adiponectin exerts anti-atherogenic properties
by increasing FA oxidation, reducing circulating free FAs,
and improving insulin resistance.
58
Adiponectin gene variations
were also reported to affect body weight changes during a 3-year
follow-up period in patients with high CVD risk, leading to obe-
sity.
59
Interestingly, adherence to a Mediterranean-style diet was
able to reverse this negative effect compared to a low-fat diet.
59
Therefore, a healthy diet may protect against obesity (and
abdominal obesity) development, even in individuals with a high
CVD risk. Similar benefits were reported for children (aged 2-9
years) in 8 European countries in the Identification and pre-
vention of Dietary- and lifestyle-induced health EFfects In
Children and infantS (IDEFICS) study,
60
thus highlighting
the importance of the early adoption of a healthy dietary
pattern.
Gotsis et al 3

Table 1. Summary of the Literature About the Effects of MedDiet on Chronic Diseases and Their Risk Factors.
Authors/Year Type of Study Disease/Syndrome MedDiet-Proposed Protective Mechanism Active Component
AQ 10
Sherzai et al, 2012
7
Systematic review Stroke prevention – MedDiet, DASH
Trichopoulou et al,
2009;
21
EPIC
(Greek segment)
Prospective cohort, 8.5 years Cancer Not defined Ethanol, fruits, vegetables, low
meat consumption, olive oil,
and legumes
Li et al, 2014
23
Prospective cohort, 11 years Head and neck cancer – aMED
Masala et al, 2012;
24
EPIC (Italian
segment)
Prospective cohort, 11.5 years Breast cancer – Leafy vegetables and fruits
Azzini et al, 2011
25
Observational CHD Higher levels of anti-inflammatory cytokines and
antioxidant markers
Holistic approach (score)
Escrich et al, 2011
29
In vitro Breast cancer Molecular changes, negative modulatory effects
in tumors
Virgin olive oil
Samoli et al, 2010
30
Case–control study Upper aerodigestive
cancer
– Holistic approach (score 0-9)
Ferrı
´s-Tortajada et al,
2012
32
Literature review Prostatic cancer – Phytochemicals with antioxidant
and anti-inflammatory
properties
Psaltopoulou et al,
2013
37
Meta-analysis Depression, stroke,
cognitive impairment,
Parkinson disease
– MedDiet adherence
Milaneschi et al, 2011
40
Prospective cohort, 9 years Mobility decline – MedDiet score
Barros et al, 2008
44
Cross-sectional Asthma – Alternate MedDiet score, high
fruit intake, and low ethanol
consumption
Garcia-Marcos et al,
2013
45
Meta-analysis Children’s asthma Lower occurrence of the 3 respiratory outcomes
(current wheeze, current severe wheeze, and
asthma ever)
MedDiet
Papandreou et al,
2012
46
Randomized trial, 6 months OSAS Reduced AHI MedDiet combined with physical
activity
Dı
´az-Lo
´pez et al,
2012
51
Intervention, 1 year Kidney function Improves of GFR but no changes in ACR MedDiet
Razquin et al, 2010
54
Intervention, 3 years Body weight Reversal of -174G/C IL-6 gene variant-related effects
on body weight
MedDiet and virgin olive oil
Romaguera et al,
2009
55
Cross-sectional Waist circumference – MedDiet
Funtikova et al, 2014
56
Prospective cohort, 10 years Waist circumference,
abdominal obesity
incidence
Lower abdominal fat gain R-MDS
Razquin et al, 2010
59
Intervention, 3 years Body weight Reversal of the adiponectin gene variant-related
effects on body weight
MedDiet enriched with virgin
olive oil or nuts
Tognon et al, 2014
60
(IDEFICS study)
Prospective cohort, 2 years Childhood obesity Inversely associated with childhood obesity fMDS
Kastorini CM et al,
2011
