Health benefits of the Mediterranean Diet: an update of research over the last 5 years.

Angiology

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Health Benefits of the Mediterranean Diet: An Update of Research Over the Last 5 Years Efthymios Gotsis, Panagiotis Anagnostis, Anargyros Mariolis, Athanasia Vlachou, Niki Katsiki and Asterios Karagiannis ANGIOLOGY published online 27 April 2014 DOI: 10.1177/0003319714532169 The online version of this article can be found at: http://ang.sagepub.com/content/early/2014/04/23/0003319714532169

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Article

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

Angiology 1-15 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319714532169 ang.sagepub.com

Efthymios Gotsis, MD, MSc1, Panagiotis Anagnostis, MD, PhD1, Anargyros Mariolis, MD, PhD2, Athanasia Vlachou1, Niki Katsiki, MD, MSc, PhD1, and Asterios Karagiannis, MD, PhD1

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

Introduction The impact of nutrition on human health has been evaluated by several case–control, prospective cohorts and randomized clinical trials which provide evidence that diet may affect the health status of a population.1 Nowadays, the World Health Organization as well as all the major scientific associations recognize that diet plays an important role in preventing noncommunicable diseases.2-4 Several studies evaluated the associations between diets, foods or nutrients, and chronic diseases, leading to general agreement about the effect of nutritional factors on the etiology of common diseases, such as cardiovascular disease (CVD), neoplastic diseases, and metabolic syndrome (MetS).5 Conversely, poor-quality diets may favor the development of pathological health outcomes and chronic diseases such as diabetes mellitus (DM), coronary artery disease (CAD), cancer, and neurodegenerative disorders.6,7 In order to explore the multiple associations between Mediterranean Diet (MedDiet) and chronic diseases, dietary scores have been developed.8 Furthermore, these scores are used to evaluate food consumption trends and to develop public health nutrition recommendations.9 Unfortunately, despite the recognition of the multiple benefits of the MedDiet, there has been a gradual abandonment of this dietary pattern by the inhabitants

of the Mediterranean basin (especially among the young) in the recent years.10 In comparison with 45 years ago, population adherence to MedDiet nowadays is diminished,11 and this is further enhanced by the observation that currently farmers from Crete are likely to be at a higher risk of developing CVD compared to earlier generations.12 These findings were confirmed recently in 12 Mediterranean Islands (the Mediterranean Island Study), which showed that these populations gradually move away from the protective traditional dietary pattern.13 However, the MedDiet still remains a prevalent nutritional option with multiple health profits. The aim of this narrative review was to consider the current evidence about the protective role of the MedDiet in

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Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece 2 Health Center, Areopoli, Greece Corresponding Author: Efthymios Gotsis, Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, 70 Leonidou Str, Sparta, 23100, Greece. Email: [email protected]


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Angiology

various chronic diseases and to elucidate potential underlying mechanisms.

The MedDiet: Elemental and Holistic Approach For decades, several studies attempted to evaluate the significance of single dietary components of the MedDiet on health outcomes. However, several recent clinical trials of singlenutrient supplementation, such as vitamins A, C, and E, failed to show any benefit regarding primary CVD prevention.14,15 People usually consume a complex of nutrients and do not generally focus on specific foods; this approach has several confounders and methodological limitations, as the components of a diet may participate in multiple synergistic and antagonist interactions.16 Therefore, several epidemiological studies, during the last 5 years, evaluated the adherence of a population to the MedDiet pattern using diet indices based on a traditional MedDiet reference pattern.17 The MedDiet indices summarize the diet by means of a single score that is affected by different components, such as foods, food groups, or a combination of foods and nutrients. Furthermore, dietary scores have been used to explore the associations between the MedDiet, as an integral entity, and health parameters such as life expectancy or the incidence of obesity, CVD, and some types of cancers. These indices are also useful tools to estimate food consumption trends and to identify the factors involved, thus contributing to the establishment of effective public health nutrition recommendations.18 In this context, a recent large study reported that a greater adherence to MedDiet was associated with higher intake of total vegetal protein, polyunsaturated fatty acids (PUFAs), mainly n-6 PUFAs, and lower intake of total saturated fat.19 Moreover, the PREvencion con DIeta MEDiterranea (PREDIMED) trial, including 7305 participants, aged 55 to 80 years, at high risk of CVD, showed that those with little education, a larger waist to height ratio, or DM as well as those who were less physically active, single, divorced, separated, or smokers were less likely to adhere to the MedDiet.20 Therefore, the beneficial impact of MedDiet on general health, despite differences in populations or research practices, remains important.

