4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Benefits and Harms of the 

Mediterranean Diet 

Compared to Other Diets

November 2015

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) 

Minneapolis VA Medical Center

Minneapolis, MN

Timothy J. Wilt, MD, MPH, Director

Investigators:

Principal Investigator: 

Hanna E. Bloomfield, MD, MPH

Co-investigators: 

Robert Kane, MD

Timothy Wilt, MD, MPH

Eva Koeller, BA

Nancy Greer, PhD

Research Associate: 

Roderick MacDonald, MS
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

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PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice 

guidelines and performance measures; and 

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations.

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov.

Recommended citation: Bloomfield H, Kane R, Koeller E, Greer N, MacDonald R, Wilt TJ. Benefits 

and Harms of the Mediterranean Diet Compared to Other Diets. VA ESP Project #09-009;2015.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the Minneapolis VA Medical Center, Minneapolis, MN, funded by the Department of Veterans Affairs, Veterans 

Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. The 

findings and conclusions in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the 

United States government. Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or 

royalties) that conflict with material presented in the report.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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TABLE OF CONTENTS

EXECUTIVE SUMMARY.......................................................................................................1

Introduction .............................................................................................................................1

Methods..................................................................................................................................2

Definition of a Mediterranean Diet ......................................................................................2

Data Sources and Searches..................................................................................................2

Study Selection....................................................................................................................2

Data Abstraction and Risk of Bias Assessment ....................................................................2

Data Synthesis and Analysis................................................................................................3

Results ....................................................................................................................................3

Results of Literature Search.................................................................................................3

Summary of Results for Key Questions...............................................................................3

Strength of Evidence ...........................................................................................................6

Discussion...............................................................................................................................6

Cardiovascular Disease and Type II Diabetes......................................................................6

Cancer.................................................................................................................................6

Other Outcomes ..................................................................................................................7

Adherence ...........................................................................................................................7

Research Gaps/Future Research ..............................................................................................7

Conclusions.............................................................................................................................7

Executive Summary Table. Strength of Evidence ....................................................................8

Abbreviations Table .............................................................................................................. 10

EVIDENCE REPORT

INTRODUCTION................................................................................................................... 11

PICOTS ................................................................................................................................ 12

METHODS.............................................................................................................................. 15

Topic Development............................................................................................................... 15

Search Strategy ..................................................................................................................... 15

Definitions ............................................................................................................................ 15

Study Selection ..................................................................................................................... 15

Data Abstraction ................................................................................................................... 16

Risk of Bias Assessment ....................................................................................................... 16
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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Data Synthesis....................................................................................................................... 17

Rating the Body of Evidence ................................................................................................. 17

Peer Review .......................................................................................................................... 17

RESULTS................................................................................................................................ 18

Literature Flow...................................................................................................................... 18

Key Question 1: Is the Mediterranean diet more effective than other diets in preventing death 

or the development of Type II diabetes mellitus, cardiovascular disease, cancer, hypertension, 

cognitive impairment, or kidney disease? .............................................................................. 19

Key Question 1a: Do the effects vary by gender, age, or BMI?............................................ 29

Key Question 2: Compared to other diets, is the Mediterranean diet associated with fewer 

adverse outcomes (including death) or less disease progression in people who already have 

diabetes, cardiovascular disease, cancer, hypertension, cognitive impairment, rheumatoid 

arthritis, or kidney disease? ................................................................................................... 34

Key Question 2a: Do the effects vary by gender, age, or BMI?............................................. 41

Key Question 3: What is the observed adherence to the Mediterranean diet in studies 

conducted in the United States or Canada? ............................................................................ 42

SUMMARY AND DISCUSSION ........................................................................................... 43

Overview of Methods............................................................................................................ 43

Summary of Evidence by Key Question ................................................................................ 44

Applicability of Findings to the VA Population..................................................................... 47

Research Gaps/Future Research ............................................................................................ 47

Strength of Evidence ............................................................................................................. 48

Conclusions........................................................................................................................... 48

REFERENCES........................................................................................................................ 49

TABLES

Table 1. Summary of Included Studies - Key Question 1....................................................... 20

Table 2. Effect of Greater Diet Conformity on Outcomes by Gender, Age, 

and BMI in Cohort Studies.................................................................................................... 31

Table 3. Strength of Evidence................................................................................................ 32

Table 4. Summary of Included Studies - Key Question 2....................................................... 35

Table 5. Dietary Interventions Used in Trials......................................................................... 36
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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FIGURES

Figure 1. Analytic Framework............................................................................................... 13

Figure 2. Overall Literature Flow (KQ1-3) ............................................................................ 18

Figure 3. Cancer Incidence by Cancer Type, Cohort Studies.................................................. 22

Figure 4. Cancer Mortality, Cohort Studies............................................................................ 24

Figure 5. Breast Cancer Incidence from PREDIMED and WHI – DM................................... 24

Figure 6. Cancer Mortality by Cancer Type, Cohort Studies.................................................. 25

Figure 7. Mild Cognitive Impairment (PREDIMED) or Cognitive Decline (Kwok)............... 26

Figure 8. Dementia................................................................................................................ 26

Figure 9. Cognitive Outcomes for Observational Studies....................................................... 28

Figure 10. Cancer-specific Mortality by Cancer Type............................................................ 39

APPENDIX A. SEARCH STRATEGIES................................................................................. 57

MEDLINE (Ovid) ................................................................................................................. 57

Cochrane............................................................................................................................... 65

CINAHL............................................................................................................................... 67

APPENDIX B. PEER REVIEW COMMENTS/AUTHOR RESPONSES................................. 70

APPENDIX C. EVIDENCE TABLES ..................................................................................... 77

Table 1. Key Question 1 – Study, Intervention, and Patient Characteristics ........................... 77

Table 2. Key Question 1 – Mortality, Quality of Life, Adverse Events, 

and Patient Satisfaction ....................................................................................................... 105

Table 3. Key Question 1 – New Onset of Cardiovascular-related Conditions 

(Myocardial Infarction, Stroke, Congestive Heart Failure) and Rhematoid Arthritis ............ 106

Table 4. Key Question 1 – New Onset of Kidney Disease, Cancer, 

and Cognitive Impairment ................................................................................................... 108

Table 5. Key Question 2 – Study, Intervention, and Patient Characteristics ......................... 132

Table 6. Key Question 2 – Outcomes for Populations with Diabetes, 

Heart Disease, Kidney Disease, and/or Hypertension (Part 1).............................................. 140

Table 7. Key Question 2 – Outcomes for Populations with Diabetes, 

Heart Disease, Kidney Disease, and/or Hypertension (Part 2).............................................. 142

Table 8. Key Question 2 – Outcomes for Populations with Diabetes, 

Heart Disease, Kidney Disease, and/or Hypertension (Part 3).............................................. 143

Table 9. Key Question 2 – Outcomes for Populations with Cancer ...................................... 144

Table 10. Key Question 2 – Outcomes for Populations with Rheumatoid Arthritis .............. 146

Table 11. Key Question 2 – Outcomes for Populations with Cognitive Impairment ............. 147
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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Table 12. Key Question 3 – Study, Intervention, and Patient Characteristics........................ 148

Table 13. Key Question 3 – Adherence ............................................................................... 149

APPENDIX D. LITERATURE FLOW .................................................................................. 150

Figure 1. Literature Flow Key Questions 1 and 2 Randomized Controlled Trials................. 150

Figure 2. Literature Flow Key Questions 1 and 2 Cohort Studies 

(Cancer, RA, Cognitive)...................................................................................................... 151

Figure 3. Literature Flow Key Question 3............................................................................ 152
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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EXECUTIVE SUMMARY

INTRODUCTION 

A large number of epidemiologic studies have investigated the association between diet and 

mortality and morbidity. Of particular recent interest is the Mediterranean diet, first described by 

Ancel Keys over 50 years ago. This diet is characterized by high intake of olive oil, fruits and 

vegetables, whole grains and cereals, legumes, fish, and nuts; low intake of red meat, dairy 

products, and sweets; and moderate intake of red wine with meals. Epidemiologic studies have 

shown that the incidence of cardiovascular disease in populations that consume such diets is 

lower than in populations that consume a more typical “Western” diet that is rich in red meat, 

dairy products, processed and artificially sweetened foods, and salt, with minimal intake of 

fruits, vegetables, fish, legumes, and whole grains. 

Based on these epidemiologic studies, several randomized controlled trials were conducted to 

test the hypothesis that adopting a Mediterranean diet in adulthood reduces chronic disease 

burden (eg, incidence of and/ or mortality from cardiovascular disease, cancer, diabetes, 

hypertension, cognitive impairment, and kidney disease) and/or all-cause mortality (viz, 

PREDIMED, Lyon Heart Study, THIS-DIET). These trials included populations from a variety 

of geographical locations and with a spectrum of demographic and clinical characteristics. 

Although several systematic reviews of the relevant observational studies and clinical trials have 

been published, the VA’s Evidence-based Synthesis Program, in conjunction with the Office of 

Quality and Performance and in response to a request from the VA’s National Center for Health 

Promotion and Disease Prevention and Primary Care Services, commissioned the present study 

to update prior reviews and to specifically assess the implications for the treatment and 

prevention of common chronic conditions in the Veteran population. With input from topic 

nominators and a Technical Expert Panel (TEP) we developed the following Key Questions:

Key Question 1: Is the Mediterranean diet more effective than other diets in preventing death or 

the development of type 2 diabetes mellitus, cardiovascular disease, cancer, hypertension, 

cognitive impairment, or kidney disease?

Key Question 1a: Do the effects vary by gender, age, or BMI?

Key Question 2: Compared to other diets, is the Mediterranean diet associated with fewer 

adverse outcomes (including death) or less disease progression in people who already have 

diabetes, cardiovascular disease, cancer, hypertension, cognitive impairment, rheumatoid 

arthritis, or kidney disease?

Key Question 2a: Do the effects vary by gender, age, or BMI?

Key Question 3: What is the observed adherence to the Mediterranean diet in studies conducted 

in the United States or Canada?
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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METHODS

Definition of a Mediterranean Diet 

We included studies whose diets met the criteria used in a recent Cochrane Review, that is to 

say, labelled a Mediterranean diet or meeting 2 or more of the following components: 1. high 

monounsaturated:saturated fat ratio (use of olive oil as main cooking ingredient); 2. high 

consumption of fruits/vegetables; 3. high consumption of legumes; 4. high consumption of 

grains/cereals; 5. moderate red wine consumption; 6. moderate consumption of dairy products; 

and 7. low consumption of meat and meat products (replaced by increased consumption of fish). 

All included studies met this minimum definition. The names for the diets included terms such as 

Mediterranean diet, prudent diet, healthy Nordic diet, and healthy pattern.

Data Sources and Searches

We searched MEDLINE (Ovid), CINAHL, and the Cochrane library for articles published from 

1990 through August 2015. Our search was limited to studies in adult humans published in the 

English language. An additional search was done in all 3 databases to address Key Question 3 in 

which the terms adherence and patient compliance were added. Supplemental searches were also 

done to find articles specific to cancer, rheumatoid arthritis (RA), and cognitive impairment. We

also obtained articles by hand-searching the reference lists of systematic reviews and included 

studies. 

Study Selection 

For studies addressing Key Questions 1 and 2 in diseases other than cancer, RA, or cognitive 

impairment and Key Question 3, we included randomized controlled trials (RCTs) or controlled 

clinical trials (CCTs) with at least 100 subjects followed for at least one year. For studies of RA 

and cognitive impairment we included RCTs, CCTs, and cohort studies with any number of 

participants and no minimum follow-up time. For studies of cancer we included RCTs and 

cohort studies with at least 100 participants followed for at least one year. Studies must have also 

reported one of our outcomes of interest, which, for Key Questions 1 and 2 included: mortality, 

quality of life, new onset or progression of disease, and functional status. 

We excluded the following:

Studies that did not involve outpatient adults; 

Studies in which the intervention diet was either not labeled a Mediterranean diet or did 

not fit our criteria for a Mediterranean diet; 

Studies in women who were pregnant or lactating; and

For Key Question 3, studies that were conducted in countries other than the US and 

Canada.

Data Abstraction and Risk of Bias Assessment 

Study characteristics (goal of intervention, inclusion/exclusion criteria, diet descriptions, followup, and patient characteristics) as well as outcomes (mortality, health-related quality of life, dietrelated adverse events, satisfaction, new onset of disease, disease progression/recurrence, and 

adherence) were extracted onto evidence tables by one investigator or research associate and 

verified by another.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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We assessed the risk of bias for trials based on the following criteria: sequence generation, 

allocation concealment, risk of bias from confounding (for non-randomized studies), blinding, 

incomplete outcome reporting, and selective outcome reporting – a modification of the Cochrane 

approach to determining risk of bias. For cohort studies risk of bias was determined based on: 

population, outcomes, measurement, and confounding. Individual studies were rated as low, 

medium, or high risk of bias. 

Data Synthesis and Analysis 

Data were summarized by outcome. If applicable, we pooled outcomes data from RCTs and 

cohort studies separately. Most of the studies reported hazard ratios (HR), which we treated as 

relative risks (RR). We extracted the HR of the highest conformity to a Mediterranean diet, 

based on Mediterranean-diet scores, that was compared to the lowest conformity (the reference). 

Random effects models were used to calculate pooled risk ratios (RR). If provided, we used the 

adjusted risk estimates from multivariate models. If HRs or RRs were not reported, we calculated 

RRs based on the numbers of events and populations reported for each of the diet groups. We 

measured the magnitude of statistical heterogeneity with the I

2 statistic (75% indicates 

substantial heterogeneity). 

RESULTS

Results of Literature Search 

Our initial literature search identified 78 papers reporting on 46 studies. An updated search 

yielded another 15 papers, bringing the totals to 93 papers reporting on 55 studies published 

between 1990 and August 2015. 

Summary of Results for Key Questions

Key Question 1: Primary Prevention

We identified 42 studies (3 RCTs and 39 cohort studies) that reported the association between 

conformity to a Mediterranean diet and the occurrence of outcomes in over 2 million people 

without a history of the outcome of interest (primary prevention). We found no studies reporting 

new onset kidney disease or hypertension. 

Cardiovascular disease, all-cause mortality, and diabetes (RCTs only). Two trials that included a 

total of 56,282 people evaluated the effect of the Mediterranean diet on major cardiovascular 

(CV) outcomes (myocardial infarction [MI], stroke, CV death) and diabetes. Three RCTs (n = 

56,711) reported all-cause mortality. 

PREvención con DIeta MEDiterránea (PREDIMED) was a Spanish trial of 7,447 people 

randomized to either a Mediterranean diet with supplemental extra virgin olive oil, a 

Mediterranean diet supplemented with nuts, or a low-fat control diet. Both of the intervention 

diets included 5 of the 7 components in our Mediterranean diet definition. After an average 

follow-up of 4.8 years, both groups assigned a Mediterranean diet had a significant 29% 

reduction in major cardiovascular events compared to the control group (HR 0.71, 95% CI 0.56, 

0.90). All-cause mortality did not differ between the diet groups. The incidence of type 2 

diabetes mellitus (T2DM) in people who did not have T2DM at baseline (N = 3,541) was 

significantly reduced compared to the control diet in the group randomized to the Mediterranean 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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diet supplemented with extra virgin olive oil (HR 0.60, 95% CI 0.43, 0.85) but not in the group 

randomized to the Mediterranean diet supplemented with nuts (HR 0.82, 95% CI 0.61, 1.10). 

The Women’s Health Initiative – Dietary Modification (WHI-DM) was a US trial of 48,835 

women, aged 50-79, assigned to either a low-fat diet (which included 2 of the 7 components of 

the Mediterranean diet) or a usual diet control. After an average follow-up of 8.1 years, there was 

no significant reduction in major cardiovascular events (either as a composite or individually), 

all-cause mortality, or incidence of T2DM in the group assigned to the intervention diet. 

Disparate results in these 2 trials may reflect differences in the diets evaluated. In PREDIMED 

the intervention diet included 5 of the 7 Mediterranean diet components and the control was a 

low-fat diet. In contrast, in WHI-DM the intervention group received a low-fat diet (which 

included advice to increase fruit and vegetable and grain intake and thus met our definition of a 

Mediterranean diet) whereas the control group received general advice only. The fact that the

intervention diet in WHI-DM is more similar to the PREDIMED control diet than to the 

PREDIMED intervention diet may explain why WHI-DM found no benefit and PREDIMED did. 

The third RCT reporting mortality followed 429 residents of 14 old-age hostels in Hong Kong 

for 33 months. The intervention group received a diet containing 2 of the 7 Mediterranean diet 

components: fruit/vegetables and fish. The mortality rate was 13% (27/204) in the intervention 

group compared to 11% (25/225) in the control group.

Cancer (RCTs and cohort studies). Two RCTs reported cancer outcomes. The WHI-DM found 

no difference in total cancer or colorectal cancer incidence or mortality. It also reported no 

difference in colorectal cancer mortality or the incidence of invasive breast, colorectal, skin, 

ovarian, uterine, or other cancers between the 2 diet groups. The PREDIMED trial reported a 

decreased risk of breast cancer in participants assigned the Mediterranean diet supplemented 

with extra virgin olive oils as compared to the control diet (HR 0.32, 95% CI 0.13, 0.79). 

Results of the 28 cohort studies that reported cancer outcomes, comparing highest to lowest

Mediterranean diet conformity, are summarized below:

Total cancer: Significant 4% reduction in incidence (k = 3) and significant 14% reduction 

in mortality (k = 13) 

Breast cancer: No reduction in breast cancer incidence (k = 13) or mortality (k = 1) 

Colorectal cancer: Significant 9% reduction in incidence (k = 9); no reduction in 

mortality (k = 1) 

Other cancers: 

o No reduction in ovarian (k = 1), pancreatic (k = 2), head and neck (k = 1), lung (k

= 1), bladder (k = 1), gastric (k = 2), or prostate (k = 3) cancer incidence 

o No reduction in pancreatic (k = 1), stomach (k = 1), prostate (k = 2), or respiratory 

tract (k = 1) cancer mortality 

Cognitive impairment (RCTs and cohort studies). Data from the 2 identified RCTs were mixed.

One site of the PREDIMED trial reported reductions in mild cognitive impairment (MCI) and 

dementia in the Mediterranean diet groups compared to control diet while another site reported 

no associations between diet and cognitive outcomes. An RCT in Hong Kong found similar rates 

of development of dementia after about 3 years of follow-up in 429 participants age > 75 who 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

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had been randomized to either a diet high in fruits, vegetables, and fish or a control diet. Results 

from the cohort studies were also mixed, although most studies reporting quantiles of 

Mediterranean-diet score found no association between diet and cognitive impairment. 

Rheumatoid Arthritis (Cohort study). One cohort study which enrolled 174,638 female registered 

nurses found similar rates of rheumatoid arthritis in participants with the highest and lowest 

Mediterranean diet scores (HR 0.98, 95% CI 0.80, 1.20). 

Gender, age, or BMI. Several studies reported outcomes stratified by gender, age, or BMI 

groups. Findings were inconsistent.

KQ2: Secondary Prevention 

We identified 15 studies (8 RCTs and 7 cohort studies, N = 19,972) that reported the association 

between conformity to a Mediterranean diet and the occurrence of outcomes in those with the 

condition of interest at baseline (secondary prevention). Of note, there is credible although not 

definitive evidence that 3 of the RCTs may contain fraudulent data. Therefore we have not 

included those data in our summary, below. 

Cardiovascular disease, cardiovascular mortality, and all-cause mortality. Three trials were 

conducted in patients with cardiovascular disease. When pooled, 2 of these trials showed that 

randomization to a Mediterranean diet significantly reduced the risk of a new MI (RR 0.32, 95% 

CI 0.15, 0.67; I2

= 0). Pooled data showed similar incidence of cardiovascular mortality (k = 3), 

stroke (k = 2), and all-cause mortality (k = 3) in the 2 diet intervention groups. 

All 3 RCTs had substantial limitations. The Lyon Heart Study was the strongest 

methodologically but it included only 605 people. The Welsh trial enrolled over 3,000 men but 

was interrupted by funding problems, leading to convoluted analyses. The Spokane Washington 

trial enrolled only 101 patients.

Cancer. In 6 cohort studies that examined outcomes in people with colon cancer (k = 2), breast 

cancer (k = 3), or prostate cancer (k = 2) there was a similar incidence of cancer recurrence and 

cancer-specific mortality in those with the highest compared to the lowest conformity to a 

Mediterranean diet.

Cognitive impairment. One cohort study in New York that enrolled 482 people with mild 

cognitive impairment reported similar incidence of progression to Alzheimer’s disease in those 

with higher conformity compared to lower conformity to a Mediterranean diet. 

Rheumatoid arthritis. Two small trials of a Mediterranean diet compared to a usual diet (n = 51, 

12-week follow-up and n = 130, 26-week follow-up) reported significant improvement in global 

pain and functional status questionnaire scores. The smaller, shorter trial reported significant 

improvement in a disease activity score but the larger, longer one did not. 

KQ3 Adherence

Two RCTs conducted in the United States reported data on adherence (N = 49,373). Results 

from these trials show that in the context of a randomized trial with intensive behavioral 

interventions it is possible to achieve sustained increases in consumption of fruits/vegetables and 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

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grains (2 components of the Mediterranean diet). Whether the same results could be achieved in 

a general population and without a labor-intensive behavioral intervention is not known.

Strength of Evidence

As can be seen in the Executive Summary Table, the strength of evidence was low or insufficient 

for all outcomes evaluated.

DISCUSSION 

Cardiovascular Disease and Type II Diabetes

Primary Prevention

PREDIMED is the only large randomized controlled trial that tested the effects of an intensive 

Mediterranean diet (5 of 7 components) on clinical outcomes. Compared to a low-fat control 

diet, either the Mediterranean diet supplemented with extra virgin olive oil or the Mediterranean

diet supplemented with nuts was associated with a significant 30% reduction in major 

cardiovascular events, the primary endpoint. This trial also reported significant reductions in 

incident diabetes but only in the group randomized to the diet supplemented with extra virgin 

olive oil.

A second primary prevention trial, the WHI-DM, found no difference in incidence of major 

cardiovascular events or diabetes between its 2 diet groups. Although this study met our 

definition of a Mediterranean diet, it only included 2 of 7 Mediterranean diet components 

(fruits/vegetables and grains) and its primary goal was to lower total fat intake. The reviewers of 

this report did not consider this intervention a true Mediterranean diet, nor would many other 

experts. Indeed, the intervention diet in WHI is more similar to the PREDIMED control diet than 

to the PREDIMED intervention diet. 

Secondary Prevention

Data from 3 RCTs indicates that a Mediterranean diet is associated with a significant reduction 

in new myocardial infarction but no reduction in cardiovascular mortality, stroke, or other 

cardiovascular events. (Three additional secondary prevention trials were identified but are not 

included in this summary because of credible evidence that they may contain fraudulent data.) 

Cancer

Primary Prevention

PREDIMED documented a significant reduction in breast cancer incidence in women 

randomized to the Mediterranean diet supplemented with extra virgin olive oil. No other RCT 

reported reduction in any cancer outcomes. Pooled results of cohort studies showed a significant 

reduction in total cancer incidence, total cancer mortality, and colorectal cancer incidence but not 

in breast cancer incidence.

Secondary Prevention 

We found no evidence that a Mediterranean diet reduces breast, prostate, or colon cancer 

recurrence or mortality. 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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Other Outcomes 

There are limited, mixed data on the effects of the Mediterranean diet on primary or secondary 

prevention of cognitive impairment or rheumatoid arthritis.

Adherence 

The available data on dietary adherence suggest that sustained increases in consumption of

fruits/vegetables and grains can be achieved, but only with labor-intensive behavioral 

interventions in select populations.

RESEARCH GAPS/FUTURE RESEARCH

A major gap is the absence of large-scale clinical outcomes trials of a Mediterranean diet in 

North American populations, both in primary and secondary prevention populations. Such trials 

are important both to confirm results of the few trials performed abroad and to determine the 

acceptability of the Mediterranean diet to the American public. In addition, the following areas 

represent important avenues for future research:

Modeling studies to ascertain if specific components or combination of components of 

the Mediterranean diet are more protective than others. 

Barriers to adoption of a Mediterranean diet in people used to consuming a traditional 

Western diet and interventions to address those barriers. 

Relative advantages of the Mediterranean diets compared to other healthy diets (eg, 

DASH diet). 

CONCLUSIONS 

In this systematic review and meta-analysis of 55 published studies we identified a single 

primary prevention trial which found that consumption of a Mediterranean diet was associated 

with a significant reduction in major cardiac events, new onset T2DM, and breast cancer 

incidence. For secondary prevention, data from 2 trials indicate that assignment to a 

Mediterranean diet reduces incidence of myocardial infarction but not other cardiovascular 

outcomes. Cohort studies indicate that conformity to a Mediterranean diet pattern is associated 

with significant reduction in total cancer incidence, total cancer mortality, and colorectal cancer 

incidence. These associations have not been confirmed in RCTs. Available data on other 

outcomes such as cognitive impairment and rheumatoid arthritis were limited. The available data 

on dietary adherence suggest that sustained increases in consumption of fruits and vegetables and 

grains can be achieved with labor-intensive behavioral interventions in select populations. 
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Executive Summary Table. Strength of Evidence 

Outcome Strength of

evidence Direction Study design;# studies (N) Summary/Rationalea

Key Question 1: Primary Prevention Studies

All-cause Mortality Low Similar

3 RCTs

PREDIMED (7,447)

WHI-DM (48,835) 

Kwok 2012 (429)

Incidence of all-cause mortality was similar between the Mediterranean-like diet and the 

control diet groups in the 2 larger studies (PREDIMED-combined diets HR 0.89 [95% CI

0.71, 1.12]; WHI HR 0.98 [95% CI 0.91, 1.07]). The trials were not pooled due to large 

dissimilarity of the study diets. Overall risk of bias is low. Consistency is unknown and 

there was imprecision (PREDIMED).

All Cancers Incidence Low

RCT

Similar

Observational

Lowered risk

1 RCT

WHI-DM (48,835)

3 Observational

(591,002) 

In WHI, all cancer incidence was similar between the Mediterranean-like diet and the 

control diet groups (HR 0.97 [95% CI 0.89, 1.05]).

Three large cohort studies reported highest conformity to a Mediterranean diet was 

associated with a reduction in total cancer incidence compared with lowest conformity 

(reference group) (pooled HR 0.96 [95% CI 0.95, 0.97]). There is inconsistency between 

WHI and the cohort studies, and overall risk of bias is medium.

Breast Cancer 

Incidence Low

RCT

Mixed

Observational

Similar

2 RCTs

WHI-DM (48,835)

PREDIMED (4,152)

12 Observational

(range 1,598 to 

355,062)

In PREDIMED, breast cancer incidence was lower in the combined Mediterranean diet 

groups compared to control (HR 0.43 [95% CI 0.21, 0.88]). In WHI, breast cancer 

incidence was similar between the Mediterranean-like diet and the control diet groups 

(HR 0.91 [95% CI 0.83, 1.01]). The trials were not pooled due to large dissimilarity of the 

study diets; consistency is unknown. 

The cohort studies found breast cancer incidence was similar between the highest and 

lowest conformity groups (RR 0.96 [95% 0.90, 1.03]). Overall risk of bias is medium.

Colorectal Cancer

Incidence Low

RCT

Similar

Observational

Lowered risk

1 RCT

WHI-DM (48,835)

9 Observational

(range 19,133 to 

397,641)

In WHI, colorectal cancer incidence was similar between the Mediterranean-like diet and 

the control diet groups (RR 1.08 [95% CI 0.90, 1.29]).

In the cohort studies, highest conformity to a Mediterranean diet was associated with a 

reduction in colorectal cancer incidence compared with the lowest conformity (RR 0.91 

[95% 0.84, 0.98]) with moderate heterogeneity between studies (I2 = 60%). There is 

inconsistency between WHI and the cohort studies, and overall risk of bias is medium.

Cognitive Functioning Low Mixed

2 RCTs 

PREDIMED (334 and 

522) 

Kwok (429)

14 Observational

(range 527 to 16,058)

A sub-study of PREDIMED involving cognitively healthy volunteers (n = 334) reported 

incidence of MCI was similar between the Mediterranean diet and the control diet 

groups. A sub-study of PREDIMED of patients with high vascular risk (n = 522) reported 

risk of MCI and dementia was lower in the Mediterranean diet group compared with the 

control diet group. An Asian trial of older nursing home residents (n = 429) found the 

proportions of patients classified as demented or with cognitive decline was similar 

between the Mediterranean-like diets and the control diet groups. The trials were not 

pooled due to the large dissimilarity of the study diets and populations, resulting in 

unknown consistency. Overall risk of bias is moderate.

The results from the observational studies were mixed. Three studies analyzing 

Mediterranean diet as a continuous score reported higher conformity to a Mediterranean 

diet slowed rates of cognitive decline; 4 did not. Six cohort studies analyzing 

Mediterranean diet as a categorical variable reported no association with levels of diet 

conformity and cognitive outcomes; 3 reported mixed results across different subgroups 

or analyses. Overall risk of bias is medium.
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Outcome Strength of

evidence Direction Study design;# studies (N) Summary/Rationalea

Key Question 2: Secondary Prevention Studies

All-cause Mortality Insufficient Similar 3 RCTs 

(2,277) 

Incidence of all-cause mortality was similar between the Mediterranean-like diets and the 

control diet groups (RR 0.95 [95% CI 0.53, 1.69]; I2 = 51%). There is large imprecision 

and inconsistency, and overall risk of bias is medium.

