Mediterranean Diet and Cardiodiabesity: A Review

Cardiodiabesity has been used to define and describe the well-known relationship between type 2 Diabetes Mellitus (T2DM), obesity, the metabolic syndrome (MetS) and cardiovascular disease (CVD). The objective of this study was to perform a scientific literature review with a systematic search to examine all the cardiovascular risk factors combined and their relationship with adherence to the Mediterranean Diet (MedDiet) pattern as primary prevention against cardiodiabesity in a holistic approach. Research was conducted using the PubMed database including clinical trials, cross-sectional and prospective cohort studies. Thirty-seven studies were reviewed: fourteen related to obesity, ten to CVD, nine to MetS, and four to T2DM. Indeed 33 provided strong evidence on the association between adherence to a MedDiet and a reduced incidence of collective cardiodiabesity risk in epidemiological studies. This scientific evidence makes the MedDiet pattern very useful for preventive strategies directed at the general population and also highlights the need to consider all these diet-related risk factors and health outcomes together in daily primary care.

preserving a good health status and quality of life [12,13], mainly through its favorable effects on cardiovascular risk factors and ultimately, by reducing cardiovascular morbidity and mortality [13]. This dietary pattern as described in the Mediterranean Diet pyramid [18] is generally characterized by a high consumption of plant foods (such as fruit, vegetables, legumes, nuts and seeds and cereals, preferably wholegrain); the seasonal choice of fresh and locally grown produce as far as possible; the presence of fruit as the main daily dessert and olive oil as the main source of dietary lipids; moderate consumption of dairy products (mainly cheese and yoghurt); low to moderate amounts of fish, poultry and eggs; consumption of red meat at a low frequency and in small amounts; and a moderate intake of wine during meals. Regarding the nutritional value of the MedDiet, this dietary pattern is low in saturated and trans fats, with an optimal nutritional quality due to the presence of healthy fats from olive oil, nuts and fish, as well as complex carbohydrates, micronutrients, antioxidants, non-nutritive factors and, furthermore, its abundant fiber and varied plant-based composition with sufficient protein intake of both plant and animal origin. The MedDiet pattern also gathers a proper ratio between the macronutrients, low energy density and low glycemic index meals [18,19].
The dietary pattern analysis approach has been imposed over the single nutrient or food approach [20,21]. Many MedDiet indexes [21] have been developed to study the relationship between the MedDiet pattern and different health parameters.
Not only the MedDiet has been stated as a health model, but also a cultural model after its recognition as an Intangible Cultural Heritage of Humanity by the United Nations Educational, Scientific and Cultural Organization (UNESCO) [22]. It is a culturally accepted and highly palatable dietary pattern that allows high compliance, food availability and affordability in the Mediterranean countries. Besides, the MedDiet pattern results in lower environmental footprints than the larger extended Western diet due to the greater emphasis on plant-over animal-derived products [23]. Among the scarce literature focused on evaluating the relationship between food costs and adherence to different food patterns [24], the MedDiet pattern is flexible and adjustable according to specific needs and preferences. Thus, the MedDiet is an extremely healthy, economically affordable and environmentally sustainable food model, especially in Mediterranean countries with a higher availability of MedDiet products. However, there has been a decrease in the adherence to the MedDiet in Mediterranean countries in the last decades [25][26][27], occurring in parallel to the "westernization" of the society (fast food, sedentary lifestyles, etc.). Although the relationship between these dietary and lifestyle changes and the increased prevalence of different illnesses has not been well established, there is a clear parallel trend between a higher prevalence of obesity, CVD or T2DM worldwide and the aforementioned changes in the dietary patterns of the population.
Although reviews of each specific disease such as obesity, T2DM or CVD in relation to the MedDiet have been published [13,15,[28][29][30][31], up to now no review of the clinical trials, cross-sectional and prospective cohort studies has been performed to examine all these risk factors combined and their relationship with the MedDiet. Therefore, the aim of this review was to introduce the term cardiodiabesity and systematically summarize scientific evidence concerning the association between adherence to the MedDiet and the collective cardiodiabesity risk in all the studies.

Materials and Methods
The literature review was focused on prospective cohort, cross-sectional and clinical trial studies on the association between adherence to a MedDiet and cardiodiabesity, i.e., MetS, T2DM, obesity and CVD as primary prevention outcomes. We excluded case-control design studies because of their related high potential selection bias.