Mediterranean Diet and Cancer Ongoing findings from the European Prospective Study into Cancer and Nutrition (EPIC) study (Greek cohort: n ¼ 23 349 men and women, not previously diagnosed with cancer, CAD, or DM, with a mean follow-up time of 8.5 years) showed that a greater adherence to a MedDiet was related to a significant reduction in total mortality.21,22 Alternate MedDiet (aMED) score was recently shown to correlate inversely with the risk of head and neck cancer.23 Furthermore, data from the Italian segment, including over 31 000 women, aged 36 to 64 years, who were followed up for 11.25 years, supported a clear protective role of fruit and vegetable consumption in breast cancer risk.24 Another Italian study25 reported that a greater adherence to a MedDiet significantly improved CVD risk as well as markers of oxidative stress and inflammation, which are molecular pathways potentially involved in

carcinogenesis.26,27 The entire EPIC study (142 605 men and 335 873 women) demonstrated that 4.7% of cancers among men and 2.4% among women might have been avoided if patients had a greater adherence to the MedDiet pattern.28 Animal studies of induced breast cancer have shown that diets rich in extra virgin olive oil (such as the MedDiet) exert a negative modulatory effect on tumors, particularly affecting cell membranes composition, signaling proteins activity, and gene expression. These influences may inhibit proliferation, induce apoptosis, and minimize DNA damage, thus supporting a potential benefit for olive oil on breast cancer risk.29 Several dietary factors have been associated with the occurrence of cancers of the upper aerodigestive tract (UADT). A recent case–control study in Greece showed that adherence to the traditional MedDiet was related to a reduced risk of UADT cancers.30 This finding is in agreement with the lower incidence of such cancers in Greece, despite the increased prevalence of smoking and drinking habits.31 Similarly, prostatic cancer risk was reduced in individuals following MedDiet compared with those adopting a Western diet.32 The increased quantity and quality of phytochemicals that MedDiet contains may contribute to these beneficial effects due to their antioxidant and anti-inflammatory properties. A dietetic approach to the anti-inflammatory action of food lipids (PUFAs, monounsaturated fatty acids [MUFAs] and saturated fatty acids [SFAs]) showed that dietary fatty acid (FA) may affect FA availability to produce prostaglandins and leukotrienes.33 Intake of fat from a Greek-style MedDiet (mostly MUFA from olive oil consumption) can be expected to influence FA-metabolizing proteins, with an emphasis on the metabolic pathways leading to the diminished formation of proinflammatory eicosanoids.34 Judging from the increasing evidence for the anti-inflammatory effects of the MedDiet, we can assume such a protective role in cancer pathophysiology, but up to date, no direct correlation exists between diet, or its components, and carcinogenic cell proliferation.

Mediterranean Diet and Neurodegenerative Diseases A higher adherence to a MedDiet has been associated with reduced cognitive decline.35 Similarly, the foods, micro-, and macronutrients that MedDiet contains have been separately reported to protect against dementia and predementia syndromes.36 A recent meta-analysis examined the association between adherence to a MedDiet and cognitive impairment, Parkinson disease, and depression.37 Partial analyses showed that a high adherence to the MedDiet significantly reduced the risk of ischemic stroke, cognitive impairment, dementia, and Alzheimer disease. A high adherence to the MedDiet also protected against depression independent of age, but the benefits of moderate adherence tended to diminish with advancing age.37 These findings for cognitive function were in agreement with the results of the PREDIMED-NAVARRA randomized trial.38 This may be of special significance, given the ongoing aging of Western societies. Previous data also reported a lower risk of Alzheimer disease following adherence to MedDiet as well as the Japanese diet.39


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A 9-year follow-up study in Tuscany, Italy (CHIANTI: Invecchiare in CHIANTI), including 935 women and men, aged 65 years and older, showed that adherence to a Mediterraneanstyle diet was related to a slower decline in mobility.40 The beneficial effect of this dietary pattern may be attributed to the protective properties of 2 components of olive oil, that is, tyrosol (Tyr) and hydroxytyrosol (OH-Tyr), against b-amyloid (Ab)-induced toxicity. Based on these findings, these 2 food components of the MedDiet have been suggested as neuroprotective agents against Ab toxicity and may at least partly explain the benefits of the MedDiet on prevention of Alzheimer disease.41 Several studies reported that adherence to a MedDiet is associated with a reduction in the incidence of dementia, but conflicting results exist.42,43 Therefore, a clear correlation of MedDiet with dementia and cognition mechanisms remains to be established in future studies.

Mediterranean Diet and Respiratory Disease A previous cross-sectional study including 174 asthmatics, 40 years of age, found that those with a high adherence to the traditional MedDiet were more likely to achieve asthma control as assessed by lung function, symptoms, and exhaled nitric oxide. Higher fresh fruit intake reduced the risk of uncontrolled disease, whereas higher ethanol intake increased this risk.44 A recent meta-analysis supported the beneficial effect of adherence to a MedDiet on asthma prevalence in children.45 Furthermore, obese adults with moderate to severe obstructive sleep apnea syndrome significantly decreased their apnea-hypopnea index (AHI) after a 6-month consumption of a MedDiet.46 There is evidence that a partial interaction exists between adherence to MedDiet and adverse health consequences of smoking.47 Two cohort studies, INfancia y Medio Ambiente (INMA; Spain) and a prospective mother–child cohort (Rhea Study in Greece), showed that a higher MedDiet adherence decreased the risk of a fetal growth-restricted infant delivery in smoking mothers, an association that was not observed in nonsmoking mothers.48 Further research is needed to elucidate the mechanisms through which nutritional components protect the respiratory tract.