RCT = randomized controlled trial; PREDIMED = Prevención con Dieta Mediterránea; WHI = Women’s Health Initiative; HR = hazard ratio; RR = risk ratio; MCI = mild 

cognitive impairment

a Strength of Evidence Definitions (Owens 2010):

Precision: Degree of certainty surrounding an effect estimate; in meta-analysis, the confidence interval around the summary effect size

Consistency: Degree to which reported effect sizes appear to have the same direction of effect

Directness: Whether the evidence links the interventions directly to health outcomes

Risk of bias: Degree to which includes studies have a high likelihood of protection against bias; 2 main elements are study design and aggregate quality of the studies
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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ABBREVIATIONS TABLE

Abbreviation Definition

AD Alzheimer’s Disease

BMI Body Mass Index

CCT Controlled Clinical Trial

CI Confidence Interval

HR Hazard Ratio

MCI Mild Cognitive Impairment

RA Rheumatoid Arthritis

RCT Randomized Controlled Trial

RR Relative Risk

T2DM Type 2 Diabetes Mellitus
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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EVIDENCE REPORT

INTRODUCTION

A large number of epidemiologic studies have investigated the association between diet and 

mortality and morbidity. Of particular recent interest is the Mediterranean diet, first described by 

Ancel Keys over 50 years ago.

1 This diet is characterized by high intake of olive oil, fruits and 

vegetables, whole grains and cereals, legumes, fish, and nuts; low intake of red meat, dairy 

products, and sweets; and moderate intake of red wine with meals.2 Epidemiologic studies have 

shown that the incidence of cardiovascular disease in populations that consume such diets is 

lower than in populations that consume a more typical “Western” diet that is rich in red meat, 

dairy products, processed and artificially sweetened foods, and salt with minimal intake of fruits, 

vegetables, fish, legumes, and whole grains.3-5

Based on these epidemiologic studies, several randomized controlled trials were conducted to 

test the hypothesis that adopting a Mediterranean diet in adulthood reduces chronic disease 

burden (eg, incidence of and/ or mortality from cardiovascular disease, cancer, type 2 diabetes

mellitus [T2DM], hypertension, cognitive impairment, and kidney disease) and/or all-cause 

mortality (viz, PREDIMED, Lyon Heart Study, THIS-DIET).

6-8 These trials included populations 

from a variety of geographical locations and with a spectrum of demographic and clinical 

characteristics. 

Although several systematic reviews of the relevant observational studies and clinical trials have 

been published,9-19 the VA’s Evidence-based Synthesis Program, in conjunction with the Office 

of Quality and Performance and in response to a request from the VA’s National Center for 

Health Promotion and Disease Prevention and Primary Care Services, commissioned the present 

study to update prior reviews and to specifically assess the implications for the treatment and 

prevention of common chronic conditions in the Veteran population. We conferred with the topic 

nominators and Technical Expert Panel (TEP) members and other experts inside and outside the 

VA to select the parameters of the review, including patient characteristics, interventions, and 

outcomes (Figure 1, Analytic Framework). 

The final Key Questions are:

Key Question 1: Is the Mediterranean diet more effective than other diets in preventing death or 

the development of type 2 diabetes mellitus, cardiovascular disease, cancer, hypertension, 

cognitive impairment, or kidney disease?

Key Question 1a: Do the effects vary by gender, age, or BMI?

Key Question 2: Compared to other diets, is the Mediterranean diet associated with fewer 

adverse outcomes (including death) or less disease progression in people who already have 

diabetes, cardiovascular disease, cancer, hypertension, cognitive impairment, rheumatoid 

arthritis, or kidney disease?

Key Question 2a: Do the effects vary by gender, age, or BMI?
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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Key Question 3: What is the observed adherence to the Mediterranean diet in studies conducted 

in the United States or Canada?

PICOTS

Population: Adults (age 18 or older), not pregnant or lactating, and not hospitalized or 

institutionalized. Subgroups of interest: people with type II diabetes, cardiovascular disease, 

rheumatoid arthritis, cancer, hypertension, cognitive impairment, or kidney disease; different 

genders, ages, and BMIs.

Interventions: A Mediterranean-style diet (ie, labelled as a Mediterranean diet or consisting of 

at least 2 of the following: 1. high monounsaturated:saturated fat ratio (use of olive oil as main 

cooking ingredient); 2. high consumption of fruits and vegetables; 3. high consumption of 

legumes; 4. high consumption of grains/cereals; 5. moderate red wine consumption; 6. moderate 

consumption dairy products; and 7. low consumption of meat and meat products (replaced by

increased consumption of fish)

Comparator: Any other type of diet (eg, Western, low fat, vegetarian)

Outcomes: NOTE: Definitions for all outcomes followed definitions used in the included studies.

T2DM, hypertension, and kidney disease were considered present only if the study recorded a 

clinical diagnosis had been made (ie, not just by laboratory values obtained in the study)

KQ1: mortality, quality of life, new onset of T2DM, hypertension, cardiovascular disease (CVD) 

(myocardial infarction [MI], stroke, or congestive heart failure), kidney disease, cancer, and 

cognitive impairment (dementia, Alzheimer’s disease [AD], or mild cognitive impairment 

[MCI])
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Figure 1. Analytic Framework

Mediterranean Diet*

OUTCOMES

1. Mortality 

2. New onset of and/or morbidity from: type 2 

diabetes mellitus, cardiovascular disease, 

cognitive impairment, kidney disease, RA, or 

cancer

3. Quality of life/patient satisfaction

*Operational Definition of a Mediterranean Diet: At 

least 2 components from this list were required for the 

Cochrane review (Rees 2014)

1. High monounsaturated:saturated fat ratio (use of 

olive oil as main cooking ingredient)

2. Moderate red wine consumption.

3. High consumption of legumes.

4. High consumption of grains/cereals.

5. High consumption of fruits/vegetables.

6. Low consumption of meat and meat products and 

increased consumption of fish.

7. Moderate consumption dairy products

KQ3

PICOTS

Patients: Adults

Intervention: Mediterranean diet

Control: Other diet (eg, Western, vegetarian)

Outcomes: See Above

Timing: at least 1 year follow-up

Setting: Outpatient

KQ1/KQ2

HARMS

ADHERENCE in US or Canadian Populations

Study Eligibility Criteria (KQ1/KQ2)

• English language

• > 12 months follow-up

• For Outcomes 1 and 3

• RCTS or systematic 

reviews of RCTs 

• > 100 participants

• For Outcome 2

• RCTs for diabetes, 

CVD, or CKD

• Cohort studies for 

cancer, cognitive 

impairment and RA

Study Eligibility Criteria (KQ3)

English language

> 12 months follow-up

US or Canadian population

RCTs

≥100 participants

KEY QUESTIONS

1. Is the Mediterranean diet more effective than other diets in preventing death or the development of 

type 2 diabetes mellitus, cardiovascular disease, cancer, hypertension, cognitive impairment, or 

kidney disease? Do the effects vary by gender, age, or BMI?

2. Compared to other diets, is the Mediterranean diet associated with fewer adverse outcomes 

(including death) or less disease progression in people who already have diabetes, cardiovascular 

disease, cancer, hypertension, cognitive impairment, rheumatoid arthritis, or kidney disease? Do 

the effects vary by gender, age, or BMI?

3. What is the observed adherence to the Mediterranean diet in studies conducted in the United 

States or Canada?
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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KQ2:

A. For populations with diabetes, heart disease, kidney disease, and/or hypertension at baseline:

1. Mortality

2. Quality of life

3. Progression of disease, ie:

a. Development of retinopathy, neuropathy, end-stage renal disease, or congestive 

heart failure

b. New amputation

c. New myocardial infarction, stroke, or revascularization procedure

B. For populations with cancer at baseline:

1. Mortality (all-cause, cancer-specific)

2. Quality of life

3. Progression of disease or recurrence

C. For populations with rheumatoid arthritis at baseline:

1. Pain 

2. Quality of life

3. Functional status

D. For populations with cognitive impairment at baseline:

1. Diagnosis of dementia

2. Quality of life

3. Functional status

KQ1, KQ2: Any adverse events related to diet in RCTs

KQ3: Adherence measures 

Timing: At least one year of follow-up, except for studies of rheumatoid arthritis or cognitive 

impairment

Setting: Outpatient

Study Type: 

KQ1 or KQ2:

Studies of patients with or at risk for cardiovascular disease, hypertension, diabetes, or kidney 

disease – RCTs of at least 100 people followed for at least one year 

Studies of patients with or at risk for cancer – RCTs or cohort studies with at least 100 

participants and at least one year follow-up

Studies of patients with or at risk for rheumatoid arthritis or cognitive impairment – randomized 

controlled trials (RCTs) or cohort studies of any size or follow-up duration

KQ3: RCTs of at least 100 people followed for at least one year
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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METHODS

TOPIC DEVELOPMENT

This topic was nominated by Linda Kinsinger, MD, MPH, Chief Consultant for Preventive 

Medicine, National Center for Health Promotion and Disease Prevention; Gordon Schectman, 

MD, Chief Consultant for Primary Care Services; and Michael Goldstein, MD, Associate Chief 

Consultant for Preventive Medicine. The evidence review examines the benefits and harms of the 

Mediterranean diet compared to other diets. Key questions and inclusion criteria were derived 

with input from the topic nominators and a technical expert panel.

SEARCH STRATEGY

We searched MEDLINE (Ovid), CINAHL, and the Cochrane library for articles published from 

1990 through August 2015. Our search was limited to studies of adults published in the English 

language. The search included the MeSH (Medical Subject Headings) terms fruit; vegetables; 

nuts; bread; cereals; seeds; fatty acids, monusaturated; seafood; and diet, Mediterranean. To 

address Key Question 3, an additional search was done in all 3 databases adding the terms 

adherence and patient compliance. The searches were also repeated with the addition of diseasespecific terms to find articles specific to cancer, rheumatoid arthritis, and cognitive impairment. 

The full search strategies are presented in Appendix A. We also obtained articles by handsearching the reference lists of systematic reviews and included studies. A separate search was 

also done in all 3 databases to identify systematic reviews of cohort studies reporting on 

cardiovascular disease, diabetes, and all-cause mortality. 

DEFINITIONS

We included studies with diets that met the criteria defined by a recent Cochrane Review, that is 

to say, labelled a Mediterranean diet or meeting 2 or more of the following components: 1. high 

monounsaturated:saturated fat ratio (use of olive oil as main cooking ingredient); 2. high 

consumption of fruits/vegetables; 3. high consumption of legumes; 4. high consumption of 

grains/cereals; 5. moderate red wine consumption; 6. moderate consumption of dairy products; 

and 7. low consumption of meat and meat products (replaced by increased consumption of fish). 

All included studies met this minimum definition. The names for the diets included terms such as 

Mediterranean diet, prudent diet, healthy Nordic diet, and healthy pattern.

STUDY SELECTION

Abstracts from MEDLINE (n = 7,672) were reviewed in duplicate independently by 

investigators and research associates. Abstracts from the CINAHL database (n = 131) and 

Cochrane Library (n = 1,799) were reviewed by a co-investigator or research associate. Trained 

researchers identified articles published in peer-reviewed journals related to one of the Key 

Questions (KQs). For studies addressing KQs 1 and 2 in diseases other than cancer, RA, or 

cognitive impairment we included RCTs or controlled clinical trials (CCTs) with at least 100 

subjects followed for at least one year. For studies of RA and cognitive impairment we included 

RCTs, CCTs, and cohort studies with any number of participants and no limit on follow-up time. 

For studies of cancer and for KQ3 we included RCTs and cohort studies with at least 100

participants followed for at least one year. In addition, in order to be included, studies addressing 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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KQ3 must have taken place in the United States or Canada. For all questions and outcomes, we 

excluded case series, case reports, qualitative reports, narrative reviews, editorials, or letters. 

Studies must have also reported one of our outcomes of interest as defined in the Analytic 

Framework (Figure 1) and PICOTS (above).

All included studies met our definition of a Mediterranean diet. In the randomized trials, the 

composition of the intervention diets were defined a priori. In the cohort studies, food frequency 

surveys (either self-administered or administered by research staff) were typically used to 

categorize subjects’ diets based on validated dietary indices. Commonly used indices include the 

Mediterranean-diet score, the alternate Mediterranean-diet score (aMED), the Healthy Eating 

Index (HEI), and the Alternate Healthy Eating Index (aHEI). For these indices we generally 

compared the highest quantile of conformity to a Mediterranean diet to the lowest. We excluded 

the following:

Studies that did not involve outpatient adults;

Studies with diets that were not labelled Mediterranean and did not test or measure a diet 

that met our criteria for a Mediterranean diet (stated above);

Studies in women who were pregnant or lactating; and

For KQ3, studies that were conducted in countries other than the US and Canada.

Full-text reports of studies identified as potentially eligible were obtained for further review 

using the inclusion and exclusion criteria described above. Each article was independently 

reviewed by 2 trained researchers. Reasons for excluding a study at full-text review were noted.

DATA ABSTRACTION

Study characteristics (goal of intervention, inclusion/exclusion criteria, diet descriptions, followup, and patient characteristics) as well as outcomes (mortality, health-related quality of life,

adverse events, satisfaction, new onset of disease, disease progression/recurrence, and 

adherence) were extracted onto evidence tables by one investigator or research associate and 

verified by another. The systematic reviews of cohort studies reporting on cardiovascular 

disease, diabetes, and all-cause mortality were summarized narratively.

RISK OF BIAS ASSESSMENT

We assessed the risk of bias for RCTs using the following criteria: sequence generation, 

allocation concealment, blinding, incomplete outcome reporting, and selective outcome reporting

– a modification of the Cochrane approach to determining risk of bias.20 For cohort studies risk 

of bias was determined based on: population (representativeness of sample, uniform application 

of inclusion/exclusion criteria), outcomes (important outcomes assessed and reported, 

appropriate length of follow-up), measurement (outcome assessment same for all participants, 

accurate and reliable tools used), and confounding (appropriate confounding factors included in 

analysis). Individual studies were rated as low, medium, or high risk of bias. Low risk of bias 

RCTs had adequate allocation concealment, blinding, and outcome reporting. Low risk of bias

cohort studies had appropriate populations, assessed important outcomes with adequate followup, used appropriate outcome measurement tools, and adjusted for important potential 

confounding factors.
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DATA SYNTHESIS

Data were summarized by outcome. If applicable, we pooled outcomes data from RCTs and 

cohort studies separately using Comprehensive Meta Analysis Version 3 (Biostat, Englewood, 

New Jersey). Most of the studies reported hazard ratios (HR), which we treated as risk ratios 

(RR). We extracted the HR of the highest conformity to a Mediterranean diet, based on 

Mediterranean-diet scores, that was compared to the lowest conformity (the reference). Random 

effects models were used to calculate pooled RRs. If provided, we used the adjusted risk 

estimates from multivariate models. If HRs or RRs were not reported, we calculated RRs based 

on the numbers of events and populations reported for each of the diet groups. We measured the 

magnitude of statistical heterogeneity with the I

2 statistic (75% indicates substantial 

heterogeneity).

21

RATING THE BODY OF EVIDENCE

We rated the overall strength of the body of evidence for select outcomes (all-cause mortality

[KQ1, KQ2], cancer incidence [KQ1], and cognitive functioning [KQ1]) using the method 

reported by Owens et al.

22

PEER REVIEW

A draft version of this report was reviewed by content experts and clinical leadership. 

Reviewers’ comments and our responses are presented in Appendix B and the report was

modified as needed.
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RESULTS 

LITERATURE FLOW 

The overall literature flow is presented below. Literature flows for each of the Key Questions are 

presented in Appendix D. We reviewed a total of 9,602 abstracts. 

Figure 2. Overall Literature Flow (KQ1-3) 

 

a Studies may have presented data for more than one KQ. 

Hand Search:

12 papers

Excluded: 219 papers

Population: 1 paper

Diet: 31 papers

Study Design, Size, or 

Follow-up: 107 papers

Outcomes: 78 papers

Setting: 2 papers

Search Results

Ovid: 7,672 abstracts

Cochrane: 1,799 abstracts

CINAHL: 131 abstracts

Total: 9,602 abstracts

Excluded:

9,302 abstracts

Full Text Review:

300 papers

Included:

93 papers on 55 studiesa 

KQ1: 42 studies

KQ2: 15 studies

KQ3: 2 studies
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KEY QUESTION 1: Is the Mediterranean diet more effective than other 

diets in preventing death or the development of Type II diabetes

mellitus, cardiovascular disease, cancer, hypertension, cognitive 

impairment, or kidney disease?

Overview of Studies (Table 1 and Appendix C, Table 1) 

We identified a total of 72 articles reporting results from 42 studies. Three were randomized 

controlled trials and 39 were cohort studies. The dietary interventions used in the 3 RCTs are 

detailed in the sections below entitled all-cause mortality and cognitive functioning. The cohort 

studies employed a variety of scales to rate each individual’s degree of conformity to the 

Mediterranean diet (see Methods section). 

We extracted all-cause mortality (number of studies reporting[k] = 3), cardiovascular outcomes 

(k = 2), and T2DM (k = 2) only from RCTs. We extracted cancer outcomes from both cohort 

studies (k = 28) and RCTs (k = 2), cognitive impairment from both cohort studies (k = 13) and 

RCTs (k = 2), and rheumatoid arthritis from one cohort study. No studies reported new-onset 

kidney disease or hypertension, or quality of life. Twenty one studies were conducted in North 

America, 17 in Europe, and 4 in Asia or Australia. The total number of participants was 

2,489,225 with a range of sample sizes from 429 to 566,407. The average age of participants was 

61 (k = 28) and the mean BMI was 26 (k = 25). For studies using mixed gender cohorts the mean 

percentage of men was 46% (k = 23). 

Outcomes (Appendix C, Tables 1 – 4)

All-Cause Mortality (RCTs only)

All-cause mortality was reported in 3 trials [WHI-DM, PREDIMED, and a smaller study from 

Hong Kong; total N = 56,711].7,23,24 PREDIMED was a multicenter trial in Spain that 

randomized 7,447 people to one of 3 diets: Mediterranean diet supplemented with extra virgin 

olive oil (EVOO), Mediterranean diet supplemented with mixed nuts, or a control diet. Each of 

the 2 intervention diets comprised 5 of the 7 components of a Mediterranean diet, including olive 

oil. The mean age of enrollees was 67 years, 57% were women, 97% were Caucasian, 25% were 

former and 14% were current smokers, the mean body mass index was 29.8, 82% had 

hypertension, 50% had diabetes, and 70% had dyslipidemia.7 Median follow-up was 4.8 years.

The primary endpoint was major cardiovascular events (myocardial infarction, stroke, or 

cardiovascular death). 
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Table 1. Summary of Included Studies - Key Question 1

Characteristic Mean (range)

Unless Otherwise Noted

Number of Studies 

Reportinga 

Total number of patients evaluated 2,489,225

(429 to 566,407) 42 

Randomized controlled trials, total number of 

patients

56,711

(429 to 48,835) 3 

Cohort studies, total number of patients 2,432,514

(723 to 566,407) 39 

Age of subjects, years 61 (36 to 83) 28 

Gender, % male patients in mixed gender 

studies 46% (15% to 66%) 23c

Mixed gender studies, total number of patients 1,571,038

(429 to 566,407) 23 

Male only studies, total number of patients 79,265

(1,044 to 47,867) 4 

Female only studies, total number of patients 838,922

(3,220 to 174,638) 15d

Body Mass Index 26 (23 to 30) 25 

Location - USA/Canada, total number of 

patients

1,487,412

(826 to 494,968) 21d

Location - Europe, total number of patients 956,992

(1,044 to 566,407) 17b

Location - Asia/Australia, total number of 

patients

44,821

(429 to 42,112) 4c

a Footnotes indicate RCTs represented in number of studies: b

PREDIMED,

7,25-28 c

Kwok 2012,

24 d

WHI-DM23,29-32

The second trial was the WHI-DM, a multi-center trial which randomized 48,835 

postmenopausal women to either a usual diet control or a dietary intervention which included 

goals of total fat intake of <20% of total calories, 5 or more servings per day of fruits and 

vegetables, and 6 or more servings per day of grains (ie, 2 of the 7 components of a 

Mediterranean diet).23 Ninety-seven percent of participants had no history of cardiovascular 

disease at baseline. Participants were followed for an average of 8.1 years. There was no 

association between diet group and total mortality in either trial. 

The third study followed 429 residents of 14 old-age hostels in Hong Kong for 33 months.24 The 

intervention group received a diet containing 2 of the 7 Mediterranean diet components:

fruit/vegetables and fish. The mortality rate was 13% (27/204) in the group following a 

Mediterranean diet compared to 11% (25/225) in the control group the statistical significance of 

this finding was not reported.

Cardiovascular Disease (RCTs only)

Cardiovascular disease outcomes were reported in 2 trials, described above [WHI-DM, 

PREDIMED, N = 56,282]. The primary endpoint in PREDIMED was major cardiovascular 

events (myocardial infarction, stroke, or cardiovascular death). Compared to the control diet, 

both Mediterranean diets were associated with a significant 30% reduction in the primary 

endpoint (HR 0.70, 95% CI 0.54, 0.92 for EVOO and HR 0.72, 95% CI 0.54, 0.96 for nuts).

7

When the 3 components of this composite endpoint were evaluated individually, only the

reduction in stroke risk was significant (HR 0.68, 95% CI 0.49, 0.96).7 There was no significant 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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21

difference between the 2 Mediterranean diets.7 In WHI-DM, the incidence of all major 

cardiovascular outcomes reported (including myocardial infarction, CHD death, stroke, 

revascularization procedures, and various combinations of these outcomes) was similar between 

the 2 intervention groups.

32

Type 2 Diabetes Mellitus (RCTs only)

T2DM was reported in 2 trials that included a total of 49,428 people. The PREDIMED study 

(described above) reported a subgroup analysis based on 3541 participants who did not have 

T2DM when enrolled in the trial.26 Compared to the control diet, persons randomized to the 

Mediterranean diet supplemented with extra virgin olive oil had a significant reduction in risk of 

developing T2DM over a median 4.1 years of follow-up (HR 0.60, 95% CI 0.43, 0.85).26 Those 

randomized to the Mediterranean diet supplemented with nuts had a non-significant reduction in 

risk of developing T2DM (HR 0.82, 95% CI 0.61, 1.10). 

The second trial reporting T2DM as an outcome was the WHI-DM, described above.

30 The 

incidence of new onset T2DM was similar between the 2 diet groups (HR 0.96, 95% CI 0.90, 

1.03). 

Cancer (RCTS and cohort studies)

Cancer as an outcome was reported in 30 studies, 2 RCTs (WHI-DM, N = 63,805 and 

PREDIMED, N = 4,282) and 28 cohort studies, N = 2.5 million.

4,23,27,29,31,33-73

Total Cancer Incidence 

Total cancer incidence was reported in 3 cohort studies and one RCT.23,56,57 Data from the 

Nurses’ Health Study (NHS, N = 71,495 women) and the Health Professionals Follow-up Study 

(HPFS, N = 41,029 men), both of which had follow-up times of more than 20 years, were 

reported in one paper. The multivariate adjusted relative risk of any cancer in the highest 

compared to the lowest quintile of conformity to the Mediterranean diet was 0.94 (95% CI 0.90, 

0.98) for men and women combined.

56 For women, higher diet conformity was associated with 

decreased risk of all cancer (RR 0.93, 95% CI 0.88, 0.99) but there was no association for men 

alone (RR 0.94, 95% CI 0.87, 1.03).56 The third cohort study was conducted in 23 centers in 10 

European countries. It enrolled 478,478 men and women and followed them for a median of 8.7 

years. Conformity to the Mediterranean diet was assessed using the Mediterranean-diet score, a 

9-point score calculated from self- or interviewer-administered food frequency questionnaires.4

Higher conformity to a Mediterranean diet was associated with a significant reduction in cancer 

incidence (HR 0.96, 95% CI 0.95, 0.97 for a 2-point increment in the Mediterranean-diet score) 

(Figure 3).57 Pooled results from these 3 studies indicated a significantly lower risk of total 

cancer incidence in people with higher compared to lower conformity to the Mediterranean diet

(RR 0.96, 95% CI 0.95, 0.97). 

The RCT (WHI-DM, described above) reported similar total cancer incidence in the 2 diet 

groups (HR 0.97, 95% CI 0.89, 1.05).23 
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22

Figure 3. Cancer Incidence by Cancer Type, Cohort Studies

I

2 breast = 53%, I2 colorectal = 60%
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Total Cancer Mortality

Total cancer mortality was reported in 13 cohort studies and one RCT.

4,23,33,34,38,39,42,43,45,54,55,63,71

Of the 13 cohort studies, 6 were conducted in Europe and 7 in North America. The studies 

included a total of 534,058 participants. In the one RCT (WHI-DM, described above) total 

cancer mortality was similar in the 2 diet groups (HR 0.95, 95% CI 0.90, 1.01) (Figure 4).23

Pooled results of the 13 cohort studies are displayed in Figure 4. There was a significant 14% 

reduction in total cancer mortality in those with the highest level of conformity to the 

Mediterranean diet compared to those with the lowest level (RR 0.86, 95% CI 0.82, 0.91; I2

= 

77%). 

Breast Cancer 

Breast cancer incidence was reported in 13 cohort studies and 2 RCTs (WHI-DM and 

PREDIMED).27,31,35,46,50,51,58,60,62,65,66,69,73,74 Seven were conducted in the United States, 2 in 

Canada, and 6 in Europe. The 15 studies included more than 800,000 participants. In WHI-DM 

(described above), breast cancer incidence was similar between the 2 diet groups (HR 0.91, 95% 

CI 0.83, 1.01)(Figure 5).

31 In the PREDIMED trial (described above) breast cancer incidence in 

4,152 women followed for 4.8 years was significantly lower compared to the control diet in 

participants assigned the Mediterranean diet with supplemental EVOO (HR 0.32, 95% CI 0.13, 

0.79) but not the Mediterranean diet supplemented with nuts.

27 

Pooled results of the 13 cohort studies are displayed in Figure 3. Breast cancer incidence was 

similar in those who had the highest level of conformity to the Mediterranean diet and those who 

had the lowest level of conformity (RR 0.96, 95% CI 0.90, 1.03; I2

= 53%). 

Breast cancer mortality was reported in one study, a prospective population-based cohort study 

conducted in Sweden (N = 77,151). It reported no association between conformity to a 

Mediterranean diet and breast cancer mortality (HR 1.12, 95% CI 0.97, 1.29) (Figure 6).54 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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24

Figure 4. Cancer Mortality, Cohort Studies 

I

2 = 77%

Figure 5. Breast Cancer Incidence from PREDIMED and WHI – DM

Colorectal Cancer 

Colorectal cancer incidence was reported in 9 cohort studies and one RCT.

23,48,53,59,61,68,72 Of the 

cohort studies, 5 were conducted in Europe, 3 in the US, and one in Japan. These 9 studies 

included over 1.3 million participants. In the RCT (WHI-DM, described previously) incidence of 

colorectal cancer and colorectal cancer mortality were similar between the 2 diet groups

(incidence: HR 1.08, 95% CI 0.90, 1.29; mortality: HR 1.26, 95% CI 0.85, 1.85).23

Pooled results of the 9 cohort studies are shown in Figure 3. The incidence of colorectal cancer 

was significantly lower in people with highest conformity to the Mediterranean diet compared to

people with the lowest conformity to the Mediterranean diet (RR 0.91, 95% CI 0.84, 0.98; I2

= 

60%). 
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A prospective population-based cohort study conducted in Sweden (N = 77,151), reported no 

association between conformity to a Mediterranean diet and colorectal cancer mortality for men 

(HR 1.07, 95% CI 0.93, 1.24) or women (HR 0.91, 95% CI 0.77, 1.08) (Figure 6).54 

Other Site-specific Cancer (Figure 3) 

In cohort studies (Figure 3), the incidence of the following cancers was similar between people 

with high and low levels of conformity to a Mediterranean diet: ovarian (k = 1), pancreatic (k = 

2), head and neck (k = 1), lung (k = 1), bladder (k = 1), prostate (k = 3), and gastric cancer (k = 

2).29,36,37,40,41,44,47,49,52,67,75 In an RCT (WHI-DM, described previously) incidence of ovarian, 

endometrial, and skin cancers were similar between the 2 diet groups.29,31

Two studies reported cancer site-specific mortality (Figure 6). In addition to the findings for 

breast and colorectal cancer mortality, the prospective population-based cohort study conducted 

in Sweden (N = 77,151), reported no association between conformity to a Mediterranean diet and

stomach, prostate, or respiratory cancer mortality.54 The authors did find an association between 

Mediterranean diet score and lower pancreatic cancer mortality but it was only significant in men 

(HR 0.82, 95% CI 0.68, 0.99).54 A prospective US population-based cohort study of 293,464 

men followed for an average of 8.9 years reported no association between conformity to a 

Mediterranean diet and incidence of fatal prostate cancer (HR 0.80, 95% CI 0.59, 1.10).

