Review Article
The Mediterranean Diet and Cardiovascular Disease
Gaps in the Evidence and Research Challenges
Norman J Temple, PhD,* Valentina Guercio, PhD,† and Alessandra Tavani, SciD‡
Abstract: In this article, we critically evaluate the evidence relating to the
effects of the Mediterranean diet (MD) on the risk of cardiovascular disease
(CVD). Strong evidence indicating that the MD prevents CVD has come
from prospective cohort studies. However, there is only weak supporting
evidence from randomized controlled trials (RCTs) as none have compared
subjects who follow an MD and those who do not. Instead, RCTs have tested
the effect of 1 or 2 features of the MD. This was the case in the Prevenciόn
con Dieta Mediterránea (PREDIMED) study: the major dietary change in the
intervention groups was the addition of either extravirgin olive oil or nuts.
Meta-analyses generally suggest that the MD causes small favorable changes
in risk factors for CVD, including blood pressure, blood glucose, and waist
circumference. However, the effect on blood lipids is generally weak. The MD
may also decrease several biomarkers of inflammation, including C-reactive
protein. The 7 key features of the MD can be divided into 2 groups. Some
are clearly protective against CVD (olive oil as the main fat; high in legumes;
high in fruits/vegetables/nuts; and low in meat/meat products and increased
in fish). However, other features of the MD have a less clear relationship with
CVD (low/moderate alcohol use, especially red wine; high in grains/cereals;
and low/moderate in milk/dairy). In conclusion, the evidence indicates that the
MD prevents CVD. There is a need for RCTs that test the effectiveness of the
MD for preventing CVD. Key design features for such a study are proposed.
Key Words: cardiovascular disease, Mediterranean diet, olive oil, nuts
(Cardiology in Review 2019;27: 127–130)
I nterest in the Mediterranean diet (MD) started in the 1960s when
it was realized that populations that consume the MD have much
lower rates of cardiovascular disease (CVD) than do populations from
Northern Europe that consume a typical Western diet. This discovery
sparked much research. Cohort studies reveal that persons who have
a high adherence to the MD are at lower risk of CVD. These findings
have been extended to total mortality and several diseases, including
cancer, type 2 diabetes, and cognitive impairment.1
The focus of this paper is CVD. The objectives are, first, to iden-
tify gaps in the evidence regarding the relationship between the MD
and CVD; and second, to discuss the challenges in conducting research
studies that help fill the gaps in our knowledge. Much of what is argued
here is also pertinent to other diseases related to the MD.
The MD has major differences from the typical Western diet.
The latter is high in sugar (including sugar-sweetened beverages),
refined cereals (such as white bread), and red meat and processed
From the *Centre for Science, Athabasca University, Alberta, Canada; †Depart-
ment of Clinical Sciences and Community Health, Università degli Studi di
Milano, Milan, Italy; and ‡IRCCS-Istituto di Ricerche Farmacologiche “Mario
Negri”, Milan, Italy.
Disclosure: The author declares no conflict of interest.
Correspondence: Norman J. Temple, PhD, Centre for Science, Athabasca Univer-
sity, Athabasca, Alberta T9S 3A3, Canada. E-mail: normant@athabascau.ca.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1061-5377/19/2703-0127
DOI: 10.1097/CRD.0000000000000222
Cardiology in Review  •  Volume 27, Number 3, May/June 2019 www.cardiologyinreview.com  |  127
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
meat but has small amounts of legumes and only 2 to 3 servings
per days of fruits and vegetables. While the MD varies from one
country to another around the Mediterranean Sea, its key features
are as follows2,3: high consumption of legumes; high consumption
of grains and cereals; high consumption of fruits, vegetables, and
nuts; low consumption of meat and meat products and low or mod-
erate amounts of fish; low or moderate consumption of milk and
dairy products; the use of olive oil as the main fat in food prepara-
tion (and therefore a high monounsaturated/saturated fat ratio); and
low to moderate alcohol consumption (especially red wine consumed
mainly at meals).
Trichopoulou et al4 developed an adherence score that esti-
mates the extent to which diets adhere to the MD. This methodology
is now commonly used. However, as discussed later, many variants
have occurred in the calculation of the adherence score to the MD.
