4.1. The Mediterranean Diet Score (MDS)
The MDS was the first index used to study adherence to the Mediterranean Diet in the population and it was developed by Trichopoulou et al. in 1995 . It was based on eight main characteristics: monounsaturated fats (MUFAs) (from olive oil): saturated fats (SFAs) ratio; cereals (with inclusion of bread and potatoes); vegetables; fruit and nuts; legumes; alcohol; meat and meat products; and milk and dairy products. The score did not take into account sugars and syrups since, at that time, they had not been documented as dangerous for the health except for the total energy intake. The gender-specific median value was used as a cut-off point for each component. The hypothesis to be verified was that a diet with a high intake of cereals, vegetables, fruit, olive oil and legumes, a low intake of meat and dairy and a moderate intake of alcohol was healthy. The index was applied to elderly people, inhabitants of three rural Greek villages, who still followed the traditional Mediterranean Diet, with the aim of evaluating the relationship between adherence to diet and overall mortality .
The MDS was then used to examine the adherence to Mediterranean Diet and its relationship with coronary heart disease (CHD) in a random sample of 1159 Jewish people in Israel. In men, the odds ratio (ORs) for myocardial infarction, coronary bypass, angioplasty and any other cardiovascular disease (CVD) were 1.23 (p = 0.04), 1.56 (p = 0.01), 1.42 (p = 0.003), and 1.28 (p < 0.01), respectively, for each decrease in the MDS (score 0–8) in the logistic regression models adjusted for hypertension, hypercholesterolemia, diabetes mellitus, age, education, body mass index, and place of birth. A similar trend was observed in women, but no statistically significance was evident. In this study the mean consumption of olive oil was 0.82 g per day per person and the major contributors to MUFAs were canola oil, sunflower oil and dairy .
Very recently, the MDS was applied to a population study of 900 Turkish people in Alanya. After 5.1 years of follow-up, men with lower adherence to the Mediterranean Diet (score 0–4) had a higher risk of CHD morbidity (multivariate adjusted OR: 2.2; 95% CI (confidence interval): 1.03, 3.9; p = 0.03) compared to men with higher adherence (score 5–8). No association was found in women. In this study CHD was defined as myocardial infarction or coronary bypass or coronary angioplasty. Note that fish consumption was very low (2%) in this cohort and the consumption of olive oil was 0.9 g per day per person; the majors contributors to MUFAs were corn and sunflower oils .
In 2003 the MDS was updated by Trichopoulou et al. with the inclusion of another component, a moderate fish consumption and, just like in the previous study , each component received a value of 0 or 1 using the cut-off value of the gender-specific median. Subjects were assigned a value of 0 if the consumption of components considered beneficial (vegetables, legumes, fruit and nuts, cereals, fish, MUFAs:SFAs ratio) was below the median, whereas individuals were assigned a value of 1 if they had a consumption of beneficial food at or above the median. Otherwise, people with consumption of components considered harmful (meat, poultry, and dairy products) below the median were assigned a value of 1, whereas people with consumption at or above the median were assigned a value of 0. With regards to alcohol, a value of 1 was assigned to subjects consuming a moderate amount (i.e., between 10 and 50 g per day for men and between 5 and 25 g per day for women) and a value of 0 otherwise. Therefore, this MDS with fish (t-MED) ranged from 0 (minimal adherence to Mediterranean Diet) to 9 (maximal adherence to Mediterranean Diet) . In the Greek cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 22,043 adults were followed for a median of 44 months, examining the relationship among diet and total mortality, CHD mortality and cancer mortality. A two-point increase in the t-MED was associated with a reduction in CHD mortality by 33% (multivariate adjusted hazard ratio (HR): 0.67; 95% CI: 0.47, 0.94) . A contemporary study showed that dietary habits resembling the traditional Mediterranean Diet were widespread in Greece .
The Greek EPIC cohort has been followed in relation to CHD  and cerebrovascular disease . During a median period of 10 years, a two-point increase in the t-MED was associated with a decrease in CHD mortality by 22% (multivariate adjusted HR: 0.78; 95% CI: 0.66, 0.92; p for trend = 0.003) and a non-significant reduction in CHD incidence (multivariate adjusted HR: 0.92; 95% CI: 0.84, 1.02; p for trend = 0.115) . A two-point increase in t-MED was inversely associated with cerebrovascular disease incidence (multivariate adjusted HR: 0.85; 95% CI: 0.74, 0.96) during a median period of 10.6 years. In the subgroups analyzed by gender, the association was significant in women (multivariate adjusted HR: 0.81; 95% CI: 0.67, 0.98) but not in men. Overall, the protective effect of adherence to the Mediterranean Diet, evaluated by the t-MED, was evident in the incidence of ischemic (multivariate adjusted HR: 0.54; 95% CI: 0.29, 1.01; p for trend = 0.048) but not on the incidence of hemorrhagic cerebrovascular disease. The association between t-MED and cerebrovascular disease mortality was not significant .
Very recently, the t-MED was evaluated in 20,197 subjects enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. In this population-based sample of US black and white adults, during a mean follow-up period of 6.5 years, a higher adherence to the Mediterranean Diet (score 5–9) was associated with a lower risk of incident ischemic stroke in comparison with a lower adherence (score 0–4) (multivariate adjusted HR: 0.79; 95% CI: 0.65, 0.96; p = 0.016). A one-point increase in t-MED was independently associated with a 5% reduction in the risk of incident ischemic stroke (95% CI: 0%, 11%). No association was found between incident hemorrhagic stroke and t-MED . With the exception of potatoes, the used dietary and the t-MED scores had the same components in this study but they were built differently.