52

Figure 6. Cancer Mortality by Cancer Type, Cohort Studies 

Cognitive Functioning

The effect of a Mediterranean diet on prevention of cognitive decline was reported in 2 RCTs 

and 14 cohort studies. A RCT conducted in Hong Kong enrolled “old age hostel” residents 75 

years of age and older.24 “Brain preservation” diet meals (fruits, vegetables, fish, reduced salt 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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intake, and less refined sugar) were provided to the residents in the intervention group. The mean 

age of the 429 participants was 83 years. At baseline, 59% of the intervention group and 66% of 

the control group had “questionable dementia” (defined as a Clinical Dementia Rating [CDR] 

score of 0.5). At 33 months follow-up, data were available for 79% of the intervention group and 

80% of the control group. The intervention and control groups were similar in the proportion of 

patients who were classified as demented (14% intervention, 17% control; RR 0.81, 95% CI

0.49, 1.35) or with cognitive decline (a worsening of the CDR score) (22% intervention, 27% 

control, RR 0.82, 95% CI 0.56, 1.19) (Figures 7 and 8).24 

The second RCT was the PREDIMED study. Two of the study sites, Barcelona and Navarra, 

evaluated the effect of diet on incidence of mild cognitive impairment (MCI) and reported their 

results independently (Figure 7).25,28 The Barcelona site, which enrolled 334 people followed for 

a median of about 4 years, reported similar Mini-Mental State Examination (MMSE) scores and 

risk of MCI for the intervention and control groups (Figure 7).28 The Navarra site, which 

enrolled 522 people followed for a mean of 6.5 years, reported that the risk of MCI was 

significantly lower in the Mediterranean diet group (RR 0.54, 95% CI 0.34, 0.88) (Figure 7).25

The Navarra site also reported a significantly lower incidence of dementia in the intervention 

groups compared to the control group (RR 0.36, 95% CI 0.19, 0.67) (Figure 8).25

Figure 7. Mild Cognitive Impairment (PREDIMED) or Cognitive Decline (Kwok)*

*Cognitive decline as defined by an increase in Clinical Dementia Rating Scale score

Figure 8. Dementia

Among the 14 cohort studies, 8 were from the US, 3 from Europe, and 3 from Australia.76-91

Enrollments ranged from 527 to 16,058 and mean ages at enrollment (reported in 12 of the 

studies) ranged from 52 to 82. One study used 24-hour dietary records to compute a 

Mediterranean diet score that ranged from 0 to 9 and a Mediterranean-Style Dietary Pattern score 

that ranged from 0 to 100%.80 The remaining studies used food frequency questionnaires to 

compute a Mediterranean-diet score, most commonly the instrument validated by Trichopoulou

(2003), with values ranging from 0 to 9.4 Follow-up periods ranged from 18 months to 28 years. 

The single most commonly used cognitive assessment tool was the mini-mental status exam 

(MMSE), although most studies used a battery of 4 to 18 tests. 
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Among these 14 cohort studies, only 7 found a significant association between higher conformity 

to a Mediterranean diet and improved cognitive outcomes (see bulleted list below). Studies 

presenting data in a way that allowed for determination of risk ratios are presented in Figure 9. 

An Australian study reported a significant correlation between baseline Mediterranean 

diet score and improvement in MMSE at 18 months, although tests of memory, verbal 

learning, and verbal fluency did not improve.78 A study from France reported similar 

results finding higher diet conformity associated with fewer MMSE errors over a 5-year 

follow-up but no association with other cognitive tests or incident dementia.77

Two studies from the US reported slower rates of cognitive decline (assessed with a 

battery of tests) were associated with higher Mediterranean diet conformity over mean 

follow-up periods of 4 years and 7.6 years.89,90 Another US study reported a similar 

outcome for MMSE scores over a mean follow-up of 10.6 years.91

A US study found a significant association between the highest tertile of Mediterraneandiet score and development of AD over a 4 year (mean) follow-up.88 The significant 

association was maintained when the model was adjusted for all vascular variables.86 In 

further analyses of the same cohort, a significant association between increased 

Mediterranean diet conformity and decreased risk of MCI was observed when diet was 

expressed as a continuous variable but the association was not significant when diet was 

expressed categorically (tertiles).

87 Another analysis found lower risk of AD in 

participants with high Mediterranean diet conformity and high levels of physical activity 

relative to those with low conformity and low activity.85

A study from the US found no association between Mediterranean diet and decline in 

modified MMSE scores in the overall population although the association was significant 

in the African-American participants.92

79-81,83,84

76,82

Five studies (2 from the US, and one each from Australia, France, and Greece) reported 

that diet conformity was not significantly associated with cognitive scores.

Two studies (one from the US and one from Australia) reported that diet conformity was 

not significantly associated with development of mild cognitive disorder (any), mild 

cognitive impairment, or dementia.
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Figure 9. Cognitive Outcomes for Observational Studies 

Rheumatoid Arthritis

Rheumatoid arthritis was an outcome of interest in one paper. They reported results from the

NHS and NHS-II, which together included 174,638 female registered nurses followed for over 

20 years. Analysis of pooled data found similar risk of developing rheumatoid arthritis in women 

who scored in the highest and lowest quartiles of the aMED score (HR 0.98, 95% CI 0.80, 

1.20).93 

Diet-related Adverse Events

Participants in the PREDIMED study reported that they experienced no diet-related adverse 

effects.
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KEY QUESTION 1A: DO THE EFFECTS VARY BY GENDER, AGE, OR 

BMI?

Gender

No RCTs reported outcomes stratified by gender. Seven cohort studies reported all cancer 

incidence and colorectal, head and neck, and pancreatic cancer incidence. Six cohort studies 

reported all cancer mortality separately in men and women (Table 2).33,34,38-40,48,54,56,57,59,61,67,68,72

Two cohort studies reported cognitive performance by gender (Table 2).80,90

Age

The WHI-DM reported risk of composite coronary heart disease and T2DM by age and found no 

significant interaction between age and risk for either (P = .58 and P = .66, respectively).30,32

Two RCTs reported cancer incidence stratified by age groups. The WHI-DM RCT reported total 

invasive cancer, invasive ovarian cancer, colorectal cancer, non-melanoma skin cancer, and 

melanoma incidence by diet group for 3 age strata: 50-59 years, 60-69 years, and 70 years and 

older.23,29,31 There were no significant interactions between age group and intervention group.

The PREDIMED trial reported a post-hoc subgroup analysis of breast cancer incidence in 

women over and under the age of 67. Breast cancer incidence was significantly reduced in 

women who were 67 years old or younger (HR 0.16, 95% CI 0.05, 0.50) but not in women over 

the age of 67 (HR 0.92, 95% CI 0.34, 2.47).27 However, a test for interaction was not reported. 

Two cohort studies reported cancer incidence by age groups and one reported cancer mortality 

by age (Table 2).63,72,75 

One cohort study reported cognitive outcomes by age (Table 2).90

BMI

The WHI-DM reported risk of composite coronary heart disease and T2DM by BMI and found 

no significant interaction between BMI and risk for either (P = .07 and P = .74, respectively).30,32

Two RCTs reported outcomes by BMI. In WHI-DM there were no differences in incidence of

total invasive, invasive ovarian, colorectal, or non-melanoma skin cancers by BMI 

category.23,29,31 The PREDIMED trial found significantly reduced breast cancer incidence in 

women with a BMI less than 30 (HR 0.29, 95% CI 0.11, 0.83) but not in those with a BMI of 30 

or greater (HR 0.57, 95% CI 0.22, 1.49). However, a test for interaction was not reported.27 

Two cohort studies reported cancer incidence by BMI groups (Table 2).51,60 One cohort study 

(WHI-OS) reported all cancer mortality in different BMI groups (Table 2).42

Summary of Findings for Key Questions 1 and 1A

There is evidence from one RCT that the Mediterranean diet significantly decreases risk of major 

cardiovascular events, development of T2DM, and incidence of breast cancer.7,26,27 Cohort 

studies suggest that the Mediterranean diet may be associated with decreased incidence of, and 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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mortality from, cancer. The data on cognitive impairment and the available subgroup analyses by 

age, gender, and BMI are limited and showed mixed results. 

Strength of Evidence for Key Questions 1 and 1A

We assessed strength of evidence for all-cause mortality, cancer incidence, and cognitive 

functioning. The strength of evidence was low for all outcomes evaluated (Table 3). 
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Table 2. Effect of Greater Diet Conformity on Outcomes by Gender, Age, and BMI in 

Cohort Studies

Outcomes and

Studies Gender Age BMI

All Cancer Incidence

NHS/HPFS56 Significantly lower in women not 

men

EPIC57 Significantly lower in women and 

men

Bladder Cancer Incidence

EPIC75 Similar in all age 

groups

Similar in all BMI groups

Breast Cancer Incidence

SMSC73 Similar in all age 

groups

BWHS60 Significantly lower with 

BMI < 25 only

Colorectal Cancer Incidence

NIH-AARP61 Significantly lower in men not 

women

Kyro 201348 Significantly lower in women not 

men

NLCS72 Similar in women and men

JPHC68 Similar in women and men

NHS/HPFS59 Similar in women and men

Head and Neck Cancer Incidence

NIH-AARP40 Significantly lower in women not 

men

Pancreatic Cancer Incidence

NHS/HPFS67 Significantly higher in men not 

women

All Cancer Mortality

MEC34 Significantly lower in women and 

men

NHS/HPFS39 Similar in women and men

NIH-AARP38 Significantly lower in women and 

men

Tognon 201254 Significantly lower in men not 

women

SNCG33 Significantly lower in men not 

women

SWLH63 Similar in all age 

groups

WHI-OS42 Significantly lower with 

BMI <30 only

Cognitive Function

MAP90 Significantly better in women and 

men

Significantly better in 

all age groups

SU.VI.MAX80 Similar in women and men
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Table 3. Strength of Evidence 

Outcome Strength of

evidence Direction Study design;# studies (N) Summary/Rationalea

Key Question 1: Primary Prevention Studies

All-cause Mortality Low Similar

3 RCTs

PREDIMED (7,447)

WHI-DM (48,835)

Kwok 2012 (429) 

Incidence of all-cause mortality was similar between the Mediterraneanlike diet and the control diet groups in the 2 larger studies (PREDIMEDcombined diets HR 0.89 [95% CI 0.71, 1.12]; WHI HR 0.98 [95% CI 0.91, 

1.07]). The trials were not pooled due to large dissimilarity of the study 

diets. Overall risk of bias is low. Consistency is unknown and there was 

imprecision (PREDIMED).

All Cancers Incidence Low

RCT

Similar

Observational

Lowered risk

1 RCT

WHI-DM (48,835)

3 Observational

(591,002) 

In WHI, all cancer incidence was similar between the Mediterranean-like 

diet and the control diet groups (HR 0.97 [95% CI 0.89, 1.05]).

Three large cohort studies reported highest conformity to a Mediterranean 

diet was associated with a reduction in total cancer incidence compared 

with lowest conformity (reference group) (pooled HR 0.96 [95% CI 0.95, 

0.97]). There is inconsistency between WHI and the cohort studies, and 

overall risk of bias is medium.

Breast Cancer 

Incidence Low

RCT

Mixed

Observational

Similar

2 RCTs 

WHI-DM (48,835)

PREDIMED (4,152)

13 Observational

(range 3,320 to 

355,062)

In PREDIMED, breast cancer incidence was lower in the combined 

Mediterranean diet groups compared to control (HR 0.43 [95% CI 0.21, 

0.88]). In WHI, breast cancer incidence was similar between the 

Mediterranean-like diet and the control diet groups (HR 0.91 [95% CI

0.83, 1.01]). The trials were not pooled due to large dissimilarity of the 

study diets; consistency is unknown. 

The cohort studies found breast cancer incidence was similar between 

the highest and lowest conformity groups (RR 0.96 [95% 0.90, 1.03]). 

Overall risk of bias is medium.

Colorectal Cancer 

Incidence Low

RCT

Similar

Observational

Lowered risk

1 RCT

WHI-DM (48,835)

9 Observational

(range 19,133 to 

397,641)

In WHI, colorectal cancer incidence was similar between the 

Mediterranean-like diet and the control diet groups (RR 1.08 [95% CI

0.90, 1.29]).

In the cohort studies, highest conformity to a Mediterranean diet was 

associated with a reduction in colorectal cancer incidence compared with 

the lowest conformity (RR 0.91 [95% 0.84, 0.98]) with moderate 

heterogeneity between studies (I2 = 60%). There is inconsistency 

between WHI and the cohort studies, and overall risk of bias is medium.
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Outcome Strength of

evidence Direction Study design;# studies (N) Summary/Rationalea

Cognitive Functioning Low Mixed

2 RCTs 

PREDIMED (334 and 

522) 

Kwok24 (429)

14 Observational

(range 527 to 16,058)

A sub-study of PREDIMED involving cognitively healthy volunteers (n = 

334) reported incidence of MCI was similar between the Mediterranean 

diet and the control diet groups. A sub-study of PREDIMED of patients 

with high vascular risk (n = 522) reported risk of MCI and dementia was 

lower in the Mediterranean diet group compared with the control diet 

group. An Asian trial of older nursing home residents (n = 429) found the 

proportions of patients classified as demented or with cognitive decline 

was similar between the Mediterranean-like diets and the control diet 

groups. The trials were not pooled due to the large dissimilarity of the 

study diets and populations, resulting in unknown consistency. Overall 

risk of bias is moderate.

The results from the observational studies were mixed. Three studies 

analyzing Mediterranean diet as a continuous score reported higher 

conformity to a Mediterranean diet slowed rates of cognitive decline; 4 did 

not. Six cohort studies analyzing Mediterranean diet as a categorical 

variable reported no association with levels of diet conformity and 

cognitive outcomes; 3 reported mixed results across different subgroups 

or analyses. Overall risk of bias is medium.

Key Question 2: Secondary Prevention Studies

All-cause Mortality Insufficient Similar 3 RCTs 

(2,277) 

Incidence of all-cause mortality was similar between the Mediterraneanlike diets and the control diet groups (RR 0.95 [95% CI 0.53, 1.69]; I2 = 

51%). There is large imprecision and inconsistency, and overall risk of 

bias is medium.

RCT = randomized controlled trial; PREDIMED = Prevención con Dieta Mediterránea; WHI = Women’s Health Initiative; HR = hazard ratio; RR = risk ratio; MCI

= mild cognitive impairment a Strength of Evidence Definitions22 

Precision: Degree of certainty surrounding an effect estimate; in meta-analysis, the confidence interval around the summary effect size

Consistency: Degree to which reported effect sizes appear to have the same direction of effect

Directness: Whether the evidence links the interventions directly to health outcomes

Risk of bias: Degree to which includes studies have a high likelihood of protection against bias; 2 main elements are study design and aggregate quality of the 

studies 
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KEY QUESTION 2: Compared to other diets, is the Mediterranean diet 

associated with fewer adverse outcomes (including death) or less 

disease progression in people who already have diabetes, 

cardiovascular disease, cancer, hypertension, cognitive impairment, 

rheumatoid arthritis, or kidney disease?

Overview of Studies (Table 4 and Appendix C, Table 5)

We identified a total of 19 articles reporting results from 15 studies (Table 4). Eight of the 

studies were randomized controlled trials and 7 were cohort studies. Six studies were conducted 

in patients with cancer, 6 in patients with cardiovascular disease, one in patients with cognitive 

impairment, and 2 in patients with rheumatoid arthritis. Seven of the 15 studies were done in the 

United States, 5 in Europe, and 3 in Asia. The total number of participants was 19,972 and the 

mean sample size was 1,331. The mean age of participants was 61.8 years (k = 9 reporting) and 

the mean BMI was 26.8 (k = 6). Of studies that included both men and women, the mean 

percentage of men was 64.2% (k = 5). The dietary interventions used in the RCTs are described 

in Table 5. The cohort studies used a variety of scales to rate each individual’s degree of 

conformity to the Mediterranean diet (see Methods section). No studies reported kidney disease 

or hypertension.
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Table 4. Summary of Included Studies - Key Question 2

Characteristic

Mean (range)

Unless Otherwise 

Noted

Number of 

Studies Reporting

Total number of patients evaluated 19,972

(51 to 4,538) 15 

Randomized controlled trials, total number of patients 5,865

(51 to 3,114) 8 

Cohort studies, total number of patients 14,107

(482 to 4,538) 7 

Secondary prevention of cancer, total number of patients 13,625

(926 to 4,538) 6 

Secondary prevention of cardiovascular disease, total number 

of patients

5,684

(101 to 3,114) 6 

Secondary prevention of cognitive impairment, total number of 

patients 482 1 

Secondary prevention of rheumatoid arthritis, total number of 

patients 181 (51 to 130) 2 

Age of subjects, years 61.8 (54 to 78) 9 

Gender, % male patients in mixed gender studies 64.2% (20 to 90) 5 

Mixed Gender studies, total number of patients 4,112

(51 to 1,009) 8 

Male only studies, total number of patients 8,578

(926 to 4,538) 3 

Female only studies, total number of patients 7,282

(130 to 2,619) 4 

Body Mass Index 26.8 (25.4 to 28) 6 

Location - USA/Canada, total number of patients 11,686

(101 to 4,538) 7 

Location - Europe, total number of patients 6,422

(51 to 3,114) 5 

Location - Asia/Australia, total number of patients 1,864

(406 to 1,000) 3 
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Table 5. Dietary Interventions Used in Trials

RCT Author , Year Intervention Diet Control Diet

Burr 200394 3 components (fruits/vegetables, 

grains/cereals, and low meat/fish)

-Fish

-Fruit/vegetables and grains/cereals

-‘Sensible eating’ non-specific advice that 

did not include the intervention

Lyon Heart Study6,95-

97 4 components (fat ratio, fruits/vegetables, 

grains/cereals, and low meat/fish)

Did not receive dietary information from the 

investigators

Singh 200298 4 components (fat ratio, fruits/vegetables, 

legumes, and grains/cereals)

National Cholesterol Education Program 

Step I Prudent Diet (low total and saturated 

fat, and low cholesterol)

Singh 199299 2 components (fruits/vegetables, low 

meat/fish)

Prudent diet reflecting the recommendations 

of the American Heart Association (low 

meat, eggs, and hydrogenated oil/butter; 

replaced by meat substitutes and nut oils)

Singh 1991100 5 components (fat ratio, fruit/vegetables, 

legumes, grains/cereals, and low meat/fish) Usual care

Tuttle 20088 7 components (fat ratio, fruit/vegetables, 

legumes, grains/cereals, red wine, dairy, and 

low meat/fish)

Low-fat diet, the American Heart Associate 

Step II diet (low saturated fat and 

cholesterol, fruits/vegetables, and 

grains/cereals)

McKellar 2007101 3 components (fat ratio, fruit/vegetables, and 

legumes)

Received readily available written 

information on healthy eating

Skoldstam 2003102 3 components (fat ratio, fruit/vegetables, and 

dairy) Usual diet

Outcomes (Appendix C, Tables 6 – 11)

Cardiovascular Disease and All-cause Mortality 

Six RCTs (N = 5,684) reported outcomes in participants with pre-existing cardiovascular disease. 

The mean sample size was 947. One study was set in the United States, 2 in Europe, and 3 in 

Asia. The outcomes reported in these studies included all-cause mortality (k = 6), cardiovascular 

mortality (k = 5), diet-related adverse events (k = 2), new myocardial infarction (k = 5), new 

stroke (k = 4), new revascularization procedure (k = 3), and development of heart failure (k = 4). 

Three of the RCTs may contain fraudulent data so we performed our analyses both including and 

excluding these studies.98-100,103 

The other 3 RCTs were:

The Lyon Heart Study which enrolled 605 people after a first myocardial infarction, 

randomized them to either a 3-component Mediterranean diet group or a no-advice group, 

and followed them for an average of 2.3 years.95 

A Welsh trial which randomized 3,114 men with a history of angina to 4 diet groups (1. 

oily fish; 2. fruit, oats, and fiber; 3. combination of 1 and 2; and 4. non-specific advice). 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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Group 3 met our definition of a Mediterranean diet. This trial was interrupted by funding 

problems. Many of the analyses were performed not by group but by specific dietary 

components (eg, fish advice, fruit advice).

94 

8

 

A trial from Spokane, Washington that enrolled 101 patients within 6 weeks of a first 

myocardial infarction and randomized them to either a “Mediterranean-style diet” (low 

fat that emphasized increased consumption of fruits and vegetables, whole grains, coldwater fish, and oils from olives, canola, and soy beans) or a low-fat diet (that emphasized 

fruits and vegetables and whole grains) and followed them for an average of 4 years.

All-cause Mortality

All 6 of the cardiovascular RCTs reported all-cause mortality. Two of these RCTs reported 

significantly decreased all-cause mortality in the participants assigned to the Mediterranean 

compared to the control diet (RR 0.44, 95% CI 0.21, 0.94 and RR 0.55, 95% CI 0.34, 0.75) 

respectively).6,97,99 Four studies found similar mortality in the Mediterranean and control diet 

groups.8,94,98,100 

Pooled results from the 6 studies showed that all-cause mortality was similar in the 

Mediterranean diet and the control diet groups (RR 0.85, 95% CI 0.59, 1.21; I2

= 57%).6,8,94,97-100

The analysis conducted without the questionable data also showed no evidence of reduction in 

all-cause mortality (RR 0.95, 95% CI 0.53, 1.69; I2= 51%).6,8,94,97

Cardiovascular Mortality

Five RCTs reported cardiovascular mortality. Two studies found decreased cardiovascular 

mortality in participants assigned a Mediterranean diet compared to controls (RR 0.35, 95% CI

0.15, 0.83 and RR 0.58, 95% CI 0.34, 0.83, respectively).

6,97,99 The other 3 studies found that 

cardiovascular mortality was similar in both diet groups.8,94,98

Pooled data from all 5 RCTs show that cardiovascular mortality was similar in groups assigned a 

Mediterranean and control diet (RR 0.69, 95% CI 0.44, 1.08; I2

= 67%).6,8,94,97-99 This result was 

essentially unchanged when the analysis was conducted without the questionable data (RR 0.68, 

95% CI 0.18, 2.47; I2= 87%).6,8,94,97

Myocardial Infarction 

New myocardial infarction was reported as an outcome in 5 RCTs. Two of the 5 studies reported 

significantly decreased rates of MI in participants assigned to the Mediterranean diet group.

98,99

A third study found similar rates of MI for both groups.8 The other 2 studies reported fewer MIs 

in the intervention group than in the control group but the statistical significance of these 

differences was not reported.

6,100 

We were able to pool data from 4 of the RCTs.6,8,98,99 The pooled data show that randomization 

to a Mediterranean diet significantly decreased risk of a new MI (RR 0.56, 95% CI 0.44, 0.72; I2

= 0%). This finding remained essentially the same when the analysis was conducted without the 

questionable data (RR 0.32, 95% CI 0.15, 0.67; I2

= 0%).6,8
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Stroke 

Four RCTs reported new stroke. Two found similar rates in both diet groups.

8,98 The other 2 

studies reported fewer strokes in the intervention group than control but did not report the 

statistical significance.

96,100

Analysis of the 3 studies that could be pooled shows that participants assigned a Mediterranean 

diet had similar incidence of new stroke as those assigned a control diet (RR 0.66, 95% CI 0.19, 

2.30; I2= 31%).8,96,98 This finding was not qualitatively different when the questionable data 

were removed (RR 0.76, 95% CI 0.04, 14.51; I2= 61%).8,96

Other Outcomes

Three RCTs reported incidence of revascularization procedures.8,95,96,98 The pooled data show 

similar incidence in the Mediterranean diet and the control diet groups (RR 0.75, 95% CI 0.42, 

1.35). This finding was the same when the questionable data were excluded (RR 0.91, 95% CI

0.54, 1.53).8,95,96

Four RCTs reported development of heart failure.6,95,96,98,100 One of the studies, whose data 

integrity has been questioned, found that participants assigned a Mediterranean diet developed 

heart failure significantly less often than participants assigned a control diet although the relative 

risk was not reported.

98 Another study from the same group reported that 2 patients in the 

Mediterranean diet group and 2 patients in the control diet group developed heart failure.

100 A 

US study reported no heart failure in either diet group.

8 The Lyon Heart study reported 6 cases of 

heart failure in the Mediterranean diet group and 11 in the control group.

6,96

Cancer

Six cohort studies reported outcomes in people with cancer at baseline (N = 13,625). Three of 

these reported breast cancer outcomes, 2 colon cancer, and 2 prostate cancer.

41,104-110 Five studies 

were conducted in the United States and one in Europe. The average sample size was 2,271 and 

the mean age of participants was 64.4 years (k = 3). 

Breast Cancer (k = 3) 

Both a German study that followed 2,522 post-menopausal breast cancer patients for a median of 

5.5 years, and a US study of 1,901 women with early stage breast cancer followed for an average 

of 3.2 years found similar rates of breast cancer recurrence and mortality across quartiles of 

conformity to the Mediterranean diet (P for trends >0.05) (Figure 10).107,109 The NHS, an 

American study following nurses for more than 6 years, found similar rates of breast cancer 

mortality across quantiles of an aMED score and, in a sub-study, conformity to a prudent 

pattern.105,106

Colon Cancer (k = 2) 

A US study of 1,009 patients with stage III colon cancer followed for an average of 5.3 years

found similar rates of colon cancer recurrence across quintiles of conformity to the 

Mediterranean diet (termed a “prudent” diet) (HR 1.13, 95% CI 0.77, 1.67).108 A second US 

study (NHS) of 1,201 women with stage I-III colon cancer followed for a median of 11.2 years 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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39

evaluated colon cancer-specific mortality and found no association with aMED score or prudent 

pattern (Figure 10).104

Prostate Cancer (k = 2) 

A US study, the Health Professionals Follow-up Study (HPFS), followed 4,538 men with 

prostate cancer for an average of 9 years and found similar incidence of prostate cancer-specific 

mortality comparing highest to lowest conformity to a Mediterranean diet (HR 1.01, 95% CI

0.74, 1.37) (Figure 10).41 Another US study, the Physicians’ Health Study (PHS), followed men 

for 9.9 years and also found similar incidence of prostate cancer specific mortality in participants 

in the highest and lowest quantiles of a prudent dietary pattern (HR 0.46, 95% CI 0.17, 1.24).

110 

Figure 10. Cancer-specific Mortality by Cancer Type

a

a Sample sizes based on numbers in highest and lowest quantiles (the comparison groups), if provided; otherwise 

sample size is for entire cohort

Cognitive Impairment

One cohort study of 482 Medicare beneficiaries in New York with mild cognitive impairment 

reported progression to Alzheimer’s Disease.87 Mean age at enrollment was 78 years and 32% of 

participants were male. Mean follow-up was 4.3 years. When conformity to a Mediterranean diet

was analyzed as a continuous variable, the hazard ratio (per unit of Mediterranean-diet score) for 

development of AD was not significant (0.89, 95% CI 0.78, 1.02). When conformity to a 

Mediterranean diet was analyzed by tertiles with the lowest tertile as the reference group, the 

hazard ratios were significant for both the middle and highest tertiles, indicating that greater

conformity to a Mediterranean diet was associated with a lower risk of developing AD. For the 

highest tertile, the hazard ratio was 0.52 (95% CI 0.30, 0.91). 

Rheumatoid Arthritis

One RCT from Sweden and one CCT from the UK enrolled patients with rheumatoid 

arthritis.101,102 The RCT included 51 patients with clinically stable disease of at least 2 years 

duration.102 Intervention group patients received dietary instructions and some food supplied at 

no cost. The control group followed a usual diet. After a 3-week outpatient rehabilitation 

program (meals provided according to group assignment), participants prepared their own meals

for the next 9 weeks. Mean age was 58 years, 20% were male, and mean disease duration was 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

40

13.6 years (significantly longer in the intervention group: 17 years vs 10 years). There were 

significant improvements at 12 weeks in the Mediterranean diet group compared to the control 

group on a global pain score, the 28 joint disease activity score, and the health assessment 

questionnaire.102

The CCT enrolled 130 women age 30 to 70 years from areas of “social deprivation.” Participants 

received either instruction on the Mediterranean diet or readily available information on healthy

eating. Mean age of the participants was 54 years; mean disease duration was 9.4 years. At 6 

months, mean global pain scores were significantly lower in the Mediterranean diet group 

compared to the control group. Mean scores on the Health Assessment Questionnaire were 

significantly better in the Mediterranean diet group at 3 months but not 6 months. Joint disease 

activity scores were similar in both groups at 3 and 6 months.

101

Diet-related Adverse Events

Four studies reported adverse events related to the diet. One found no side effects8 while the 

other 3 reported minor digestive problems such as diarrhea, dyspepsia, and mild belching in a 

couple of patients assigned to the intervention diet.

8,95,99,102
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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KEY QUESTION 2A: Do the effects vary by gender, age, or BMI?

The reported data did not allow for subgroup analysis by age, gender, or BMI.

Summary of Findings for Key Question 2

Randomization to a Mediterranean diet significantly reduced myocardial infarction but had no 

significant effects on cardiovascular mortality, stroke, revascularization procedures, or 

congestive heart failure. There is no evidence that a Mediterranean diet reduces incidence of 

recurrent breast or colon cancer or mortality associated with breast, colon, or prostate cancer. 

There is limited, mixed data on the effects of the Mediterranean diet on progression of cognitive 

impairment and rheumatoid arthritis.

Strength of Evidence for Key Question 2

We assessed strength of evidence for all-cause mortality only and it was rated as insufficient 

(Table 3).
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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KEY QUESTION 3: What is the observed adherence to the 

Mediterranean diet in studies conducted in the United States or 

Canada?

Two RCTs, conducted in the United States, reported data on adherence (Appendix C, Tables 12 

and 13). The WHI-DM, described above in Key Question 1, reported significant changes (all 

P<0.001) at year 3 in the intervention compared to the control group in consumption of red meat 

(20% reduction), grains (18% increase), and vegetables and fruit (47% increase).

23

The second study was a 4-site population-based multicenter trial that enrolled 810 adults with 

mildly elevated blood pressure.

111 About a third of the participants were African-American and 

all were recruited from the community. Subjects were randomized to one of 3 groups: general 

advice on diet, physical activity, and weight loss delivered in 2 30-minute sessions (Group A);

behavioral interventions including group and individual counseling sessions designed to 

encourage weight loss and increase physical activity (Group B); and Group C, which in addition 

to the Group B interventions received specific advice on increased consumption of fruits and 

vegetables and low-fat dairy products and reduced consumption of total and saturated fat. At 18 

months of follow-up, there was a significant increase of 2.6 (95% CI 2.2, 3.2) servings per day of 

fruits and vegetables in group C compared to either of the other 2 groups.

111
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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SUMMARY AND DISCUSSION

The Mediterranean diet was first described over 50 years ago by Ancel Keys.