61
Meta-analysis Metabolic syndrome Lower mean levels of systolic and diastolic blood
pressure, glucose, lipid profile
MedDiet pattern
(continued)
4

Table 1. (continued)
Authors/Year Type of Study Disease/Syndrome MedDiet-Proposed Protective Mechanism Active Component
Esposito et al, 2010
62
Systematic review Glycemic control – MedDiet
Esposito et al, 2009
63
Randomized trial, 4 years Glycemic control – MedDiet
Lasa et al, 2014
64
Cross-sectional , multicenter
parallel trial
Glycemic control Increased values of adiponectin–leptin ratio,
adiponectin–HOMA-IR ratio, and decreased values
of waist circumference
MedDiet plus mixed nuts and
MedDiet plus olive oil
Itsiopoulos et al,
2011
65
Intervention Glycemic control – MedDiet
Rossi et al, 2013 EPIC
(Greek segment)
66
Prospective cohort, 11.3 years Diabetes occurrence A higher MDS was inversely associated with diabetes
risk
MDS
Mosharraf et al, 2013
67
Prospective cohort study,
1 year
MACCE Improve long-term outcome including death/MACCE
in diabetic patients with CAD
Med-DQI
Karamanos et al,
2014
71
Observational study, 9 months Incidence of gestational
diabetes mellitus (GDM)
Lower incidence of GDM with better degree of
glucose tolerance, even without GDM
Mediterranean Diet Index (MDI)
Esposito et al, 2013
74
Systematic review Metabolic syndrome Beneficial role of adherence to the Mediterranean
dietary pattern regarding metabolic syndrome
presence and progression
MedDiet
Kesse-Guyot et al,
2013
75
Prospective study, 6 years Metabolic syndrome Beneficial role of MedDiet against components of
MetS or MetS incidence
MDS, an updated Mediterranean
score (MED), and MSDPS
Viscogliosi et al,
2013
76
Cross-sectional Metabolic syndrome
(NCEP III criteria)
– MedDiet
Richard et al, 2012
79
Intervention, 35 weeks Metabolic syndrome/body
weight
Reduction of inflammation markers without weight loss MedDiet
Defoort et al, 2011
80
(Medi-RIVAGE)
Intervention, 3 months Postprandial lipemia Diminishes TAGs and Apo B48 MedDiet
Salas-Salvado
´et al,
2014
83
Randomized trial; subgroup
analysis, 4.1 years
Incidence of type 2 DM
(new onset)
Reduced diabetes risk MedDiet enriched with olive oil
Sanchez-Tainta et al,
2008
88
Cross-sectional assessment in
a cohort study
CVD risk factors and their
clustering
Inverse relationship MedDiet
Nunez-Cordoba et al,
2009
90
SUN
Prospective cohort, 4.2 years CHD Lower mean levels of systolic and diastolic blood
pressure
Adherence to the MedDiet
Mente et al, 2009
92
Systematic review CHD – Vegetables, nuts, MUFA, fruits
Fung et al, 2009
93
(Nurse’s Health
Study)
Prospective cohort, 20 years CHD Reduced rate, lower mortality from CHD MedDiet
Buckland G et al,
2009
94
Prospective cohort, 10.4 years CVD Lower incidence of CHD events MedDiet
Hoevenaar-Blom et al,
2012
95
Prospective cohort, 10-15 years CVD Lower incidence of CVD events MedDiet
Misirli et al, 2012
96
(EPIC Greek
segment)
Prospective cohort, 10.6 years CVD Decreased total mortality and CBVD incidence MedDiet score
Kastorini et al, 2011
97
Case/case–control CVD Protective on ischemic stroke development MedDiet score
Chrysohoou et al,
2012
98
Cross-sectional CHF Biventricular systolic and diastolic improvement
in patients with CHF
MedDiet Score
(continued)
5

Table 1. (continued)
Authors/Year Type of Study Disease/Syndrome MedDiet-Proposed Protective Mechanism Active Component
Corella et al, 2013
99
Randomized trial, 4.8 years CVD Regulates polymorphism of TCF7L2-rs7903146 MedDiet