The t-MED, applied to the Seguimiento Universidad de Navarra (SUN) study, a Spanish cohort of 13,609 young graduates, followed for a median of 4.9 years, was inversely associated with CVD and CHD. CVD was a composite outcome of myocardial infarction mortality, stroke mortality, acute coronary syndromes, revascularization procedures, and stroke. A higher adherence to the Mediterranean Diet (score 7–9) was associated with a lower risk of developing CVD (multivariate adjusted HR: 0.41; 95% CI: 0.18, 0.95; p for trend = 0.07) and CHD (multivariate adjusted HR: 0.42; 95% CI: 0.16, 1.11; p for trend = 0.04). A two-point increase in the t-MED was associated with a 20% decrease in CVD risk (multivariate adjusted HR: 0.80; 95% CI: 0.62, 1.02) and a 26% reduction in CHD risk (multivariate adjusted HR: 0.74; 95% CI: 0.55, 0.99). It is noteworthy that using a t-MED built without cereals, namely a score with eight components, the inverse association between adherence to the Mediterranean Diet and CVD became significant (p for trend = 0.03) and the negative relationship between adherence to the Mediterranean Diet and CHD became more evident (p for trend = 0.01). Since both refined cereals and whole grains are considered a unique category in the t-MED, the authors hypothesized a negative impact from refined cereals on CVD risk . Refined cereals have a negative impact on CVD risk because they raise the diet glycemic load, which has been associated with a decrease in HDL cholesterol, increase in fasting plasma triglycerides and fasting insulin, promotion of oxidative stress, low-grade systemic inflammation, and procoagulant activity .
In the Northern Manhattan Study (NOMAS), a multiethnic cohort of 2568 subjects followed for a mean period of 9 years, the association between adherence to Mediterranean Diet (estimated by the t-MED) and CVD events was not statistically significant for ischemic stroke and myocardial infarction but it was for vascular death (multivariate adjusted HR: 0.71; 95% CI: 0.49, 1.04; p for trend = 0.04 between the highest and the lowest quintile of the t-MED). A one-point increase in the t-MED was associated with a 9% decrease of the risk of vascular death (multivariate adjusted HR: 0.91; 95% CI: 0.85, 0.98; p for trend < 0.05). Consumption of alcohol, fish and legumes were the components driving the inverse association of t-MED with vascular death . Also in this study, with the exception of potatoes, the used dietary and the t-MED scores had the same components but were built differently.
The t-MED applied to the Italian cohort of the long-tErm follow-up of antithrombotic management Patterns In acute CORonary syndrome patients (EPICOR) study involving 40,681 volunteers recruited from five cities uniformly distributed in the Italian territory and followed for a mean of 7.9 years was inversely associated with the risk of ischemic stroke, but the trend among the tertiles of intake was not significant. The association with the risk of hemorrhagic stroke was positive without a statistic significance .
In a hospital-based case-control study performed in a northern Italian City, 760 patients with a first episode of non-fatal myocardial infarction were matched with 682 controls by gender and age, admitted to the hospital for non-neoplastic conditions, unrelated to known risks for myocardial infarction or dietary modification. Adherence to the Mediterranean Diet was assessed by the t-MED. The risk of a first episode of myocardial infarction was reduced by 45% (multivariate adjusted OR: 0.55; 95% CI: 0.40, 0.75; p for trend < 0.01) in subjects with higher adherence to the Mediterranean Diet (score ≥ 6) as compared to subjects with lower adherence (score < 4). A one-point increase in the t-MED was associated with a reduced risk of a first episode of myocardial infarction by 9% (multivariate adjusted OR: 0.91; 95% CI: 0.85, 0.98). High consumption of vegetables and legumes were inversely associated with non-fatal myocardial infarction risk .
A modification of the t-MED was proposed by Trichopoulou et al. in 2005, with the aim of making the application of t-MED to non-Mediterranean populations, in which the intake of MUFAs from olive oil was minimal, possible. The modified t-MED (m-MED) was achieved by replacing the MUFAs:SFAs ratio with the MUFAs + Polyunsaturated fats (PUFAs): SFAs ratio .
The m-MED was applied to the Dutch cohort of the EPIC study, EPIC-NL, that included 34,708 participants followed for a mean of 11.8 years. A two-point increase in the m-MED was inversely and significantly associated with fatal CVD (multivariate adjusted HR: 0.78; 95% CI: 0.69, 0.88), composite CVD (fatal CVD, non-fatal myocardial infarction, non-fatal stroke) (multivariate adjusted HR: 0.85; CI 95%: 0.80, 0.91), incident myocardial infarction (multivariate adjusted HR: 0.86; 95% CI: 0.79, 0.93), incident stroke (multivariate adjusted HR: 0.88; 95% CI: 0.78, 1.00) and pulmonary embolism (multivariate adjusted HR: 0.74; 95% CI: 0.59, 0.92). No association was found between m-MED and incident angina pectoris, transient ischemic attack and peripheral arterial disease. Interestingly, the association of m-MED to fatal CVD, CVD incidence, composite CVD and myocardial infarction was mostly mitigated when alcohol was excluded from m-MED .
In the literature, we identified four variants of t-MED—the score according to Knoops et al. , the alternate Mediterranean Diet Index (a-MED) , the relative Mediterranean Diet Index (r-MED) , and the Italian Mediterranean Index —and three variants of m-MED: the score according to Sjögren et al.  and the scores according to Tognon et al. [26,27].