Mediterranean Diet and Kidney Disease Improvements in kidney function were previously reported in patients with chronic kidney disease (CKD) after adhering to a MedDiet.49 Epidemiological data from 3044 healthy men and women showed that a greater adherence to MedDiet was independently correlated with decreased urea and creatinine levels and raised creatinine clearance rates.50 In a report from the PREDIMED study, 785 participants were randomly assigned to 3 dietary approaches: a MedDiet supplemented with virgin olive oil (MedDiet þ olive oil), a MedDiet supplemented with mixed nuts (MedDiet þ nuts), and a control low-fat diet for 1 year.51 All these approaches significantly improved kidney function, with similar mean increases in estimated glomerular filtration rate but unchanged urinary albumin–creatinine ratio (ACR). The results do not support that MedDiet is more

beneficial than a low-fat diet with regard to renal function in such patients at high CVD risk.51 In contrast, in the 3 L (Leontio Lyceum ALbuminuria) study,52 a Greek cohort study on adolescents, those who adhered to a MedDiet, had reduced levels of albuminuria, independent of demographic and hemodynamic cofactors compared with those who adhered less. Furthermore, KIDMED score (an index that includes 16 components and summarizes the principles of the MedDiet by an arithmetic score ranging from 0 to 12) was inversely associated with ACR.52 Obviously, more targeted research is needed in order to clarify the relationship between MedDiet and CKD.

Mediterranean Diet and Obesity The Dietary Intervention Randomized Controlled Trial (DIRECT), a 2-year randomized study including 322 moderately obese patients, showed that good adherence to a MedDiet resulted in a more favorable health status as reflected by improved CVD risk factors, such as lipid profile, blood pressure (BP), and glucose, especially in persons with diabetes and compared with a low-carbohydrate diet.53 Another interventional study showed a significant association between interleukin 6 (IL-6) gene-174G/C polymorphism, (C) being the minor allele frequency and (G) the major, and nutritional pattern; CC patients following the MedDiet enriched with virgin olive oil had the greatest weight decrease compared with those on a low-fat diet and with GG þ GC polymorphisms.54 Researchers from 10 European countries assessed the cross-sectional association between adherence to a modified MedDiet (rich in foods of vegetable origin and unsaturated FAs) and obesity markers (ie, body mass index [BMI] and waist circumference [WC]) in 497 308 individuals, aged 25 to 70 years.55 Waist circumference was significantly lower in men and women with a higher adherence to modified MedDiet for a given BMI, the association being greater in Northern European regions.55 Similarly, a MedDiet score (ie, REGICOR-Mediterranean diet score [R-MDS]) was inversely correlated with WC increase in a Spanish population.56 Furthermore, recent studies concluded that adipokines are involved in the regulation of BP, coagulation, food intake and energy balance, insulin resistance, lipid and glucose metabolism, angiogenesis, and vascular remodeling.57 Among them, adiponectin exerts anti-atherogenic properties by increasing FA oxidation, reducing circulating free FAs, and improving insulin resistance.58 Adiponectin gene variations were also reported to affect body weight changes during a 3-year follow-up period in patients with high CVD risk, leading to obesity.59 Interestingly, adherence to a Mediterranean-style diet was able to reverse this negative effect compared to a low-fat diet.59 Therefore, a healthy diet may protect against obesity (and abdominal obesity) development, even in individuals with a high CVD risk. Similar benefits were reported for children (aged 2-9 years) in 8 European countries in the Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study,60 thus highlighting


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Head and neck cancer Breast cancer

CHD

OSAS Kidney function Body weight Waist circumference Waist circumference, abdominal obesity incidence Body weight Childhood obesity Metabolic syndrome

Prospective cohort, 11 years Prospective cohort, 11.5 years

Observational

In vitro

Case–control study

Literature review

Meta-analysis

Prospective cohort, 9 years Cross-sectional

Meta-analysis

Randomized trial, 6 months

Intervention, 1 year

Intervention, 3 years

Cross-sectional

Prospective cohort, 10 years

Intervention, 3 years

Prospective cohort, 2 years

Meta-analysis

Escrich et al, 201129

Samoli et al, 201030

Ferrı´s-Tortajada et al, 201232

Psaltopoulou et al, 201337

Milaneschi et al, 201140 Barros et al, 200844

Garcia-Marcos et al, 201345

Papandreou et al, 201246 Dıáz-Lo´pez et al, 201251 Razquin et al, 201054

Romaguera et al, 200955 Funtikova et al, 201456

Razquin et al, 201059

Tognon et al, 201460 (IDEFICS study) Kastorini CM et al, 201161

Children’s asthma

Depression, stroke, cognitive impairment, Parkinson disease Mobility decline Asthma

Upper aerodigestive cancer Prostatic cancer

Breast cancer

Stroke prevention Cancer

Systematic review Prospective cohort, 8.5 years

Sherzai et al, 20127 Trichopoulou et al, 2009;21 EPIC (Greek segment) Li et al, 201423 Masala et al, 2012;24 EPIC (Italian segment) Azzini et al, 201125

Disease/Syndrome

Type of Study

Authors/Year

– –

–

Lower mean levels of systolic and diastolic blood pressure, glucose, lipid profile

MedDiet pattern (continued)

MedDiet enriched with virgin olive oil or nuts fMDS

R-MDS

Lower abdominal fat gain

Reversal of the adiponectin gene variant-related effects on body weight Inversely associated with childhood obesity

MedDiet

MedDiet and virgin olive oil

MedDiet combined with physical activity MedDiet

MedDiet score Alternate MedDiet score, high fruit intake, and low ethanol consumption MedDiet

Phytochemicals with antioxidant and anti-inflammatory properties MedDiet adherence

Holistic approach (score 0-9)

Virgin olive oil

Holistic approach (score)

MedDiet, DASH Ethanol, fruits, vegetables, low meat consumption, olive oil, and legumes aMED Leafy vegetables and fruits

Active Component

Reversal of -174G/C IL-6 gene variant-related effects on body weight –

Improves of GFR but no changes in ACR

Lower occurrence of the 3 respiratory outcomes (current wheeze, current severe wheeze, and asthma ever) Reduced AHI

– –

–

–

Higher levels of anti-inflammatory cytokines and antioxidant markers Molecular changes, negative modulatory effects in tumors –

Not defined

MedDiet-Proposed Protective Mechanism

Table 1. Summary of the Literature About the Effects of MedDiet on Chronic Diseases and Their Risk Factors.