1 Interest in this diet 

has intensified in recent years as many developed and developing countries confront a dramatic 

increase in obesity and chronic diseases linked to consumption of a typical Western diet rich in 

red meat, dairy products, processed and artificially sweetened foods, and salt.

112 In contrast, the 

diet typically consumed in Mediterranean countries in the 1960s emphasized consumption of 

olive oil, fruits, vegetables, legumes, and whole grains. Many epidemiologic studies, and more 

recently RCTs, have investigated the effect of this diet on incidence of, and morbidity from,

common chronic conditions such as cardiovascular disease, T2DM, and cancer.3-8 The purpose 

of this review was to provide an updated summary of the available evidence on the health 

benefits of the Mediterranean diet. 

The Key Questions we addressed were: 

Key Question 1: Is the Mediterranean diet more effective than other diets in preventing death or 

the development of type 2 diabetes mellitus, cardiovascular disease, cancer, hypertension, 

cognitive impairment, or kidney disease?

Key Question 1a: Do the effects vary by gender, age, or BMI?

Key Question 2: Compared to other diets, is the Mediterranean diet associated with fewer 

adverse outcomes (including death) or less disease progression in people who already have 

diabetes, cardiovascular disease, cancer, hypertension, cognitive impairment, rheumatoid 

arthritis, or kidney disease?

Key Question 2a: Do the effects vary by gender, age, or BMI?

Key Question 3: What is the observed adherence to the Mediterranean diet in studies conducted 

in the United States or Canada?

OVERVIEW OF METHODS

This systematic review included a total of 55 studies published in English between 1990 and 

August 2015 that enrolled free-living, non-pregnant, non-lactating adults. We included RCTs 

that enrolled at least 100 people and followed them for at least a year. For select outcomes 

(cancer, cognitive impairment, and rheumatoid arthritis) we also included cohort studies. 

We included studies whose diets met the criteria used in a recent Cochrane Review17 (ie, labelled 

a Mediterranean diet or meeting 2 or more of the following components: 1. high 

monounsaturated:saturated fat ratio (use of olive oil as main cooking ingredient); 2. high 

consumption of fruits/vegetables; 3. high consumption of legumes; 4. high consumption of 

grains/cereals; 5. moderate red wine consumption; 6. moderate consumption of dairy products; 

and 7. low consumption of meat and meat products replaced by increased consumption of fish). 

All included studies met this minimum definition. The names for the diets included terms such as 

Mediterranean diet, prudent diet, healthy Nordic diet, and healthy pattern.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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SUMMARY OF EVIDENCE BY KEY QUESTION

KQ1: Primary Prevention

We identified 42 studies (3 RCTs and 39 cohort studies) that reported the association between 

conformity to a Mediterranean diet and the occurrence of outcomes in over 2 million people 

without a history of the outcome of interest (primary prevention). We found no studies reporting 

new onset kidney disease or hypertension. 

Cardiovascular disease and all-cause mortality (RCTs only). Three trials that included a total of 

56,711 people evaluated the effect of the Mediterranean diet on major cardiovascular outcomes 

(MI, stroke, and CV death) and all-cause mortality.7,23,24,32 All-cause mortality was similar 

between diet groups in the 2 trials that reported statistical significance.

7,23

The PREvencion con DIeta MEDiterranea (PREDIMED) was a Spanish trial of 7,447 people 

randomized to either a Mediterranean diet with supplemental extra virgin olive oil, a 

Mediterranean diet supplemented with nuts, or a low-fat control diet. Both of the intervention 

diets included 5 of the 7 components in our Mediterranean diet definition. After an average 

follow-up of 4.8 years, both intervention groups had a significant 30% reduction in major 

cardiovascular events compared to the control group. When the individual components of the 

composite endpoint were evaluated, only stroke was significantly reduced in the Mediterranean 

diet group compared to the control group. 

The WHI-DM was a US trial of 48,835 women, aged 50-79, assigned either a low-fat diet (which 

included 2 of the 7 components of the Mediterranean diet) or a usual diet control. After an 

average follow-up of 8.1 years, there was no significant reduction in major cardiovascular events

(either as a composite or individually) in the group assigned to the intervention diet. 

Disparate results in these 2 trials may reflect differences in the diets evaluated. In PREDIMED 

the intervention diet included 5 of the 7 Mediterranean diet components and the control was a 

low-fat diet. In contrast, in WHI-DM the intervention group received a low-fat diet (which 

included advice to increase fruit and vegetable and grain intake and thus met our definition of a 

Mediterranean diet) whereas the control group received general advice only. The fact that the

intervention diet in WHI-DM is more similar to the PREDIMED control diet than to the 

PREDIMED intervention diet may explain why WHI-DM found no benefit and PREDIMED did. 

A recent Cochrane review (N = 52,044; k = 11) evaluated the efficacy of a Mediterranean diet 

for primary prevention of cardiovascular disease.17 This review included only RCTs of at least 3 

months duration with a control group that received either no or only a minimal intervention. 

RCTs reporting only laboratory endpoints were included. The only study included in both the 

Cochrane review and the present review was the WHI-DM. Of note, the Cochrane review did not 

include the PREDIMED study because the comparator intervention did not meet the criterion of

“no or minimal” intervention. 

We did not include cohort studies in our analysis of total mortality or cardiovascular outcomes. 

A recent review of prospective cohort studies that included a total of 4.2 million participants 

without a history of cardiovascular disease reported that a 2-point increase in a Mediterranean 

diet conformity score was associated with an 8% reduction in all-cause mortality (RR 0.92, 95% 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

45

CI 0.87, 0.92) and a 10% decrease in cardiovascular disease incidence and/or mortality (RR 0.90,

95% CI 0.87, 0.92).

18 In addition, a recent meta-analysis that included primary and secondary 

prevention case-control, cross-sectional, and cohort studies (N = 162,092; k = 9) found that 

higher conformity to a Mediterranean diet (ie, a score of 6 to 9 on the Mediterranean-diet score)

was associated with a significant 29% reduction in stroke risk (0.71, 95% CI 0.57, 0.89).

4,16

Type 2 diabetes mellitus (RCTs only). T2DM was reported in 2 RCTs (N = 49,428), PREDIMED 

and WHI-DM.26,30 In WHI-DM there was a similar incidence of T2DM in the intervention and 

control diet groups.

30 In PREDIMED the incidence of T2DM over 4.1 years of follow-up in 

people who did not have T2DM at baseline (N = 3,541) was significantly reduced compared to 

the control diet in the group randomized to the Mediterranean diet supplemented with EVOO

(HR 0.60, 95% CI 0.43, 0.85) but not the Mediterranean diet supplemented with nuts (0.82, 95% 

CI 0.61, 1.10).

26 The disparate findings between WHI-DM and PREDIMED may be related to 

the differences in these 2 studies’ dietary interventions, as discussed above. 

A recent systematic review evaluated the association between conformity to the Mediterranean 

diet and development of T2DM. A pooled analysis of one clinical trial (a single-site report from 

PREDIMED) and 9 prospective cohort studies (N = 136,846) found a significant association 

between people with the highest versus lowest conformity to the Mediterranean diet and 

incidence of T2DM (RR 0.77, 95% CI 0.66, 0.89).10

Cancer (RCTs and cohort studies). Two RCTs reported cancer outcomes.23,27,31 The WHI-DM

found no difference in total cancer incidence or mortality. It also reported no difference in 

colorectal cancer mortality or incidence of breast, colorectal, skin, ovarian, uterine or other

cancers between the 2 diet groups. The PREDIMED trial reported a decreased risk of breast 

cancer in participants assigned the Mediterranean diet supplemented with extra virgin olive oils 

as compared to the control diet (HR 0.32, 95% CI 0.13, 0.79).

Results of the 28 cohort studies that reported cancer outcomes, comparing highest to lowest

Mediterranean diet conformity, are summarized below:

Total cancer: Significant 4% reduction in incidence (k = 3) and significant 14% reduction 

in mortality (k = 13)

Breast cancer: No reduction in breast cancer incidence (k = 13) or mortality (k = 1)

Colorectal cancer: Significant 9% reduction in incidence (k = 9); no reduction in 

mortality (k = 1) 

Other cancers:

o No reduction in ovarian (k = 1), pancreatic (k = 2), head and neck (k = 1), lung (k

= 1), bladder (k = 1), gastric (k = 2), or prostate (k = 3), cancer incidence 

o No reduction in pancreatic (k = 1), stomach (k = 1), prostate (k = 2), or respiratory 

tract (k = 1) cancer mortality

Our findings from the observational data that total cancer incidence and mortality and colorectal

cancer incidence were significantly lower in those with the highest conformity to a 

Mediterranean diet compared to lowest conformity is consistent with findings from a recent

systematic review.

18 These findings, however, were not confirmed by the WHI-DM. Although 

this difference is likely due to the fact that cohort studies are subject to confounding, it is also
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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46

possible that a RCT that utilized a more intensive Mediterranean diet intervention than was used 

in WHI-DM would have corroborated the cohort studies. As noted above, PREDIMED, which 

did test an intensive Mediterranean diet intervention, reported a significant reduction in breast 

cancer incidence in the intervention group.

Cognitive impairment. Data from the 2 identified RCTs were mixed.24,25,28 One site of the 

PREDIMED trial reported reductions in mild cognitive impairment and dementia in the 

Mediterranean diet groups compared to control diet while another site reported no associations 

between diet and cognitive outcomes.25,28 An RCT in Hong Kong found similar rates of 

development of dementia after about 3 years of follow-up in 429 participants age > 75 who had 

been randomized to either a diet high in fruits, vegetables, and fish or a control diet.24 Results 

from the cohort studies were also mixed although most studies reporting quantiles of 

Mediterranean-diet score found no association between diet and cognitive impairment.

Rheumatoid arthritis. One cohort study which enrolled 174,638 female registered nurses found 

similar rates of rheumatoid arthritis in participants with the highest and lowest Mediterranean 

diet scores (HR 0.98, 95% CI 0.8, 1.2).93

Gender, age, or BMI. Several studies reported outcomes stratified by gender, age, or BMI 

groups. Findings were inconsistent.

KQ2: Secondary Prevention

We identified 15 studies (8 RCTs and 7 cohort studies, N = 19,972) that reported the association 

between conformity to a Mediterranean diet and the occurrence of outcomes in those with the 

condition of interest at baseline (secondary prevention). No studies reported kidney disease,

hypertension or diabetes. Of note, there is credible although not definitive evidence that 3 of the 

RCTs may contain fraudulent data.

98-100,103 Therefore we have not included those data in our 

summary, below. 

Cardiovascular disease, cardiovascular mortality, and all-cause mortality. Pooled results from 3 

RCTs that enrolled people with cardiovascular disease at baseline showed similar all-cause 

mortality in those assigned the Mediterranean diet compared to those assigned a control 

diet.

6,8,94,97

Pooled data from 2 of the 3 RCTs showed that randomization to a Mediterranean diet 

significantly reduced the risk of myocardial infarction.6,8 Pooled data showed similar incidence 

of cardiovascular mortality (k = 2), stroke (k = 2), and revascularization procedures (k = 3) in the 

2 diet intervention groups.6,8,94,96,97

Of note, all 3 RCTs had substantial limitations. The Lyon Heart Study was the strongest 

methodologically but it included only 605 people.6,95-97 The Welsh trial enrolled over 3,000 men 

but was interrupted by funding problems, leading to convoluted analyses.

94 The Spokane,

Washington trial enrolled only 101 patients.8

We did not include studies whose only outcome was cardiac risk factors, but other systematic 

reviews have found that the Mediterranean diet is associated with significant reductions in total 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

47

and LDL cholesterol, body weight, blood pressure, fasting plasma glucose, and C-reactive 

protein.

14,17

Cancer. In 6 cohort studies that examined outcomes in people with colon cancer (k = 2), breast 

cancer (k = 3), or prostate cancer (k = 2) there was a similar incidence of cancer recurrence and 

cancer-specific mortality in those with the highest compared to the lowest conformity to a 

Mediterranean diet.41,104-110

Cognitive impairment. One cohort study in New York that enrolled 482 people with mild 

cognitive impairment reported similar incidence of progression to Alzheimer’s disease in those 

with higher conformity compared to lower conformity to a Mediterranean diet.

87

Rheumatoid arthritis. Two small trials of a Mediterranean diet compared to a usual diet (n = 51, 

12 week follow-up and n = 130, 26 week follow-up) reported significant improvement in global 

pain and functional status questionnaire scores. The smaller and shorter trial reported significant 

improvement in a disease activity score but the larger, longer one did not.101,102

KQ3: Adherence

Two RCTs conducted in the United States reported data on adherence.

111,113 Results from these 

trials show that in the context of a randomized trial with intensive behavioral interventions it is 

possible to achieve sustained increases in consumption of fruits and vegetables and grains (2 

components of the Mediterranean diet). Whether the same results could be achieved in a general

population and without a labor-intensive behavioral intervention is not known. 

A recent systematic review summarized the effects of interventions to promote a Mediterranean 

diet or healthy eating pattern in primary health care settings.

12 This review included only RCTs 

but did not require enrollment of at least 100 subjects or follow-up of at least one year. Fourteen 

studies were included, only 2 of which studied a Mediterranean diet. Neither of these studies was 

included in our review as one was conducted in Spain and one in inpatients in the United 

Kingdom.114,115 The review concluded that there is moderate evidence that nutritional 

counselling moderately increases intake of fruits and vegetables and that more intensive 

interventions with more frequent patient contact are most effective.

APPLICABILITY OF FINDINGS TO THE VA POPULATION

Although the data are limited in that there were few randomized controlled trials and the 

majority of included studies (whether trials or cohort studies) were not conducted in North 

American populations, we believe that the available outcome data are applicable to the general 

VA population.

RESEARCH GAPS/FUTURE RESEARCH

A major gap is the absence of large-scale clinical outcomes trials of a Mediterranean diet in 

North American populations, both in primary and secondary prevention populations. Such trials 

are important both to confirm results of the few trials performed abroad and to determine the 

acceptability of the Mediterranean diet to the American public. In addition, the following areas 

represent important avenues for future research:
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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modeling studies to ascertain if specific components or combination of components of the 

Mediterranean diet are more protective than others;

barriers to adoption of a Mediterranean diet in people used to consuming a traditional 

Western diet and interventions to address those barriers; and

relative advantages of the Mediterranean diets compared to other healthy diets (eg,

DASH diet).

STRENGTH OF EVIDENCE

The strength of evidence was low or insufficient for all outcomes evaluated.

CONCLUSIONS 

In this systematic review and meta-analysis of 55 published studies we identified a single 

primary prevention trial which found that consumption of a Mediterranean diet was associated 

with a significant reduction in major cardiac events, new onset T2DM, and breast cancer 

incidence. For secondary prevention, data from 2 trials indicate that assignment to a 

Mediterranean diet reduces incidence of myocardial infarction but not other cardiovascular 

outcomes. Cohort studies indicate that conformity to a Mediterranean diet pattern is associated 

with significant reduction in total cancer incidence, total cancer mortality, and colorectal cancer 

incidence. These associations have not been confirmed in RCTs. Available data on other 

outcomes, such as cognitive impairment and rheumatoid arthritis, were limited. The available 

data on dietary adherence suggest that sustained increases in consumption of fruits and 

vegetables and grains can be achieved with labor intensive behavioral interventions in select 

populations. 
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survival in women. PLoS One. 2014;9(12):e115377.

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postmenopausal breast cancer survival. Nutr Cancer. 2011;63(3):381-388.

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107. Kwan ML, Weltzien E, Kushi LH, Castillo A, Slattery ML, Caan BJ. Dietary patterns and 

breast cancer recurrence and survival among women with early-stage breast cancer. J 

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cancer recurrence and survival in patients with stage III colon cancer. JAMA. 

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Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

57

APPENDIX A. SEARCH STRATEGIES

MEDLINE (OVID)

Key Questions 1 and 2 Randomized Controlled Trials

1. exp Fruit/

2. fruit*.tw.

3. exp Vegetables/

4. Vegetable Proteins/

5. vegetable*.tw.

6. exp Fabaceae/

7. fabaceae.tw.

8. bean*.tw.

9. legume*.tw.

10. Lycopersicon esculentum/

11. lycopersicon esculent*.tw.

12. tomato*.tw.

13. solanum lycopersicum.tw.

14. Nuts/

15. (nut or nuts).tw.

16. Bread/

17. bread*.tw.

18. exp Cereals/

19. cereal*.tw.

20. grain*.tw.

21. Solanum tuberosum/

22. solanum tuberosum.tw.

23. potato*.tw.

24. Seeds/

25. (seed or seeds).tw.

26. olive oil.tw.

27. Fatty Acids, Monounsaturated/

28. monounsaturated fat*.tw.

29. mono-unsaturated fat*.tw.

30. exp Seafood/

31. exp Fish Oils/

32. fish.tw.

33. seafood*.tw.

34. shellfish.tw.

35. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34

36. ((high or more or increase* or elevat* or much or rais*) adj6 (intake or consumption or 

consume or eat* or amount*)).tw.

37. 35 and 36

38. exp Dairy Products/

39. exp Milk Proteins/
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

58

40. milk*.tw.

41. marg?rine*.tw.

42. butter*.tw.

43. dairy.tw.

44. cheese*.tw.

45. red meat*.tw.

46. processed meat*.tw.

47. yog?urt*.tw.

48. red wine*.tw.

49. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48

50. ((low or little or medium or moderate or less or decrease* or reduc* or restrict*) adj6 (intake 

or consumption or consume or eat* or amount*)).tw.

51. 49 and 50

52. Diet, Mediterranean/

53. (mediterranean adj3 diet*).tw.

54. (mediterranean adj6 food*).tw.

55. (mediterranean adj6 nutrition*).tw.

56. (mediterranean adj6 eat*).tw.

57. 52 or 53 or 54 or 55 or 56

58. 37 or 51 or 57

59. randomized controlled trial.pt.

60. controlled clinical trial.pt.

61. randomized.ab.

62. placebo.ab.

63. clinical trials as topic.sh.

64. randomly.ab.

65. trial.ti.

66. 59 or 60 or 61 or 62 or 63 or 64 or 65

67. 58 and 66

68. exp animal/ not humans.sh.

69. 67 not 68

70. limit 69 to (english language and yr = "1990 -Current")

71. limit 70 to "all child (0 to 18 years)"

72. limit 71 to "all adult (19 plus years)"

73. 71 not 72

74. 70 not 73

Key Questions 1 and 2 Cancer 

1. exp Fruit/

2. fruit*.tw.

3. exp Vegetables/

4. Vegetable Proteins/

5. vegetable*.tw.

6. exp Fabaceae/

7. fabaceae.tw.

8. bean*.tw.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

59

9. legume*.tw.

10. Lycopersicon esculentum/

11. lycopersicon esculent*.tw.

12. tomato*.tw.

13. solanum lycopersicum.tw.

14. Nuts/

15. (nut or nuts).tw.

16. Bread/

17. bread*.tw.

18. exp Cereals/

19. cereal*.tw.

20. grain*.tw.

21. Solanum tuberosum/

22. solanum tuberosum.tw.

23. potato*.tw.

24. Seeds/

25. (seed or seeds).tw.

26. olive oil.tw.

27. Fatty Acids, Monounsaturated/

28. monounsaturated fat*.tw.

29. mono-unsaturated fat*.tw.

30. exp Seafood/

31. exp Fish Oils/

32. fish.tw.

33. seafood*.tw.

34. shellfish.tw.

35. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34

36. ((high or more or increase* or elevat* or much or rais*) adj6 (intake or consumption or 

consume or eat* or amount*)).tw.

37. 35 and 36

38. exp Dairy Products/

39. exp Milk Proteins/

40. milk*.tw.

41. marg?rine*.tw.

42. butter*.tw.

43. dairy.tw.

44. cheese*.tw.

45. red meat*.tw.

46. processed meat*.tw.

47. yog?urt*.tw.

48. red wine*.tw.

49. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48

50. ((low or little or medium or moderate or less or decrease* or reduc* or restrict*) adj6 (intake 

or consumption or consume or eat* or amount*)).tw.

51. 49 and 50

52. Diet, Mediterranean/
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

60

53. (mediterranean adj3 diet*).tw.

54. (mediterranean adj6 food*).tw.

55. (mediterranean adj6 nutrition*).tw.

56. (mediterranean adj6 eat*).tw.

57. 52 or 53 or 54 or 55 or 56

58. 37 or 51 or 57

59. exp animal/ not humans.sh.

60. 58 not 59

61. limit 60 to (english language and yr = "1990 -Current")

62. limit 61 to "all child (0 to 18 years)"

63. limit 62 to "all adult (19 plus years)"

64. 62 not 63

65. 61 not 64

66. cancer.mp. or Neoplasms/

67. 65 and 66

Key Questions 1 and 2 Rheumatoid Arthritis

1. exp Fruit/

2. fruit*.tw.

3. exp Vegetables/

4. Vegetable Proteins/

5. vegetable*.tw.

6. exp Fabaceae/

7. fabaceae.tw.

8. bean*.tw.

9. legume*.tw.

10. Lycopersicon esculentum/

11. lycopersicon esculent*.tw.

12. tomato*.tw.

13. solanum lycopersicum.tw.

14. Nuts/

15. (nut or nuts).tw.

16. Bread/

17. bread*.tw.

18. exp Cereals/

19. cereal*.tw.

20. grain*.tw.

21. Solanum tuberosum/

22. solanum tuberosum.tw.

23. potato*.tw.

24. Seeds/

25. (seed or seeds).tw.

26. olive oil.tw.

27. Fatty Acids, Monounsaturated/

28. monounsaturated fat*.tw.

29. mono-unsaturated fat*.tw.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

61

30. exp Seafood/

31. exp Fish Oils/

32. fish.tw.

33. seafood*.tw.

34. shellfish.tw.

35. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34

36. ((high or more or increase* or elevat* or much or rais*) adj6 (intake or consumption or 

consume or eat* or amount*)).tw.

37. 35 and 36

38. exp Dairy Products/ 

39. exp Milk Proteins/

40. milk*.tw.

41. marg?rine*.tw.

42. butter*.tw.

43. dairy.tw.

44. cheese*.tw.

45. red meat*.tw.

46. processed meat*.tw.

47. yog?urt*.tw.

48. red wine*.tw.

49. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48

50. ((low or little or medium or moderate or less or decrease* or reduc* or restrict*) adj6 (intake 

or consumption or consume or eat* or amount*)).tw.

51. 49 and 50

52. Diet, Mediterranean/

53. (mediterranean adj3 diet*).tw.

54. (mediterranean adj6 food*).tw.

55. (mediterranean adj6 nutrition*).tw.

56. (mediterranean adj6 eat*).tw.

57. 52 or 53 or 54 or 55 or 56

58. 37 or 51 or 57

59. exp animal/ not humans.sh.

60. 58 not 59

61. limit 60 to (english language and yr = "1990 -Current")

62. limit 61 to "all child (0 to 18 years)"

63. limit 62 to "all adult (19 plus years)"

64. 62 not 63

65. 61 not 64

66. Arthritis, Rheumatoid/ or Arthritis/

67. 65 and 66

Key Questions 1 and 2 Cognitive Function

1. exp Fruit/

2. fruit*.tw.

3. exp Vegetables/
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

62

4. Vegetable Proteins/

5. vegetable*.tw.

6. exp Fabaceae/

7. fabaceae.tw.

8. bean*.tw.

9. legume*.tw.

10. Lycopersicon esculentum/

11. lycopersicon esculent*.tw.

12. tomato*.tw.

13. solanum lycopersicum.tw.

14. Nuts/

15. (nut or nuts).tw.

16. Bread/

17. bread*.tw.

18. exp Cereals/

19. cereal*.tw.

20. grain*.tw.

21. Solanum tuberosum/

22. solanum tuberosum.tw.

23. potato*.tw.

24. Seeds/

25. (seed or seeds).tw.

26. olive oil.tw.

27. Fatty Acids, Monounsaturated/

28. monounsaturated fat*.tw.

29. mono-unsaturated fat*.tw.

30. exp Seafood/

31. exp Fish Oils/

32. fish.tw.

33. seafood*.tw.

34. shellfish.tw.

35. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34

36. ((high or more or increase* or elevat* or much or rais*) adj6 (intake or consumption or 

consume or eat* or amount*)).tw.

37. 35 and 36

38. exp Dairy Products/

39. exp Milk Proteins/

40. milk*.tw.

41. marg?rine*.tw.

42. butter*.tw.

43. dairy.tw.

44. cheese*.tw.

45. red meat*.tw.

46. processed meat*.tw.

47. yog?urt*.tw.

48. red wine*.tw.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

63

49. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48

50. ((low or little or medium or moderate or less or decrease* or reduc* or restrict*) adj6 (intake 

or consumption or consume or eat* or amount*)).tw.

51. 49 and 50

52. Diet, Mediterranean/

53. (mediterranean adj3 diet*).tw.

54. (mediterranean adj6 food*).tw.

55. (mediterranean adj6 nutrition*).tw.

56. (mediterranean adj6 eat*).tw.

57. 52 or 53 or 54 or 55 or 56

58. 37 or 51 or 57

59. exp animal/ not humans.sh.

60. 58 not 59

61. limit 60 to (english language and yr = "1990 -Current")

62. limit 61 to "all child (0 to 18 years)"

63. limit 62 to "all adult (19 plus years)"

64. 62 not 63

65. 61 not 64

66. Mild Cognitive Impairment/

67. Delirium, Dementia, Amnestic, Cognitive Disorders/ or Dementia/ or Dementia, MultiInfarct/

68. Dementia/ or Alzheimer Disease/

69. 66 or 67 or 68

70. 65 and 69

Key Question 3

1. exp Fruit/

2. fruit*.tw.

3. exp Vegetables/

4. Vegetable Proteins/

5. vegetable*.tw.

6. exp Fabaceae/

7. fabaceae.tw.

8. bean*.tw.

9. legume*.tw.

10. Lycopersicon esculentum/

11. lycopersicon esculent*.tw.

12. tomato*.tw.

13. solanum lycopersicum.tw.

14. Nuts/

15. (nut or nuts).tw.

16. Bread/

17. bread*.tw.

18. exp Cereals/

19. cereal*.tw.

20. grain*.tw.
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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64

21. Solanum tuberosum/

22. solanum tuberosum.tw.

23. potato*.tw.

24. Seeds/

25. (seed or seeds).tw.

26. olive oil.tw.

27. Fatty Acids, Monounsaturated/

28. monounsaturated fat*.tw.

29. mono-unsaturated fat*.tw.

30. exp Seafood/

31. exp Fish Oils/

32. fish.tw.

33. seafood*.tw.

34. shellfish.tw.

35. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 

19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34

36. ((high or more or increase* or elevat* or much or rais*) adj6 (intake or consumption or 

consume or eat* or amount*)).tw.

37. 35 and 36

38. exp Dairy Products/

39. exp Milk Proteins/

40. milk*.tw.

41. marg?rine*.tw.

42. butter*.tw.

43. dairy.tw.

44. cheese*.tw.

45. red meat*.tw.

46. processed meat*.tw.

47. yog?urt*.tw.

48. red wine*.tw.

49. 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48

50. ((low or little or medium or moderate or less or decrease* or reduc* or restrict*) adj6 (intake 

or consumption or consume or eat* or amount*)).tw.

51. 49 and 50

52. Diet, Mediterranean/

53. (mediterranean adj3 diet*).tw.

54. (mediterranean adj6 food*).tw.

55. (mediterranean adj6 nutrition*).tw.

56. (mediterranean adj6 eat*).tw.

57. 52 or 53 or 54 or 55 or 56

58. 37 or 51 or 57

59. exp animal/ not humans.sh.

60. 58 not 59

61. limit 60 to (english language and yr = "1990 -Current")

62. limit 61 to "all child (0 to 18 years)"

63. limit 62 to "all adult (19 plus years)"

64. 62 not 63
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

65

65. 61 not 64

66. adherence.mp.