In the Healthy Ageing: a Longitudinal study in Europe (HALE) study, performed in 2339 elderly people of 11 European countries, Knoops et al. used a modified t-MED based on eight components: MUFAs:SFAs ratio; legumes, nuts and seeds; cereals; fruit; vegetables and potatoes; fish; meat and meat products; and dairy products. The intake of each component was adjusted to daily intakes of 2500 kcal for men and 2000 kcal for women. For the first six components considered to be healthy, a value of 1 was assigned to people whose consumption was at least as high as the gender-specific median value, and a value of 0 to the others. Reverse values were assigned to the last two components considered unhealthy. Alcohol was evaluated as a separate lifestyle factor since many studies observed an independent effect of alcohol on survival. The score ranged from 0 (minimal adherence to the Mediterranean Diet) to 9 (maximal adherence to the Mediterranean Diet). A score of at least four points was associated with lower CHD mortality (multivariate adjusted HR: 0.61; 95% CI: 0.43, 0.88) and CVD mortality (multivariate adjusted HR: 0.71; 95% CI: 0.58, 0.88). The combination of four healthy lifestyles (high adherence to the Mediterranean Diet, moderate alcohol intake, moderate-high physical activity levels, nonsmoking) reduced the CHD mortality and the CVD mortality more than 50% in comparison with none or one healthy lifestyle .
The a-MED is a t-MED modified by excluding potatoes from the vegetable group, separating fruit and nuts into two groups, eliminating the dairy group, including whole-grain products only, including only red and processed meats for the meat group, and assigning alcohol intake between 5 and 15 g per day for 1 point. These changes were based on dietary patterns that were consistently associated with lower risk of chronic disease in clinical and epidemiological studies. The a-MED ranged from 0 to 9 . In the Nurses Health Study (NHS) a cohort of 74,886 female nurses followed for 20 years, the risk of total (non-fatal and fatal cases) CHD was lower in the highest quintile of the a-MED compared with the lowest quintile (multivariate adjusted relative risk (RR): 0.71; 95% CI: 0.62, 0.82; p for trend < 0.0001). Total stroke (non-fatal and fatal cases) was lower in the highest quintile compared with the lowest quintile of a-MED (multivariate adjusted RR: 0.87; 95% CI: 0.73, 1.02; p for trend = 0.03). In the a-MED, alcohol intake could result from regular consumption of beer, spirits or wine while MUFAs resulted mainly from meat and only minimally from olive oil .
In the National Institutes of Health-AARP Diet and Health Study cohort, consisting of 380,296 people followed for 5 years, the risk of mortality for CVD was significantly lower in men and women with a higher adherence to the Mediterranean Diet (score 6–9) compared to those with a lower adherence (score 0–3), evaluated by the a-MED (men: multivariate adjusted HR: 0.78; 95% CI 0.69, 0.87; p for trend < 0.001; women: multivariate adjusted HR: 0.71; 95% CI: 0.68, 0.97; p for trend = 0.01) .
The r-MED was used to evaluate the exposure to the Mediterranean Diet in the Spanish cohort of EPIC. It derived from t-MED and consisted of nine components. Among these, six components were considered typical of Mediterranean diet: fruit (including nuts and seeds but excluding fruit juices); vegetables (excluding potatoes); legumes; cereals (whole and refined grains); fresh fish and sea foods; and olive oil. Two components were considered not typical of the Mediterranean Diet: meat and meat products; and dairy products (including low-fat and high-fat milk, yogurt, cheese, cream desserts, and dairy and nondairy creams). Each component, except alcohol, was measured as grams per 1000 kcal/day and was divided into tertiles of dietary intakes. A value of 0, 1 and 2 to the first, second and third tertiles of intake, respectively was assigned to typical components. Non-typical components were assigned with an inverted score. Alcohol was scored as a dichotomous variable and 2 points was assigned for an intake from 5 to 25 g per day for women and from 10 to 50 g per day for men. Intakes above or below these ranges were scored 0 points. Then, the theoretical r-MED ranged between 0 (no adherence) to 18 (maximal adherence). In the multivariate analysis performed on data for 40,757 subjects of the cohort, followed for a mean of 10.4 years, the risk of fatal and non-fatal (myocardial infarction or unstable angina requiring revascularization) incident CHD was lower in subjects with higher adherence to the Mediterranean Diet (score 11–18) compared to subjects with lower adherence (score 0–6) (multivariate adjusted HR: 0.60; 95% CI: 0.47, 0.77; p for trend < 0.001). A one-point increase in the r-MED was associated with a 6% lower risk of CHD (multivariate adjusted HR: 0.94; 95% CI: 0.91, 0.97; p for trend < 0.001). The use of t-MED instead of r-MED was associated with an almost identical decrease in CHD risk for a two-point increase in both scores .
The Italian Mediterranean Index was developed to adapt the t-MED to Italian eating behavior . It consisted of 11 components: six typical Mediterranean food (pasta; typical Mediterranean vegetables; fruit; legumes; olive oil; and fish), four non-Mediterranean foods (soft drinks; butter; red meat; and potatoes), and alcohol. People whose consumption of typical Mediterranean foods was in the 3rd tertile of distribution received 1 point whereas all others received 0 points. People whose consumption of non-Mediterranean foods was in the first tertile of the distribution, received 1 point, and all others received 0 points. For alcohol, people whose consumption was up to 12 g per day received 1 point, whereas abstainers and people whose consumption was >12 g per day received 0 points. The theoretical score ranged from 0 to 11. This score applied to 40,681 subjects of EPICOR study, followed for a mean of 7.9 years, was inversely associated with ischemic stroke (multivariate adjusted HR: 0.37; 95% CI: 0.19–0.70; p for trend = 0.001 ) and hemorrhagic stroke (multivariate adjusted HR: 0.51; 95% CI: 0.22–1.20; p for trend = 0.07 ) .