A systematic search was conducted up to September 2013 through a computer-assisted published data search (PubMed; MEDLINE, National Library of Medicine, Bethesda, MD, USA). In PubMed, the MeSH terms used were "Mediterranean diet" along with other key words: "Diabetes Mellitus", "Coronary Disease", "Myocardial Ischemia", "Heart Diseases", "Metabolic Syndrome X", and "Obesity". The search was limited to human studies and restricted to articles in English. All studies with full text were considered. The initial search resulted in 740 articles. The search was then narrowed to include only articles examining the effect on the four outcomes (T2DM, obesity, CVD and MetS) as the main outcome and evaluating adherence to the MedDiet pattern as a whole. Studies focused on primary prevention of outcome events were selected. Additional publications were identified from references provided in original papers. The relevance of the studies was assessed with a hierarchical approach on the basis of title, abstract and the full manuscript.
A total of 740 articles were selected with these Mesh terms and then analyzed. The topic distribution was 80 for MetS, 170 for obesity, 108 for T2DM and 382 for CVD. Among the original research articles, 523 were excluded on the basis of the title and including reviews. From the total of 217 articles and on the basis of abstracts, 122 were excluded, resulting in 95 articles: 11 on MetS, 21 on obesity, 20 on T2DM and 43 on CVD. After reading the whole article, 37 were selected, resulting in the final inclusion of 14 studies on obesity, 9 on the MetS, 4 on T2DM and 10 on CVD ( Figure 1).

Characteristics of Study Sample
Most of the studies were from Mediterranean countries, specifically in Southern Europe, except for three conducted in the USA [32][33][34], two in Canada [35,36] and three in European countries outside the Mediterranean area [37][38][39]. Most had been conducted in both men and women, three studies only included females [35,38,40] and three involved children or adolescents [41][42][43]. All the studies were published between 2003 and 2013. The health status of the subjects varied among studies, but in the current review only includes studies on primary prevention. The criteria of quality considered for the studies selected were the sample size, follow-up period and adjustment for potential confounders (demographic, anthropometric and traditional cardiovascular risk factors). Information regarding the methodology and weight-related results for these studies are summarized in Table 1. The sample sizes varied from 77 [35] and 497,308 [37] individuals. The potential confounders considered in the statistical analysis varied among studies, but the most common were age, sex, energy intake, smoking, physical activity and educational level, and also body mass index, marital status, family history of disease or pharmacological treatment.
To assess adherence to the MedDiet pattern, most of the studies included used the Mediterranean diet score established in 2003 by Trichopolou et al. [44,45], albeit with some modifications in many studies (detailed on Table 1). In addition, a considerable number of studies established their own score, for instance in the PREDIMED trial [46] the score for adherence to the MedDiet is based on a 14-item index.

Association between the MedDiet and Cardiodiabesity
Out of the 37 studies, 33 reported a significant association between adherence to MedDiet and reduced incidence and prevalence of cardiodiabesity, but in four there was no association between MedDiet, T2DM, obesity, MetS and CVD [33,37,54,65]. Figure 2 describes the overall diet-related cardiodiabesity parameters and cardiovascular risk factors used in the different studies reviewed. Regarding the association between adherence to the MedDiet pattern and T2DM, Abiemo et al. [33] reported that a greater consistency with a MedDiet style was cross-sectionally associated with lower serum insulin concentrations among non-diabetics and with lower blood glucose before adjustment for obesity but not with a lower incidence of DM. However, three out of the four studies selected found that a higher MedDiet score was predictive of a lower incidence of T2DM [47,49,50]. The greatest relative reduction in T2DM risk (52%) was observed in the PREDIMED nutritional intervention trial in subjects at high CVD risk who showed high adherence to the traditional MedDiet [50]. The incidence of T2DM was reduced by 35% in the cohort study of Martínez-González et al. [49] in association with a two-point increase in the Trichopoulou score, adjusting for confounders. Panagiotakos et al. [47] described that a 10-unit increase in the diet score was associated with 21% lower odds of T2DM, while the combination of greater adherence to the MedDiet and light physical activity reduced the risk of diabetes by 35% after adjustment for various factors.