67. 65 and 66

68. Patient Compliance/

69. 66 or 68

70. 65 and 69

COCHRANE

Key Questions 1 and 2 Randomized Controlled Trials

1. fruit or vegetable or legume or nut? or bread or cereal or grain or (olive next oil) or 

(monounsaturated next fat) or (mono unsaturated next fat) or fish

2. (fruit or vegetable or nuts or bread or cereals or fatty acids, monounsaturated or 

seafood):kw 

3. ((high or more or increase or elevat or much or rais) near (intake or consumption or 

consume or eat or amount))

4. (#1 or #2) and #3

5. red next meat or red next wine

6. MeSH descriptor: [Dairy Products] explode all trees

7. ((low or little or medium or moderate or less or decrease or reduc or restrict) near (intake 

or consumption or consume or eat or amount))

8. (#5 or #6) and #7

9. mediterranean near diet

10. MeSH descriptor: [Diet, Mediterranean] explode all trees

11. #4 or #8 or #10 (Publication year from 1990 to 2015)

Key Questions 1 and 2 Cancer

1. fruit or vegetable or legume or nut? or bread or cereal or grain or (olive next oil) or 

(monounsaturated next fat) or (mono unsaturated next fat) or fish

2. (fruit or vegetable or nuts or bread or cereals or fatty acids, monounsaturated or 

seafood):kw 

3. ((high or more or increase or elevat or much or rais) near (intake or consumption or 

consume or eat or amount))

4. (#1 or #2) and #3

5. red next meat or red next wine

6. MeSH descriptor: [Dairy Products] explode all trees

7. ((low or little or medium or moderate or less or decrease or reduc or restrict) near (intake 

or consumption or consume or eat or amount))

8. (#5 or #6) and #7

9. mediterranean near diet

10. MeSH descriptor: [Diet, Mediterranean] explode all trees

11. #4 or #8 or #10 (Publication year from 1990 to 2015)

12. Cancer

13. MeSH descriptor: [Neoplasms] explode all trees

14. #12 or #13 

15. #14 and #11
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

66

Key Questions 1 and 2 Rheumatoid Arthritis

1. fruit or vegetable or legume or nut? or bread or cereal or grain or (olive next oil) or 

(monounsaturated next fat) or (mono unsaturated next fat) or fish

2. (fruit or vegetable or nuts or bread or cereals or fatty acids, monounsaturated or 

seafood):kw 

3. ((high or more or increase or elevat or much or rais) near (intake or consumption or 

consume or eat or amount))

4. (#1 or #2) and #3

5. red next meat or red next wine

6. MeSH descriptor: [Dairy Products] explode all trees

7. ((low or little or medium or moderate or less or decrease or reduc or restrict) near (intake 

or consumption or consume or eat or amount))

8. (#5 or #6) and #7

9. mediterranean near diet

10. MeSH descriptor: [Diet, Mediterranean] explode all trees

11. #4 or #8 or #10 (Publication year from 1990 to 2015)

12. MeSH descriptor: [Arthritis, Rheumatoid] explode all trees

13. #11 and #12

Key Questions 1 and 2 Cognitive Function

1. fruit or vegetable or legume or nut? or bread or cereal or grain or (olive next oil) or 

(monounsaturated next fat) or (mono unsaturated next fat) or fish

2. (fruit or vegetable or nuts or bread or cereals or fatty acids, monounsaturated or 

seafood):kw 

3. ((high or more or increase or elevat or much or rais) near (intake or consumption or 

consume or eat or amount))

4. (#1 or #2) and #3

5. red next meat or red next wine

6. MeSH descriptor: [Dairy Products] explode all trees

7. ((low or little or medium or moderate or less or decrease or reduc or restrict) near (intake 

or consumption or consume or eat or amount))

8. (#5 or #6) and #7

9. mediterranean near diet

10. MeSH descriptor: [Diet, Mediterranean] explode all trees

11. #4 or #8 or #10 (Publication year from 1990 to 2015)

12. Mild cognitive impairment

13. MeSH descriptor: [Dementia] explode all trees

14. MeSH descriptor: [Alzheimer Disease] explode all trees

15. #12 or #13 or #14

16. #15 or #11

Key Question 3

1. fruit or vegetable or legume or nut? or bread or cereal or grain or (olive next oil) or 

(monounsaturated next fat) or (mono unsaturated next fat) or fish

2. (fruit or vegetable or nuts or bread or cereals or fatty acids, monounsaturated or 

seafood):kw 
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

67

3. ((high or more or increase or elevat or much or rais) near (intake or consumption or 

consume or eat or amount))

4. (#1 or #2) and #3

5. red next meat or red next wine

6. MeSH descriptor: [Dairy Products] explode all trees

7. ((low or little or medium or moderate or less or decrease or reduc or restrict) near (intake 

or consumption or consume or eat or amount))

8. (#5 or #6) and #7

9. mediterranean near diet

10. MeSH descriptor: [Diet, Mediterranean] explode all trees

11. #4 or #8 or #10 (Publication year from 1990 to 2015)

12. Adherence

13. MeSH descriptor: [Patient Compliance] explode all trees

14. #12 or #13

15. #11 or #14

CINAHL

Key Questions 1 and 2 Randomized Controlled Trials

1. Fruit* vegetable* legume* nut nuts bread breads cereal* “olive oil” “monounsaturared 

fat*” “mono-unsaturated fat*” fish

2. (MH “Fruit+”) OR (MH “Vegetables+”) OR (MH “Legumes+”) OR (MH “Nuts+”) OR 

(MH “BREAD”) OR (MH “Cereals+”) OR (MH “Olive Oil”) OR (MH “Fatty Acids, 

Monounsaturated+”) OR (MH “Seafood+”)

3. High more increase elevat* much rais*

4. Intake consumption consume eat* amount*

5. 3 AND 4

6. 1 OR 2

7. 5 AND 6

8. “red meat*” “red wine*”

9. (MH “Dairy Products+”)

10. Low little medium moderate less decreas* reduc* restrict*

11. 4 AND 10

12. 8 OR 9

13. 11 AND 12

14. (MH “Mediterranean Diet”)

15. 7 OR 13 OR 14 (published date: 19900101-2015; English Language; Exclude MEDLINE 

records; Human; Age Groups: All Adult)

Key Questions 1 and 2 Cancer

1. Fruit* vegetable* legume* nut nuts bread breads cereal* “olive oil” “monounsaturared 

fat*” “mono-unsaturated fat*” fish

2. (MH “Fruit+”) OR (MH “Vegetables+”) OR (MH “Legumes+”) OR (MH “Nuts+”) OR 

(MH “BREAD”) OR (MH “Cereals+”) OR (MH “Olive Oil”) OR (MH “Fatty Acids, 

Monounsaturated+”) OR (MH “Seafood+”)

3. High more increase elevat* much rais*
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

Compared to Other Diets

68

4. Intake consumption consume eat* amount*

5. 3 AND 4

6. 1 OR 2

7. 5 AND 6

8. “red meat*” “red wine*”

9. (MH “Dairy Products+”)

10. Low little medium moderate less decreas* reduc* restrict*

11. 4 AND 10

12. 8 OR 9

13. 11 AND 12

14. (MH “Mediterranean Diet”)

15. 7 OR 13 OR 14 (published date: 19900101-2015; English Language; Exclude MEDLINE 

records; Human; Age Groups: All Adult)

16. Cancer

17. 15 AND 16

Key Questions 1 and 2 Rheumatoid Arthritis

1. Fruit* vegetable* legume* nut nuts bread breads cereal* “olive oil” “monounsaturared 

fat*” “mono-unsaturated fat*” fish

2. (MH “Fruit+”) OR (MH “Vegetables+”) OR (MH “Legumes+”) OR (MH “Nuts+”) OR 

(MH “BREAD”) OR (MH “Cereals+”) OR (MH “Olive Oil”) OR (MH “Fatty Acids, 

Monounsaturated+”) OR (MH “Seafood+”)

3. High more increase elevat* much rais*

4. Intake consumption consume eat* amount*

5. 3 AND 4

6. 1 OR 2

7. 5 AND 6

8. “red meat*” “red wine*”

9. (MH “Dairy Products+”)

10. Low little medium moderate less decreas* reduc* restrict*

11. 4 AND 10

12. 8 OR 9

13. 11 AND 12

14. (MH “Mediterranean Diet”)

15. 7 OR 13 OR 14 (published date: 19900101-2015; English Language; Exclude MEDLINE 

records; Human; Age Groups: All Adult)

16. Rheumatoid arthritis

17. Arthritis

18. 16 OR 17

19. 15 AND 18

Key Questions 1 and 2 Cognitive Function

1. Fruit* vegetable* legume* nut nuts bread breads cereal* “olive oil” “monounsaturared 

fat*” “mono-unsaturated fat*” fish
Benefits and Harms of the Mediterranean Diet Evidence-based Synthesis Program

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69

2. (MH “Fruit+”) OR (MH “Vegetables+”) OR (MH “Legumes+”) OR (MH “Nuts+”) OR 

(MH “BREAD”) OR (MH “Cereals+”) OR (MH “Olive Oil”) OR (MH “Fatty Acids, 

Monounsaturated+”) OR (MH “Seafood+”)

3. High more increase elevat* much rais*

4. Intake consumption consume eat* amount*

5. 3 AND 4

6. 1 OR 2

7. 5 AND 6

8. “red meat*” “red wine*”

9. (MH “Dairy Products+”)

10. Low little medium moderate less decreas* reduc* restrict*

11. 4 AND 10

12. 8 OR 9

13. 11 AND 12

14. (MH “Mediterranean Diet”)

15. 7 OR 13 OR 14 (published date: 19900101-2015; English Language; Exclude MEDLINE 

records; Human; Age Groups: All Adult)

16. Mild cognitive impairment

17. Dementia

18. Alzheimer disease

19. 16 OR 17 OR 18

20. 15 AND 19

Key Question 3

1. Fruit* vegetable* legume* nut nuts bread breads cereal* “olive oil” “monounsaturared 

fat*” “mono-unsaturated fat*” fish

2. (MH “Fruit+”) OR (MH “Vegetables+”) OR (MH “Legumes+”) OR (MH “Nuts+”) OR 

(MH “BREAD”) OR (MH “Cereals+”) OR (MH “Olive Oil”) OR (MH “Fatty Acids, 

Monounsaturated+”) OR (MH “Seafood+”)

3. High more increase elevat* much rais*

4. Intake consumption consume eat* amount*

5. 3 AND 4

6. 1 OR 2

7. 5 AND 6

8. “red meat*” “red wine*”

9. (MH “Dairy Products+”)

10. Low little medium moderate less decreas* reduc* restrict*

11. 4 AND 10

12. 8 OR 9

13. 11 AND 12

14. (MH “Mediterranean Diet”)

15. 7 OR 13 OR 14 (published date: 19900101-2015; English Language; Exclude MEDLINE 

records; Human; Age Groups: All Adult)

16. Adherence

17. 15 AND 16
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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APPENDIX B. PEER REVIEW COMMENTS/AUTHOR RESPONSES

Question 

Text Comment Response

Are the 

objectives, 

scope, and 

methods for 

this review 

clearly 

described?

Yes Thank you

Yes 

Yes 

Yes

Yes 

Yes 

Is there any 

indication of 

bias in our 

synthesis of 

the 

evidence?

No Thank you

No 

No 

No

No 

No 

Are there 

any 

published or 

unpublished

studies that 

we may 

have 

overlooked?

No No response needed

No 

No 

No

No 

No 

Additional 

suggestions 

or 

comments 

can be 

provided 

below. If 

applicable, 

please 

indicate the 

page and 

page 5 lines 45-53. The Women's Health Initiative is called out in the text but 

PREDIMED is not. Seems that consistency should be greater.

page 6, line 41 and page 44, line 25. is there really evidence that a low fat diet is 

healthy? Isn't this all called into question? I think there is greater evidence of the 

healthiness of a vegetarian diet.

Page 12: What is the "T" in "PICOTS"?

Pge 18, line 23. It would help to define "k" somewhere. Some readers may not be 

acquainted with the terminology.

Page 43, line 12; I wonder whether you want to use "possibly" rather than "likely". 

Although I would really like to believe that the difference in outcomes for WHI 

compared with PREDIMED is the difference in the diet, do we have enough evidence 

page 5. We have named the PREDIMED 

study in this statement.

page 6. Thank you for the suggestion. We 

have removed low fat diet from these lines.

page 12. The “T” is for Timing (now added to 

the PICOTS)

page 18. We have defined k in several places.

page 43 and General comment: We revised 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

71

line 

numbers 

from the 

draft report.

to write that it is "likely"?

General comment: I would like to see text in the conclusion that states something to

the effect that "in retrospect, the definition of 'Mediterranean diet' may have been 

overly broad, and in turn, this may have influenced the conclusions of the analysis. 

For example, a diet of hamburgers and French fries would qualify as long at it was 

eaten with red wine and no milk." I acknowledge the paragraph about asking which 

components are the active ingredients in the Mediterranean diet, but I think that 

directly pointing to the issue of defining the diet is also very important.

the language in the report to address both of 

these comments. 

The authors reviewed and synthesized the literature and conducted a meta-analysis 

for randomized clinical trials and observations studies about the benefits (or not) of 

the Mediterranean diet (MedDiet) pattern in the primary and secondary prevention of 

disease or chronic conditions. 

Comments:

1. Title: I suggest changing the title of the paper as not all studies included in the 

meta-analysis were interventions. Dietary intake as an exposure in an observational 

study was observed.

2. I disagree with the authors’ definition of the MedDiet and the statement (page 14 

Methods) that ‘there is no universally accepted definition of the Mediterranean diet’. 

There are a numerous publications and a couple reviews below about the MedDiet 

which clearly describe the components of the MedDiet pattern (references a and b). 

a) Trichopoulou et al. Definitions and potential health benefits of the Mediterranean 

diet: views from experts around the world. BMC Medicine 2014, 12:112. 

b) Willett WC et al; Mediterranean Diet Pyramid: A cultural model for healthy eating. 

Am J Clin Nutr. 1995; 61(suppl): 1402S-1406S. 

In addition, the MedDiet is not a ‘low fat’ diet even though the ‘low fat’ diet may 

include many of the components the authors describe in their definition. The key 

component of the MedDiet is olive oil, as reported in numerous publications including 

the ones I suggest above. Therefore, it seems that the definition of a MedDiet should 

include olive oil plus 2 of the other components. The authors use a commonly used 

ratio [monounsaturated fat (MUFA)/saturated fat ratio] as one of the components to 

define the MedDiet and further explain that most of the MUFA should come from 

olive oil. However, it is not clear to me if the source of monounsaturated fat intake is 

known (ie, was the source of MUFA reported in published papers). Given that most 

of the instruments used in studies to assess dietary intake are food frequency 

questionnaires, it is not clear if source of MUFA was available. As you may know, a 

large source of MUFA in the US diet is from meat. And meat has been positively 

related to numerous chronic diseases. In the U.S., very little olive oil is consumed. 

Olive oil is not the main cooking oil used in the U.S.

Finally, several studies categorized as ‘Mediterranean’ in the current study were in 

fact ‘low fat’ diets (e.g. WHI diet modification trial). In WHI, one of the goals of the 

1. Thank you for the suggestion. We have 

changed the title

2. We chose our definition based on the recent 

Cochrane review and with approval from our 

stakeholders and Technical Expert Panel.

We have examined the references cited in the 

reviewer comment and believe that these 

references, and others, do, in fact, emphasize 

that there is no universally accepted definition 

of the Mediterranean diet.

3. We did an exploratory analysis creating 

forest plots with outcomes based on country 

and found no pattern.

4. We have added more references to the text.
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

72

diet intervention was to reduce fat intake to 20% of calories which is clearly low fat. 

However, fat intake for a MedDiet pattern is about 40% from calories. Further, the 

PREDIMED study investigators compared a MedDiet pattern to a low fat diet pattern 

– and found the MedDiet to be beneficial in reducing incident CVD events compared 

to the low fat diet pattern. So it is puzzling that the WHI diet pattern (which is low fat) 

was labeled as ‘Mediterranean-like diet’ in this review. Thus, the study investigators 

meta-analyzed very different diet patterns (although according to their study 

definition – they were labeled the Mediterranean diet). 

I believe the authors have combined diet patterns that are very different - apples and 

oranges – which may explain their study results. If the authors changed their 

definition for the MedDiet pattern, then the meta-analysis should be conducted 

again.

3. For key question 3, I suggest the authors compare the results of studies 

conducted in European countries to the studies conducted in the U.S. given that the 

diet patterns defined as ‘Mediterranean’ would be quite different between the 2 

continents. In Europe – the Mediterranean diet would include ‘olive oil’ while in the 

U.S. the Med diet pattern would not include ‘olive oil’ and most likely be ‘low fat’ diet 

patterns.

4. Throughout the text, the authors refer to some number of RCTs and observational 

studies. Perhaps these studies can be referenced so the reader is aware of which 

study the author is referring. Also, in the Discussion – mention is made of a ‘high 

quality RCT or lower quality RCT.....’, so again, please reference these.

Thank you for the opportunity to serve as an expert reviewer for this comprehensive 

evidence-based review of the impact of the Mediterranean diet on health outcomes 

important to our nation’s veterans. My comments follow.

My principal concern is how predominantly findings from the Women’s Health 

Initiative - Dietary Modification (WHI-DM) trial are featured throughout the document. 

I understand that the authors decided to adhere to the Cochrane definition of a 

Mediterranean diet and included studies that reported at least two of the following 

components:

• high monounsaturated/saturated fat ratio

• low to moderate red wine consumption

• high consumption of legumes

• high consumption of grains and cereals

• high consumption of fruits and vegetables

• low consumption of meat and meat products and increased consumption of fish

• moderate consumption of milk and dairy products

As noted, the WHI-DM trial met our study 

inclusion criteria. We have clarified the dietary 

components in WHI-DM and noted how they 

differ from PREDIMED.

We have clarified that the diabetes outcome 

was type 2 diabetes mellitus (T2DM) 

throughout the report.

Page 31, Table 2. We have added definitions 

to the Strength of Evidence Tables. For the 

outcome noted, consistency is unknown 

because there is a single trial. The 

assessment of precision is based on the width 

of the confidence interval. The suggested 

thresholds for precision are 0.75 to 1.25 and 

the lower bound of the PREDIMED study was 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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The WHI-DM intervention diet met this low bar of having 2 of the 7 components. 

However, the WHI-DM intervention diet was missing one of the key components - a 

high monounsaturated/saturated fat ratio. Several papers stress the importance of 

the inclusion of a source of monounsaturated fats in the Mediterranean diet. For 

example, see the following:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916858/

The Mediterranean diet is a plant-based pattern, where vegetables, fruits, cereals 

(preferably as whole grain), legumes, and nuts should be consumed in high amount 

and frequency. The Mediterranean dietary pattern (MDP) also includes moderate 

consumption of fish and shellfish, white meat, eggs, and dairy products. On the 

contrary, consumption of red meat, processed meats, and foods rich in sugars and in 

fats should be small in both quantity and frequency. The principal source of dietary 

lipids of the MDP is olive oil and an adequate daily intake of water should be 

guaranteed, as well as moderate consumption of wine is recommended.

And,

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222885/

The traditional Mediterranean diet is characterized by high consumption of 

vegetables, fruits and nuts, legumes, and unprocessed cereals; low consumption of 

meat and meat products; and low consumption of dairy products (with the exception 

of the long-preservable cheeses). Alcohol consumption was common in the 

traditional Mediterranean diet, but generally in moderation and in the form of wine 

and, as a rule, during meals- in the spirit of the ancient Greek word ‘symposium’. 

Total intake of lipids could be high (around or in excess of 40% of total energy 

intake, as in Greece), or moderate (around 30% of total energy intake, as in Italy) 

but, in all instances, the ratio of the beneficial monounsaturated to the non-beneficial 

saturated lipids is high, because of the high monounsaturated content of the liberally 

used olive oil. Finally, fish consumption has in the past been a function of the 

distance from the sea but has been, overall, at a moderate level.

Including the WHI-DM as a randomized controlled clinical trial testing the efficacy of 

the Mediterranean diet seems like an immense leap when one of the key features of 

the WHI-DM intervention was a low-fat diet. See the NIH WHI website 

(https://www.nhlbi.nih.gov/whi/diet.htm) where it states that the dietary modification 

(DM) clinical trial component of the WHI studied the effect of a low-fat, high fruit, 

vegetable and grain diet on breast cancer, colorectal cancer and heart disease in 

postmenopausal women. Furthermore, the participants were counseled to decrease 

0.71.

Page 39. We have modified this statement.

Page 42. Thank you for the suggestion. We 

have added this information to the Executive 

Summary. 

Page 45. Thank you for the suggestion. We 

have removed low fat diet from the statements 

about other healthy diets.
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

74

their fat intake to 20 percent of their total daily calories. 

This reviewer would like further justification for defining a Mediterranean diet as one 

that only includes two of the key components of the diet and most importantly 

prominently featuring the WHI-DM in the Executive Summary, Findings and 

Conclusions when it did not include one of the key, critical components of a 

Mediterranean diet; a high intake of monounsaturated fat. 

Please be clear throughout the manuscript that you are referring to type II diabetes 

mellitus and not “diabetes.” 

Page 31 - Table 2

Please explain how you defined consistency and precision in the studies. For 

example, in the first row of Table 2 you stated that “consistency is unknown and 

there was imprecision (PREDIMED).” What benchmark did you use to make this 

statement?

Page 39 

The statement “We evaluated strength of evidence for all-cause mortality finding 

insufficient evidence that mortality was similar between Mediterranean diet and 

control diet groups” is confusing. This could be interpreted to mean you found 

sufficient evidence that mortality was different between the Mediterranean diet and 

control diet groups. However, I don’t think this was the intent of this statement.

Page 42 - paragraph 3

The authors provide a good explanation of why the results are likely different 

between the PREDIMED studies and the WHI studies. This discussion should be 

prominent in the Executive Summary.

Page 45 - Research Gaps - 

The authors refer to a “low fat diet” as another “healthy diet.” A diet low in total fat is

no longer promoted by government and other important health organizations. For 

example the 2015 Dietary Guidelines Advisory Committee recommended dropping 

past recommendations to restrict total fat and rather emphasize the importance of 

reducing saturated fat and replace it with monounsaturated and polyunsaturated fats 

(see http://health.gov/dietaryguidelines/2015-scientific-report/pdfs/scientific-report-ofthe-2015-dietary-guidelines-advisory-committee.pdf). Furthermore, the American 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Heart Association no longer promotes a “low-fat” diet but rather stresses the 

importance of including monounsaturated and polyunsaturated fats in a heart healthy 

diet (see 

http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/TheAmerican-Heart-Associations-Diet-and-LifestyleRecommendations_UCM_305855_Article.jsp). 

Thus, I recommend not including a “low fat” diet as an example of a healthy diet.

1. I would like to see more details about the subjects in the PREDIMED study (age, 

CVD risk factors, etc.). The number of subjects should be noted consistently ("7000 

people" on page 3, line 44 and page 42, line 14 but "7447 people" on page 19, line 

14). 

2. Why does the Strength of Evidence table (Executive Summary, page 7-8, and 

paragraph on page 30 and Table 2 on pages 31-32) NOT include cardiovascular 

incidence and mortality, with the other outcomes?

3. The comments differentiating the PREDIMED study and the WHI study address 

the concerns raised by reviewers on the conference call earlier.

1. We have added more details about the 

subjects and have made sure that we 

consistently report the number of subjects. 

2. Systematic reviews typically only assess 

Strength of Evidence for key outcomes. We 

focused on outcomes we considered most 

clinically relevant. We have added more 

information in the Methods section.

3. Thank you.

Pages 5 - 6; Key Findings and Strength of Evidence - 3rd bullet: As noted on the 

conference call, and in the complete results section of the ESP below, the 

intervention diet in this study was more similar to the control diet than the 

intervention diet in the PREDIMED trial! Suggest including this in the bullet in both 

this Summary section and the Summary section of the complete ESP.

Page 6; Key Findings and Strength of Evidence - 6th bullet: Suggest the following 

edit to this bullet: "can be achieved in the setting of a controlled trial, but may require 

labor intensive behavioral interventions and monitoring." Same comment applies to 

the corresponding sections in the complete ESP

Page 6: Applicability: As noted in the Research Gaps section below, applicability of 

the available data to Veterans is limited by the presence of only 1 RCT in a 

comparable North American population and 1 RCT in an all-female population. 

Shouldn't this be included as a comment? Same comment applies to the 

corresponding sections in the complete ESP.

Page 7: Executive Summary Table - Strength of Evidence. For Key Question #1, the 

Table is missing the evidence regarding reduction in CV events. Not sure why this 

key finding was not included in the Table. Same comment applies to the 

corresponding Table in the complete ESP.

Pages 5-6, Thank you. We have modified the 

Discussion/Conclusions section and this bullet 

has been eliminated. We emphasize 

differences between the trials.

Page 6, We have modified the 

Discussion/Conclusions Section and 

eliminated the bullet points. We have included 

the suggested language.

Page 6. Thank you. We have modified the 

Applicability section.
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

76

Page 43, 3rd Paragraph from bottom on Total Cancer Incidence and Mortality- ; 

Again, the fact that the WHI intervention diet is a very low intensity Mediterranean 

diet should be mentioned here as well.

Page 7. As noted above, systematic reviews 

typically only assess Strength of Evidence for 

key outcomes. We focused on outcomes we 

considered most clinically relevant.

Page 43. Thank you. The WHI-DM diet is 

noted in this section.
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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APPENDIX C. EVIDENCE TABLES

KEY QUESTION 1

Table 1. Key Question 1 – Study, Intervention, and Patient Characteristics

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Buckland 201536

Europe (10 

countries)

EPIC

Funding: World 

Cancer Research 

Fund

Cohort

Cohort: 

-520,000 apparently healthy men and women

-aged 25-70

-recruited between 1992 and 2000 in 23 centers 

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed

through a center-specific FFQ that addressed 

usual diet over previous year

Excluded:

-prevalent cancer at recruitment

-incomplete follow-up

-missing dietary and lifestyle data

-ratio for energy intake versus energy expenditure 

in the top and bottom 1%

-missing information for the components used to 

construct the healthy lifestyle index

rMED: incorporates fruit, 

vegetables, olive oil, legumes, 

dairy, fish, seafood, and cereals; 

alcohol excluded

Scored from 0 to 16

Follow-up: 11.4 years

N = 461,550

Gender (% male) 29.8

BMI: 25.4

Age: 51.2

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Catsburg 201535

Canada

CSDLH and 

NBSS

Funding: Breast 

Cancer Research 

Foundation

Cohort 

Cohorts:

CSDLH

-Canadian men and women predominantly 

alumni of Universities of Alberta, Toronto, and 

Western Ontario (1995 to1998) 

-small contingent also recruited through Canadian 

cancer society in 1992

-actually used a sub-cohort of 3,320 randomly 

selected women

NBSS

-RCT of breast cancer screening

-women aged 40-59 from 15 Canadian clinical 

centers between 1980 and 1985

Healthy pattern: predominantly 

vegetable and legume food groups

Follow-Up:

CSDLH 13 years

NBSS 20-25 years 

CSDLH

N = 3,320 women

Age: 60

BMI: 23.8

Race: 95.8% white

NBSS

N = 89,835 women

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: unclear

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Gardener 201579

Australia

Australian 

Imaging, 

Biomarkers and 

Lifestyle (ABL) 

Funding: CSIRO 

Flagship 

Collaboration 

Fund, Science 

and Industry 

Endowment 

Fund, National 

Health and 

Medical 

Research 

Council, and 

other 

government and 

foundation 

sources

Cohort

Included: 

-Healthy (cognitively “normal”) participants from 

ABL study who completed FFQ at baseline

-ABL participants were age 60 or over at baseline

Excluded: 

-Alzheimer’s disease or mild cognitive impairment

-non-Alzheimer’s disease dementia, 

schizophrenia, bipolar disorder, significant current 

depression, Parkinson’s disease, cancer (other 

than basal cell skin carcinoma) in past 2 years, 

symptomatic stroke, insulin-dependent diabetes, 

uncontrolled diabetes mellitus, or current regular 

alcohol use exceeding 2 standard drinks/day 

(women) or 4/day (men)

FFQ (Cancer Council of Victoria): 

used to determined Australian-style 

Mediterranean Diet (AusMeDi) 

score, Western dietary pattern, and 

prudent 

Follow-up: 3 years

N = 527

Age (mean): 69

Gender (% male): 40

BMI: 26

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low 

Risk of Bias: medium

Harmon 201534

USA

Multiethnic 

Cohort

Funding: 

National Cancer 

Institute

Cohort

Cohort: 

-recruited a multiethnic population

->215,000 men and women aged 45-75y at 

recruitment living in Hawaii or Los Angeles

-enrolled between 1993-1996

-baseline questionnaire including food intake over 

past 12m

Included:

-identified with one of 5 main MEC ethnic groups 

(white, African American, Japanese American, 

native Hawaiian, and Latino)

-valid dietary information

-no previous history of cancer, heart attack, or 

stroke at baseline

aMED: 

a) 1 point for ≥ median 

consumption of vegetables 

(excluding potatoes), total fruit, 

nuts, legumes, fish, whole grains, 

and MUFA:SA ratio 

b) 1 point for < median 

consumption of red and processed 

meats

c) 1 point for alcohol consumption 

between 5-15g/d for women or 10-

25g/d for men

Follow-up: 13-18 years

Men 

N = 70,170 (45%)

Age: 56.6-61.3

BMI: 25.9-26.9

Women 

N = 86,634 (55%)

Age: 56.4-61.5

BMI: 25.3-27.2

Population:

Unclear

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Hu 201593

USA 

Nurses’ Health 

Study (NHS) and 

Nurses’ Health 

Study II

Funding: 

National 

Institutes of 

Health

Cohort

Included: 

-Nurses’ Health Study (NHS) (1976): female 

registered nurse, age 30-55

-Nurses’ Health Study II (NHS II) (1989): female 

registered nurse, age 25-42

Excluded: 

-70 or more missing items on FFQ

-total energy intake < 500 or > 3,500 kcal/day

-missing aMED score 

FFQ in 1980 for NHS, 191 for NHS 

II; updated approximately every 4 

years; aMED score (0 to 9 points, 

higher score indicated stronger 

conformity

Follow-up: 28 years for NHS, 20 

years for NHS II

Total N = 174,638

N = 83,245 NHS

N = 91,393 NHS II

Age (mean): 43.4

Gender (% male): 0

BMI: 24.9

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Koyama 201592

USA 

Health, Aging, 

and Body 

Composition 

(Health ABC)

Funding: 

National Institute 

of Aging and

Alzheimer’s 

Association

Cohort

Included: 

-Medicare-eligible

-community-dwelling

-age 70-79

-residing in Memphis, TN or Pittsburgh, PA

-no difficulty walking a quarter of a mile, climbing 

10 steps without resting, and performing any 

activities of daily living

-free of life-threatening cancers (no treatment in 

past 3 years)

-plan to remain in study area for at least 3 years

FFQ (Block Dietary Data System); 

participants interviewed by trained 

examiners; information used to 

construct MedDiet scores (0-55 

with higher score representing 

stronger conformity

Follow-up: 8 years

N = 2,326

Age (mean): 75

Gender (% male): 49

BMI: 27.3

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Toledo 201527

Spain

PREDIMED

Funding: Instituto 

de Salud Carlos 

III 

RCT

Included:

-women aged 60-80

-free of CVD at enrollment

-either type II diabetes mellitus or at least 3 of the 

following major cardiovascular risk factors: 

smoking, hypertension, elevated LDL, low HDL, 

overweight or obesity, or family history of 

premature coronary heart disease

Excluded:

-prior diagnosis of breast cancer

-probable breast tumors

MeDiet +EVOO, MeDiet+ nuts, or 

advice to reduce dietary fat

-dietary training at baseline visit

-personalized advice

-group sessions

Follow-up: 4.8 years

N = 4,284 women

Age: 67.7

BMI: 30.4

Sequence 

generation: low

Allocation 

concealment: low

Blinding: low 

Incomplete outcome 

data: low

Selective outcome 

reporting: low 

Risk of Bias: low

Vormund 201533

Switzerland

Swiss National 

Cohort Group

Cohort:

-pooled data from 2 cross-sectional studies in 

Switzerland: National Research Program 1A 

(1977-1979) and the Swiss Monitoring of Trends 

Individuals assigned a value of 1 

for each beneficial component 

preferred (salad, vegetables, fruits, 

whole grains, white meat, fish, 

N = 17,861 

8,665 men

9,196 women

Mean age 45.2

Population: low

Outcomes: low

Measurement: 

unclear
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Funding: Swiss 

National Science 

Foundation

Cohort

and Determinants in Cardiovascular Disease 

(MONICA) study

-diet assessed using a simplified 24-h recall

monounsaturated lipids, and 

alcohol) or detrimental component 

avoided (red or processed meat); 

also assigned a value of 1 for 

consumption of dairy products

Follow-up: 21.4 years

Normal BMI: 52.9%

Underweight: 2.5%

Overweight: 34.3%

Obese: 10.2%

Confounding: low

Risk of Bias: low

Ax 201444

Sweden

ULSAM

Funding: 

Uppsala 

University, 

Uppsala City 

Council 

Research Fund, 

and Swedish 

Research 

Council

Cohort

Cohort:

-initiated in 1970

-all men born between 1920 and 1924 living in 

Uppsala municipality were invited

Included:

-participated in 70-year investigation between 

1991 and 1995

Excluded:

-self-reported type II diabetes

-reported extreme energy intake

-for subgroup of adequate reports excluded 

inadequate reporters, as defined by the Golderg 

equation

-previously diagnosed prostate cancer

mMDS:

a) 1 point for > median fat quality 

(MUFA:SFA) and consumption of 

vegetables, fruits, cereals including 

potatoes, and fish

b) 1 point for below median 

consumption of meat

c) 1 point for alcohol intake 

between 10-50g/day

Follow-up: 13.2 years

N = 1,044

Adequate reporters n

= 566

BMI: 26.1

Population: unclear

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Buckland 201475

Europe

EPIC

Funding: Europe 

Against Cancer 

Program of the 

European 

Commission and 

other 

government 

agencies

Cohort

Cohort:

-520,000 apparently healthy men and women

-aged 25-70

-recruited between 1992 and 2000 in 23 centers 

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed 

through center-specific FFQ that addressed usual 

diet over previous year

Excluded:

-registered as having cancer previously

-missing end of follow-up data

-missing information on diet or lifestyle

-ratio for energy intake versus energy expenditure 

in the top or bottom 1%

Relative Mediterranean Diet Score: 

18pt linear score that incorporates 

9 key dietary components; 7 

components presumed to reflect 

the MD (fruit, nuts and seeds, 

vegetables, legumes, fish, olive oil, 

and cereals) and 2 components 

presumed not to reflect the MD 

(dairy products and meat); 

calculated as a function of energy 

density and divided into tertiles;

also includes alcohol, scored by 

assigning 2 to moderate 

consumers (5-25g/day for women, 

10-50g/day for men) and 0 to 

participants outside this range

Follow-up: 11 years

N = 477,312 

Gender (% male): 30

Age at enrollment: 

51.2 (9.9)

BMI: 25.4 (4.3)

Population: unclear

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Cuenca-Garcia 

201443

USA

Aerobics Center 

Longitudinal 

Study (ACLS) 

Funding: 

National 

Institutes of 

Health, CocaCola Company, 

and Spanish 

Grants from the 

Ministry of 

Economy and 

Competitiveness

Cohort

Cohort:

-received a preventive medical examination at the 

Cooper Clinic in Dallas, TX 

Included:

-completed a standardized medical history 

questionnaire

-underwent an extensive clinical evaluation

-completed a 3-day dietary record

-Complete and valid data for all the main 

exposures and confounders studied

Excluded: 

-personal history of CVD or cancer

-didn’t achieve at least 85% of their age-predicted 

maximal heart rate during the graded modified 

Balke treadmill exercise testing

-less than one year of follow-up

MDS (using sex-specific median 

cut-offs) 

a) 1 point for above median intake 

of vegetables, legumes, fruits and 

nuts, cereals, fish and seafood, 

and monounsaturated/saturated 

fats ratio

b) 1 point for below median intake 

of dairy products and meat/meat 

products

c) 1 point for alcohol intake 2 

drinks or less per day in men and 1 

drink or less per day for women

Follow-up: 11.6 years

N = 12,449 

Gender (% male): 78

Age: 20-82 

Population: unclear

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: Low 

George 201442

USA

Women’s Health 

Initiative 

Observational 

Study (WHI OS)

Funding: 

National Heart, 

Lung, and Blood 

Institute

Cohort

Cohort:

-between 1993 and 1998

-40 clinical centers

-postmenopausal women age 50-79 at study 

entry

-clinical trial component and WHI OS study closed 

in 2004-2005, extension study continued through 

2010

-diet measured at enrollment using a selfadministered FFQ

Included:

-93,676 women participating in the WHI OS

Excluded:

-incomplete diet data

-implausible energy intakes of < 600kcals/day or 

> 5,000 kcals/day

-prior diagnosis of CVD or cancer

aMED: 

a) 5-15g alcohol

b) ≥ median consumption of fish, 

fruit, legumes, nuts and seeds, 

ratio of MUFA to SFA, vegetables, 

and whole grains

c) < median consumption of red 

and processed meats

Follow-up: 12.9 years

N = 63,805 women

aMED Quintile 1: 

11,685

aMED Quintile 5: 

15,708

Age, years: 61.9 to 

64.2

BMI: 25.6 to 28.9

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Kenfield 201441

USA

Health 

Professionals 

Follow-up Study 

(HPFS) 

Funding: 

National Cancer 

Institute and the 

Prostate Cancer 

Foundation

Cohort

Cohort:

-initiated in 1986 among US male health 

professionals aged 40-75 yr

-completed FFQ for past year, updated every 4 

years

Excluded:

-men reporting implausible energy intake (<800 or 

>4200 kcal/d)

-missing ≥70 food items on the baseline FFQ

-men diagnosed with cancer, except nonmelanoma skin cancer

Traditional Mediterranean diet

score: 

a) 1 point each for < median dairy 

and meat intake

b) 1 point for alcohol intake 10-

50g/day

c) 1 point each for >median intake 

of vegetables, legumes, fruits and 

nuts, grains, fish, and the ratio of 

polyunsaturated to saturated lipids

Follow-Up: 23.2 years

N = 47,867 men

Age at start: 52.6-55.3

BMI: 25.1-25.8

Population: unclear

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Li 201440

USA-6 states or 

2 metropolitan 

areas

NIH-AARP

Funding: 

National Cancer 

Institute

Cohort

Cohort:

-mailed population-based survey linked with 

cancer registry data and death databases (for 

outcomes)

Included: 

-age 50-71

Excluded: 

-proxy respondents

-extreme daily caloric intake (either high or low)

-cancer at baseline

Dietary Assessment: 2 dietary 

quality indices HEI-2005 and 

aMED constructed based on FFQ

Follow-up: 

Men – 1,466 head and neck cancer 

cases over 2,838,422 person-years

Women – 402 cases over 

1,964,936 person-years

N = 494,967

Age: 62.1 (men); 61.9 

(women) 

Gender (% male): 60

BMI: 27 (men and 

women)

Population: low

Outcomes: unclear

Measurement: low

Confounding: low 

Risk of Bias: low

Lopez-Garcia 

201439

USA

HPFS/NHS

Funding: 

National 

Institutes of 

Health

Cohort

Cohort: 

HPFS

-initiated in 1986 among US male health 

professionals aged 40-75 yr

-completed FFQ for past year, updated every 4 

years

NHS 

-female, registered nurse, 30-55 years in 1976 

(start of NHS), residing in 11 US states; 

completed mailed questionnaire about health and 

lifestyle

Included:

-men and women with a nonfatal CVD event 

(myocardial infarction, stroke, angina pectoris, 

coronary bypass, and coronary angioplasty) 

diagnosed from beginning of follow-up through 

2006

aMED: 

a) 1 point if intake > cohort-specific 

median for vegetables, legumes, 

fruit, nuts, whole grain cereals, fish, 

and MUFA:SFA

b) 1 point for intake < cohortspecific median for red and 

processed meats

c) 1 point for alcohol intake of 5-15 

g/d for women and 10-15 g/d for 

men 

Follow-up: 7.7 years for men and 

5.8 years for women

N = 17,415

(6,137 men, 11,278 

women) 

Men:

Age: 69

BMI: 26

Women:

Age: 67

BMI: 26.6

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Reedy 201438

USA-6 states or 

2 metropolitan 

areas

NIH-AARP

Funding: Not 

reported

Cohort

Cohort:

-mailed population-based survey linked with 

cancer registry data and death databases (for 

outcomes)

Included: 

-age 50-71

Excluded: 

-proxy respondents

-cancer, ESRD, heart disease, stroke, or diabetes 

at baseline 

-extreme daily caloric intake (either high or low)

Dietary Assessment: aMED 

constructed based on FFQ

Follow-up: 15 years

N = 242,321 men

182,342 women

Age: 62 (men), 62 

(women)

Gender (% male): 57

BMI: 26 (men), 25 

(women)

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Salas-Salvadó 

201426

See Estruch 

20137

RCT

Cohort: See Estruch 2013

Included: 

-no diabetes at baseline

-incidence of diabetes could be ascertained 

during follow-up 

-required to meet American Diabetes Association 

criteria for diabetes on 2 tests within 3 months to 

be included as an incident case (fasting glucose 

126.1 mg/dL or higher or 2-hour glucose 200 

mg/dL or higher after 75-g oral glucose load)

Same as Estruch 2013

Follow-up: 4.1 years

N = 3,541 (of 7,447 in 

trial)

Age (mean): 67 

Gender (% male): 38

Race: NR

BMI: 30

Sequence 

generation: low

Allocation 

concealment: low

Blinding: low 

Confounding: low 

Incomplete outcome 

data: high 

Selective outcome 

reporting: low 

Risk of Bias: medium

Tangney 201490

USA 

Memory and 

Aging Project 

(MAP)

Funding: 

National Institute 

on Aging

Cohort

Cohort:

-started in MAP (cognitively normal older persons 

living in retirement communities and subsidized 

housing) in 1997

Included:

-dementia-free at start of study 

-agreed to annual clinical neurologic evaluations

-agreed to be in nutrition component of study 

(started in 2004) 

-had 2 or more cognitive assessments and 

completed valid FFQ

FFQ data used to determine

MedDietScore (0-55); higher 

scores connote greater accordance 

with diets

Follow-up: 4.1 years (range 1 to 

10)

N = 826

Age (mean): 82

Gender (% male): 26

Race: NR

BMI: 27.1

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium 

 

Xie 201437

USA

NHS

Funding: 

National 

Institutes of 

Health

Cohort: 

-female, registered nurses, 30-55 years in 1976 

(start of NHS) 

-residing in 11 US states

-completed mailed questionnaire about health and 

lifestyle

aMDS: considers the consumption 

of certain fatty acids, legumes, 

cereals, fruits, nuts, vegetables, 

meat, dairy, and alcohol and 

ranges from 0 to 10

Follow-up: 24 years

N = 82,984 women

Age: 64 

BMI: 27

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Cohort

Bamia 201353

Europe (10 

countries) with

France also 

reported 

separately64

EPIC

Funding: World 

Cancer Research 

Fund

Cohort

Cohort: 

-520,000 apparently healthy men and women

-age 25-70

-recruited between 1992 and 2000 in 23 centers 

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed

through center-specific FFQ that addressed usual 

diet over previous year

Excluded:

-verified or self-reported prevalent cancer

-insufficient follow-up information or no dietary 

information

MMDS:

a) 1 point for intake ≥ cohort sexspecific medians for each 

component (vegetables, legumes, 

fruit/nuts, fish/seafood, and 

cereals) 

b) 1 point for consumption of 

meat/meat products and dairy 

products < median

c) 1 point for ethanol intake 

between 5-25g/d for women and 

10-50g/d for men

d) 1 point for ≥ median ratio of 

unsaturated to saturated fats

CSMMDS (center-specific): 

-calculated MMDS using sex and 

center specific medians

Follow-up: 11.6 years

N = 143,752 men

Age <45: 23%

45 to <55: 35%

55 to <65: 34%

≥ 65: 7%

BMI ≤25: 36%

>25 to <30: 49%

≥30: 15%

N = 336,556 women

Age <45: 26%

45 to <55: 41%

55 to <65: 27%

≥65: 6%

BMI ≤25: 58%

>25 to <30: 29%

≥30: 13%

France64

N = 68,442

Healthy Pattern:

Age: 52.7-52.8

BMI: 22.5-23.6

Population: unclear

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: medium

Bosire, 201352

USA-6 states or 

2 metropolitan 

areas

NIH-AARP

Funding: 

National Cancer 

Institute

Cohort

Cohort:

-mailed population-based survey linked with 

cancer registry data and death databases (for 

outcomes)

Included: 

-men age 50-71

Excluded: 

-proxy respondents

-people with other cancers (except nonmelanoma skin); ESRD 

-extreme daily caloric intake (either high or low)

Dietary Assessment: 3 dietary 

quality indices HEI-2005, AHEI2010, and aMED constructed 

based on FFQ

Follow-up: 8.9 years

N = 293,464

Age (mean): 62

Gender (% male): 100

Race (%white): 93

BMI: 27

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Buckland 201351

Europe

EPIC

Funding: The 

Cohort:

-520,000 apparently healthy men and women

-age 25-70

-recruited between 1992 and 2000 in 23 centers 

Adapted relative Mediterranean 

diet score (ARMED); 16 point 

scale: 

a) score of 0-2 assigned to country 

N = 355,062

Age at Recruitment: 

50.8

BMI: 25.0

Population: unclear

Outcomes: low

Measurement: low

Confounding: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

European 

Commission FP5 

Project

Cohort

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed

through center-specific FFQ that addressed usual 

diet over the previous year

Excluded:

-no follow-up information

-prevalent cancer at recruitment

-incomplete information on diet or lifestyle

-implausible dietary data top and bottom 1% of 

the total energy intake to energy requirement ratio

specific tertiles of intake for 6

components presumed to fit MD; 

fruits (including nuts and seeds), 

vegetables (excluding potatoes), 

legumes, fish (fresh or frozen, 

excluding fish products and 

preserved fish), olive oil, and 

cereals

b) scoring inverted for components 

presumed to not fit MD (meat and 

dairy products) 

c) for olive oil: 0 to non-consumers, 

1 for subjects< median, and 2 for 

subjects ≥median

Follow-up: 11.0 years

Risk of Bias: low

Couto, 201350

Sweden

Swedish 

Women’s 

Lifestyle and 

Health (SWLH) 

Funding: 

Swedish 

Research 

Council and 

Swedish Cancer 

Society

Cohort

Cohort:

-from 1991-1992, women age 30-49 living in 

Uppsala Health Care Region

-96,000 women randomly selected from Swedish 

central population registry to receive an invitation 

letter and questionnaire 

-follow-up questionnaire mailed to previous 

respondents in 2003

-questionnaires asked about diet in previous 6 

months

Included: 

-completed a baseline questionnaire

Excluded: 

-diagnosed with breast cancer before or at 

recruitment

-total energy intake outside the 1st and 99th

percentiles

-missing information on BMI, height, age at first 

birth and total number of children, age at 

menarche, or use of oral contraceptives

-Conformity measured using 

variant of the Mediterranean diet 

score (Low = 0, High = 9) 

a) 1 point for > median 

consumption of vegetables, fruits 

and nuts, legumes, cereals, fish, 

and high ratio of unsaturated to 

saturated fat

b) 1 point for < median 

consumption of dairy and meat 

products

c) 1 point for alcohol consumption 

between 5-25 g/day

Follow-up: 16 years

At baseline:

N = 44,840

Age: 30-49

BMI: ≤20: 12%

21-24: 62%

≥25: 26%

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

 

Estruch, 20137

Valls-Predret 

201528

MartinezLapiscina 201325

Included: 

-community-dwelling women 60-80 years or men 

55-80 years

-no CV disease but high CV risk (either type II

diabetes, or at least 3 major risk factors) 

MD+EVOO (approx. 1 liter/week): 

n = 2,543

MD+nuts (30 g/day); n = 2,454

(both MD groups had individual 

and group dietary training at 

N = 7,447

Age (mean): 67 

Gender (% male): 43

Race: 97% white (from 

Europe); 1.4% 

Sequence 

generation: low

Allocation 

concealment: low

Blinding: low 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Spain

PREDIMED

Funding: Instituto 

de Salud Carlos 

III (ISCIII)

RCT

Excluded: 

-documented history of previous CV disease

-severe medical condition that may impair ability 

to participate in nutrition intervention study

-life expectancy <1 year

-immunodeficiency or HIV-positive status

-illegal drug use or chronic alcoholism or total 

daily alcohol intake >80g/day

-BMI >40 kg/m2

 

-impossible to follow Mediterranean-type diet

-low predicted likelihood to change dietary habits

-history of food allergy to any components

-participation in any drug trial or use of 

investigational drug in last year

-unable to attend clinic visits every 3 months

-illiteracy

baseline and quarterly thereafter 

with conformity evaluation) 

Control: n = 2,450 (low fat diet)

Dietary training at baseline with 

conformity evaluation; yearly leaflet 

explaining low-fat dieta 

No total caloric restriction advised

No promotion of physical activity

Follow-up: 4.8 years 

Hispanic (Central or 

South America)

BMI: 30

Incomplete outcome 

data: low

Selective outcome 

reporting: low 

Risk of Bias: low

Gamba 201329

USA

Women’s Health 

Initiative Dietary 

Modification Trial

(WHI-DM)

Funding: 

National Institute 

of Arthritis and 

Musculoskeletal 

and Skin 

Diseases; 

National Heart, 

Lung, and Blood 

Institute; National 

Institutes of 

Health; and US 

Department of 

Health and 

Human Services

RCT

Included: 

-postmenopausal women

-age 50-79 years 

Included:

-interested in one or more components of the

clinical trials

-willing to be randomized to intervention or 

comparison group 

-fat intake at baseline of 32% or more

Excluded: 

-previous history of breast, colorectal, or any 

cancer other than non-melanoma skin cancer in

the past 10 years

-predicted survival of less than 3 years

-type I diabetes mellitus and other conditions that 

posed adherence and retention concerns (eg,

alcoholism, dementia). Participants had to have a 

baseline fat intake 32% or more of total energy

Intervention: intensive behavioral 

modification program using 18 

group sessions in first year and 

then quarterly sessions 

decrease total fat intake to 20% or 

less of energy and consume 5 or 

more servings per day of 

vegetables and fruits and 6 or 

more servings per day of grains; 

Comparison: received a copy of 

the US Department of Health and 

Human Services ’ Dietary 

Guidelines for Americans

Follow-up: 8.1 years

N = 48,835

IG: 19,541 CG: 29,294

Age (mean): 62.3

BMI: 29.1

Sequence 

generation: low

Allocation 

concealment: low 

Blinding: unclear

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Gnagnarella 

201349

Italy

COSMOS

Funding: Italian 

Association for 

Cancer 

Research, Italian 

Foundation for 

Cancer 

Research, and 

European 

Institute of 

Oncology

Cohort

Cohort:

-5203 asymptomatic volunteers

-age ≥ 50 years

-current smoker or had quit smoking for <10 years 

and had smoked at least 20 pack-years

-Enrolled between October 2004 and October 

2005

-underwent annual LD-CT

-baseline FFQ about intake over preceding year

Included:

-completed FFQ returned

Excluded:

-abnormal dietary values (total caloric intake less 

than or greater than 3 standard deviations) 

aMED score:

a) 1 point for intakes > median 

value reported by all participants 

for vegetables, fruits, nuts, cereals, 

legumes, and fish (otherwise 0 

points) 

b) 1 point for red and processed 

meat consumption < median

c) 1 point for alcohol intake of 5-

15g/day 

Follow-up: 5.7 years

N = 4,336

Gender (% male): 66 

Age (median): 57 

BMI ≤18.5: 1%

BMI 18.5-24: 45.2%

BMI 25-30: 41.4%

BMI ≥30: 11.6%

Population: unclear

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Kesse-Guyot 

201380

France

SU.VI.MAX 

(Supplementatio

n with Vitamins 

and Mineral 

Antioxidants)

Funding: Agence 

Nationale de la 

Recherche, 

Direction 

Generale de la 

Sante (Ministry of 

Health), Mederic,

Sodexo, Ipsen, 

Mutuelle 

Generale de 

l’Education 

Nationale 

(MGEN), and

Pierre Fabre

Cohort 

Cohort:

-participants from SU.VI.MAX and SU.VI.MAX 

-dietary pattern assessed 1994-1996 and 

cognitive outcomes assessed 2007-2009

Excluded: 

-missing neuropsychological test scores 

-<3 dietary records during first 2 years of followup

-younger than 45 years at baseline 

-missing data on one or more covariates

Food and nutrient intakes 

determined from patient-completed 

24-hr dietary records during first 2 

years of follow-up

Mediterranean Diet Score (MDS)

(max score of 9; higher scores 

indicated better conformity) 

a) 1 point for > sex-specific mean 

consumption of vegetables, fruits, 

grains, fish, nuts, legumes, and the 

ratio of MUFAs to SFAs

b) 1 point for < median 

consumption of meat and dairy 

products

c) 1 point for alcohol consumption 

between 5-25g/d for women and 

10-50g/day for men

Mediterranean-Style Dietary 

Pattern Score (MSDPS) (scores 

range from 0 (0%) to 1 (100%) 

reflecting % of energy from foods 

included in Med Diet pyramid) 

a) each component (except olive 

oil) scored 0-10 according to level 

N = 3083

Age (mean): 52 at 

baseline; 65 at time of 

cognitive evaluation

Gender (% male): 54

Race: NR

BMI: 24

Population: unclear

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

of conformity

b) exclusive olive oil use = 10 

points, no use = 0, and use of olive 

oil and other fats = 5 

Follow-up: 13 years

Kyro 201348

Denmark

Funding: 

NordForsk and 

the Danish 

Cancer Society

Cohort

Included: 

-age 50-64 years 

-born in Denmark

-reside in certain areas of Denmark

Excluded: 

-cancer

Dietary Assessment: selfadministered FFQ converted into a 

“healthy Nordic food index” 

comprised of fish, cabbage, rye 

bread, oatmeal, apples & pears, 

and root vegetables

Follow-up: 13 years

N = 57,053

Men (n = 26,664): 

Age: median 56

BMI: median 26

Women (n = 29,216):

Age: median 56

BMI: median 25

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Li 201347

USA-6 states or 

2 metropolitan 

areas

NIH-AARP

Funding: 

National Cancer 

Institute

Cohort

Cohort:

-mailed population-based survey linked with 

cancer registry data and death databases (for 

outcomes)

Included: 

-age 50-71

Excluded: 

-proxy respondents 

-extreme daily caloric intake (either high or low)

-cancer at baseline

Dietary Assessment: 2 dietary 

quality indices HEI-2005 and 

aMED constructed based on FFQ

Follow-up: 9.7 years

N = 494,968

Age (mean): 62

Gender (% male): 60

Race (%white): 93

BMI: 27

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Link 201346

USA

California 

Teachers Study 

(CTS)

Funding: 

National Cancer 

Institute, 

California Breast 

Cancer Research 

Fund, and other 

government

sources

Cohort

Included:

-active and retired female teachers and 

administrators residing in California

Excluded: 

-history of breast cancer 

-extremely low or high caloric intake

Dietary assessment: selfadministered FFQ reduced to 5 

patterns using factor analysis; 

“salad and wine” and “ethnic” diets 

fit our definition of Mediterranean

diet

Follow-up: 14.1 years

N = 91,779

Age (median): 50

Gender (% male): 0

Race 88% non-Latina 

white

BMI: median 23.7

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Mursu 201345

USA

IWHS

Funding: 

National Cancer 

Institute, 

Academy of 

Finland, Finnish 

Cultural 

Foundation, and 

Fulbright 

program

Cohort

Cohort:

-started in 1986, 41,836 women age 55-69 

completed a 16-page self-administered 

questionnaire

Included:

-for 2004 follow-up analysis only women with 

complete baseline and FFQ follow-up data

Excluded:

-premenopausal, diabetes, CVD, cancer

-did not adequately complete a FFQ at baseline in 

1986

AHEI components (each 

component had potential to 

contribute 0-10 points to total 

score): vegetables, whole fruit, 

whole grains, sugar-sweetened 

beverages/fruit juices, nuts and 

legumes, red and processed meat, 

fat quality, sodium, and alcohol 

intake 

Baseline N = 29,634

2004 follow-up 

analysis: n = 15,076

Age: 61.2

BMI: 26.7

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Samieri 201384

USA 

NHS

Funding: 

National Cancer 

Institute, 

Fulbright 

Research 

Scholar program, 

and Pole de 

Recherche et 

d”Enseignement 

Superieur

Cohort

Cohort:

NHS: female, registered nurse, 30-55 years in 

1976 (start of NHS), residing in 11 US states; 

completed mailed questionnaire about health and 

lifestyle

Cognitive sub-study: age 70 or older in 1995, free 

of stroke, completed at least one expanded FFQ 

in 1984 or 1986, completed at least one cognitive 

assessment, no missing data for energy intake 

and physical activity 

FFQ: expanded 116-item version 

introduced in 1984; used 

information to estimate daily 

energy intake and construct 

alternative MD 9 point score

a) 1 point for > median intake of 

vegetables (excluding potatoes), 

fruits, nuts, whole grains, legumes, 

fish, and MUFA:SFA ratio

b) 1 point for < median intake of 

red/processed meats

c) 1 point for alcohol intake of 5-

15g/d

Follow-up: 6 years

N = 16,058

Age (mean): 74 at first 

cognitive exam

Gender (% male): 0

Race: NR

BMI: 

20% 21 or lower 

17% 30 or higher 

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

 

Samieri 201383

USA 

Women’s Health 

Study

Funding: 

National Cancer 

Institute, 

Fulbright 

Research 

Scholar program,

and Pole de 

Included: 

-no history of coronary heart disease, 

cerebrovascular disease, cancer (except 

nonmelanoma skin cancer), or chronic kidney or 

liver disease

-age 65 years or older (for sub-study)

-complete dietary data

-at least one complete cognitive assessment

FFQ completed at baseline; used 

to construct alternate 

Mediterranean diet conformity

score (9 point)

Follow-up: 4 years

N = 6,174

Age (mean): 72

Gender (% male): 0

BMI: 26

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Recherche et 

d”Enseignement 

Superieur

Cohort

Wengreen 

201391

USA 

Cache County 

Memory Study 

(CCMS) 

Funding: 

National 

Institutes of 

Health, General 

Mills Bell Institute 

of Health, and 

Utah State 

University

Cohort

Cohort: 

-elderly (age 65 and older) residents of Cache 

County, UT

-completed baseline interview and FFQ

Invited to participate: 1995-96

Reassessed: 1998-99, 2003-03, 2005-06

Excluded: 

-dementia at baseline

-implausible energy intakes on FFQ

FFQ: 142-item, self-administered

MD score: 8 components (no 

moderate alcohol consumption 

component)

-participants ranked on 

consumption of fruit, vegetables, 

total grains, nuts and legumes, 

MUFA:SFA ratio, and fish

-ranked in reverse order of intake 

of red and processed meat and 

full-fat dairy

-rank scores summed and 

participants put into quintiles 

Follow-up: 10.6 years 

N = 3,580

Age (mean): 74

Gender (% male): 43

Race: NR

BMI: 26

Population: low

Outcomes: low

Measurement: low

Confounding: low 

Risk of Bias: low

Cherbuin 201276

Australia

PATH Through 

Life

Funding: 

National Health 

and Medical 

Research 

Council

Cohort

Included: 

-resident of Canberra, Australia 

-randomly selected from electoral roll

-middle-aged cohort (age 60-64 at Wave 1 [2001-

2])

-valid neuropsychological assessment at Wave 1 

and follow-up (5 years)

-available dietary and APOE*E4 data 

FFQ: 215 food items (from

Commonwealth Scientific and 

Industrial Research Organisation); 

used to calculate daily nutrient 

intake and caloric intake; weekly 

alcohol consumption determined 

with Alcohol Use Disorders 

Identification Test

Follow-up: 4 years

N = 1,557

Gender (% male): 49 

Age (mean): 62.5

BMI: NR

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Chiuve 201256

USA

NHS/HPFS

Funding: 

National 

Institutes of 

Health and 

American Heart 

Cohort:

HPFS

-initiated in 1986 among US male health 

professionals age 40-75 yr

-completed FFQ for past year, updated every 4 

years

NHS 

-female, registered nurse, 30-55 years in 1976 

AHEI: food and nutrients that have 

been associated consistently with 

lower risk of chronic disease in 

clinical and epidemiologic 

investigations (vegetables, fruits, 

whole grains, nuts and legumes, 

fat quality, low-sugar beverages, 

and red/processed meat plus low 

N = 71,495 women 

(NHS)

N = 41,029 men 

(HPFS)

Age: NR

BMI: NR

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Association

Cohort

(start of NHS), residing in 11 US state

-completed mailed questionnaire about health and 

lifestyle

Excluded:

-previously diagnosed CVD, diabetes, or cancer

-invalid FFQ data

sodium and alcohol intake 0.5-1.5 

or 2g/d depending on gender

Follow-up: NHS 24 years, HPFS 

22 years

Gardener 201278

Australia

Australian 

Imaging, 

Biomarkers and 

Lifestyle Study of 

Ageing (AIBL) 

Funding: CSIRO 

Flagship 

Collaboration 

Fund and 

Science and 

Industry 

Endowment 

Fund with other 

sources

Cohort

Cohort: 

-volunteers

-healthy control, MCI, and AD individuals 

-age ≥60 (longitudinal analysis of healthy controls 

reported)

Included:

-completed the CCVFFQ, returned for follow-up 

assessment at 18m

Excluded: 

-history of non-AD dementia, schizophrenia, 

bipolar disorder, significant current depression, 

Parkinson’s disease, cancer (other than basal cell 

skin carcinoma) within last 2 years

-symptomatic stroke, insulin-dependent diabetes, 

uncontrolled diabetes mellitus

-current regular alcohol use exceeding 2 standard 

drinks/day for women or 4/day for men

-incomplete neuropsychological test results

Cancer Council of Victoria FFQ: 74 

items, self-administered, assesses 

intake over preceding 12 months

MD Score (0-low conformity, 9 = 

high conformity): 

a) 1 point for >sex-specific median 

consumption of fruits, vegetables, 

legumes, cereals, fish, and 

MUFA:SFA

b) 1 point for < median 

consumption of meat and dairy 

products

c) 1 point for alcohol consumption 

5-25g/d for women, 10-50g/d for 

men. 