The score according to Sjögren et al. was a variant of the m-MED and was applied to a population-based longitudinal study of 924 Swedish men. Due to a very low intake, nuts and seeds were excluded by the score and leguminous plants were pooled with vegetables. PUFAs replaced MUFAs because the consumption of the olive oil in this population was very low and SFAs and MUFAs had similar food origins and therefore strongly correlated. During a mean follow-up of 10 years, a higher adherence to the Mediterranean Diet (score 6–8) was associated with a lower risk of CVD mortality by 81% (multivariate adjusted HR: 0.19; 95% CI: 0.04, 0.86; p for trend = 0.009) as compared to lower adherence (score 0–2) .
The score according to Tognon et al. was based on eight components: vegetables and potatoes; fruit and juices; whole grain cereals; fish and fish products; MUFAs + PUFAs:SFAs ratio; alcohol intake; meat and meat products; and dairy products. The cut-off points were the gender-specific medians and the value of 0 was assigned to people whose consumption was under the gender-specific median for the first six components and above for the last two components. The value of 1 was assigned to people whose consumption was above the gender-specific median for the first six components and under the gender-specific median for the last two components. The final score varied from 0 (low adherence) to 8 (high adherence) . In a population based study performed in Västerbotten, a North Sweden County with 77,151 subjects followed for 17 years, the score was significantly associated, only in women and not in men, with CVD mortality (multivariate adjusted HR: 0.90; 95% CI: 0.82, 0.99; p for trend < 0.05), and with mortality for myocardial infarction (multivariate adjusted HR: 0.84; 95% CI: 0.71, 0.99; p for trend < 0.05). The mortality for stroke was not associated with the Mediterranean Diet in men and women. Only alcohol intake was independently and inversely associated with CVD mortality among the eight components of the score .
A score that was very similar to the previous one  was used to evaluate the relationship between Mediterranean Diet and CVD in a Danish cohort of the MONItoring trends and determinants of Cardiovascular disease (MONICA) project . It was based on eight components: MUFAs + PUFAs: SFAs ratio; alcohol intake; vegetables; fruit; cereal grains; fish and fish products; meat, meat products and eggs; and dairy products. The cut-off points were the gender-specific medians and the value of 0 was assigned to people whose consumption was under the median for the first six components and above for the last two components. The value of 1 was assigned to people whose consumption was above the median for the first six components and under the median for the last two components. Two different procedures were used to produce two different scores. The first procedure excluded mixed dishes (score 1), and the second included ingredients extrapolated from mixed dishes or recipes (score 2). A third score was created in the same way as score 2 except considering wine instead of total alcohol intake (score 3). None of the scores were associated with stroke mortality and incidence (fatal and non-fatal cases) in the multivariate analysis. The score 1 was inversely associated with CVD mortality and incidence (fatal and non-fatal cases) and with myocardial infarction but without statistical significance. The score 2 was associated with CVD incidence (fatal and non-fatal cases) (multivariate adjusted HR: 0.94; 95% CI:0.89, 0.99; p for trend < 0.05), CVD mortality (multivariate adjusted HR: 0.90; 95% CI: 0.82, 0.99; p for trend < 0.05), myocardial infarction incidence (fatal and non-fatal cases) (multivariate adjusted HR: 0.89; 95% CI: 0.80, 1.00; p for trend < 0.05), and myocardial infarction mortality (multivariate adjusted HR: 0.80; 95% CI 0.67, 0.96; p for trend < 0.05). Score 3 was associated with the same outcomes slightly more than score 2 .
4.2. The Dietary Score (DS)
The DS, proposed in 2005 and inspired by the dietary guidelines of the Greek Mediterranean Diet pyramid for adults , was directly associated with antioxidant capacity and inversely correlated with oxidized LDL-cholesterol serum concentrations, in a random sample of healthy adults in the ATTICA study . It consisted of 11 components: whole grains; fruit; vegetables; potatoes; legumes; olive oil; fish; meat and meat products; poultry; full fat dairy; and alcohol. With the exclusion of alcohol, the frequency of intakes was categorized as never, rare (1–4 servings per month), frequent (5–8 servings per month), very frequent (9–12 servings per month), weekly (13–18 servings per month) and daily (>18 servings per month). For these intake frequencies a value of 0, 1, 2, 3, 4, and 5 respectively was assigned for the first seven components. The values were reversed for frequency of intakes of red meat, poultry, and full fat dairy foods. The alcohol intake was scored 5 if <300 mL per day of wine, 0 for consumption >700 mL per day or none, and scored 4, 3, 2, 1, for intakes of 300–400, 400–500, 500–600, and 600–700 mL per day, respectively. It was stated that 100 mL of wine contained 12 g of alcohol. The theoretical range of the score varied from 0 to 55. The adherence to the Mediterranean Diet decreased the CVD risk in the ATTICA study that involved 2583 participants: during 10 years of follow-up, a one-point increase in the score decreased the risk by 4% (multivariate adjusted RR: 0.96; 95% CI: 0.93, 1.00) independently of socio-demographic variables, lifestyle, and clinical factors. The protective effect of Mediterranean Diet was also evident in participants at risk such as smokers, sedentary individuals, and obese people. No component of the dietary score was significantly associated with CVD risk, in line with the hypothesis that the Mediterranean pattern acts as a whole .