Gardener et al,
2011
101
Prospective cohort, 9 years CVD events incidence Lower incidence of vascular events MedDiet
Sofi et al, 2008
102
Meta-analysis CVD, cancer, and
neurodegenerative
diseases
Inverse relationship MedDiet
Lopez-Garcia et al,
2014
104
Prospective Cohort, 5.8 years
(women) and 7.7 years (men)
CVD, cancer Decreased total mortality and stroke incidence aMED
Tognon et al, 2014
105
Prospective cohort, 11 years CVD incidence, MI Decreased total mortality and MI incidence MedDiet
Urpi-Sarda et al,
2012
108
(PREDIMED)
Intervention Atherosclerotic vascular
disease
Downregulates cellular and circulating biomarkers MedDiet enriched with virgin
olive oil and vegetables
Marı
´n et al, 2013
111
Cross-sectional/intervention Atherosclerotic vascular
disease
Downregulates endothelial cellular apoptosis MedDiet enriched with virgin
olive oil
Giordano et al,
2012
114
Review Chronic inflammation in
atherosclerosis
Scavenging and lowering free radicals, reactive oxygen
species (ROS)
Fruits and vegetables carotenoids
Dai et al, 2008
116
Case–control study Atherosclerotic vascular
disease
Decrease oxidative stress MedDiet components
Carluccio, et al
117
In vitro Atherosclerotic vascular
disease
Inhibit endothelial adhesion molecule expression Phytochemicals in olive oil and
red wine
Llorente-Corte
´setal,
2010
119
Intervention, 3 months Atherosclerotic vascular
disease
Modulate the expression of pro-atherothrombotic
genes
Virgin olive oil and MedDiet
Scoditti et al, 2012
121
In vitro Atherosclerotic vascular
disease
Polyphenols reduce inflammatory angiogenesis
through MMP-9 and COX-2 inhibition
Olive oil, red wine
Murie-Fernandez, et al,
2011
131
Intervention, 1 year Atherosclerotic vascular
disease
Reduction of cIMT (for elevated baseline IMTs >0.9 mm) MedDiet enriched with virgin
olive oil or nuts
Sala-Vila et al, 2014
132
Intervention, 2.4 years Atherosclerotic vascular
disease
Delayed progression of ICA-IMT and plaque MedDiet enriched with nuts
Giannini et al, 2014
133
Intervention 1 year in
prepubertal children with
hypercholesterolemia
Hypercholesterolemia Reduction of both lipid profile and cIMT MedDiet
Abbreviations: CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition; CHD, congenital heart disease; DM, diabetes mellitus; NCEP III, National Cholesterol Education
Program; MMP-9, matrix metalloproteinase-9; COX-2, cyclooxygenase-2; PREDIMED study, PREvencio
´n con DIeta MEDiterra
´nea study; MedDiet, Mediterranean Diet; Apo B48, apolipoprotein B48; TAGs,
triacylglycerols; IL-6, interleukin 6; GFR, glomerular filtration rate; ACR; albumin–creatinine ratio; MUFA, monounsaturated fat; DASH, dietary approaches to stop hypertension; ROS, reactive oxygen species;
aMED, alternate Mediterranean diet; TCF7L2-rs7903146, transcription factor 7-like 2; MI, myocardial infarction; CBVD, cerebrovascular disease; OSAS, obstructive sleep apnoea syndrome; AHI, apnoea-
hypopnoea index; R-MDS, REGICOR-Mediterranean diet score; fMDS, food frequency-based Mediterranean Diet Score; MDS, Mediterranean Diet Score; Med-DQI, Mediterranean diet quality index; MSDPS,
Mediterranean style-dietary pattern score; IDEFICS study, Identification and prevention of Dietary—and lifestyle—induced health Effects In Children and infants; HOMA-IR, homeostatic model of insulin resis-
tance; MACCE, major adverse cardiac and cerebrovascular event; cIMT, carotid intima–media thickness; MetS, metabolic syndrome.