Follow-up: 1.5 years

N = 723 healthy 

controls (652 in 

analysis)

Age (mean): 70

Gender (% male): 42

Race: NR (72% born 

in 

Australia)

BMI: 26.5

Population: unclear

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: medium 

Kwok 201224

Hong Kong

Funding: Tung 

Wah Group

RCT

Included: 

-old-age hostel resident

-75 or older 

Excluded: 

tube-fed 

-on special diet due to chronic renal failure

Control (CG): PI and dietician gave

1h talk to residents/staff on

prevention of dementia; promoted 

brain preservation diet (2 portions 

of fruit/day, 3 portions of 

vegetables/day, 5 portions of 

fish/wk, avoidance of salty foods)

Intervention (IG): Control plus 

dietary support groups every 3 

weeks for first year and then every 

6 weeks for 21 months; at each 

group session: information sharing, 

interactive games to reinforce 

learning, and promotion of brain 

preservation diet; dietician also 

liaised closely with hostel and 

N = 429

Age (mean): 83

Gender (% male)

IG: 22

CG: 9.3

BMI: 23

Sequence 

generation: unclear

Allocation 

concealment: unclear

Blinding: unclear

Incomplete outcome 

data: low

Selective outcome 

reporting: unclear

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

kitchen staff on menu and cooking 

methods

Follow-up: 33 months

Tognon 201254

Sweden

Funding: 

Swedish Council 

on Working Life 

and Social 

Research EpiLife 

Center, Nordic 

Health Whole 

Grain 

Food/NordForsk, 

Swedish Council 

for Working Life 

and Social 

Research, and 

Swedish 

Research 

Council

Cohort

Cohort:

-between Jan 1, 1990 to Dec 31, 2008 residents 

of Vasterbotten county in northern Sweden invited 

to participate in a health survey when turning 30 

(between 1990-1996), 40, 50, or 60

-in 1996 and 2008, 70-year-olds were also 

included in cohort

Included: 

-underwent anthropometric measurements as well 

as measurement of blood pressure, lipids, and 

oral glucose tolerance

-completed a dietary questionnaire

Excluded:

-missing body weight or height

-unrealistic food intake levels (lowest 5% or 

highest 2.5%)

-completed <10% of food items on questionnaire

-reported alcohol intake >50g/d

Modified Mediterranean Diet 

Score: 

a) 1 point for > sex/questionnairespecific median consumption of 

vegetables and potatoes, fruit and 

juices, whole-grain cereals, fish 

and fish products, ratio of MUFA + 

PUFA to SFA, and alcohol intake

b) 1 point for < median 

consumption of meat/meat 

products and dairy products

Follow-up: 10 years for all-cause 

mortality 9 years for cause-specific 

N = 77,151 

Age: predominantly

30-60 y olds

Gender (% male): 47

BMI ≥ 30 (obese): 61%

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Cade 201158

United Kingdom

UKWCS

Funding: World 

Cancer Research 

Fund

Cohort

Cohort:

-recruited 35,372 women aged 35-69y between 

1995 and 1998

-cohort was selected from about 500,000 

responders to a survey

-selected each vegetarian then the next nonvegetarian in the survey aged within 10 years of 

the vegetarian

-Baseline FFQ

Excluded: 

-prevalent breast cancer

-couldn’t be flagged for cancer registration with 

the Office of National Statistics 

-energy intake outside of the expected levels

-no form date

Mediterranean Diet Score:

a) 0 or 1 point for each component 

using the cohort median as cut off

b) 1 point for > median intake of 

vegetables, legumes, fruit and 

nuts, cereal, fish, and ratio of 

monounsaturated fatty acids to 

saturated fatty acids

c) 1 point for < median intake of 

meat, poultry, and dairy products 

d) 1 point for alcohol consumption 

of 5-25g/d 

Follow-up: 9 years

N = 33,731 women

Age (mean): 52

BMI: 24.5

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Couto 201157

Europe

EPIC

Funding: 

European 

Commission and 

International 

Agency for 

Research on 

Cancer

Cohort

Cohort:

-520,000 apparently healthy men and women

-age 25-70

-recruited between 1992 and 2000 in 23 centers 

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed

through center-specific FFQ that addressed usual 

diet over previous year

Included:

-complete exposure information

Excluded:

-prevalent cases of cancer

-incomplete follow-up

- ratio of energy intake vs energy expenditure in 

the top or bottom 1% 

a) 1 point for > country sex-specific 

median consumption of 

vegetables, legumes, fruits and 

nuts, cereals, fish, and a high ratio 

of unsaturated to saturated lipids

b) 1 point for < median 

consumption of dairy, meat, and 

meat products

c) 1 point for alcohol consumption 

between 10-50g/d for men, 5-25g/d

for women

Follow-up: 8.7 years

N = 478,478

Men (n = 142,605) 

Age (mean): 52

Mean BMI: 26.5

Women, (n = 335,873) 

Age (mean): 51

BMI: 25

Population: unclear

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Menotti 201155

Italy

Seven Countries 

Study

Funding: No 

funding received

Cohort

Cohort:

-population-based prospective cohort 

Included: 

-men age 40-59 in 2 communities in Italy

Excluded: 

-none

Dietary Assessment: food intake 

data collected by dietitians and 

categorized into 17 food groups; 

factor analysis reduced diet to 3 

factors, one of which (factor 2) 

“was similar to the pattern 

considered a typical Mediterranean

diet rich in vegetables, oil, and fish” 

Follow-up: 40 years for mortality, 

20 years for CHD events

N = 1,221 for mortality

N = 1,153 for CHD 

events

For mortality sample:

Age (mean): 54.9 

Gender (% male): 100

Race: NR

BMI: 25.7

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: unclear

Risk of Bias: medium

Tangney 201189

USA 

Chicago Health 

and Aging 

Project (CHAP) 

Funding: 

National Institute 

on Aging

Cohort

Cohort:

-enrollment beginning in 1993 

-age ≥65 

-≥2 cognitive assessments

Included: 

-living on south side of Chicago; 

Excluded: 

-died before follow-up

-invalid dietary data

-only one cognitive assessment

MedDiet score based on FFQ (139 

items) over past year; maximum 

score of 55 (greatest conformity) 

a) consumption of fruit, vegetables, 

legumes, nuts and beans, fish, 

olive oil, potatoes, and nonrefined 

cereals assigned a score of 5 for at 

least daily consumption and < 5

points for fewer servings (0 if rarely 

consumed)

b) opposite scoring for red meat 

and meat products (0 if > 10 

times/week and 5 if ≤ 1 time/ week)

c) 0 for alcohol intake >700 mL/d or 

N = 3,790

Age (mean): 75

Gender (% male): 38

Race: 60% black

BMI: 27.1

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low 

Risk of Bias: medium
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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

none at all; 5 for < 300 mL/d

MedDiet Wine score same as 

above but alcohol consumption 

only includes wine 

Follow-up: 7.6 years (mean)

Fung 201059

USA

NHS and HPFS

Funding: 

National 

Institutes of 

Health

Cohort

Cohort:

NHS

-121,700 female nurses, age 30-55

-questionnaires sent biennially since 1976

-first FFQ in 1980, expanded in 1984 (baseline); 

designed to measure intake for previous year

Included:

-completed 1980 FFQ with <10 missing items

-realistic total energy intake (500-3500 kcal/d)

HPFS:

-initiated in 1986 among US male health 

professionals age 40-75 years

-completed FFQ for past year, updated every 4 

years

Excluded:

-history of cancer, except non-melanoma skin 

cancers or ulcerative colitis

aMED

a) 1 point if intake is >median for 

vegetables, legumes, fruit, nuts, 

whole-grain cereals, fish, and 

monounsaturated:saturated fat 

ratio

b) 1 point for intake< median for 

red and processed meats

c) 1 point for alcohol intake of 5-

15g/d 

Follow-up: 26 years

NHS

N = 87,312 women

HPFS

N = 45,080 men

Age: 30-55 for women, 

40-75 for men)

BMI = 24

Population: unclear

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Roberts 201082

USA 

Mayo Clinic 

Study of Aging

Funding: 

National 

Institutes of 

Health and

private 

foundation

Cohort

Cohort:

-randomly selected from all Olmsted County (MN) 

residents age 70-89 on 10/1/2004 (longitudinal 

analysis of cognitively normal or MCI reported)

Excluded: 

-died before contacted 

-terminally ill and in hospice 

-previously diagnosed confirmed dementia

-could not be contacted

-missing FFQ or responses on more than 10 

questions

-reported extreme caloric intake

Health Habits and History 

Questionnaire (128 items) to 

assess eating habits in past year; 

portion size and frequency; used to 

calculate MD score (0 = minimal, 9

= maximal conformity) 

a) 1 point for ≥ median 

consumption of vegetables, 

legumes, fruits, cereal, MUFA:SFA, 

and fish

b) 1 point for < median 

consumption of meat and dairy 

products

c) 1 point for alcohol consumption 

of 0-30g/d

Follow-up: 2.2 years 

N = 1141 in follow-up 

cohort (1233 with 

baseline data)

Age (median): 80

Gender (% male): 51%

Race: NR

BMI

<25: 32%

25-29: 40%

≥30: 28%

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Agurs-Collins

200960 Cohort:-African-American women from across US

Prudent Pattern: higher intakes of 

cruciferous and other vegetables, 

N = 50,778

Age (mean): 38.5

Population: unclear

Outcomes: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

USA

Black Women’s 

Health Study

Funding: 

National Cancer 

Institute

Cohort

-enrolled 59,000 women in 1995

-age 21-69

-baseline FFQ to assess average food intake over 

previous year

-follow-up questionnaires sent every 2 years

Included:

-completed 1995 baseline FFQ

-missing data on ≤ 10 questions on FFQ 

-total caloric intake of 500 to 3800 kcal/d

-completed at least one follow-up questionnaire

-did not report breast cancer at baseline

fruit, whole grains, cereals, beans, 

low-fat dairy products, fish, and 

poultry

Follow-up: 12 years 

BMI: 27.9 Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Féart 200977

France 

Three-City (3C) 

Study

Funding: Institut 

National de la 

Sante et de la 

Recherche

Medicale, Institut 

de Sante

Publique et 

Developpement, 

and SanofiAventis

Cohort

Cohort: 

-community-dwelling, identified in 1999-2000 from 

electoral rolls in Bordeaux

Included: 

-age ≥65 

-at least one follow-up re-examination over 5 

years

Excluded: 

-missing dietary data 

-did not complete screening for dementia

-dementia at baseline 

FFQ: aggregated into 20 food and 

beverage groups with focus on MD 

foods: vegetables, fruits, legumes, 

cereals, fish, meat, dairy, and 

alcohol; score from 0 to 9 (higher 

score = higher conformity) 

a) 1 point for > sex median of 

vegetables, fruits, legumes, 

cereals, and fish

b) 1 point for < median 

consumption of meat and dairy 

products

c) 1 point for 10-20g/d of alcohol 

for men and 1.4-5.7g/d for women

d) 1 point for > median ratio of 

MUFA:SFA

24-hour Dietary Recall: for nutrient 

intake, total energy intake, and 

ratio of MSFA to SFAs

Follow-up: 2, 4, and 7 years 

N = 1410

Age (mean): 76

Gender (% male): 40%

Race: NR

BMI: 26 

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Scarmeas 200985

See Scarmeas 

200688

Cohort

Cohort: see below

Excluded: 

-missing dietary or physical activity evaluation

-death or loss to follow-up

Same as above

Follow-up: 5.4 years 

N = 1880

Age (mean): 77

Gender (% male): 31

BMI: 27.4

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Scarmeas 200987

See Scarmeas 

200688

Cohort: see below

Excluded: 

-dementia or MCI at baseline (including CDR = 

0.5)

Same as above

Follow-up: 4.5 years 

N = 1393 cognitively 

normal at baseline

Age (mean): 77

Gender (% male): 32

Population: low

Outcomes: low

Measurement: low

Confounding: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Cohort -missing dietary information BMI: 27.5 Risk of Bias: low

Psaltopoulou 

200881

Greece

ILIDA (nested in 

EPIC-Greece)

Funding: 

European 

Commission, 

Greek Ministry of 

Health, Greek 

Ministry of 

Education, 

private grant, and 

Hellenic Health 

Foundation

Cohort

Included: 

-residence in Attica region 

-age ≥60 at enrollment 

-agreed to participate

Excluded: 

-died during follow-up

-missing information on diet, anthropometric, or 

lifestyle variables

-reported a stroke at baseline

Conformity to MD based on 9 

components: vegetables, legumes, 

fruit and nuts, cereals, fish, meat, 

dairy, ethanol, and lipids; 10-point 

score (0 = minimal conformity, 9 = 

maximal conformity) 

a) 1 point for > median 

consumption of vegetables, 

legumes, fruit and nuts, cereals, 

and fish

b) 1 point for < median 

consumption of meat and dairy

c) 1 point for 10-50g/d alcohol for 

men 5-25g/d for women

d) 1 point for ≥ median MUFA:SFA 

ratio

Follow-up: 8 years

N = 732

Age (mean)

60-64 yrs: 40%

65-69 yrs: 33%

≥70 yrs: 26%

Gender (% male): 35

Race: NR

BMI: 

≤24.99: 15%

25.00-29.00: 45%

≥30.00: 40%

Population: low

Outcomes: low

Measurement: low

Confounding: unclear

Risk of Bias: low

Reedy 200861

USA-6 states or 

2 metropolitan 

areas

NIH-AARP

Funding: 

National Cancer 

Institute

Cohort

Cohort:

-Mailed population-based survey linked with 

cancer registry data and death databases (for 

outcomes)

Included: 

-age 50-71

Excluded: 

-proxy respondents 

-cancer, ESRD 

-extreme daily caloric intake (either high or low)

Dietary Assessment: MED score 

constructed based on FFQ

Follow-up: 5 years

N = 492,382 Population: low

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: low 

Tinker 200830

USA

WHI-DM

Funding: 

National Heart, 

Lung, and Blood 

Institute

RCT

Cohort: 

-postmenopausal women

-age 50-79 years 

-interested in one or more components of the 

clinical trials 

Included:

-willing to be randomized to an intervention or 

comparison group

-fat intake at baseline of 32% or more

Excluded: 

-any prior colorectal or breast cancer

-other cancers in the last 10 years except nonIntervention (IG): intensive 

behavioral modification program 

using 18 group sessions in first 

year and then quarterly sessions

a) reduce total fat to 20% of energy 

intake

b) increase vegetables and fruits to 

at least 5 servings daily and grains 

to at least 6 servings daily

c) anticipated that saturated fat 

would also be reduced 

Comparison (CG): received US 

N = 45,887

IG: 18,376 CG: 27,511

Age (mean): 62

Race: 82% white

10% black 8% other

BMI: 28.9

Sequence 

generation: low

Allocation 

concealment: low

Blinding: unclear

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

97

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

melanoma skin cancer

-medical conditions with predicted survival < 3 

years 

-adherence or retention concerns 

-current dietary intake of <32% of energy from fat

-type 1 diabetes mellitus

Department of Health and Human 

Services Dietary Guidelines for 

Americans and other health-related 

materials but not asked to make 

any dietary changes

Follow-up: 8.1 years

Prentice 200731

USA

WHI-RCDM

Funding: 

National Institute 

of Arthritis and 

Musculoskeletal 

and Skin 

Diseases, 

National Heart, 

Lung, and Blood 

Institute, National 

Institutes of 

Health, and US 

Department of 

Health and 

Human Services

RCT

Cohort: 

-postmenopausal women

-age 50-79 years

-interested in one or more components of the 

clinical trials

Included:

-willingness to be randomized to an intervention 

or comparison group

Excluded: 

-prior breast or colorectal cancer

-other cancer except non-melanoma skin cancer 

within the past 10 years 

-medical conditions yielding predicted survival of 

< 3 years 

-adherence or retention concerns 

-baseline diet estimated to have less than 32% of 

energy from fat

Intervention (IG): intensive 

behavioral modification program 

using 18 group sessions in first 

year and then quarterly sessions

a) decrease total fat intake to 20% 

or less of energy

b) consume 5 or more servings per 

day of vegetables and fruits and 6 

or more servings per day of grains

Comparison (CG): received US 

Department of Health and Human 

Services Dietary Guidelines for 

Americans

Follow-up: 8.1 years

N = 48,835 

IG: 19,541 (40%); CG: 

29,294 (60%)

Age (mean): 62.3

BMI≥25: 75%

Sequence 

generation: low

Allocation 

concealment: low 

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low

Sant 2007 and 

Sieri 2004 62,70

Italy

ORDET study

Funding: Italian 

Association for 

Research on 

Cancer

Cohort

Cohort:

-population-based, prospective

Included: 

-healthy women age 34-70 in one Northern Italy 

province 

Excluded: 

-history of cancer, bilateral oophorectomy, or

chronic or acute liver disease 

-on hormone therapy in the 3 months before 

recruitment

Dietary Assessment: selfadministered semi-quantitative 

FFQ from which 4 diet patterns 

were derived (2 relevant for 

Mediterranean diet review)

a) salad vegetables: raw 

vegetables and olive oil

b) prudent: cooked vegetables, 

rice, poultry, fish, and low alcohol 

consumption

Follow-up: 9.5 years (Sieri 2004)

N = 8,984

Age: NR

Gender (% male): 0 

Race: NR

BMI: NR

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low 

Risk of Bias: low

Beresford 200623

USA

WHI-DM

Funding: 

Cohort: 

-postmenopausal women

-age 50-79 years 

-interested in one or more components of the 

Intervention (IG): intensive 

behavioral modification program 

using 18 group sessions in first 

year then quarterly sessions 

N = 48,835 IG: 19,541 

(40%) CG: 29,294 

(60%)

Age 50-59: 36.9%

Sequence 

generation: low

Allocation 

concealment: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

National Heart, 

Lung, and Blood 

Institute and 

Department of 

Health and 

Human Services

RCT

clinical trials

Included:

-willing to be randomized to an intervention or 

comparison group

-fat intake at baseline of 32% or more

Excluded: 

-any prior colorectal or breast cancer

-other cancers in the last 10 years 

-type 1 diabetes

-medical conditions with predicted survival of < 3 

years 

-adherence concerns 

a) reduce total fat to 20% of energy 

intake

b) increase vegetables and fruits to 

at least 5 servings daily and grains 

to at least 6 servings daily

c) anticipated that saturated fat 

would also be reduced 

Comparison (CG): received US 

Department of Health and Human 

Services Dietary Guidelines for 

Americans and other health-related 

materials but not asked to make 

any dietary changes

Follow-up: 8.1 years

60-69: 46.5%

70-79: 16.6%

Gender (% male): 0

Race: 81% black, 11% 

white, 4% Hispanic, 

0.5% American Indian, 

2% Asian/pacific 

islander, and 1.3% 

unknown

BMI: NR

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low

Fung 200665

USA

NHS

Funding: 

National 

Institutes of 

Health

Cohort

Cohort:

-121,700 female nurses, aged 30-55, 

questionnaires sent out biennially since 1976

-First FFQ in 1980, expanded in 1984 (baseline), 

designed to measure intake for previous year

Included:

-completed the 1984 FFQ with fewer than 70 

missing items

-total caloric range between 500 and 3500 

kcal/day

Excluded:

-women with a history of cancer, except nonmelanoma skin cancers

aMED (higher score is more 

healthful): vegetables (except 

potatoes), legumes, fruits, nuts, 

cereals (whole grain only), red and 

processed meat, fish, alcohol, and 

the monounsaturated:saturated fat 

ratio

a) 1 point for > median intake of 

foods listed except 1 point for < 

median consumption of meat 

b) 1 point for alcohol consumption 

5-15g/d. 

Follow-up:18 years

N = 71,058

BMI: 24.5

Population: unclear

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: medium

Howard 200632

USA

WHI-DM

Funding: 

National Heart, 

Lung, and Blood 

Institute, 

Department of 

Health and 

Human Services

RCT

Cohort:

-postmenopausal women

-age 50-79 years 

Included:

-fat intake at baseline of 32% or more

Excluded: 

-any prior colorectal or breast cancer

-other cancers except non-melanoma skin cancer 

in the last 10 years

-type 1 diabetes

-medical conditions with predicted survival of < 3 

years 

-adherence concerns (alcoholism)

Intervention (IG): intensive 

behavioral modification program 

using 18 group sessions in first 

year then quarterly sessions 

a) reduce total fat to 20% of energy 

intake

b) increase vegetables and fruits to 

at least 5 servings daily and grains 

to at least 6 servings daily

c) anticipated that saturated fat 

would also be reduced 

Comparison (CG): received US 

Department of Health and Human 

N = 48,835

IG: 19,541 (40%) CG: 

29,294 (60%)

Age (mean): 62.3

BMI: 29.1

Sequence 

generation: low

Allocation 

concealment: low

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

99

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

-frequent consumption of meals not made at 

home

Services Dietary Guidelines for 

Americans and other health-related 

materials but not asked to make 

any dietary changes

Follow-up: 8.1 years

Lagiou, 200663

Sweden

Swedish WLH

Funding: 

Swedish 

Research 

Council and 

Swedish Cancer 

Society

Cohort

Cohort:

-from 1991-1992 recruited women age 30-49

years who lived in Uppsala Health Care Region

-96,000 women randomly selected from Swedish 

central population registry to receive invitation 

letter and questionnaire 

-follow up questionnaire mailed to previous 

respondents in 2003

-questionnaires asked about diet in previous 6 

months

Included: 

-completed a baseline questionnaire

Excluded: 

-emigrated without re-immigration prior to start of 

study

-prevalent cancer (excluding non-melanoma skin 

cancer), CHD, or diabetes at enrollment

-missing information on any covariates studied

-total energy intake outside 1st and 99th

percentiles

Dietary Assessment: FFQ about 

diet for 6 preceding months; 

conformity measured using variant 

of Mediterranean diet score (Low = 

0 High = 9): 

a) 1 point for > median 

consumption of vegetables, fruits 

and nuts, legumes, cereals, fish, 

and high ratio of unsaturated to 

saturated fat

b) 1 point for < median 

consumption of dairy and meat 

products

c) 1 point for alcohol consumption 

between 5-25 g/day

Follow-up: 12.01 years

n = 42,237

Age 29-34: 24%

35-39: 26%

40-44: 26%

45-49: 24%

BMI <25: 73%

25-29.9: 22%

≥30: 5%

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Scarmeas 200688

USA 

Washington 

Heights-Inwood 

Columbia Aging 

Project

(WHICAP) 

Funding: 

National Institute 

on Aging and

private 

foundation

Cohort 

Cohort: 

-participant in cohort (WHICAP 1992, WHICAP 

1999) 

-identified from probability sample of Medicare 

beneficiaries residing in an area of 3 contiguous 

census tracts in northern Manhattan

Excluded: 

-missing or incomplete dietary information

-died within 1.5 years from baseline assessment

-follow-up not available

Semi-quantitative FFQ (61 items) 

used to determine MD score (0 = 

minimal conformity, 9 = maximum) 

a) 1 point for > median 

consumption of fruits, vegetables, 

legumes, cereals, and fish

b) 1 point for < median

consumption of meat and dairy

c) 1 point for > median ratio of 

MUFA:SFA

d) 1 point for alcohol 0-30gm/d. 

Follow-up: 4 years 

N = 2226

Age (mean): 77

Gender (% male): 32

BMI: 27.4

Population: low

Outcomes: low

Measurement: low

Confounding: low 

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Scarmeas 2006-

286

See above

Cohort

Cohort: see above

Excluded: 

-non-demented at baseline but developed 

dementia at follow-up 

-deemed non-demented but had Clinical 

Dementia Rating (CDR) > 0

-deemed demented but had either a non-AD 

diagnosis or a CDR > 1

-missing dietary information 

Same as above N = 1984

Age (mean): 76

Gender (% male): 32

BMI: 27.7

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Adebamowo 

200569

USA

NHS II

Funding: Not 

reported

Cohort

Cohort:

-116,671 female registered nurses

-age 25-42

-questionnaires mailed biennially

Included: 

-free of cancer

-responded to baseline questionnaire 

Excluded:

-implausible values for total energy intake 

(<600kcal or >3500kcal/day)

-left more than 70 items on the FFQ blank

-diagnosis of cancer, except non-melanoma skin 

cancer before the start of follow-up

-in situ breast cancer

-postmenopausal at baseline 

Prudent: vegetables, fruit, 

legumes, whole grains, fish, 

poultry, and low-fat dairy products

Follow-up: 8 years

Mean age: 36 (4.6)

Prudent:

Quartile 1 (lowest): N

= 17934, Age 35.5, 

BMI: 24.7

Q3: N = 18452, Age 

36, BMI: 24.4

Q5: N = 17470, age 

36.4, BMI: 24.7

Population: unclear

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium 

 

Kim 200568

Japan

JPHC

Funding: Ministry 

of Health, Labor, 

and Welfare of 

Japan

Cohort

Cohort:

-54,498 residents

-age 40-59 years at beginning of study (1/1990)

-FFQ covered past month

Included:

-returned questionnaire

Excluded:

-self-reported serious illness (cancer, ischemic 

heart disease, cerebrovascular disease, or 

chronic liver disease) at baseline

-not Japanese

-moved away at baseline

-reported extreme total energy intake (upper 2.5% 

or lower 2.5%) 

-reported a past history of cancer

Healthy: heavily loaded with 

vegetables, fruits, soy products, 

seaweeds, mushroom, milk, beans, 

and yogurt

Follow-up: 9 years

N = 42,112 

Men (n = 20,300)

Age: 48-50.7

BMI: 23-24

Women (n = 21,812)

Age: 48.6-50.9

BMI: 23-24

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

101

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Mannisto 200574

Europe

DIETSCAN 

(NLCS)

Funding:

Dutch Cancer 

Society and 

Commission of 

the European 

Communities

Cohort

Cohort:

-DIETSCAN looked at 3 cohorts (NLCS, SMC, 

and ORDET); only NLCS was extracted because 

data from other studies had been reported 

previously

Included:

-women selected from 204 Dutch municipalities

-age 55-69 years 

Vegetable pattern: high intake of 

vegetables, legumes, fruit, pasta, 

fish, and oil

Follow-up: 7 years

N = 62,537

Age (mean): 61.4

Gender (% male): 0

BMI: 25.1

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low

Michaud 200567

USA

NHS/HPFS

Funding: Public 

Health Service 

Grants from 

National 

Institutes of 

Health

Cohort

NHS Cohort:

-121,700 female nurses

-age 30-55 years

-questionnaires sent out biennially since 1976

-first FFQ in 1980, expanded in 1984 (baseline), 

designed to measure intake for previous year

Inclusion:

-responded to 1984 FFQ

Excluded: 

-diagnosed with cancer other than non-melanoma 

skin cancer before 1984

-implausibly low or high daily energy intake (<500 

or >3500kcal/day)

HPFS Cohort:

-initiated in 1986 among US male health 

professionals

-age 40-75 years

-completed FFQ for past year, updated every 4 

years

Excluded:

-men reporting implausible energy intake (<800 or 

>4200 kcal/d)

-missing ≥70 food items on baseline FFQ

-diagnosed with cancer, except non-melanoma 

skin cancer

Prudent: high consumption of 

vegetables, legumes, fruit, whole 

grains, fish, and poultry.