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MACCE

Prospective cohort study, 1 year Observational study, 9 months

Defoort et al, 201180 (Medi-RIVAGE) Salas-Salvado´ et al, 201483 Sanchez-Tainta et al, 200888 Nunez-Cordoba et al, 200990 SUN Mente et al, 200992 Fung et al, 200993 (Nurse’s Health Study) Buckland G et al, 200994 Hoevenaar-Blom et al, 201295 Misirli et al, 201296 (EPIC Greek segment) Kastorini et al, 201197 Chrysohoou et al, 201298

Kesse-Guyot et al, 201375 Viscogliosi et al, 201376 Richard et al, 201279 Metabolic syndrome (NCEP III criteria) Metabolic syndrome/body weight Postprandial lipemia Incidence of type 2 DM (new onset) CVD risk factors and their clustering CHD CHD CHD

CVD CVD CVD

CVD CHF

Cross-sectional

Intervention, 3 months

Randomized trial; subgroup analysis, 4.1 years Cross-sectional assessment in a cohort study Prospective cohort, 4.2 years

Systematic review Prospective cohort, 20 years

Prospective cohort, 10.4 years

Prospective cohort, 10-15 years


Case/case–control Cross-sectional

Intervention, 35 weeks

Metabolic syndrome

Incidence of gestational diabetes mellitus (GDM) Metabolic syndrome

Prospective study, 6 years

Systematic review

Diabetes occurrence


Karamanos et al, 201471 Esposito et al, 201374

Glycemic control

Intervention

Itsiopoulos et al, 201165 Rossi et al, 2013 EPIC (Greek segment)66 Mosharraf et al, 201367

Glycemic control Glycemic control Glycemic control

Systematic review Randomized trial, 4 years Cross-sectional , multicenter parallel trial

Esposito et al, 201062 Esposito et al, 200963 Lasa et al, 201464

Disease/Syndrome

Type of Study

Authors/Year

Table 1. (continued)

Adherence to the MedDiet

Lower mean levels of systolic and diastolic blood pressure – Reduced rate, lower mortality from CHD

Protective on ischemic stroke development Biventricular systolic and diastolic improvement in patients with CHF

Decreased total mortality and CBVD incidence

Lower incidence of CVD events

Lower incidence of CHD events

MedDiet

Inverse relationship

MedDiet score MedDiet Score

MedDiet score

MedDiet

MedDiet

(continued)

Vegetables, nuts, MUFA, fruits MedDiet

MedDiet enriched with olive oil

MedDiet

MedDiet

MDS, an updated Mediterranean score (MED), and MSDPS MedDiet

MedDiet

Mediterranean Diet Index (MDI)

Med-DQI

MDS

MedDiet

MedDiet MedDiet MedDiet plus mixed nuts and MedDiet plus olive oil

Active Component

Reduced diabetes risk

Diminishes TAGs and Apo B48

Reduction of inflammation markers without weight loss

A higher MDS was inversely associated with diabetes risk Improve long-term outcome including death/MACCE in diabetic patients with CAD Lower incidence of GDM with better degree of glucose tolerance, even without GDM Beneficial role of adherence to the Mediterranean dietary pattern regarding metabolic syndrome presence and progression Beneficial role of MedDiet against components of MetS or MetS incidence –

– – Increased values of adiponectin–leptin ratio, adiponectin–HOMA-IR ratio, and decreased values of waist circumference –


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Intervention, 3 months

Llorente-Corte´s et al, 2010119 Scoditti et al, 2012121

Intervention 1 year in prepubertal children with hypercholesterolemia

Intervention, 2.4 years

Intervention, 1 year

Atherosclerotic vascular disease Chronic inflammation in atherosclerosis Atherosclerotic vascular disease Atherosclerotic vascular disease Atherosclerotic vascular disease Atherosclerotic vascular disease Atherosclerotic vascular disease Atherosclerotic vascular disease Hypercholesterolemia

CVD incidence, MI Atherosclerotic vascular disease

Reduction of both lipid profile and cIMT

Delayed progression of ICA-IMT and plaque

Modulate the expression of pro-atherothrombotic genes Polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition Reduction of cIMT (for elevated baseline IMTs >0.9 mm)

Inhibit endothelial adhesion molecule expression

Scavenging and lowering free radicals, reactive oxygen species (ROS) Decrease oxidative stress

Downregulates endothelial cellular apoptosis

Decreased total mortality and MI incidence Downregulates cellular and circulating biomarkers