The impact of the MedDiet pattern on the prevalence of the MetS was evaluated in five cross-sectional studies selected in this review [43,52,54,58,61]. In all these studies, the MetS criteria were defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III [79], which includes hypertriglyceridemia, low HDL-cholesterol, hypertension, hyperglycemia and central obesity. People who fulfilled three or more of these conditions were defined as having MetS. Alvarez-León et al. [54] concluded that MedDiet adherence was not related to MetS prevalence even though some components of the MedDiet showed a protective effect on the MetS and its components. The ATTICA study [52] determined that the odds ratio of having MetS decreased when the participants consumed a MedDiet and reported little-to-moderate physical activity. Other cross-sectional studies reported significant inverse associations between high adherence to the MetDiet and the prevalence of MetS criteria in elderly men with high CVD risk [58], in adolescents [43] and in overweight/obese subjects [61], respectively. Moreover, the three cohort studies selected, with a follow-up of 6 to 7 years, found the lowest incidence of MetS in subjects with the highest adherence to the MedDiet [34,56,62]. In addition, the overall prevalence of MetS at the first year assessment of the PREDIMED cohort showed a higher reduction in participants who consumed a MedDiet supplemented with mixed nuts compared with patients given advice to follow a low-fat diet [57]. It should be noted that in some studies individual components of the MetS, especially hyperglycemia, were not always significantly affected [56,57,62].
Most of the studies selected showed that the prevalence of overweight, obesity and central obesity was inversely associated with the MedDiet score. Classified according to study type, three cohort studies [67,69,70] reported that adherence to a MedDiet pattern was significantly associated with a reduced weight gain, and that the risk to develop overweight and obesity was also less likely. Specifically, Mendez et al. [67] reported a decrease in obesity with MedDiet adherence, albeit only being significant among the overweight population. All the interventional dietary studies [35,40,73] found that adherence to a MedDiet significantly decreased weight/BMI and, specifically, abdominal obesity. Regarding the cross-sectional studies, the EPIC-PANACEA study by Romaguera et al. [37] found that higher adherence to the MedDiet was significantly associated with lower abdominal adiposity for a given BMI, measured by waist circumference, while the MedDiet was not significantly associated with general obesity (BMI). Tripocholou et al. [65] did not find any association between MedDiet adherence and weight either. In contrast, five of the seven cross-sectional studies [36,41,64,66,68] found that greater adherence to a MedDiet had a significantly negative association with overweight/obesity. The strongest association was reported in the ATTICA study by Panagiatakos et al. [66] who found that individuals with high MedDiet adherence were 51% less likely to have both central adiposity and obesity, after adjustment for potential confounders. Note that in the CYKIDS study by Lazarou et al. [41] although adherence to the MedDiet was inversely associated with childhood obesity, when physical activity was taken into account, this relationship became less significant. Furthermore, children with higher adherence to a MedDiet reported to practice higher physical activity levels [42].
All the studies on the primary prevention of CVD showed a statistically significant association between the MedDiet pattern and the incidence of CVD [32,38,39,45,46,71,[74][75][76]78]. In the PREDIMED trial, the largest randomized trial aimed to assess the effect of a dietary intervention using MedDiet on CVD outcomes; Estruch et al. [46] found that among persons at high cardiovascular risk, a MedDiet supplemented with extra-virgin olive oil or mixed nuts reduced the incidence of major cardiovascular events by 30%. Regarding cohort studies, adherence to the MedDiet was associated with a lower risk of coronary heart disease (CHD) in the large Spanish cohort of the EPIC study [71,75,78]. This MedDiet association has been assessed by either by using a priori [71,75] or a posteriori scales [78] during a median follow-up period of 10 years. The longest follow-up period was conducted in the Italian cohort study by Menotti et al. [76] in which individuals with a higher adherence to the MedDiet showed a protective effect against the occurrence of fatal CHD events at 20 and 40 years (CHD mortality reduction of 26% and 22%, respectively). Additionally, Tripochoulou et al. [45] (from the Greek cohort of the EPIC study) reported that the MedDiet was associated with a significant reduction in mortality due to CHD. Moreover, an inverse association with greater adherence to a MedDiet was observed for all-cause mortality and cause-specific death such as CHD and CVD [39], lower risk of stroke [38] and other vascular events, such as myocardial infarction and vascular death [32].