THE MEDITERRANEAN DIET AND
CARDIOVASCULAR DISEASE
Epidemiological Evidence
A meta-analysis of 14 prospective cohort studies reported that
people with a higher adherence to the MD are at a significantly lower
risk of CVD incidence and mortality.5 A more recent meta-analysis
of 20 cohort studies produced similar results.6 We recently carried
out a meta-analysis of cohort studies.7 Our search was conducted in
2016 (3 and 2 years, respectively, later than the previous meta-analy-
ses) and included 21 cohort studies. We calculated the pooled relative
risk for the highest versus the lowest category of the MD adherence
score: for coronary heart disease (CHD) it was 0.70 (based on 11
cohort studies), for stroke it was 0.73 (6 studies), and for unspecified
CVD it was 0.81 (11 studies). We also included 5 case-control studies
in the meta-analysis. The relative risk was 0.41 for CHD (2 studies)
and 0.13 for stroke (1 study).
Observational studies are prone to important sources of error.
This may occur in the estimation of usual food intake.8 Another prob-
lem is that foods are often classified in a way that makes it prob-
lematic to accurately calculate an adherence score for the MD. For
example, red meat and related meat products have been grouped with
poultry in some studies, nuts have sometimes been grouped with fruit
or legumes, while some studies have failed to state the intake of milk,
milk products, or fish.9
Several additional problems have been identified in the calcu-
lation of the adherence score for the MD:
1.  The amount consumed of each class of foods is typically catego-
rized as being above or below the median intake within the stud-
ied population. However, the actual amount of different types of
food consumed varies greatly between different countries. This
makes comparisons between countries difficult to interpret and is
a limitation when pooling results in meta-analyses.
2.  Many variants have been used in the calculation of the adherence
score to the MD.10 Zaragoza-Martí et al11 recently made a com-
parison of 28 different adherence scoring systems. With respect
to alcoholic beverages, some studies have included all alcoholic
Temple et al Cardiology in Review  •  Volume 27, Number 3, May/June 2019
beverages, some have included wine only, while others have in-
cluded red wine only. Seemingly, minor changes can have a strong
impact on the findings concerning the relationship between the
adherence score and the risk of disease. This was demonstrated by
Agnoli et al9 in an investigation of the relationship between the MD
and risk of stroke. Two scoring systems were used: (1) the original
method devised by Trichopoulous et al4 (the Greek Mediterranean
Index score); and (2) an adaptation of this for the Italian diet (the
Italian Mediterranean Index score). There are several differences
in the way the 2 scores were calculated. For example, the Italian
score added olive oil and butter as separate components instead
of using monounsaturated-to-saturated fat ratio and used tertiles
of intake rather the median intake. These differences resulted in
very different conclusions: the MD adherence score was inversely
related to the risk of stroke using the Italian index but not with the
Greek index.
3.  Foods may be misclassified. One key component of the MD is a
high consumption of grains and cereals; all grains are considered
together, both whole grains and refined grains. However, whole
grains rather than all grains have sometimes been used as part of
the MD adherence score. In the meta-analysis carried out by Sofi
et al5,12,13 on the association between the MD and risk of total mor-
tality, CVD, and cancer, 6 of 24 of the cohort studies based their
estimation of the adherence score on whole grains rather than re-
fined grains. However, strong evidence suggests that the 2 types
of grains have distinct effects on the risk of CVD (and of other
diseases): whole grains are protective, whereas refined grains are
not protective and may even increase the risk of CVD.14–16 Basing
the estimation of the adherence score on whole grains rather than
all grains is likely to exaggerate the magnitude of the inverse as-
sociation between the adherence score and the risk of CVD. This
can materially affect the results, especially where most grains are
refined. That is the case in many countries, such as the United
States.17 A survey in Italy reported that the mean intake of whole
grains among Italian adults is only 3.7 g/d.18
Another problem with the research evidence is that meta-anal-
yses and systematic reviews that have evaluated the effect of the MD
on risk of CVD have often failed to follow proper procedures.19
Randomized Controlled Trials
The effectiveness of the MD for the prevention of CVD has
also been investigated in randomized controlled trials (RCTs). A
Cochrane review published in 2013 assessed this evidence based on
11 RCTs that were carried out on healthy adults and adults at high
risk of CVD.20 However, the review classified intervention diets as
being an “MD” even if they included only 2 of the 7 features of the
MD. A key finding is that no well-designed RCT was found that actu-
ally investigated whether a diet that contains most or all of the com-
ponents of the MD produces a lower risk of CVD when compared
with a non-MD diet.