This score was also applied in some case-control studies.
In the CARDIO2000, a case-control study, 848 patients who had been hospitalized for a first symptom of coronary heart disease were matched with 1078 controls by age, gender and the region they came from. The subjects in the highest tertile of the score had a reduced odds of having acute coronary syndromes by 46% (multivariate adjusted OR: 0.54; 95% CI: 0.44, 0.66) compared with subjects in the lowest tertile. An 11/55-unit increase in DS was associated with a reduced odds of having acute coronary syndromes by 27% (multivariate adjusted OR: 0.73; 95% CI: 0.66–0.89) .
In a case-control study of 250 consecutive patients with a first episode of acute coronary syndrome and 250 consecutive patients with a first ischemic stroke, matched with 500 healthy subjects by gender and age, a one-point increase in the score reduced the odds of having acute coronary syndrome (multivariate adjusted OR: 0.91; 95% CI: 0.87, 0.96) and ischemic stroke (multivariate adjusted OR: 0.88; 95% CI: 0.82, 0.94) .
In a case-control study of 250 consecutive patients with a first ischemic stroke matched with 250 controls by gender, age and region, a one-point increase in DS reduced the odds of having a first ischemic stroke by 17% (multivariate adjusted OR: 0.83; 95% CI: 0.72, 0.96) in non-hypercolesterolemic participants and by 10% (multivariate adjusted OR: 0.90; 95% CI: 0.81, 0.99) in hypercolesterolemic participants .
4.3. The Mediterranean Adequacy Index (MAI)
The MAI is a dietary score built taking into account the Mediterranean Diet of Nicotera as a reference. In the early 1960s this diet was very similar to the Corfu and Crete diets , with low CHD mortality rate at 25-year of follow-up of the Seven Countries Study . This score, consisting of 18 food or food groups, is computed by dividing the sum of the total energy percentages of the food groups typical of the reference Mediterranean Diet (bread; cereals; legumes; potatoes; vegetables; fresh fruit; nuts; fish; wine; and vegetable oil) by the sum of the total energy percentages of the food groups less typical of the reference Mediterranean Diet (milk; cheese; meat; eggs; animal fats and margarines; sweet beverages; cakes, pies, cookies; and sugar). The higher the MAI, the greater the amount of energy derived from typical Mediterranean foods . The MAI could be expressed as g per day, or g per 1000 kcal, or g per 4.2 MJ .
The MAI, computed in random samples of men surveyed for their eating habits and belonging to 16 cohorts of the Seven Countries Study, was inversely associated with the 25-year death rates from CHD (r = −0.72; p = 0.001) . The HR for 1 unit of natural log of MAI (approximately corresponding to 2.7 units of MAI) was associated with a CHD mortality decrease of 26% (multivariate adjusted RR: 0.74; 95% CI: 0.55, 0.99) in 20 years of follow-ups and of 21% (multivariate adjusted RR: 0.79; 95% CI: 0.64, 0.97) in 40 years of follow-ups in two Italian rural cohorts of the Seven Countries Study, Crevalcore and Montegiorgio. The statistical analysis was multivariate adjusted for the covariates .
4.4. A Priori Mediterranean Dietary Pattern
This score was applied to a case-control study of 171 patients with a first myocardial infarction matched with 171 controls by gender and age, hospitalized for diseases considered not to be related to the diet. It is based on six food groups or nutrients considered as protective, and two groups of foods of the Mediterranean Diet considered harmful. The first consisted of: olive oil; fibers; fruit; vegetables; fish; and alcohol. For each of these items the distribution according to quintiles within the study was calculated and each subject received points from 1 to 5 corresponding to the quintile of intake from the lowest to the highest quintile. The latter consisted of: meat and meat products; foods with high glycemic load as white bread, pasta and rice. For these components each subject received 1 for the highest quintile and 5 for the lowest quintile. For each subject the score was obtained summing the eight quintiles values. The theoretical score ranged between 0 and 40. This score was applied to 342 subjects of the study. The subjects with score ≥30 had a risk of a first myocardial infarction lower of 79% (multivariate adjusted OR: 0.21; 95% CI: 0.06, 0.73; p for trend = 0.01) compared with subjects scored <20. The risk was reduced by 8% for a one-point increase in the score (multivariate adjusted OR: 0.92; 95% CI: 0.86, 0.98; p for trend = 0.01) .
4.5. The (PREDIMED) Score
The PREDIMED is a Spanish multi-center trial of 7447 people at high risk for CVD, randomly assigned to one of three groups: participants that received advise to reduce dietary fat (control diet); participants that received advice on Mediterranean Diet and provision of extra-virgin olive oil (approximately 1 liter per week); participants that received advice on Mediterranean Diet and provision of mixed nuts (30 g per day: 15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds) . The adherence to the Mediterranean Diet was evaluated at baseline and during the study by a 14-point Mediterranean Diet Adherence Screener (MEDAS). It consists of 12 questions on food intake frequency and two questions on dietary habits characteristic of the Spanish Mediterranean Diet . A value of 1 point was assigned if these criteria were met:
≥4 tablespoons of olive oil per day (including that used in frying, salads etc.) (1 tablespoon = 13.5 g
≥2 servings of vegetables per day (at least 1 portion raw or as salad) (1 serving = 200 g)
≥3 fruit units (including natural fruit juices) per day
<1 serving of red meat or meat products (1 serving =100–150 g) per day
<1 serving of animal fat per day (1 serving = 12 g)
<1 cup of sugar-sweetened beverage per day (1 cup = 100 mL)
≥7 glasses of red wine per week
≥3 servings of legumes per week (1 serving = 150 g)
≥3 servings of fish or shellfish per week (1 serving: 100–150 g fish, or 4–5 units, 200 g shellfish)
<3 commercial sweets or pastries per week (not homemade)
≥3 servings of nuts (including peanuts) per week
≥2 times per week of a dish with a traditional sauce of tomatoes, garlic, onion, or leeks sautéed in olive oil
olive oil as main culinary fat
preferential consumption of chicken, turkey, rabbit meat instead of veal, pork, hamburger or sausage
A value of 0 point was assigned if these criteria were not met. The final PREDIMED score ranged from 0 to 14.
