Abstract
Introduction
In the context of the unprecedented Covid-19 pandemic, major risk factors for its severity include cardiometabolic conditions, especially obesity, cardiovascular disease and diabetes. 1,2 These are amenable to preventive interventions through population changes in dietary habits. The Mediterranean diet (MedDiet) can represent the ideal model for this preventative effort. In fact, this dietary model has attracted considerable interest in the last 3 decades because of its potential advantages in the prevention of cardiometabolic conditions. 3 -7
The term MedDiet is usually defined as the dietary pattern found in the olive-growing areas of the Mediterranean region during the early 1960s characterized by: *High olive oil consumption *High consumption of legumes *High consumption of unrefined cereals *High consumption of fruits and nuts *High consumption of vegetables *Moderate to high consumption of fish *Moderate to low consumption of dairy products, mostly as cheese and yogurts *Low consumption of meat and meat products
The yearly number of medical publications on the MedDiet has substantially increased since 1990 (Table 1). Observational studies, particularly, large longitudinal nutritional epidemiological studies 5 -7,9 have been instrumental to achieve sound evidence-based recommendations of utmost interest in public health. This is important since most of the scientific articles published are observational epidemiological studies.
Emergence of the Mediterranean Diet (MedDiet) in Medical Publications.
Source: PubMed (January 2020).
In a hallmark study conducted in Greece and published in 2003, 5 the definition of the MedDiet was operationally defined with an a priori 10-point score, subsequently referred to as the Mediterranean Diet Score (MDS). A value of 0 or 1 was assigned to each of 9 indicated elements with the use of the sex-specific medians as the cut-off points. For beneficial components (vegetables, legumes, fruits and nuts, cereal, and fish), persons whose consumption was below the median were assigned a value of 0, and a value of 1 otherwise. For elements presumed to be detrimental (meat and dairy products), persons whose consumption was below the median were assigned a value of 1, and a value of 0 otherwise. A value of 1 was given to men consuming from 10 g to less than 50 g of alcohol per day and to women consuming from 5 g to 25 g. For lipid intake, the ratio of monounsaturates to saturates (MUFA/SFA ratio) was calculated. Those above the sex-specific median in the MUFA/SFA ratio were given 1 point. Thus, the MDS ranged from 0 (minimal adherence to the traditional Mediterranean diet) to 9 (maximal adherence). In a large sample of the general Greek population, 5 and in elderly participants of the EPIC study, 6 after adjusting for potential confounders, the MedDiet was inversely associated with total mortality, cardiovascular mortality and cancer mortality.
The SUN Study is a Spanish dynamic cohort of university graduates. 9,10 It began in 1999 and as of September 2020, it included 23,000 participants.
After adjusting for potential confounders, an inverse association was found between better conformity with the traditional MedDiet and all-cause mortality, fatal and non-fatal major cardiovascular disease (CVD), type 2 diabetes, weight gain, metabolic syndrome, depression, cognitive decline, and nephrolithiasis. An inverse dose-response relationship was found for many of these associations. 10
Martinez-González et al. conducted in 2019 a comprehensive review of the available evidence on the Mediterranean diet and cardiovascular health. 7 They summarized all observational longitudinal studies relating adherence to the MedDiet with CVD included in 5 previous meta-analyses, plus other 6 studies not included in any of these 5 meta-analyses. They standardized all indexes of conformity to the MedDiet to be adapted to the 0 to 9 values of the MDS in order to make them comparable. In total, they summarized 32 estimates of relative risks in observational studies for hard clinical events of CVD published up to 2011. In addition, they also summarized, with the same approach, other 54 estimates reported between 2012 and 2019, thus totaling 86 estimates of relative risks from 32 reports of independent cohort studies. All estimates were computed to assess the relative risk of major CVD outcomes for every 2 additional points in the MDS, i.e. using a common metric. The consistency on the inverse association was really impressive. They concluded that there is no other dietary pattern with such a huge accrual of prospective observational evidence to support it. Importantly, the variety of definitions used in different observational studies had little impact on the cardiovascular health effects and there is no evidence to support that the differences in the definitions of the MedDiet may have affected the available results on prevention of CVD. 7 The MedDiet, relatively rich in fat (even to levels of 40% of calories from fat) but with an optimal MUFA: SFA ratio, thus appears as an ideal model for cardiovascular health. All these facts were in accordance with the long-lasting experience of use of this dietary pattern in relatively poor sectors of the world with high rates of smoking and, nevertheless, with a very-low-CHD mortality.
Beyond observational studies, the PREDIMED (Prevencion con Dieta Mediterránea, meaning Prevention with Mediterranean Diet) study was a large-scale multicenter, randomized, primary prevention trial conducted in a high risk population to assess the effects of 3 healthy diets, namely, low-fat diet, Mediterranean diet rich in extra virgin olive oil (EVOO), and Mediterranean diet rich in tree nuts, on cardiovascular outcomes (www.predimed.es). 11 It was the largest nutritional trial ever conducted in Europe. Personalized dietary advice during a 30-minute quarterly session was given to each participant, which included recommendations on the desired frequency of intake of specific foods, advice to reduce intake of all types of fat (only in the low-fat group) and the provision of a variety of behavioral and educational interventions. Depending on the groups, participants allocated to the 2 Mediterranean-type diets were also given either complimentary EVOO (to consume 45-50 g/d) or walnuts (15 g/d), hazelnuts (7.5 g/d), and almonds (7.5 g/d). No energy restriction and no special intervention on physical activity were applied.