The following RCT illustrates the limitations of the findings
of the Cochrane review. The Women’s Health Initiative (WHI) was
included in the review as it provided some limited evidence.21 The
WHI was carried out in the United States and investigated whether
a diet that has an increased amount of fruit and vegetables and of
cereals is effective for preventing CVD in 48,800 postmenopausal
women. This dietary change represents a partial move from a typi-
cal American diet to an MD. However, the diet also reduced the
consumption of monounsaturated fat which is a step away from
the MD. No reduction in risk of CVD was seen after 8 years of
follow-up.
The RCT that has attracted the most attention is Prevenciόn
con Dieta Mediterránea (PREDIMED).2 This study was excluded
from the above Cochrane review. The study, conducted in Spain,
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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
randomly assigned 7400 persons at high risk for CVD (but who were
free of CVD) to 1 of 3 groups: MD plus extravirgin olive oil (EVOO),
MD plus mixed nuts, and a control group who were advised to reduce
dietary fat. An editorial that accompanied the paper pointed out that
the diet consumed by the control group was essentially a variation
of the MD.22
The following data were obtained from Tables S6 and S7 of the
supplementary appendix of the PREDIMED publication (available
from the authors). The fat content of the diet eaten by the control group
was only slightly lower than the 2 intervention diets (37% vs 41% of
energy). The intake of saturated fat was marginally higher in the inter-
vention diets (by 0.2% of energy) while dietary fiber was higher (by
1.7 g/d in the EVOO group and 3.3 g/d in the nuts group). The total
intake of fruit and vegetables was higher in the intervention diets (by
0.2 servings/d in the EVOO group and by 1.1 servings/d in the nuts
group). There was no difference in intake of meat/meat products, whole
grains, or refined grains. The 2 intervention groups (compared with the
control group) had a modestly higher intake of legumes and fish, by
0.4 and 0.3 servings per week, respectively. By comparison, in order to
receive 1 point for legumes and fish on the adherence scale used by the
PREDIMED researchers, a subject must consume 3 or more servings
per week of each food.23 The dominant difference between the 3 diets
was in a single food. At the end of follow-up, the average energy intake
from olive oil was 22.0% in the group receiving EVOO (vs 16.4% in
the control group); the average energy intake from nuts was 8.2% in
the group receiving nuts (vs 1.6% in the control group). This RCT was
therefore, in essence, a study of whether CVD can be reduced by either
(1) an increased intake of olive oil, combined with the replacement of
regular olive oil by EVOO; or (2) an increased intake of nuts. Remark-
ably, CVD was reduced by approximately 30% in both intervention
groups after 4.8 years of follow-up.
This study is often cited as demonstrating that the MD pre-
vents CVD. However, apart from the large increase in intake of
EVOO and nuts, the other dietary changes were either small or neg-
ligible, and it is therefore very unlikely that they could account for
more than a small proportion of the dramatic reduction in risk of
CVD. For that reason, the most plausible interpretation of the find-
ings is that the addition of EVOO or nuts to the diet is highly effective
for preventing CVD. The most likely explanation for the beneficial
action of these foods is their content of phytochemicals.24–26 Nuts are
also rich in polyunsaturated fat, including alpha-linolenic acid (an
n-3 fatty acid).
THE MEDITERRANEAN DIET AND RISK FACTORS
FOR CARDIOVASCULAR DISEASE
The impact of the MD on risk factors for CVD has been inves-
tigated in both observational studies (cohort studies and case-control
studies) and RCTs. Dinu et al1 recently published an analysis of
the available findings. The MD often brings about small reductions
in blood pressure, body weight and waist circumference, and total
blood cholesterol. It may also lower the blood glucose and improve
glycemic control. Weaker evidence suggests that the MD may also
help lower the blood triglyceride level and increase the high-density
lipoprotein cholesterol. However, there seems to be no impact on the
blood level of low-density lipoprotein cholesterol. Several of these
risk factors are known collectively as the metabolic syndrome. These
include increased blood pressure and waist circumference, elevated
blood levels of triglyceride and blood glucose, and a depressed blood
level of high-density lipoprotein cholesterol. Adherence to the MD
was found to have a weak inverse association with the development
of the metabolic syndrome.