MedDiet

MedDiet enriched with virgin olive oil or nuts MedDiet enriched with nuts

Olive oil, red wine

Phytochemicals in olive oil and red wine Virgin olive oil and MedDiet

MedDiet components

MedDiet enriched with virgin olive oil Fruits and vegetables carotenoids

MedDiet MedDiet enriched with virgin olive oil and vegetables

aMED

MedDiet

Inverse relationship

Decreased total mortality and stroke incidence

MedDiet MedDiet

Active Component

Regulates polymorphism of TCF7L2-rs7903146 Lower incidence of vascular events


Abbreviations: CVD, cardiovascular disease; EPIC, European Prospective Investigation into Cancer and Nutrition; CHD, congenital heart disease; DM, diabetes mellitus; NCEP III, National Cholesterol Education Program; MMP-9, matrix metalloproteinase-9; COX-2, cyclooxygenase-2; PREDIMED study, PREvencioń con DIeta MEDiterrańea study; MedDiet, Mediterranean Diet; Apo B48, apolipoprotein B48; TAGs, triacylglycerols; IL-6, interleukin 6; GFR, glomerular filtration rate; ACR; albumin–creatinine ratio; MUFA, monounsaturated fat; DASH, dietary approaches to stop hypertension; ROS, reactive oxygen species; aMED, alternate Mediterranean diet; TCF7L2-rs7903146, transcription factor 7-like 2; MI, myocardial infarction; CBVD, cerebrovascular disease; OSAS, obstructive sleep apnoea syndrome; AHI, apnoeahypopnoea index; R-MDS, REGICOR-Mediterranean diet score; fMDS, food frequency-based Mediterranean Diet Score; MDS, Mediterranean Diet Score; Med-DQI, Mediterranean diet quality index; MSDPS, Mediterranean style-dietary pattern score; IDEFICS study, Identification and prevention of Dietary—and lifestyle—induced health Effects In Children and infants; HOMA-IR, homeostatic model of insulin resistance; MACCE, major adverse cardiac and cerebrovascular event; cIMT, carotid intima–media thickness; MetS, metabolic syndrome.

Giannini et al, 2014133

Murie-Fernandez, et al, 2011131 Sala-Vila et al, 2014132

In vitro

Carluccio, et al117

In vitro

Case–control study

Review

Giordano et al, 2012114 Dai et al, 2008116

Cross-sectional/intervention

Prospective Cohort, 5.8 years (women) and 7.7 years (men) Prospective cohort, 11 years Intervention

CVD, cancer, and neurodegenerative diseases CVD, cancer

Meta-analysis

Lopez-Garcia et al, 2014104 Tognon et al, 2014105 Urpi-Sarda et al, 2012108 (PREDIMED) Marıń et al, 2013111

CVD CVD events incidence

Randomized trial, 4.8 years Prospective cohort, 9 years

Corella et al, 201399 Gardener et al, 2011101 Sofi et al, 2008102

Disease/Syndrome

Type of Study

Authors/Year

Table 1. (continued)

Gotsis et al

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the importance of the early adoption of a healthy dietary pattern.

Mediterranean Diet and DM, MetS, and Dyslipideamia A previous meta-analysis of 50 studies (2 prospective, 13 crosssectional, and 35 clinical trials; n ¼ 534 906) found that adherence to the MedDiet was related to a decreased risk of MetS (log hazard ratio: 0.69; 95% confidence interval [CI]: 1.24 to 1.16) as well as to lower values of WC (0.42 cm; 95% CI: 0.82 to 0.02), glucose (3.89 mg/dL; 95% CI:5.84 to 1.95), triglycerides (TGs; 6.14 mg/dL; 95% CI: 10.35 to 1.93), systolic (2.35 mm Hg; 95% CI: 3.51 to 1.18) and diastolic BP (1.58 mm Hg; 95% CI: 2.02 to 1.13), and higher levels of high-density lipoprotein cholesterol (HDL-C; 1.17 mg/dL; 95% CI: 0.38 to 1.96) compared with the same parameters before adhering to the MedDiet.61 Improvement in fasting glucose and glycosylated hemoglobin (HbA1c) levels was greater by adhering to a MedDiet pattern versus commonly used diets and ranged from 7 to 40 mg/dL for fasting glucose and from 0.1% to 0.6% for HbA1c in patients with type 2 DM (T2DM).62 In another study from the same group,63 weight loss and improvements in glycemic control and coronary risk parameters were significantly greater in overweight patients with newly diagnosed T2DM that were assigned to a low-carbohydrate, Mediterranean-style diet compared with those adhering to a low-fat diet; the initiation of antihyperglycemic drugs was also delayed in the MedDiet group.63 However, in the PREDIMED study, patients with T2DM in both MedDiet group (supplemented with olive oil or nuts) and low-fat diet group achieved similar weight and glucose reductions.64 In another study,65 a moderate-fat MedDiet intervention significantly improved HAb1c (falling from 7.1%-6.8%; P ¼ .012) and diet quality in 27 patients (47-77 years) with well-controlled T2DM compared with their usual diet without leading to weight gain.65 Previous randomized trials showed that adoption of a MedDiet pattern may help in preventing T2DM, as reported in the Greek cohort of the EPIC study,66 and in improving glycemic control and CVD risk in patients with DM.67 In this context, the Mediterranean Island Study (MEDIS) including 1190 men and women, aged > 65 years, showed that animal protein consumption was associated with a higher prevalence of DM among the elderly individuals, whereas no such relation was observed with protein intake from cereals and vegetables.68 Moreover, the Seguimiento Universidad de Navarra (SUN) trial, a prospective cohort study conducted in a population of 13 380 Spanish university graduates,69 showed that patients who adhered closely to the MedDiet had a lower risk of developing DM over 4.4 years of follow-up; a 2-point increase in the adherence score was associated with a 35% relative reduction in the risk of DM (P < .03). Similarly, lifestyle modification (including a healthy diet and exercise) can prevent or at least delay T2DM onset in patients with impaired glucose tolerance or impaired fasting glucose (IFG); drug therapy is needed to achieve residual risk reduction.70 A protective effect of MedDiet on the development of gestational DM has also been suggested.71