Discussion
This review is focused on the potential beneficial role of a MedDiet pattern for overall primary cardiodiabesity prevention taking into account the most solid, epidemiological and updated scientific evidence available. Several reviews have previously reported the beneficial effect of the MedDiet on obesity [30], T2DM, MetS [80] and CVD [81] risk factors. In this review, cardiodiabesity is considered as a term that embodies the overall diet-related diseases, which are the first causes of death worldwide, as well as others that affect and worsen health conditions.
Of the 37 studies reviewed in this report, 33 provided strong evidence on the association between adherence to a MedDiet and CDV, T2DM, MetS and obesity. Moreover, results from the large scale randomized intervention study, the PREDIMED trial, have pointed out that after 5 years of intervention among high-risk persons who were initially free of CVD, a MedDiet (with no caloric restriction) supplemented with one daily serving of mixed nuts or up to 50 mL of extra-virgin olive oil reduced the incidence of three major cardiovascular events (cardiovascular death, myocardial infarction and stroke) [46] by 30%, suggesting a higher protective effect against cardiovascular risk factors with a MedDiet compared to a low-fat diet, with the added strength of higher compliance among the followers of the MedDiet [46,51]. This protective effect of the MedDiet observed appears early after starting the dietary change and is similar to the effects of statin and antihypertensive drug treatments but without side effects. In addition, the Portfolio diet described by Jenkins and colleagues, which comprised four key components as foods rich in soluble fiber, soy protein, plant sterols and almonds, reported a 29% reduction in LDL-cholesterol comparable to that observed with a small dose of a statin [82].
To increase the quality and level of scientific evidence, in this review we included prospective observational cohorts and clinical trials. Case-control studies were excluded because of the related bias as mentioned. Nevertheless, the results among the studies reviewed were not completely consistent. Romaguera et al. [37] and Trichopoulou et al. [65] found no significant relationship between adherence to a MedDiet and BMI, but they did find a relationship with a lower waist circumference for a given BMI in both genders. Abiemo et al. [33] reported that higher adherence to MedDiet was associated with lower insulin concentrations even though it did not decrease the incidence of T2DM, and the MeDiet also showed protective effects on some MetS components although the Alvarez et al. [54] study did not fulfill the conditions that-according to NCEP-ATPIII criteria-more than three components have to be present to diagnose MetS. Thus some studies reported no clear association between adherence to a traditional MedDiet and main outcomes although they did find positive associations with intermediate risks factors [33,37,54,65]. The variability of the associations observed and the strength between adherence to a MedDiet and cardiodiabesity could also be linked to several aspects and limitations inherent to differences between studies and samples. Similarly, other potential limitations were adjustments for different confounders and indexes used as described in the table. Moreover, specifically designed studies should be carried out to assess these outcomes simultaneously in order to determine the synergy of interventions in several health parameters involved in cardiodiabesity.
According to the American Public Health Association (APHA), in the USA obesity has about 152 billion dollars/year and 73 billion dollars/year in direct and indirect (lost productivity, absenteeism, etc.) costs, respectively [83]. In the current economic context, variables related to health management and the cost-benefit ratio are particularly relevant to health policies and clinical protocols, and, thus, to action guidelines. Current recommendations highlight the importance of dietary counseling in clinical practice. Even though the MedDiet is a diet with a high fat intake, and fat sources are derived primarily from monounsaturated oils, in their last guideline on T2DM, pre-diabetes, and CVD [6], the European Society of Cardiology together with the European Association for the Study of Diabetes group (ESC/EASD) stated, that the MedDiet is an acceptable alternative to the traditionally proposed DASH diets, which are mostly prescribed in clinical practice today. Besides, ESC/EASD support the consideration that T2DM treatment and prevention should be firmly based on complex and non-pharmacological therapies [84]. The ADA 2013 nutrition therapy recommendations provide a summary of strong scientific evidence supporting the effectiveness of nutrition therapy across the continuum of diabetes management [84], which has reported that non-drug treatment is as effective as hypoglycemic drug-treatment, involving a mean reduction of 1.0%-1.5% in HbA1c [84]. The role of nutrition in the prevention of CVD has been extensively reviewed [85][86][87] and strong evidence of the influence of dietary factors in atherogenesis both directly and through effects on traditional risk factors, such as lipid profile, blood pressure or plasma glucose concentration has been reported [88]. Thus, management of obesity and prevention of CVD and T2DM should be aimed at reducing the overall risk of cardiodiabesity in a holistic manner.