C-reactive protein is a biomarker of inflammation and is asso-
ciated with the risk of CVD.27 The MD leads to a decrease in C-reac-
tive protein, as well as several other biomarkers of inflammation.1
Cardiology in Review  •  Volume 27, Number 3, May/June 2019 Mediterranean Diet and CVD
Taken as a whole, the above evidence indicates that the
MD brings about favorable changes in the level of a range of risk
factors for CVD. However, findings have not been consistent.
Various factors may account for these inconsistencies, including
that the “MD” in many studies had only 2 or 3 of the 7 features
of the MD.
AN OVERVIEW OF THE EVIDENCE
There is little doubt that if everyone who presently eats a West-
ern diet switched to the MD, rates of CVD would be reduced. However,
there are notable gaps and weaknesses in the evidence. The strongest
evidence demonstrating the efficacy of the MD for the prevention
of CVD has come from cohort studies. However, those studies have
various limitations. No RCT has been carried out that clearly demon-
strates that the MD prevents CVD. This gap in the evidence is of major
importance as a well-designed RCT is potentially a powerful tool for
investigating the extent to which the MD prevents CVD. Instead, cur-
rently available RCTs, such as the PREDIMED study, tested only 2 or
3 components of the MD. This problem extends to some meta-analyses
of RCTs: even if only 2 of the 7 key features of the MD were part of
the dietary change, then the diet as a whole was classed as an MD.20
Moreover, no RCT has tested whether a complete MD diet favorably
affects risk factors for CVD.
Because of these various gaps and weaknesses in the evidence,
there is still much uncertainty over important questions, in particular
the magnitude of the decrease in risk of CVD and which components
of the MD are most responsible for the benefit.
WHICH FOODS IN THE MEDITERRANEAN DIET
PREVENT CARDIOVASCULAR DISEASE?
Although the research evidence strongly supports the health
benefits of the MD in comparison with the Western diet, this does
not imply that the MD is the ideal diet for the prevention of CVD.
Indeed, common sense tells us that while it is well within the laws of
chance that the population of a particular geographical region con-
sumes a diet that leads to low rates of CVD, it is extremely unlikely
that a population will fortuitously select a diet that is optimal for the
prevention of CVD. Not surprisingly, therefore, a careful evaluation
of the components of the MD reveals that while several components
of the diet are protective against CVD, others are not.
The introduction to this paper lists the 7 features of the MD.
These can be divided into 2 distinct groups based on the totality of
the research evidence regarding their relationship with CVD.
Components of the Mediterranean Diet That Are
Protective Against CVD
1.  The use of olive oil as the main fat in food preparation. Strong
evidence indicates that olive oil is protective against CVD.28,29
Olive oil appears to exert beneficial effects on endothelial func-
tion and on markers of inflammation.30 The PREDIMED study
suggests that EVOO may have an especially strong protective
benefit against CVD.2
A feature of the MD diet is its relatively high content of mono-
unsaturated fat and relatively low content of saturated fat. This is
because the MD usually includes much olive oil (which has a high
content of monounsaturated fat) and relatively low amounts of foods
rich in saturated fat (meat, meat products, milk, and dairy products).
However, it is a mistake to make the assumption that these fats have
more than a minor effect on the risk of CVD. A more plausible inter-
pretation of the evidence is that foods rich in monounsaturated are
protective while foods rich in saturated fat increase risk. Indeed, cur-
rent evidence indicates that saturated fat has little association with
© 2018 Wolters Kluwer Health, Inc. All rights reserved. www.cardiologyinreview.com | 129
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
CHD.15,31 However, foods that are often rich in saturated fat, espe-
cially meat, are linked to the risk of CHD.15
1.  High consumption of legumes
2.  High consumption of fruits, vegetables, and nuts
3.  Low consumption of meat and meat products and increased con-
sumption of fish.