In addition, in a cross-sectional analysis of the PREDIMED study, including patients with a high CVD risk profile, adherence to a MedDiet was significantly related to MetS prevalence, even after adjusting for age, gender, smoking, physical activity, and energy intake.72 Recently published reviews support the inverse link between the incidence of MedDiet and MetS.73,74 A large French prospective study (n ¼ 3232; 6 years of follow-up) including individuals from the Supple´mentation en Vitamines et Mine´raux AntioXydants (SU.VI.MAX) study showed that all MetS components were significantly related to a MedDiet score (inverse associations for WC, systolic BP, and TG and direct association with HDL-C).75 Similarly, in an Italian study, lower MedDiet adherence was associated with higher MetS and prevalence of MetS components as well as with higher values of homeostasis model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP).76 However, no associations were observed between individual items of MedDiet and the development of MetS or IFG. This finding seems to support the holistic approach rather than the elemental one for MedDiet protective role. MedDiet-related beneficial effects on hemostasis may also be observed in patients with MetS.77 Even in children with type 1 DM, training to a Mediterraneanstyle diet improved the quality of nutrient intakes (ie, increased fiber consumption and reduced lipids intake) and led to decreased low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels after 6-month follow-up.78 Similarly, MedDiet was reported to enhance LDL-C clearance and decrease cholesterol absorption, thus leading to LDL-C lowering, independent of weight reduction.79 The MedDiet was also shown to improve postprandial lipemia (as assessed by reductions in triacylglycerols [TAGs] and apolipoprotein B48 levels) in a 3-month period in patients at moderate CVD risk.80 Taking the aforementioned data into account, we would associate MedDiet main component, virgin olive oil, and its anti-inflammatory effect with a lower MetS prevalence81,82 as also supported by the PREDIMED study.83 In contrast, dietary patterns including meat, alcohol, and fish intake, in 1442 adults from Hyvar Island (Adriatic Sea/Croatia) were significantly associated with MetS as defined by the International Diabetes Federation criteria (P ¼ .027).84

Mediterranean Diet and CVD Cardiovascular disease remains the leading cause of death and disability in developed countries, thus increasing the interest in enhancing dietary practices for CVD prevention.85 Several investigators have demonstrated an association between MedDiet and reduced prevalence of traditional CVD risk factors such as hypertension, dyslipidemia, and DM.7,86,87 Similarly, in a cross-sectional analysis of 3204 asymptomatic high-risk patients, an inverse relationship between MedDiet score and the presence of CVD risk factors (ie, DM, obesity, dyslipidemia, and hypertension), both separately and as a whole, was observed.88 Furthermore, significant reductions in BP, hsCRP, total cholesterol (TC), LDL-C, and TG levels were observed in patients with mild hypercholesterolemia following


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a 4-month adherence to MedDiet.89 However, the SUN trial found that higher adherence to a MedDiet was associated with lower mean levels of systolic and diastolic BP after 6 years of follow-up but not with a reduced risk of hypertension.90 Of note, when exercise (in the form of moderate- to highintensity endurance training) was added to MedDiet, greater improvements in cardiorespiratory fitness, endothelial progenitor cell (EPC) numbers, BP, weight reduction, insulin sensitivity, and TAG were observed compared with MedDiet alone91; ischemic reactive hyperemia was beneficially affected only in the exercise group. According to a previous meta-analysis,92 MedDiet and vegetable and nut consumption were protective against occurrence of coronary heart disease (CHD). In this context, a higher aMED score was linked to reduced CHD and stroke prevalence in a large cohort of women (n ¼ 74 886; aged 30-63 years) from the Nurses’ Health Study.93 Similarly, higher adherence to the MedDiet was associated with significantly lower CHD risk in the Spanish (n ¼ 41 078; mean follow-up ¼ 10.4 years) and the Netherlands cohorts (n ¼ 40 011; follow-up ¼ 10-15 years) of the EPIC study.94,95 Furthermore, in the Greek cohort of EPIC (n ¼ 23 601; median follow-up ¼ 10.6 years), morbidity and mortality of cerebrovascular disease (CBVD) significantly decreased with increasing adherence to the MedDiet.96 Additionally, the comparative analysis of a case/case–control study in 1000 Greek participants showed that adoption of the MedDiet protected against acute coronary syndromes and stroke occurrence.97 In another cross-sectional study involving 372 consecutive Greek patients with chronic heart failure, MedDiet consumption improved systolic and diastolic ventricular function.98 Moreover, at the cellular level, a randomized trial with 7018 participants from the PREDIMED study99 reported that the increased risk of T2DM and dyslipidemia (defined as high levels of TC, LDL-C, and TG), which characterized patients with transcription factor 7-like 2 (TCF7L2-rs7903146; C > T) polymorphism, was significantly reduced in those on the MedDiet compared with those on control diet; stroke prevalence was also decreased in the MedDiet groups.99 Furthermore, MedDiet (supplemented with either extravirgin olive oil or nuts) consumption was associated with significantly fewer major CVD events (ie, myocardial infarction, stroke, or CVD mortality) than a low-fat diet in high-risk individuals as shown in the recent PREDIMED trial.100 Consistent with these findings in Mediterranean populations, the Northern Manhattan Study,101 a population-based cohort study (n ¼ 2568), also found that higher adherence to a MedDiet correlated with decreased reduced risk of myocardial infarction, stroke, or vascular mortality. A higher MedDiet adherence was related to decreased mortality from all causes, CVD and cancer, as well as reduced morbidity from cancer, Parkinson, and Alzheimer diseases in a meta-analysis involving 1 574 299 individuals.102 An updated meta-analysis by the same group103 confirmed the significant protection provided by the adherence to a MedDiet against CVD and cancer morbidity and mortality as well as against development of neurodegenerative diseases.103