6

Mediterranean Diet and DM, MetS, and Dyslipideamia
A previous meta-analysis of 50 studies (2 prospective, 13 cross-
sectional, and 35 clinical trials; n ¼534 906) found that adher-
ence to the MedDiet was related to a decreased risk of MetS
(log hazard ratio: 0.69; 95%confidence interval [CI]: 1.24
to 1.16) as well as to lower values of WC (0.42 cm; 95%
CI: 0.82 to 0.02), glucose (3.89 mg/dL; 95%CI:5.84
to 1.95), triglycerides (TGs; 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 BP (1.58 mm Hg; 95%CI: 2.02 to 1.13), and
higher levels of high-density lipoprotein cholesterol (HDL-C;
1.17 mg/dL; 95%CI: 0.38 to 1.96) compared with the same
parameters before adhering to the MedDiet.
61
Improvement in
fasting glucose and glycosylated hemoglobin (HbA
1c
)levelswas
greater by adhering to a MedDiet pattern versus commonly used
diets and ranged from 7 to 40 mg/dL for fasting glucose and
from 0.1%to 0.6%for HbA
1c
in patients with type 2 DM
(T2DM).
62
In another study from the same group,
63
weight loss
and improvements in glycemic control and coronary risk
parameters were significantly greater in overweight patients with
newly diagnosed T2DM that were assigned to a low-
carbohydrate, Mediterranean-style diet compared with those
adhering to a low-fat diet; the initiation of antihyperglycemic
drugs was also delayed in the MedDiet group.
63
However, in the
PREDIMED study, patients with T2DM in both MedDiet group
(supplemented with olive oil or nuts) and low-fat diet group
achieved similar weight and glucose reductions.
64
In another
study,
65
a moderate-fat MedDiet intervention significantly
improved HAb
1c
(falling from 7.1%-6.8%;P¼.012) and diet
quality in 27 patients (47-77 years) with well-controlled
T2DM compared with their usual diet without leading to weight
gain.
65
Previous randomized trials showed that adoption of a
MedDiet pattern may help in preventing T2DM, as reported in
the Greek cohort of the EPIC study,
66
and in improving
glycemic control and CVD risk in patients with DM.
67
In this
context, the Mediterranean Island Study (MEDIS) including
1190 men and women, aged > 65 years, showed that animal pro-
tein consumption was associated with a higher prevalence of
DM among the elderly individuals, whereas no such relation was
observed with protein intake from cereals and vegetables.
68
Moreover, the Seguimiento Universidad de Navarra (SUN) trial,
a prospective cohort study conducted in a population of 13 380
Spanish university graduates,
69
showed that patients who
adhered closely to the MedDiet had a lower risk of developing
DM over 4.4 years of follow-up; a 2-point increase in the adher-
ence score was associated with a 35%relative reduction in the
risk of DM (P< .03). Similarly, lifestyle modification (including
a healthy diet and exercise) can prevent or at least delay T2DM
onset in patients with impaired glucose tolerance or impaired
fasting glucose (IFG); drug therapy is needed to achieve residual
risk reduction.
70
A protective effect of MedDiet on the develop-
ment of gestational DM has also been suggested.
71
In addition, in a cross-sectional analysis of the PREDIMED
study, including patients with a high CVD risk profile, adherence
to a MedDiet was significantly related to MetS prevalence, even
after adjusting for age, gender, smoking, physical activity, and
energy intake.
72
Recently published reviews support the inverse
link between the incidence of MedDiet and MetS.
73,74
A large
French prospective study (n ¼3232; 6 years of follow-up)
including individuals from the Supple´mentation en Vitamines
et Mine´raux AntioXydants (SU.VI.MAX) study showed that all
MetS components were significantly related to a MedDiet score
(inverse associations for WC, systolic BP, and TG and direct
association with HDL-C).
75
Similarly, in an Italian study, lower
MedDiet adherence was associated with higher MetS and preva-
lence of MetS components as well as with higher values of
homeostasis model assessment of insulin resistance (HOMA-IR)
and high-sensitivity C-reactive protein (hsCRP).