Despite the beneficial effects of the MedDiet, there are discrepancies among nutrition experts because of the high-fat content of this diet (up to >40% of total energy intake), which is in conflict with the usual recommendation to follow a low-fat diet in order to avoid overweight/obesity and to prevent CHD [89][90][91]. A recent meta-analysis [92] argued that current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats. However, it should be remarked that the PREDIMED trial demonstrated with the highest level of scientific evidence that the MedDiet is a useful tool to prevent CVD end-points in high-risk subjects [46]. On the other hand, the higher palatability, acceptance and compliance with MedDiets in comparison with low-fat diets should also be taken into account [93].
This review shows that most of the diet-related risk factors of cardiodiabesity may be preventable through healthy lifestyles and specifically with a healthy dietary pattern. Note that all the studies included took into account the physical activity of the participants but no study undertook active intervention controlling of this variable. Thus, all evidence on the reported beneficial effect was mainly due to the overall composition of the dietary pattern, without other lifestyle changes. Preventive medicine should be part of current and future public health strategies in the global context of high rates of chronic diseases around the world. Nowadays, important cultural and economic changes are affecting the population lifestyle, and consequently its health. In recent decades, there has been a strong social transformation that has led to poorer food habits, a decline in traditional customs and a change in the MedDiet pattern [48,91,94]. Promotion of a healthy lifestyle can be used for the prevention or treatment of several factors contributing to cardiodiabesity and lead to the avoidance of progression and the need for pharmacological interventions. The Spanish Society of Family and Community Medicine (SEMFYC) agrees that there is sufficient evidence on the benefits of the dietary advice carried out by trained personnel on the prevention of several chronic diseases, but, on the other hand, there is little evidence on the effectiveness of dietary advice in primary care, probably due to inadequate dietary assessment and other factors. Thus, the dietary advice targeted at apparently healthy or low-risk asymptomatic individuals should be simple and easy to comply with [95]. The new MedDiet pyramid [18] is the result of an international consensus based on the latest scientific evidence on nutrition and health, and provides key elements for the quantitative and qualitative selection of foods. This new MedDiet pyramid is meant for use and promotion without any restrictions, and the nutritional recommendations based on a MedDiet pattern may lead to the prevention of chronic diseases, especially if dietary recommendations take into account individual preferences, thereby ensuring long-time adherence. In this sense, the MedDiet could be translated into daily clinical primary care practice in the setting of public health promotion programs. In order to facilitate this step and achieve greater compliance with dietary advice, the development of the following points should be taken into account: (i) To develop simple, objective and useful tools to determine the degree of patient adherence to the MedDiet pattern for its application in the clinical setting and general practice. (ii) To establish consensual recommendations about the MedDiet pattern and psychological approaches to eating habits and lifestyle improvements. Moreover, it is important to foster knowledge of and accessibility to this dietary pattern to health professionals, particularly in primary care where preventive medicine is of greatest, albeit not exclusive, significance. Multidisciplinary approaches and strategies are needed to increase compliance to treatments and even dietary and lifestyle interventions [96].

Conclusions
Most of the reviewed studies provided strong evidence on the association between adherence to a MedDiet and CDV, T2DM, MetS and obesity, remarking the relationship between all these interconnected illnesses and supporting the term cardiodiabesity. The results of the current review of epidemiological and clinical trial studies support the role of the MedDiet in the prevention of cardiodiabesity. The prevention of cardiodiabesity by good adherence to the MedDiet is supported by the latest most solid scientific evidence, and further by its low environmental footprints and economic accessibility in Mediterranean countries. Furthermore, the high palatability of the MedDiet makes this dietary pattern very useful for preventive strategies applied to the general population in primary care medicine for optimal collaborative management of these patients.

Author Contributions
Elena, G.-F. and Anna, B.-F. designed the review. All authors participated in the process, although Elena, G.-F. conducted the PubMed search and made the table. Laura, R.-C. wrote the manuscript and