The participants in the three groups at the beginning of the study had a similar score. During the study, the score of participants in the Mediterranean Diet group increased in comparison with the control group, and after three years the differences were significant for 12 out of 14 components of the score. An evaluation of biomarkers (urinary hydroxytyrosol in the group receiving extra-virgin oil, plasma alpha-linolenic acid levels in the group receiving nuts) confirmed the compliance to dietary advice. After a median follow-up of 4.8 years, the rate of major CVD events (myocardial infarction, stroke, death for CVD) was reduced by 30% (multivariate adjusted OR: 0.70; 95% CI: 0.54, 0.92; p = 0.01) in the group assigned to the Mediterranean Diet with extra-virgin olive oil and by 28% (multivariate adjusted OR: 0.72; 95% CI: 0.54, 0.96; p = 0.03) in the group assigned to the Mediterranean Diet with nuts, compared with the control group. In the subgroup analysis, the supplemented Mediterranean Diet had a clear protective effect on stroke (multivariate adjusted OR: 0.61; 95% CI: 0.44, 0.86; p = 0.005) but the protective effect on myocardial infarction and CVD death in comparison with the control diet did not reach statistical significance .
4.6. The Mediterranean-Style Dietary Pattern Score (MSDPS)
The MSDPS was elaborated by Rumawas et al.  using the Greek Mediterranean Diet pyramid for adults as a reference  and was based on 13 components corresponding to 13 food groups of the pyramid: whole grains; fruit; vegetables; milk and dairy products; wine; fish; poultry; olives, legumes, nuts; potatoes; eggs; sweets; meat; and olive oil. With the exception of olive oil, each group was scored from 0 to 10 depending on the compliance to the numbers of servings suggested in the pyramid. A penalty was assigned for a possible overconsumption by subtracting a point proportionally to the number of servings consumed that exceeded the recommended intake for the considered food group. If the score became negative it was defaulted to zero. Olive oil was scored 10 if its use was exclusive, 5 if its use was along with other vegetable oils, 0 for no use. For each subject the MSDPS was calculated by summing the values of 13 components, and dividing this sum by the theoretical maximum sum of 130 and multiplying by 100 by the aim to obtain a scale of standardized values ranging from 0 to 100. In view of the mixture of Mediterranean and non-Mediterranean foods that real patterns have, the previous score was corrected by a continuous factor ranging from 0 to 1 depending on the proportion of energy intake derived by foods not included in the pyramid. The MSDPS was applied to dietary data collected during the 7th examination of the Framingham Offspring Cohort. The quintiles of MSDPS were significantly and positively associated with the dietary intakes of fiber, n-3 PUFAs (linolenic acid, eicosapentaenoic acid, docosahexaenoic acid), antioxidant vitamins (β-carotene, folate, vitamin C, vitamin E, lycopene), calcium, magnesium, potassium, and inversely and significantly with added sugars, glycemic index, SFAs, trans-fat acids, n-6 PUFAs (linoleic acid and arachidonic acid): n-3 PUFAs ratio, MUFAs, and oleic acid. The inverse association of MSDPS with MUFAs and oleic acid depended on a large intake of meat (including poultry). The authors concluded that the MSDPS was a useful tool to evaluate the adherence to traditional Mediterranean Diet in a non-Mediterranean population .
We could not find any study investigating the relationship between Mediterranean Diet and CVD risk using this score.
Back in the early 20th century, heart disease had become a huge problem.
At that time, researchers studying the cause of heart disease noted a striking pattern...
The people in certain countries around the Mediterranean sea (like Italy and Greece) had very little heart disease compared to Americans.
The researchers believed that the reason for their low heart disease rates was their healthy diet.
This diet was high in plants, including fruits, vegetables, whole grains, breads, legumes, potatoes, nuts and seeds.
They also used hefty amounts of both extra virgin olive oil and red wine, along with moderate amounts of fish, poultry, dairy and eggs. Red meat was eaten only rarely.
Although this type of diet has been consumed for a long time around the Mediterranean, it only recently gained mainstream popularity as a good way to improve health and prevent disease.
Since then, numerous studies have been conducted on this diet, including several randomized controlled trials... which are the gold standard in science.
This article takes an objective look at 5 long-term controlled trials on the Mediterranean Diet. All of them are published in respected, peer-reviewed journals.
Most of the participants are people who already have health problems such as diabetes and metabolic syndrome, or are at a high risk of heart disease.
The majority of the studies looked at common health markers like weight, heart disease risk factors and markers of diabetes. The larger and longer-term studies also looked at hard end points like heart attacks and death.
1. The PREDIMED Study
The PREDIMED study made headlines in 2013 for having caused a substantial reduction in cardiovascular disease.