After a median follow-up time of 4.8 years, the 2 Mediterranean diets attained substantial beneficial effects as compared to the control (low-fat) group.
The primary end-point was a composite of myocardial infarction, stroke or CVD death. The incidence of this primary end-point was lowered by ≈30% when compared to the control group. Respective hazard ratios for incident diabetes (273 cases) among 3541 non-diabetic participants were 0.60 (95% confidence interval (CI): 0.43-0.85) for MeDiet+EVOO and 0.82 (0.61-1.10) and MeDiet+nuts, versus control. 12,13
Beneficial effects in the MedDiet+EVOO group versus control were also apparent for breast cancer among women 14 and for atrial fibrillation 15 in the whole sample. Clinically meaningful improvements in classical and emerging CVD risk factors also supported a favorable effect of both MedDiets on blood pressure, insulin sensitivity, lipoprotein particles, inflammation, oxidative stress, carotid atherosclerosis and peripheral artery disease. 12,16 A minor issue related to small imbalances in some baseline characteristics of participants in the PREDIMED trial prompted authors of the original PREDIMED final report, to withdraw it, and to simultaneously replace it with a republished version that included a more comprehensive and expanded version of the analyses, with a multitude of sensitivity analyses. These minor imbalances consisted only in a slightly higher percentage of women in the control group (5.7% higher in control than in the MedDiet+nuts group and 1% higher in control than in the MedDiet+EVOO group) and a 5.3% higher percentage of patients with high levels of LDL-C (low-density lipoprotein cholesterol) in the MedDiet+EVOO than in the control group. Both issues would, in any case, operate against the hypothesis of the trial and therefore did not provide any alternative non-causal explanation of the PREDIMED findings. The many new ancillary analyses included in the republished version showed no changes with respect to the original results of PREDIMED and sufficiently demonstrated that these issues were of no importance. 7,13
Among observational studies, few investigated the relationship between changes in food patterns over time and the risk of death or major chronic disease. Sotos-Prieto et al evaluated among 47,994 women in the Nurses’ Health Study and 25,745 men in the Health Professionals Follow-up Study whether changes in the Alternate Mediterranean Diet score over the preceding 12 years (1986-1998) were associated with all-cause mortality in the next subsequent 12 years (from 1998 through 2010). Using this elegant and robust methodological approach, they found an inverse association, with an adjusted hazard ratio of 0.84 (95 confidence interval%, 0.78 to 0.91) for participants who exhibited the greatest improvement in the Alternate Mediterranean Diet score as compared to those who remained stable. 17
Sotos-Prieto was also leader in another paper that proposed to comprehensively assess other dimensions of the Mediterranean diet (physical activity, rest and social interaction habits), in addition to dietary habits, with an operationally defined index of Mediterranean lifestyle (MEDLIFE). 18 In the SUN cohort, better conformity with the MedDiet combined with higher amounts of physical activity showed a hazard ratio of 0.36 (95% CI: 0.19-0.67) for all-cause mortality as compared with poor adherence to the MedDiet and a sedentary lifestyle. The combined effect of better adherence to the MedDiet with increased physical activity exerted multiplicative effects on mortality risk reduction. 19
Mediterranean diet has emerged as a pattern that promotes good health. Indeed, in observational epidemiology, it is rare to have so consistent evidence of the beneficial effects of an exposure as it has been shown for the Mediterranean diet: a diet that maximizes longevity, improves health-related quality of life and is ecologically sustainable and environmentally friendly. During the last decade, the Mediterranean diet has evolved from a healthy dietary pattern to a sustainable dietary pattern, with low environmental impacts, in which nutrition, food, cultures, people, environment, and sustainability all interact with each other. In part for this reason, in 2010 the Mediterranean diet was included in UNESCO’s Lists of Intangible Cultural Heritage. Of note, the EAT-Lancet Commission report on “Healthy Diets From Sustainable Food Systems”, details a universal healthy “reference diet” to provide a basis for the health and environmental effects of adopting an alternative diet to standard current diets, many of which are high in unhealthy or unsustainable foods. The EAT reference diet is similar to the traditional Mediterranean diet. 20
Footnotes
Funding
The PREDIMED project was funded by the Spanish Government (Spanish National Institute of Health “Instituto de Salud Carlos III” [ISCIII], RD06/0045 (Network Coordinated by MAM-G), CIBER CB06/03 and PI070240). The SUN cohort was publicly funded by several competitive grants from the ISCIII (see 
), particularly, grants PI17/01795 and PI20/00564.