76
However, no
associations were observed between individual items of Med-
Diet and the development of MetS or IFG. This finding seems
to support the holistic approach rather than the elemental one for
MedDiet protective role. MedDiet-related beneficial effects on
hemostasismayalsobeobservedinpatientswithMetS.
77
Even in children with type 1 DM, training to a Mediterranean-
style diet improved the quality of nutrient intakes (ie, increased
fiber consumption and reduced lipids intake) and led to
decreased low-density lipoprotein cholesterol (LDL-C) and
non-HDL-C levels after 6-month follow-up.
78
Similarly,
MedDiet was reported to enhance LDL-C clearance and
decrease cholesterol absorption, thus leading to LDL-C lower-
ing, independent of weight reduction.
79
The MedDiet was also
shown to improve postprandial lipemia (as assessed by reduc-
tions in triacylglycerols [TAGs] and apolipoprotein B48 levels)
in a 3-month period in patients at moderate CVD risk.
80
Taking the aforementioned data into account, we would
associate MedDiet main component, virgin olive oil, and its
anti-inflammatory effect with a lower MetS prevalence
81,82
as also supported by the PREDIMED study.
83
In contrast, diet-
ary patterns including meat, alcohol, and fish intake, in 1442
adults from Hyvar Island (Adriatic Sea/Croatia) were signifi-
cantly associated with MetS as defined by the International
Diabetes Federation criteria (P¼.027).
84
Mediterranean Diet and CVD
Cardiovascular disease remains the leading cause of death and
disability in developed countries, thus increasing the interest in
enhancing dietary practices for CVD prevention.
85
Several
investigators have demonstrated an association between
MedDiet and reduced prevalence of traditional CVD risk
factors such as hypertension, dyslipidemia, and DM.
7,86,87
Similarly, in a cross-sectional analysis of 3204 asymptomatic
high-risk patients, an inverse relationship between MedDiet
score and the presence of CVD risk factors (ie, DM, obesity,
dyslipidemia, and hypertension), both separately and as a
whole, was observed.
88
Furthermore, significant reductions in
BP, hsCRP, total cholesterol (TC), LDL-C, and TG levels were
observed in patients with mild hypercholesterolemia following
a 4-month adherence to MedDiet.
89
However, the SUN trial
found that higher adherence to a MedDiet was associated with
Gotsis et al 7

lower mean levels of systolic and diastolic BP after 6 years of
follow-up but not with a reduced risk of hypertension.
90
Of
note, when exercise (in the form of moderate- to high-
intensity endurance training) was added to MedDiet, greater
improvements in cardiorespiratory fitness, endothelial progeni-
tor cell (EPC) numbers, BP, weight reduction, insulin sensitiv-
ity, and TAG were observed compared with MedDiet alone
91
;
ischemic reactive hyperemia was beneficially affected only in
the exercise group.
According to a previous meta-analysis,
92
MedDiet and
vegetable and nut consumption were protective against occur-
rence of coronary heart disease (CHD). In this context, a higher
aMED score was linked to reduced CHD and stroke prevalence
in a large cohort of women (n ¼74 886; aged 30-63 years) from
the Nurses’ Health Study.
93
Similarly, higher adherence to the
MedDiet was associated with significantly lower CHD risk in
the Spanish (n ¼41 078; mean follow-up ¼10.4 years) and the
Netherlands cohorts (n ¼40 011; follow-up ¼10-15 years) of
the EPIC study.
94,95
Furthermore, in the Greek cohort of EPIC
(n ¼23 601; median follow-up ¼10.6 years), morbidity and
mortality of cerebrovascular disease (CBVD) significantly
decreased with increasing adherence to the MedDiet.
96
Addi-
tionally, the comparative analysis of a case/case–control study
in 1000 Greek participants showed that adoption of the Med-
Diet protected against acute coronary syndromes and stroke
occurrence.
97
In another cross-sectional study involving 372
consecutive Greek patients with chronic heart failure, MedDiet
consumption improved systolic and diastolic ventricular func-
tion.