Similarly, a recent prospective cohort study (n ¼ 17 415 patients with CVD, median follow-up of 5.8 years for women and 7.7 years for men) found that a higher adherence to the aMED was associated with a lower risk of CVD, cancer, and total mortality104; for every 2-point increase in aMED score, a 7% decrease in total mortality risk was observed.105 Interestingly, a Danish Cohort study (n ¼ 1849, 11 years of follow-up) reported that the Mediterranean Diet Score was negatively correlated with morbidity and mortality of myocardial infarction as well as to all-cause death but not with stroke prevalence and mortality.105 Overall, adoption of the MedDiet is associated with a lower prevalence of fatal or nonfatal CVD events in both Mediterranean and non-Mediterranean populations.

The Effects of MedDiet on Systemic Inflammation and Atherosclerotic Disease Several anti-inflammatory mechanisms have been proposed correlating MedDiet and/or its components with the different steps of the atherosclerotic process. Therefore, the MedDiet could be a part of the therapeutic strategy for chronic inflammation-related diseases.106 In this context, a previous multicenter, longitudinal study of 1003 myocardial infarction survivors from several European regions showed a protective, inverse relationship between a MedDiet score and the development of a proinflammatory state (as defined by levels of CRP and IL-6).107 Similarly, other established plasma inflammation biomarkers, cellular and circulating (ie, tumor necrosis factor receptor 60 and 80 and intercellular adhesion molecule 1), were significantly decreased after 1 year of adhesion to the MedDiet-type pattern in patients with high CVD risk.108-110 The primary induction of atherosclerosis comes from the oxidative stress that activates the inflammation process and impairs the nitric oxide pathway and affects telomerase activity.111 The LDL-C particle oxidation is one of the initial steps of atherosclerosis, consequentially leading to CVD and CBVD.112 Fruits and vegetables (typically included in the MedDiet) are very rich in carotenoids that exert significant antioxidant action; carotenoids were inversely related to MetS, HOMA-IR, and CRP in adolescents.113 Carotenoids may act as scavengers of singlet oxygen (1O2) and free radicals, thus downregulating the concentrations of reactive oxygen species (ROS).114 Furthermore, MedDiet was reported to reduce the production of ROS and cellular apoptosis of endothelial cells115 which can partially explain the anti-atherogenic properties of the MedDiet. In the same context, the ratio of reduced glutathione to oxidized glutathione, in a well-controlled study of twins, was strongly associated with the MedDiet and this relationship was not confounded by genetic or environmental parameters.116 It is known from previous studies that monocyte/leukocyte adhesion to the endothelium is important in early atherogenesis; antioxidant polyphenols of olive oil and red wine, within the concentration range expected from MedDiet, inhibited the expression of vascular cell adhesion molecule 1 and decreased monocyte adhesion to the endothelium.117,118 A 3-month dietary intervention in 49 asymptomatic individuals with high CVD risk


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found that MedDiet affected the expression of genes involved in inflammation, foam cell formation, and thrombosis by increasing cyclooxygenase 2 (COX-2) and LDL-C receptorrelated protein while decreasing expression of monocyte chemoattractant protein 1.119 In addition to its effect on the above-mentioned proatherothrombotic genes, MedDiet can also beneficially modulate the expression of genes related to plaque stability (such as matrix metalloproteinase [MMP] 9), even in an elderly high-risk population and after a short period (ie, 3 weeks).120 Inflammatory angiogenesis is a key pathogenic process in atherosclerosis; MedDiet was reported to inhibit the expression of the proinflammatory enzyme COX-2 and the degrading enzymes MMPs, thus exerting anti-inflammatory and anti-angiogenic properties.121 As the inflammation progresses, different signaling pathways are activated affecting cellular senescence. In this way, a study on patients with MetS showed that adherence to MedDiet reduces postprandial levels of oxidative stress biomarkers such as lipid peroxide, protein carbonyl, superoxide dismutase activity, and plasma H2O2 and attenuated the postprandial inflammatory state, including nuclear transcription factor kB (NF-kb), MMP-9, and tumor necrosis factor a compared with a saturated fat-rich diet.122 Furthermore, MedDiet reduced the release of endothelial microparticles and increased the production of EPCs, indicating an improvement in endothelial dysfunction in healthy elderly individuals after a 4-week consumption.123 The accumulation of senescent cells provokes vascular aging, an important determinant of atherosclerosis development rate, mainly by maintaining a chronic low-grade inflammation state. The MedDiet adherence was negatively related to the risk of peripheral artery disease (PAD), thus suggesting its potential contribution to PAD prevention.123 Considering the multiple actions of MedDiet on the sequence of the atherosclerotic process, we can support that this diet pattern may represent a multivariate anti-atherosclerotic factor.