This was a large study, with a total of 7447 individuals who were at a high risk of cardiovascular disease. They were randomized to three different diets:
- A Mediterranean Diet with added extra virgin olive oil (Med + Olive Oil).
- A Mediterranean Diet with added nuts (Med + Nuts).
- A low-fat control group.
No one was instructed to reduce calories or increase physical activity. This study went on for almost 5 years and many papers have been written about it, some of them looking at different risk factors and end points.
Here are 6 papers (1.1 to 1.6) from the PREDIMED study.
1.1 Estruch R, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. The New England Journal of Medicine, 2013.
Details: 7447 individuals at a high cardiovascular risk were randomized to a Mediterranean diet with added olive oil, a Mediterranean diet with added nuts, or a low-fat control group. The study went on for 4.8 years.
In this paper, researchers primarily looked at the pooled risk of heart attack, stroke and death from cardiovascular causes.
Results: The risk of of combined heart attack, stroke and death from cardiovascular disease was reduced by 30% in the Med + Olive Oil group, and 28% in the Med + Nuts group.
Some more details:
- The results were only significant in men, not women.
- The risk of stroke went down by 39% in the Mediterranean diet groups.
- There was no statistically significant difference in heart attacks.
- Dropout rates were twice as high in the control group (11.3%), compared to the Mediterranean diet groups (4.9%).
- When looking at subgroups, people with high blood pressure, lipid problems or obesity responded best to the Mediterranean diet.
- Despite this study being hailed as a success story, there was no statistically significant difference in total mortality (risk of death).
Conclusion: A mediterranean diet with either olive oil or nuts may reduce the combined risk of stroke, heart attack and death from cardiovascular disease. There was no statistically significant effect in women and no reduction in mortality.
1.2 Salas-Salvado J, et al. Effect of a Mediterranean Diet Supplemented With Nuts on Metabolic Syndrome Status. JAMA Internal Medicine, 2008.
Details: Data from 1224 individuals in the PREDIMED study was analyzed after 1 year, examining whether the diet helped individuals reverse the metabolic syndrome.
Results: The prevalence of metabolic syndrome decreased by 6.7% in the Med + Olive Oil group and 13.7% in the Med + Nuts group. The results were statistically significant only for the Med + Nuts group.
Conclusion: A mediterranean diet supplemented with nuts may help to reverse the metabolic syndrome.
1.3 Montserrat F, et al. Effect of a Traditional Mediterranean Diet on Lipoprotein Oxidation. JAMA Internal Medicine, 2007.
Details: 372 individuals from the PREDIMED study who were at a high cardiovascular risk were assessed after 3 months, looking at changes in oxidative stress markers like oxidized LDL (ox-LDL).
Results: The levels of oxidized LDL decreased in both Mediterranean Diet groups, but did not reach statistical significance in the low-fat control group.
Conclusion: The mediterranean diet caused reductions in oxidized LDL cholesterol, along with improvements in several other heart disease risk factors.
1.4 Salas-Salvado J, et al. Reduction in the Incidence of Type 2 Diabetes With the Mediterranean Diet: Results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care, 2011.
Details: 418 non-diabetic participants in the PREDIMED study were assessed after 4 years, looking at their risk of having developed type 2 diabetes.
Results: 10 and 11% of the individuals in the Mediterranean diet groups became diabetic, compared to 17.9% in the low-fat control group. The Mediterranean diet reduced the risk of developing type 2 diabetes by 52%.
Conclusion: A Mediterranean diet without calorie restriction appears to be effective in preventing the development of type 2 diabetes.
1.5 Estruch R, et al. Effects of a Mediterranean-Style Diet on Cardiovascular Risk Factors. Annals of Internal medicine, 2006.
Details: 772 participants in the PREDIMED study were analyzed with regards to cardiovascular risk factors, after a study period of 3 months.
Results: The Mediterranean diet caused improvements in various cardiovascular risk factors, including blood sugar levels, blood pressure, Total:HDL Cholesterol Ratio, and C-Reactive Protein (CRP).
Some more details:
- Blood Sugar: Went down by 0.30-0.39 mmol/L in the Mediterranean diet groups.
- Systolic Blood Pressure: Went down by 5.9 and 7.1 mmHG in the Mediterranean diet groups.
- Total:HDL Ratio: Went down by 0.38 and 0.26 in the Mediterranean diet groups, compared to the low-fat group.
- C-reactive protein: Went down by 0.54 mg/L in the Med + Olive Oil group, but did not change in the other groups.
Conclusion: Compared to a low-fat control group, a Mediterranean diet can have beneficial effects on various risk factors for cardiovascular disease.
1.6 Ferre GM, et al. Frequency of nut consumption and mortality risk in the PREDIMED nutrition intervention trial. BMC Medicine, 2013.
Details: 7216 participants in the PREDIMED study were evaluated after 5 years.
Results: After 5 years, a total of 323 people had died, with 81 cardiovascular deaths and 130 cancer deaths. Consuming nuts was linked to a 16-63% lower risk of death during the study period.
Conclusion: Consuming nuts was associated with a significantly reduced risk of death over a period of 5 years.
2. De Lorgeril M, et al. Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction: Final Report of the Lyon Diet Heart Study. Circulation, 1999.
Details: This study enrolled 605 middle-aged men and women who had suffered a heart attack.
They were split into two groups, a Mediterranean-type diet (supplemented with an Omega-3 rich margarine) and a "prudent" Western-type diet, and followed for 4 years.
Results: After 4 years, the group eating the Mediterranean diet was 72% less likely to have gotten a heart attack, or died from heart disease.