98
Moreover, at the cellular level, a randomized trial with
7018 participants from the PREDIMED study
99
reported that
the increased risk of T2DM and dyslipidemia (defined as high
levels of TC, LDL-C, and TG), which characterized patients
with transcription factor 7-like 2 (TCF7L2-rs7903146; C > T)
polymorphism, was significantly reduced in those on the
MedDiet compared with those on control diet; stroke prevalence
was also decreased in the MedDiet groups.
99
Furthermore,
MedDiet (supplemented with either extravirgin olive oil or nuts)
consumption was associated with significantly fewer major
CVD events (ie, myocardial infarction, stroke, or CVD mortal-
ity) than a low-fat diet in high-risk individuals as shown in the
recent PREDIMED trial.
100
Consistent with these findings in Mediterranean popula-
tions, the Northern Manhattan Study,
101
a population-based
cohort study (n ¼2568), also found that higher adherence to
a MedDiet correlated with decreased reduced risk of myocar-
dial infarction, stroke, or vascular mortality.
A higher MedDiet adherence was related to decreased
mortality from all causes, CVD and cancer, as well as reduced
morbidity from cancer, Parkinson, and Alzheimer diseases in a
meta-analysis involving 1 574 299 individuals.
102
An updated meta-analysis by the same group
103
confirmed
the significant protection provided by the adherence to a
MedDiet against CVD and cancer morbidity and mortality as
well as against development of neurodegenerative diseases.
103
Similarly, a recent prospective cohort study (n ¼17 415 patients
with CVD, median follow-up of 5.8 years for women and 7.7
years for men) found that a higher adherence to the aMED was
associated with a lower risk of CVD, cancer, and total mortal-
ity
104
; for every 2-point increase in aMED score, a 7%decrease
in total mortality risk was observed.
105
Interestingly, a Danish
Cohort study (n ¼1849, 11 years of follow-up) reported that the
Mediterranean Diet Score was negatively correlated with mor-
bidity and mortality of myocardial infarction as well as to
all-cause death but not with stroke prevalence and mortality.
105
Overall, adoption of the MedDiet is associated with a lower pre-
valence of fatal or nonfatal CVD events in both Mediterranean
and non-Mediterranean populations.
The Effects of MedDiet on Systemic Inflammation
and Atherosclerotic Disease
Several anti-inflammatory mechanisms have been proposed cor-
relating MedDiet and/or its components with the different steps
of the atherosclerotic process. Therefore, the MedDiet could be a
part of the therapeutic strategy for chronic inflammation-related
diseases.
106
In this context, a previous multicenter, longitudinal
study of 1003 myocardial infarction survivors from several
European regions showed a protective, inverse relationship
between a MedDiet score and the development of a proinflam-
matory state (as defined by levels of CRP and IL-6).
107
Similarly, other established plasma inflammation biomarkers,
cellular and circulating (ie, tumor necrosis factor receptor 60 and
80 and intercellular adhesion molecule 1), were significantly
decreased after 1 year of adhesion to the MedDiet-type pattern
in patients with high CVD risk.
108-110
The primary induction of atherosclerosis comes from the oxi-
dative stress that activates the inflammation process and impairs
the nitric oxide pathway and affects telomerase activity.
111
The
LDL-C particle oxidation is one of the initial steps of athero-
sclerosis, consequentially leading to CVD and CBVD.
112
Fruits
and vegetables (typically included in the MedDiet) are very rich
in carotenoids that exert significant antioxidant action; carote-
noids were inversely related to MetS, HOMA-IR, and CRP in
adolescents.
113
Carotenoids may act as scavengers of singlet
oxygen (1O
2
) and free radicals, thus downregulating the concen-
trations of reactive oxygen species (ROS).
114
Furthermore,
MedDiet was reported to reduce the production of ROS and cel-
lular apoptosis of endothelial cells
115
which can partially explain
the anti-atherogenic properties of the MedDiet. In the same con-
text, the ratio of reduced glutathione to oxidized glutathione, in a
well-controlled study of twins, was strongly associated with the
MedDiet and this relationship was not confounded by genetic or
environmental parameters.