Mediterranean Diet and Carotid Intima–Media Thickness Carotid intima–media thickness (cIMT) is a valid marker for generalized vascular disease.124 B-mode ultrasonographic imaging of the carotid arterial walls occupies a unique position in atherosclerosis research because it enables sensitive, reproducible, and noninvasive assessment of cIMT as a continuous variable. The cIMT can be used to evaluate CVD risk and monitor disease progression in clinical trials.125 Since it can be measured relatively simply and noninvasively, it is well suited for use in large-scale population studies. The superiority of cIMT over other modalities is that it does not involve radiation exposure such as that caused by computerized tomography and is not as time consuming and technically demanding with high associated costs as magnetic resonance imaging. Based on epidemiological and clinical data, cIMT is considered a validated marker for atherosclerosis and vascular disease risk.126 A previous meta-analysis127 supported that cIMT may predict future vascular events. Furthermore, traditional CVD risk factors

(such as smoking, obesity, hypertension, DM, and dyslipidemia) were associated with increases in cIMT.128 With regard to MedDiet, cIMT was inversely associated with fiber intake as shown in a cross-sectional study from 2 centers of the PREDIMED trial.129 Furthermore, fruit, whole grain, and olive oil intake have been related to lower cIMT in high-risk patients.130 Interestingly, 1-year adherence to MedDiet in PREDIMED trial131 was related to significant reductions in cIMT only in those individuals with elevated cIMT at baseline (ie, 0.9 mm) compared to those with baseline cIMT < 0.9 mm. Similar findings have also been reported.131 Of note, MedDiet supplemented with nuts seemed to exert more beneficial effect in terms of cIMT changes compared with MedDiet supplemented with olive oil.132 The beneficial effects of MedDiet on lipids and cIMT were also observed in children with hypercholesterolemia after a 12-month follow-up.133 We correlated MedDiet-related antiatherogenic effect on the carotid arterial wall, taking under consideration common cofounders. In our preliminary analysis of 231 participants (105 men and 126 women) without CVD event from General Hospitals and Health Centres, we found that a 20-point increase in the MedDiet score correlated inversely with a 0.14 mm decrease (P < .05) in right common cIMT in women aged older than 60 years (Gotsis et al, unpublished data). Taking all the above-mentioned data into account, the MedDiet seems to exert protective vascular properties on the carotid wall which is evaluated by cIMT measurements.

MedDiet and Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease (NAFLD) is the hepatic expression of MetS; both conditions are characterized by increased vascular risk.134-137 Of note, MetS prevalence as well as vascular risk depends on the diagnostic criteria used.138-140 Such discrepancies led to the Joint Interim Societies (JIS) MetS definition.141 With regard to NAFLD, adherence to the MedDiet was associated with improved insulin resistance and hepatic steatosis, thus reducing NAFLD severity.142-145 The effects of the MedDiet may reflect the changes in abdominal obesity.56 Both MetS and NAFLD have been linked to hyperuricemia.146,147 Furthermore, elevated serum uric acid (SUA) levels have been related to increased vascular risk.148-150 Adherence to the MedDiet was associated with lower SUA concentrations.151

General Comments This narrative review cannot mention every condition that has been linked with the MedDiet. We selected conditions that are common and where the evidence is convincing. A summary of the literature about the effects of MedDiet on chronic diseases and their risk factors is provided in Table 1. It is also worth mentioning that the MedDiet has been linked with beneficial effects on heart failure, bone mineral density, and erectile dysfunction.152-154 Similarly, we cannot discuss in detail every vascular risk factor. In this context, it is of interest that there


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is evidence that the MedDiet exerts beneficial effects on LDL subfractions as well as postprandial lipemia.80,155,156 In turn, small, dense LDL and postprandial TG levels are potential predictors of vascular risk.157-159 There is even evidence of effects on lipoprotein(a) levels.160 The effects of the MedDiet on coagulation, platelets, and fibrinolysis are complex but largely beneficial.161,162 The MedDiet may also favorably affect emerging predictors of vascular risk such as arterial stiffness and adipokine levels.163-165 It is also encouraging that implementing the MedDiet seems to be a cost-effective preventive measure.166

Conclusions A growing body of evidence supports the concept that the MedDiet is one of the healthiest diets. This dietary pattern can be adopted by different population groups and various cultures and beneficial in terms of primary and secondary prevention from several chronic diseases. During the last 5 years, the findings of several studies supported the protective role of MedDiet against atherosclerosis, cancer, CVD, obesity, MetS, and DM as well as respiratory, neurodegenerative, and kidney diseases. The MedDiet and its components were shown to interfere with the atherosclerotic inflammatory process by beneficially altering oxidative stress, plasma inflammation biomarkers, adhesion molecules, and cellular senescence as well as by improving the regenerative capacity of the endothelium. The application of a MedDiet adherence score may be helpful to assess and understand the degree to which a community is modifying or improving its dietary habits. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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