Conclusion: A mediterranean diet supplemented with Omega-3s may be effective at preventing heart attacks in people who have already had heart attacks (secondary prevention).
3. Esposito K, et al. Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular Inflammation in the Metabolic Syndrome. The Journal of the American Medical Association, 2004.
Details: 180 patients with metabolic syndrome were randomized to follow either a Mediterranean diet or a "prudent" low-fat diet for 2.5 years.
Results: At the end of the study, 44% of patients in the Mediterranean diet group still had metabolic syndrome, compared to 86% in the control group. The Mediterranean diet group also had improvements in several risk factors.
Some more details:
- Weight loss: Body weight decreased by 4.0 kg (8.8 lbs) in the Mediterranean diet group, compared to 1.2 kg (2.6 lbs) in the low-fat control group.
- Endothelial function score: Improved in the Mediterranean diet group, but remained stable in the low-fat control group.
- Other markers: Inflammatory markers (hs-CRP, IL-6, IL-7 and IL-18) and insulin resistance decreased significantly in the Mediterranean diet group.
Conclusion: A Mediterranean diet appears to be effective in reducing metabolic syndrome and other cardiovascular risk factor.
4. Shai I, et al. Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. The New England Journal of Medicine, 2008.
Details: 322 obese individuals were randomly assigned to a calorie restricted low-fat diet, a calorie restricted Mediterranean diet, or an unrestricted low-carb diet.
Results: The low-fat group lost 2.9 kg (6.4 lbs), the low-carb group lost 4.7 kg (10.3 lbs) and the Mediterranean diet group lost 4.4 kg (9.7 lbs).
Diabetic participants had improved blood glucose and insulin levels on the Mediterranean diet, compared to the low-fat diet.
Conclusion: A Mediterranean diet may be more effective for weight loss and improving symptoms of diabetes, when compared to a low-fat diet.
5. Esposito K, et al. Effects of a Mediterranean-Style Diet on the Need for Antihyperglycemic Drug Therapy in Patients With Newly Diagnosed Type 2 Diabetes. Annals of Internal Medicine, 2009.
Details: 215 overweight people who had recently been diagnosed with type 2 diabetes were randomly assigned to a low-carb Mediterranean diet, or a low-fat diet. This study went on for 4 years.
Results: After 4 years, 44% of the Mediterranean diet group and 70% of the low-fat diet group had needed treatment with medication.
The Mediterranean diet group had more favorable changes in glycemic control and heart disease risk factors.
Conclusion: A low-carb Mediterranean diet may delay or prevent the need for drug therapy in patients with newly diagnosed type 2 diabetes.
Risk of Death (Mortality)
Two of the studies, the PREDIMED study and the Lyon Diet Heart study, were both large enough and long enough to get results about mortality, or the risk of death during the study period (1.1 and 2).
In order to make the comparison easier, I combined the two Mediterranean diet arms of the PREDIMED study (Olive oil vs Nuts) into one.
In the Lyon Diet Heart Study, the Mediterranean diet group was 45% less likely to die over the 4 year period (compared to the low-fat group). This study is often hailed as the most successful diet intervention trial in history.
The Mediterranean diet group in the PREDIMED study was 9.4% less likely to die, but the difference was not statistically significant.
Risk of Death From Cardiovascular Disease (Heart Attacks and Strokes)
Both the PREDIMED and Lyon Diet Heart Study (1.1 and 2) looked at mortality from heart attacks and strokes.
As you can see, the risk of dying from cardiovascular disease was reduced by 16% in the PREDIMED study (not statistically significant) and 70% in the Lyon Diet Heart Study.
The risk of stroke was reduced by 39% in the PREDIMED study (31% with olive oil and 47% with nuts), which was statistically significant. In the Lyon Diet Heart Study, 4 people in the low-fat group had a stroke, compared to 0 in the Mediterranean diet group.
The Mediterranean diet is usually not prescribed as a weight loss diet, it is rather seen as a healthy diet that can help prevent cardiovascular disease and premature death.
That being said, people usually tend to lose some weight on the Mediterranean diet.
Three of the papers reported weight loss numbers (3, 4, 5):
In every study, the Mediterranean group lost more weight than the low-fat group, but it was only statistically significant in one of the studies (3).
Metabolic Syndrome and Type 2 Diabetes
Several of these studies showed that the Mediterranean diet can have benefits for people with metabolic syndrome and type 2 diabetes.
- The PREDIMED study (1.2) showed that a Mediterranean diet with nuts helped 13.7% of patients with metabolic syndrome reverse their condition.
- Another paper from the same study (1.4) showed that the Mediterranean diet reduced the risk of developing type 2 diabetes by 52%.
- Esposito, 2004 (3) showed that the diet helped reduce insulin resistance, one feature of metabolic syndrome and type 2 diabetes.
- The Shai study (4) showed that the Mediterranean diet improved blood glucose and insulin levels compared to the low-fat diet.
- Esposito, 2009 (5) showed that the diet could delay or prevent the need for drugs in patients with newly diagnosed type 2 diabetes.
It seems pretty clear that the Mediterranean diet is a much better option for type 2 diabetic patients than a low-fat diet.
Number of People Who Dropped Out of The Studies
All studies reported dropout rates. That is, the percentage of people who abandoned the study.
No clear patterns emerged in the dropout rates between the Mediterranean and the low-fat diet.
Take Home Message
It seems clear from looking at the evidence that the Mediterranean diet is very healthy and may help prevent some of the world's leading killers.
It is obviously a much better option than the standard low-fat diet that is still being recommended all around the world.