116
It is known from previous studies that monocyte/leukocyte
adhesion to the endothelium is important in early atherogenesis;
antioxidant polyphenols of olive oil and red wine, within the
concentration range expected from MedDiet, inhibited the
expression of vascular cell adhesion molecule 1 and decreased
monocyte adhesion to the endothelium.
117,118
A 3-month dietary
intervention in 49 asymptomatic individuals with high CVD risk
found that MedDiet affected the expression of genes involved
in inflammation, foam cell formation, and thrombosis by
8Angiology

increasing cyclooxygenase 2 (COX-2) and LDL-C receptor-
related protein while decreasing expression of monocyte che-
moattractant protein 1.
119
In addition to its effect on the
above-mentioned proatherothrombotic genes, MedDiet can
also beneficially modulate the expression of genes related to
plaque stability (such as matrix metalloproteinase [MMP] 9),
even in an elderly high-risk population and after a short period
(ie, 3 weeks).
120
Inflammatory angiogenesis is a key patho-
genic process in atherosclerosis; MedDiet was reported to inhi-
bit the expression of the proinflammatory enzyme COX-2 and
the degrading enzymes MMPs, thus exerting anti-inflammatory
and anti-angiogenic properties.
121
As the inflammation progresses, different signaling pathways
are activated affecting cellular senescence. In this way, a study
on patients with MetS showed that adherence to MedDiet
reduces postprandial levels of oxidative stress biomarkers such
as lipid peroxide, protein carbonyl, superoxide dismutase activ-
ity, and plasma H
2
O
2
and attenuated the postprandial inflamma-
tory state, including nuclear transcription factor kB(NF-kb),
MMP-9, and tumor necrosis factor acompared with a saturated
fat-rich diet.
122
Furthermore, MedDiet reduced the release of
endothelial microparticles and increased the production of EPCs,
indicating an improvement in endothelial dysfunction in healthy
elderly individuals after a 4-week consumption.
123
The accumu-
lation of senescent cells provokes vascular aging, an important
determinant of atherosclerosis development rate, mainly by
maintaining a chronic low-grade inflammation state.
The MedDiet adherence was negatively related to the risk of
peripheral artery disease (PAD), thus suggesting its potential
contribution to PAD prevention.
123
Considering the multiple actions of MedDiet on the sequence
of the atherosclerotic process, we can support that this diet pat-
tern may represent a multivariate anti-atherosclerotic factor.
Mediterranean Diet and Carotid Intima–Media
Thickness
Carotid intima–media thickness (cIMT) is a valid marker for
generalized vascular disease.
124
B-mode ultrasonographic ima-
ging of the carotid arterial walls occupies a unique position in
atherosclerosis research because it enables sensitive, reproduci-
ble, and noninvasive assessment of cIMT as a continuous vari-
able. The cIMT can be used to evaluate CVD risk and monitor
disease progression in clinical trials.
125
Since it can be mea-
sured relatively simply and noninvasively, it is well suited for
use in large-scale population studies. The superiority of cIMT
over other modalities is that it does not involve radiation expo-
sure such as that caused by computerized tomography and is
not as time consuming and technically demanding with high
associated costs as magnetic resonance imaging. Based on epi-
demiological and clinical data, cIMT is considered a validated
marker for atherosclerosis and vascular disease risk.
126
A pre-
vious meta-analysis
127
supported that cIMT may predict future
vascular events. Furthermore, traditional CVD risk factors
(such as smoking, obesity, hypertension, DM, and dyslipide-
mia) were associated with increases in cIMT.
128
With regard to MedDiet, cIMT was inversely associated
with fiber intake as shown in a cross-sectional study from 2 cen-
ters of the PREDIMED trial.
129
Furthermore, fruit, whole grain,
and olive oil intake have been related to lower cIMT in high-risk
patients.