Much evidence demonstrates that these last 3 features of the
MD are protective against CVD.15,16
Components of the Mediterranean Diet Where the
Relationship With Risk of CVD Is Complex
1.  Low to moderate alcohol consumption (especially red wine).
Numerous epidemiological studies have reported that alcohol
consumption, in moderation, is protective again CHD. There has
been much speculation that wine, particularly red wine, may be
more potent than beer or spirits in preventing CHD. This is largely
based on findings from ecological studies (ie, countries with a
high intake of wine tend to have relatively low rates of CHD).32
As France is the country most closely associated with this obser-
vation, it has often been referred to as the “French paradox.” The
popularity of red wine in that country has been suggested as be-
ing responsible for this. However, findings from case-control and
cohort studies show no clear trend for one type of alcohol to be
more consistently associated with protection from CHD.32–34 This
suggests, therefore, that all types of alcoholic beverages—wine,
beer, and spirits—are equally effective for the prevention of CHD.
But in one respect, red wine, as part of the MD, may indeed
be protective against CVD: it is typically consumed in moderate
amounts before or during meals rather than in large quantities at a
single session (“binge drinking”). This drinking pattern is associated
with a lower risk of CHD.35,36
1.  High consumption of grains and cereals. The MD combines
together all types of grain, both whole grains and refined
grains. But, as noted earlier, the effects of whole grains and
refined grains on CVD risk are quite distinct. Based on these
considerations, it is therefore unwarranted to conclude that
when a study shows an inverse association between the ad-
herence score to the MD and risk of CVD, this implies that all
grains, including refined grains, are protective against CVD.
2.  Moderate consumption of milk and dairy products. Our best evi-
dence is that milk and other dairy foods have little association
with CVD although confirmation of this is required.15 This sug-
gests that a relatively high intake of milk and dairy products does
not increase risk of CVD.
The evidence examined above demonstrates that it is an
oversimplification to characterize the MD as being ideal for the
prevention of MD. It is more accurate to say that several compo-
nents of the MD are protective against CVD, whereas others are
not. A recent review by D’Alessandro and De Pergola10 came to a
similar conclusion. This has implications for the design of future
RCTs in this area.
DESIGN OF FUTURE RANDOMIZED CONTROLLED
TRIALS
As stressed earlier, a major gap in the evidence concerning
the efficacy of the MD in the prevention of CVD is that no RCT has
been carried out that clearly demonstrates this. Carrying out such
a study should therefore be a priority. Based on the evidence and
arguments presented in this paper, an RCT should have the follow-
ing design features:
Temple et al Cardiology in Review  •  Volume 27, Number 3, May/June 2019
1.  The intervention group would be instructed to consume a modified
MD that emphasizes only those features of the MD where there is
strong evidence for a protective benefit against CVD. Accordingly, the
intervention group would be instructed to base their diet mainly on
legumes (such as, beans, lentils, and peas), fruits, vegetables, nuts,
and whole grains (but low in refined grains). The diet should be low in
meat/meat products but increased in fish. Olive oil, especially EVOO,
would serve as the main fat. The intake of added sugar, especially
sugar-sweetened beverages, should be much reduced.
2.  Carrying out an RCT in a Mediterranean country creates problems as
most subjects are likely to be consuming a diet similar to the MD. This
was the problem with the PREDIMED study that was done in Spain.
The study population should, therefore, be one that consumes a typical
Western diet rather than an MD. For that reason, the trial should be
done in Northern Europe or North America. Martínez-González et al37
suggested how the MD could be adapted to North America. Their sug-
gestions are also highly valid for Northern Europe.
A major challenge in conducting RCTs along the lines sug-
gested above is ensuring adherence to the prescribed dietary changes.
The WHI provides some assurance that such RCTs are feasible.21 The
subjects in that study followed several major dietary changes and
adhered to the intervention diet for 8 years.
CONCLUSIONS
The MD is effective for the prevention of CVD. However, it is
an error to see the MD as an optimal diet. Strong evidence indicates
that a diet that is closer to optimal is a modified MD based on foods
clearly shown to be protective benefit against CVD. There are vari-
ous gaps and weaknesses in the evidence concerning the relationship
between the MD and CVD. There is a need for improved methodol-
ogy in the conduct of observational studies that investigate how the
MD affects the risk of CVD and risk factors for CVD. A research
priority should be the launching of a well-planned RCT that tests the
effectiveness of a modified MD for the prevention of CVD.
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