130
Interestingly, 1-year adherence to MedDiet in PRE-
DIMED trial
131
was related to significant reductions in cIMT
only in those individuals with elevated cIMT at baseline (ie,
0.9 mm) compared to those with baseline cIMT < 0.9 mm.
Similar findings have also been reported.
131
Of note, MedDiet
supplemented with nuts seemed to exert more beneficial effect
in terms of cIMT changes compared with MedDiet supplemen-
ted with olive oil.
132
The beneficial effects of MedDiet on lipids
andcIMTwerealsoobservedinchildrenwithhypercholestero-
lemiaaftera12-monthfollow-up.
133
We correlated MedDiet-related antiatherogenic effect on the
carotid arterial wall, taking under consideration common
cofounders. In our preliminary analysis of 231 participants
(105 men and 126 women) without CVD event from General
Hospitals and Health Centres, we found that a 20-point increase
in the MedDiet score correlated inversely with a 0.14 mm
decrease (P< .05) in right common cIMT in women aged older
than 60 years (Gotsis et al, unpublished data). Taking all the
above-mentioned data into account, the MedDiet seems to
exert protective vascular properties on the carotid wall which
is evaluated by cIMT measurements.
MedDiet and Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) is the hepatic
expression of MetS; both conditions are characterized by
increased vascular risk.
134-137
Of note, MetS prevalence as well
as vascular risk depends on the diagnostic criteria used.
138-140
Such discrepancies led to the Joint Interim Societies (JIS) MetS
definition.
141
With regard to NAFLD, adherence to the
MedDiet was associated with improved insulin resistance and
hepatic steatosis, thus reducing NAFLD severity.
142-145
Of
note, the effects of the MedDiet may reflect the changes in
abdominal obesity.
56
Both MetS and NAFLD have been linked to hyperurice-
mia.
146,147
Furthermore, elevated serum uric acid (SUA) levels
have been related to increased vascular risk.
148-150
Adherence
to the MedDiet was associated with lowerSUA concentrations.
151
General Comments
This narrative review cannot mention every condition that has
been linked with the MedDiet. We selected conditions that are
common and where the evidence is convincing. It is also worth
mentioning that the MedDiet has been linked with beneficial
effects on heart failure, bone mineral density, and erectile dys-
function.
152-154
Similarly, we cannot discuss in detail every
vascular risk factor. In this context, it is of interest that there
is evidence that the MedDiet exerts beneficial effects on LDL
subfractions as well as postprandial lipemia.
80,155,156
In turn,
small, dense LDL and postprandial TG levels are potential pre-
dictors of vascular risk.
157-159
There is even evidence of effects
Gotsis et al 9
deleted as it was
used again in a
previous sentence
A summary of the literature
about the effects of MedDiet
on chronic diseases and
their risk factors is provided
in Table 1

on lipoprotein(a) levels.
160
The effects of the MedDiet on coa-
gulation, platelets, and fibrinolysis are complex but largely
beneficial.
161,162
The MedDiet may also favorably affect
emerging predictors of vascular risk such as arterial stiffness
and adipokine levels.
163-165
It is also encouraging that imple-
menting the MedDiet seems to be a cost-effective preventive
measure.
166
Conclusions
A growing body of evidence supports the concept that the
MedDiet is one of the healthiest diets. This dietary pattern can
be adopted by different population groups and various cultures
and benefit in terms of primary and secondary prevention from
several chronic diseases. During the last 5 years, the findings of
several studies supported the protective role of MedDiet
against atherosclerosis, cancer, CVD, obesity, MetS, and DM
as well as respiratory, neurodegenerative, and kidney diseases.
The MedDiet and its components were shown to interfere with
the atherosclerotic inflammatory process by beneficially
altering oxidative stress, plasma inflammation biomarkers,
adhesion molecules, and cellular senescence as well as by
improving the regenerative capacity of the endothelium. The
application of a MedDiet adherencescoremaybehelpto
assess and understand the degree to which a community is
modifying or improving its dietary habits.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
AQ 4
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
AQ 5
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