Follow up: 16 years

NHS: N = 77,179

Prudent

Q1: N = 16,351, age 

50.8, BMI: 24.9 

Q3: N = 16,352 age 

50.8, BMI: 25.1 

Q5: N = 16,351, age 

50.9, BMI: 25.3 

HPFS: N = 47,493

Prudent

Q1: N = 9,175, age 

54.3, BMI: 25.1 

Q2: N = 9,659, age 

54.3, BMI: 25, 

Q3: N = 9,374, age 

54.4, BMI: 24.8

Population: unclear

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

102

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Velie 200566

USA

BCDDP

Funding: 

National Cancer 

Institute Cancer 

Prevention 

Fellowship 

Program

Cohort

Cohort:

-participants selected from >280,000 past 

participants in BCDDP breast cancer screening 

program (1973 to 1981) 

Included:

-diagnosis of breast cancer, non-malignant or 

benign breast disease determined by biopsy or 

surgery

-recommended for biopsy or breast surgery but 

did not have surgery performed

-sample of women with no evidence of breast 

disease also included

-data collected 5 times

-FFQ about food intake over past year

-completed survey

Excluded:

-caloric intake <400 or ≥3800kcal/day

-≥ 300 skipped food items

-premenopausal at fourth data collection

-received diagnosis of breast cancer before or at 

time of 2nd data collection

-unknown or missing menopausal data

-did not complete 2nd data collection

-FFQ unusable

-inappropriate entry and exit dates

-missing information for parity, age at first live 

birth, and education

Vegetable-Fish/Poultry-Fruit:

a) high intakes of vegetables, 

broiled or baked fish, and chicken 

b) low intakes of sweets and white 

bread

Follow-up: 8 years

N = 40,559 women, 

4005 lost to follow-up

Age (mean); 62 (range 

40-91 at study start) 

BMI <18.5: 2-3.1%

18.5 to <25: 46.8-

61.8%

25 to <30: 28-34.4%

≥30: 7.2-16.7%

 

Population: low

Outcomes: unclear

Measurement: 

unclear

Confounding: low

Risk of Bias: medium

Dixon 200472

Europe

DIETSCAN

Funding: 

Commission of 

the European 

Communities 

Cohort

Cohort:

-3 European cohorts* 

-ATBC: RCT of male smokers in Northern 

Finland, 29,113 men, age 50-69y, completed 

FFQ before randomization asking about diet for 

previous year

-NLCS on Diet and Cancer: prospective cohort 

study of 58,279 men and 62,5347 women age 55-

69y 

-SMC: 61,462 women from Sweden born between 

1914-1948 and invited to participate in 

population-based mammography screening 

program in 1987-1990; FFQ about intake for 

Vegetable pattern: characterized 

by intake of vegetables and 

legumes, citrus fruit and berries, 

pasta and rice, poultry and fish, 

and oil and salad dressings. 

Correlated with intakes of Vitamins 

A,C, and E; folate; and 

polyunsaturated fatty acids

Follow-up: 6-14 years

ATBC men: 

N = 29,133

Age (mean): 57.2 

BMI: 26.3

NLCS men:

N = 58,279

Age (mean): 61.4

BMI: 25

NLCS women:

N = 62,573

Age (mean): 61.4

BMI: 25.1 

SMC women:

Population: unclear

Outcomes: low

Measurement: low

Confounding: unclear

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

103

Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

previous 6 months

*Fourth cohort (ORDET) in DIETSCAN did not 

provide necessary follow-up data

N = 61,463

Age (mean): 53.7

BMI: 24.8 (4.4)

Knoops 200471

Europe

HALE

Funding: 

European Union

Cohort

Cohort:

-SENECA started in 1988, random age- and sexstratified sample of inhabitants, born 1913-1918 

of 19 towns; HALE project included13 centers that 

carried out mortality follow-up; survey at baseline 

and repeated in 1993 and 1999; asked about diet 

in month before

-FINE: survivors of 5 cohorts of the Seven

Countries Study in Finland, Italy, and the 

Netherlands; started in 1984 and continued to 

2000; recruited men born 1900-1920; HALE 

included 1989-1991 baseline measurement of 

men aged 70-90; asked about previous 2-4wk diet

Excluded: 

-CHD, CVD, cancer, or diabetes at baseline

Modified Mediterranean Diet 

Score: 

a) 1 point for > sex specific median 

consumption of monounsaturated 

fatty acids to saturated fatty acids 

ratio, fruits and fruit products, 

vegetable and potatoes, legumes, 

nuts and seeds, fish, and grains

b) 1 point for < median 

consumption of meat and meat 

products and dairy products

Follow-up: 10 years

SENECA

Women (n = 832)

Age (mean): 73

BMI <25 : 41%

Men (n = 781)

Age (mean): 73

BMI <25: 39%

FINE

Men (n = 726)

Age (mean): 77

BMI <25: 42%

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Trichopoulou 

20034

Greece

EPIC-Greek 

cohort

Funding: Europe 

Against Cancer 

Program 

(European 

Commission), 

Greek Ministry of 

Health, and 

Greek Ministry of 

Education

Cohort

Cohort:

-520,000 apparently healthy men and women

-age 25-70

-recruited between 1992 and 2000 in 23 centers 

from 10 European countries, some countries had 

specialized cohorts (eg, just women in France)

-usual dietary intakes at enrollment assessed

through center-specific FFQ that addressed usual 

diet over previous year

Included: 

-Greek component of EPIC

-vital status could be ascertained

-complete information on dietary, lifestyle, and 

anthropometric variables

Excluded:

-diagnoses of coronary heart disease, diabetes 

mellitus, or cancer at enrollment

a) 1 point for > sex-specific median 

consumption of vegetables, 

legumes, fruits and nuts, cereal, 

and fish

b) 1 point for < median 

consumption of meat, poultry, and 

dairy products

c) 1 point for alcohol consumption 

between 10-50g/day for men or 5-

25g/day for women

d) fat intake measured using ratio 

of monounsaturated lipids to 

saturated lipids.

Follow-up: 3.7 years

N = 22,043

Age <55: 57%

55-64: 23%

≥65: 20%

Gender (% male): 40

BMI

Men: 28.1

Women: 28.8

 

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source 

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient 

Characteristics Risk of Bias

Terry 200173

Sweden

Swedish 

Mammography 

Screening Cohort

Funding: 

Swedish Cancer 

Society, Swedish 

Research 

Council, and 

World Cancer 

Research Fund

Cohort

Cohort:

-questionnaires and mailed invitations to be 

screened by mammography sent to women born 

between 1917 and 1948 in Vastmanland county 

and women born between 1914 and 1948 in 

Uppsala County

-questionnaire asked about diet for previous 6 

months

Excluded:

-women outside the age range 40-76y

-missing or incorrect identification numbers

-lacking date on questionnaire, date for moving 

out of study area, or date of death

-extreme energy intake estimates below 416kcal 

or above 3,729kcal (+/- 3SDs)

-previous cancer diagnosis other than nonmelanoma skin cancer

Healthy: fruit and vegetables, fish 

and poultry, cereal and whole grain 

breads, fruit juice, and low fat dairy 

products

Follow-up: 9.6 years

61,463 women

Healthy:

Q1: median 54y, BMI: 

24.3

Q3: 52y, BMI: 24.1

Q5: 52y ,BMI: 24.2

Population: low

Outcomes: low

Measurement: 

unclear

Confounding: unclear

Risk of Bias: medium

a Protocol modified approximately half-way through enrollment to follow intervention schedule of MD groups including completion of 9-item conformity scale 

AD = Alzheimer’s disease; aMED = alternate Mediterranean diet score; BMI = body mass index; CV = cardiovascular; EVOO = Extra Virgin Olive Oil; FFQ = food 

frequency questionnaire; MCI = mild cognitive impairment; MD = Mediterranean diet; MUF = monounsaturated fat; NR = not reported; Q = quantile; RCT = 

randomized controlled trial; SF = saturated fat
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Table 2. Key Question 1 – Mortality, Quality of Life, Adverse Events, and Patient Satisfaction 

Study

Intervention (n)

Control (n)

All-cause Mortality

% (n/N)

Health-related Quality of 

Life (describe)

Patients with any

Adverse Event % (n/N)

Adverse Events Related 

to Diet (describe) % (n/N)

Patient Satisfaction 

(describe)

Intervention Control Intervention Control Intervention Control Intervention Control Intervention Control

Cancer

Beresford 

200623

N = 48,835

950/19541 

(0.6%)

End points 

accrued 

through 

3/05

1454 

(0.61%)

HR 0.97 

(0.89, 1.05)

Cardiovascular Disease

Estruch 20137

N = 7,447

Group 1: 

4.6% 

(118/2543)

10.0/

1000 p-y 

HR 0.82

(0.64, 1.07)

Group 2: 

4.7% 

(116/2454)

11.2/

1000 p-y 

HR 0.97 

(0.74, 1.26)

4.7% 

(114/2450)

11.7

1000 p-y 

(P = NS)

No relevant 

diet-related 

adverse 

events 

reported

Cognitive Impairment

Kwok 201224

N = 429

13% 

(27/204)

11% 

(25/225)

HR = hazard ratio; NS = not statistically significant
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Table 3. Key Question 1 – New Onset of Cardiovascular-related Conditions (Myocardial Infarction, Stroke, Congestive Heart 

Failure) and Rhematoid Arthritis

Study

Intervention (n)

Control (n)

MI

% (n/N)

Stroke

% (n/N)

Rheumatoid Arthritis

% (n/N)

Other (specify)

% (n/N)

Other (specify)

% (n/N)

Interventio

n

Control Intervention Control Interventio

n

Control Intervention Control Interventio

n

Control

Cardiovascular Disease

Estruch 20137

N = 7,447

Group 1: 

1.5%

(37/2543)

3.1/1000 p-y 

HR 0.80 

(0.51, 1.26)

Group 2:

1.3%

(31/2454)

3.0/1000 p-y 

HR 0.74 

(0.46, 1.19)

1.6%

(38/2450

) 

3.9/

1000 p-y 

(P = NS)

Group 1: 

1.9%

(49/2543)

4.1/1000 p-y 

HR 0.67 

(0.46, 0.98)

Group 2: 

1.3%

(32/2454)

3.1/1000 p-y 

HR 0.54 

(0.35, 0.84)

2.4%

(58/2450)

5.9/

1000 p-y 

(P < .05 

vs Groups 

1 and 2)

Death from CV 

Cause

Group 1: 1.0%

26/2543

2.2/1000 p-y 

HR 0.69 (0.41, 

1.16)

Group 2: 1.3%

31/2454

3.0/1000 p-y 

HR 1.01 (0.61, 

1.66)

1.2%

30/2450

3.1/

1000 p-y 

(P = NS)

MI, Stroke, 

Death from 

CV Cause

Group 1:

2.7%

69/2543

8.1/1000 p-y 

HR adj 0.70 

(0.54, 0.92)

Group 2:

3.4%

83/2454

8.0/1000 p-y 

HR adj 0.72 

(0.54, 0.96)

4.4%

109/2450

11.2/

1000 p-y 

(P < .05 

vs 

Groups 1 

and 2)

Howard 200632

N = 48,835

435/19541 

HR 0.98 

(0.87, 1.11)

671/29,2

94

379/19541

HR 1.03 

(0.90, 1.06)

556/2929

4 

CHD death

158/19541 

HR 1.02 (0.84, 

1.25)

CABG/PCI

717/19541

HR 0.96 (0.88, 

1.06)

Composite 

CHD

1000/19541

HR 0.97 (0.90, 

1.06)

CHD 

death

234/2929

4 

CABG/PC

I 

1113/292

94

Composit

e CHD

1549/292

94
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

MI

% (n/N)

Stroke

% (n/N)

Rheumatoid Arthritis

% (n/N)

Other (specify)

% (n/N)

Other (specify)

% (n/N)

Interventio

n

Control Intervention Control Interventio

n

Control Intervention Control Interventio

n

Control

Diabetes

Salas-Salvado 

201426

N = 3,541

Diabetes

New cases

Group 1: 6.9% 

(80/1154) 16.0 

per 1000 PY

HR 0.60 (0.43, 

0.85) vs control

Group 2: 7.4% 

(92/1240) 18.7 

per 1000 PY

HR 0.82 (0.61, 

1.10) vs control

8.8% 

(101/

1147) 

23.6 per 

1000 PY

Tinker 200830

N = 45,887

New diagnoses 

of diabetes

1303 (7.1%)

2039 

(7.4%)

HR 0.96 

(0.9, 1.03)

Rheumatoid Arthritis (RA)

Hu 201593

N = 174,638

Highest quartile vs 

lowest quartile

HR of RA: 0.98 (0.80, 

1.20), P = .85 for trend

CABG = coronary artery bypass graft; CHD = coronary heart disease; CI = confidence interval; CV = cardiovascular; HR = hazard ratio; MD = Mediterranean 

diet; MI = myocardial infarction; NR = not reported; PY = person year; RR = risk ratio
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Table 4. Key Question 1 – New Onset of Kidney Disease, Cancer, and Cognitive Impairment

Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Cancer

Buckland 201536

N = 461,550

Gastric Cancer Risk

>8 points 220/192,337 

HR 0.87 (0.69, 1.09) P = .22

Catsburg 201535

CSDLH N = 3,320

NBSS N = 89,835

CSDLH

Healthy

Q5: 452 cases/14,799 py

HR 0.73 (0.58, 0.91) P trend = .001

NBSS

Healthy

Q5: 688 cases/160,145 py

HR 0.84 (0.65, 1.10) P trend = .199

Harmon 201534

N = 156,804

Cancer Mortality

Men

aMED

Q1: 1267

Q2: 1053 HR 0.92 (0.88, 1.00) 

Q3: 1165 HR 0.92 (0.85, 0.99)

Q4: 1032 HR 0.88 (0.81, 0.96)

Q5: 1336 HR 0.81 (0.75, 0.89)

Women

aMED

Q1: 1107

Q2: 939 HR 0.96 (0.88, 1.05)

Q3: 886 HR 0.85 (0.77, 0.93)

Q4: 946 HR 0.95 (0.86, 1.04)

Q5: 1152 HR 0.84 (0.76, 0.92)
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Toledo 201527

N = 4,282

Breast Cancer 

Risk

MeDiet+EVOO 

8/1,476

HR 0.32 (0.12, 

0.79)

MeDiet+nuts

10/1,285

HR 0.59 (0.26, 

1.35)

Both 18/2,761

HR 0.43 (0.21, 

0.88)

Both MDs 

≤67: HR 0.16 

(0.05, 0.5)

>67: HR 0.92 

(0.34, 2.47)

BMI<30: HR 0.29 

(0.11, 0.83)

BMI≥30: HR 0.57 

(0.22, 1.49)

17/1391

Vormund 201533

N = 17,861 

Cancer Mortality

Per 1 point increase in MDS

Classical MDS, dairy bad

HR 0.97 (0.93, 1)

Men HR 0.94 (0.89, 0.99) 

P<.05

Women HR 1.0 (0.94, 1.06)

Alternative MDS, dairy good

HR 0.95 (0.92, 0.99) P<.05

Men HR 0.92 (0.88, 0.97) 

P<.05

Women HR 0.98 (0.93, 1.04)

Compared to MDS<4

MDS 4-6 HR 0.87

MDS 6-9 HR 0.86
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Ax 201444

N = 1,044

Adequate reporters 

566

Risk of Prostate Cancer

Entire study population (1,044) 

P trend = .32

Adequate reporters (566)

Continuous HR 1.01 (0.75, 1.37)

High Score 9/73 HR 1.04 (0.43, 2.49)

P = .9
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Buckland 201475

N = 477,312

Per 4-unit increase in rMED for 

Urothelial Cell Carcinomas (UCC) 

HR 0.95 (0.87, 1.03)

In current smokers, UCC, high versus 

low rMED score

HR 0.66 (0.47, 0.93)

Overall

1,425cases/477,312

Low score: 588/131,522 HR 1 

Medium score: 565/206,353

HR 0.94 (0.83, 1.07)

High Score: 272/139,437 

HR 0.84 (0.69, 1.03), P trend = .107

Age at diagnosis <65

Low score: HR 1 

Medium Score: HR 0.84 (0.69, 1.02)

High Score: HR 0.81 (0.61, 1.07) P = 

.102

Age>65 Low score HR 1 

Medium score HR 1.02 (0.86, 1.21)

High Score HR 0.86 (0.64, 1.14) 

P trend = .504

Men:

Medium score: HR 0.95 (0.81, 1.01)

High score: HR 0.79 (0.62, 1.01) 

P trend = .094

Women

Medium score: HR 0.92 (0.73, 1.18)

High Score: HR 0.95 (0.68, 1.33) 

P trend = .692

BMI<25

Medium: HR 0.98 (0.79, 1.21)

High: HR 0.92 (0.66, 1.28) P trend = 

.637

BMI>25

Medium: HR 0.93 (0.79, 1.10)

High: HR 0.82 (0.64, 1.06)

P trend = .138

Cuenca-Garcia 

201443

N = 12,449

Cancer Mortality

Q4: 33 deaths/2,123

HR 1.63 (0.91, 2.92)

P trend = .432
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

George 201442

N = 63,805 

Cancer Deaths

aMED

Q1: 509/11,685 HR 1 

Q2: 428/11,416 HR 0.87 

(0.76, 0.99)

Q3: 485/12,919 HR 0.88 

(0.77, 1.00) 

Q4: 428/12,077

HR 0.83 (0.73, 0.95)

Q5: 534/15,708 HR 0.8 (0.7, 

0.92) P = .001

BMI<25: HR 0.73 (0.59, 0.9) P

= .003

BMI 25-29.9: HR 0.78 (0.62, 

0.98) P = .032

BMI≥30: HR 0.98 (0.75, 1.27) 

P = .87, Pinteraction = .331

Kenfield 201441

N = 47,867

Risk of Prostate Cancer

Score 6-9: 2,054 cases HR 0.95 (0.9, 

1.02), P trend = .13

Li 201440

N = 494,967

MVA HR (comparing highest quintile to 

lowest quintile on aMED score)

Men: 0.80 (0.64, 1.01), P trend = .002)

Women: 0.42 (0.24, 0.74) 

P trend <.0001

Lopez-Garcia 

201439

N = 17,415

Death from Cancer

Men

Q5: 71 cases RR 0.88 (0.63, 

1.21), P trend = .14

2-point increase RR 0.9 (0.79, 

1.03)

Women

Q5: 26 cases RR 0.80 (0.48, 

1.33), P trend = .48 

2 point increase RR 0.94 

(0.78, 1.13)

Pooled

Q5: RR 0.85 (0.65, 1.11) P 

trend = .1

2 point increase RR 0.91 

(0.82, 1.02)
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Reedy 201438

N = 424,662

Cancer Mortality

MVA HR (comparing highest 

to lowest aMED score quintile)

Women: 0.79 (0.74, 0.85)

Men: 0.80 (0.77, 0.84)

Xie 201437

N = 82,984

Ovarian cancer

Q5: 159 cases, HR 0.91 (0.71, 1.18) 

P trend = .44
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Bamia 201353

N = 397,641 

Colorectal Cancer

MMDS* HR 0.96 (0.92, 1.00)

6-9: HR 0.89 (0.80, 0.99) P = .02

CSMMDS* HR 0.97 (0.93, 1.01)

6-9: 0.92 (0.84, 1.00) P = .05

Men

MMDS* HR 0.97 (0.90, 1.03)

6-9: 0.89 (0.76, 1.04) P trend = .14

CSMMDS* HR 0.98 (0.92, 1.04)

6-9: 0.91 (0.8, 1.03) P trend = .14

Women

MMDS* HR 0.95 (0.90, 1.01)

6-9: 0.88 (0.77, 1.01) P trend = .05

CSMMDS* HR 0.96 (0.91, 1.01)

6-9: 0.93 (0.83, 1.05) P trend = .19

MMDS 

Colon Cancer* HR 0.95 (0.89, 1.00) 

6-9: HR 0.88 (0.78, 1.00) P = .03

Proximal colon cancer* 

HR 0.98 (0.90, 1.06)

6-9: HR 0.92 (0.76, 1.11) P = .31

Distal colon cancer* 

HR 0.92 (0.84, 0.99)

6-9: HR 0.83 (0.68, 1.00) 

P = .04

Rectal Cancer* 

HR 0.99 (0.92, 1.07)

6-9: HR 0.90 (0.76, 1.07) P = .3

France64

Relative Risks of Colorectal Cancer

Healthy

Q1: RR 1 

Q2: RR 0.92 (0.61, 1.38)

Q3: RR 0.81 (0.53, 1.23)

Q4: RR 0.77 (0.49, 1.20) P trend = .20

*Per 2 unit increment in scale

France64

Adenomas

(RR)

Healthy:

Q2: 0.97 (0.76, 

1.25)

Q3: 1.02 (0.79, 

1.30) 

Q4:0.85 (0.65, 

1.10) 

P trend = .29

*Also looked at 

RR for high-risk 

adenomas, no 

significant 

results64

Western:

Q2: 0.98 

(0.76, 

1.27)

Q3: 1.21 

(0.92, 

1.59)

Q4: 1.39 

(1, 1.94)

P trend = 

.03

Drinker

Q2:1.06 

(0.83, 

1.36)

Q3:1.09 

(0.85, 

1.41)

Q4:1.42 

(1.10,

1.83) 

P trend = 

.01

Meat 

Eaters

Q2: 1.23 

(0.96, 

1.57)

Q3: 1.03 

(0.80, 

1.33)

Q4: 1.13 

(0.87, 

1.46)

Bosire 201352

N = 293,464

Total Prostate Cancer (with reported 

PSA screening in preceding 3 years)

MVA HR (aMED score)

0.97 (0.91, 1.03), P trend = .09

Advanced Prostate Cancer

MVA HR (aMED score) 

1.0 (0.87, 1.15), P trend = .82 

Fatal Prostate Cancer

0.8 (0.59, 1.10), P trend = .23
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Buckland 201351

N = 355,062

arMED score

Low(0-5): 2,187 tumors/68,676 women 

HR 1 

Medium(6-9): 5,664/182,710 

HR 0.97 (0.92, 1.02)

High (10-16): 2,374/83,676 

HR 0.94 (0.88, 1.00) 

P trend = .048

Couto 201350

N = 44,840

Breast Cancer Cases

6-7: 297 RR 1.10 (0.92, 1.33)

8-9: 35 RR 1.42 (0.99, 2.05)

2-point increment in score: 1,278 cases 

RR 1.08 (1.00, 1.15)

Gamba 201329

N = 48,835

Non-Melanoma Skin Cancer

Cases: 

IG:1,923 CG: 2,984

HR 0.98 (0.92, 1.04)

Age 50-59: 505 HR 0.93 (0.83, 1.04)

60-69: 953 HR 0.98 (0.91, 1.07)

70-79: 465 HR 1.03 (0.91, 1.15)

P = .17

BMI: <25: 641 HR 1.06 (0.96, 1.17)

25 to <30: 687 HR 0.92 (0.84, 1.01)

≥30: 589 HR 0.97 (0.88, 1.08)

P = .26

Melanoma cases: 

IG: 114 

HR 1.04 (0.82, 1.32)

Age 50-59: 41 HR 0.99 (0.67, 1.47)

60-69: 54 HR 1.04 (0.73, 1.46)

70-79: 19 HR 1.15 (0.63, 2.09)

P = .25

BMI: <25: 28 HR 0.91 (0.57, 1.46)

25 to <30: 36 HR 0.83 (0.55, 1.24)

≥30: 50 HR 1.43 (0.97, 2.11)

P = .13
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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Gnagnarella 201349

N = 4,336

Lung Cancers

N (rate/100-year)

6-7: 38 (0.68)

HR 0.63 (0.35, 1.14)

8-9: 1.0 (0.11) HR 0.10 (0.01, 0.77)

P trend = .045

Kyro 201348

N = 57,053

Colorectal Cancer

HR (highest to lowest quintile) 

Men: 0.87 (0.61, 1.25), P trend = .94

Women: 0.65 (0.46, 0.94), P trend = .02

Li 201347

N = 494,968

Cardia adenocarcinoma

HR 1.10 (0.76, 1.61)

Noncardia adenocarcinoma

HR 0.75 (0.52, 1.09)

Esophageal Squamous Cell

HR (highest quintile to lowest quintile 

aMED score): 0.44 (0.22, 0.88); P trend 

= .03

Link 201346

N = 91,779

HR (highest to lowest quintile)

Salad: 1.12 (1.01, 1.25), P trend = 0.01

Ethnic: 0.94 (0.85, 1.05), P trend = 0.24

Mursu 201345

Baseline N = 29,634

Follow-up N = 

15,076

Cancer Mortality

Baseline cohort

757 cases/7,408

RR 0.88 (0.79, 0.98) 

P trend<.001

Follow-up cohort

98 cases/3,769

RR 0.83 (0.63, 1.09)

P trend = .037

Chiuve 201256

N = 112,524

Cancer Risk

Women (NHS)

Q4: 2,627 cases RR 0.93 (0.88, 0.99)

P trend = .01

Men (HPFS)

Q4: 1,205 cases RR 0.94 (0.87, 1.03) 

P trend = .13

Pooled

Q4: RR 0.94 (0.89, 0.98), P trend = .003
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Tognon 201254

N = 77,151

Cancer Specific Mortality

All Cancer

Men: 493 cases 

HR 0.92 (0.87, 0.98) 

Women: 481 

HR 0.98 (0.92, 1.03)

Pancreas

Men: 47 cases

HR 0.82 (0.68, 0.99)

Women: 45 HR 0.83 (0.69, 

1.00) 

Breast

Women: 80 HR 1.12 (0.97, 

1.28)

Colorectal

Men: 73 HR 1.07 (0.93, 1.24)

Women: 54 HR 0.91 (0.77, 

1.08)

Stomach

Men: 31 HR 1.07 (0.85, 1.34)

Women: 21 HR 1.24 (0.95, 

1.64)

Prostate

Men: 61 HR 0.88 (0.74, 1.03)

Respiratory

Men: 68 HR 0.86 (0.73, 1.00)

Women: 54 HR 1.05 (0.88, 

1.24)

Cade 201158

N = 33,731

Med diet Score

0-2: 94 cases/3,668 HR 1 

3: 123/4,486; HR 1.06 (0.77, 1.46)

4: 140/6,008; HR 0.98 (0.72, 1.33)

5: 165/6,272; HR 0.99 (0.73, 1.35)

6: 124/5,755; HR 0.84 (0.60, 1.17)

7-10: 182/7,542; HR 0.96 (0.70, 1.32)

P trend = .4
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Couto 201157

N = 478,478

All Cancers

HR for 2 point increment of MD score

All: 30,731 cases; HR 0.96 (0.95, 0.98)

Males: 9,669 cases; HR 0.97 (0.95, 

1.00) 

Females: 21,062; HR 0.96 (0.95, 0.98)

Score 6-9: 7308/118,818; HR 0.93 (0.9, 

0.96); P trend = .00001

Men

6-9: 2,455/38,908; HR 0.93 (0.88, 0.99)

P trend = .02

Women

6-9: 4,853/79,910; HR 0.93 (0.89, 0.96)

P trend = .0001

Menotti 201155

N = 1,221

Cancer mortality

Factor 2 HR 0.84 (0.74, 0.96)

Fung 201059

N = 87,312

aMED

Colorectal P = .14

Men: Q5 RR 0.88 (0.71, 1.09)

Women: Q5: RR 0.88 (0.74, 1.05)

Agurs-Collins 

200960

N = 50,778

Breast Cancer Cases

Prudent

Q1:182/87,582py RR 1 

Q2: 202/88,780py RR 0.97 (0.78, 1.20) 

Q3: 239/89,353py RR 0.99 (0.79, 1.22)

Q4: 214/89,554py RR 0.80 (0.64, 0.99)

Q5: 257/88,473py RR 0.86 (0.68, 1.08)

P trend = .06

BMI<25*

Q1: 55/28,165py RR 1 

Q5: 72/27,862py RR 0.64 (0.43, 0.93)

P trend = .01

BMI: 25 to <30*

Q1: 61/27,143py RR 1 

Q5: 94/30,528 RR 1.11 (0.73, 1.66)

P trend = .88

BMI≥30*

Q1: 66/32,274py RR 1 

Q5: 90/30,083 py RR 0.94 (0.62, 1.42)

P trend = .44
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Reedy 200861

N = 492,382

Colorectal Cancer

MVA HR (highest to lowest quintile of 

Mediterranean diet score0 

Men: 0.72 (0.63, 0.83)

Women: 0.89 (0.72, 1.11)

Prentice 200731

N = 48,835

Invasive Cancer

Ovary 0.36 (57)* HR 0.83 (0.60, 1.14)

Endometrium 0.79 (125)* HR 1.11 

(0.88, 1.40) 

Breast 4.15 (655)* HR 0.91 (0.83, 1.01)

Colorectal 1.27 (201)* HR 1.08 (0.90, 

1.29)

All other sites 4.56 (720)* HR 0.95 

(0.86, 1.04)

Total 10.69 (1,687)* HR 0.95 (0.89, 

1.01)

*Incidence of Invasive Cancer per 1000 

py (N cases) for Intervention Group

Invasive Ovarian Cancer (57 cases) 

Age 50-59: 0.26 (16) HR 0.70 (0.39, 

1.27)

60-69: 0.32 (23) HR 0.65 (0.40, 1.05)

70-79: 0.72 (18) HR 1.69 (0.86, 3.31); 

BMI: <25.9: 0.42 (22) HR 1.01 (0.59, 

1.73)

25.9 to <30.9: 0.3 (16) HR 0.60 (0.34, 

1.07)

≥30.9: 0.35 (18) HR 0.89 (0.50, 1.60) 

Total Invasive Cancer (1,687 cases) 

Age 50-59: 7.95 (483) HR 0.94 (0.84, 

1.06)

60-69: 11.41 (821) HR 0.93 (0.86, 1.02)

70-79: 15.27 (383) HR 0.99 (0.87, 1.13)

BMI: <24.9 9.56 (396)

HR 0.91 (0.81, 1.04)

24.9 to <28.2: 10.61 (596) HR 0.97 

(0.88, 1.08)

28.2 to <32.5: 11.5 (412)

HR 0.94 (0.83, 1.06)

≥32.5: 11.59 (275) HR 0.98 (0.84, 1.14)
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Sant 2007, Sieri 

2004 62,70

N = 8,861

Breast Cancer

MVA HR (highest tertile to lowest tertile 

of dietary conformity) (Sieri 2004)

Salad vegetable 0.66 (0.47, 0.95); P 

trend = .016

Prudent: 1.28 (0.90, 1.83); P trend = 

.169

HER-2 positive (Sant 2007)

Salad vegetable: 0.25 (0.10, 0.64) P 

trend = .001)

Prudent: 0.72 (0.35, 1.48); P trend = 

.372) 

HER-2 negative (Sant 2007)

No associations between any diet and 

breast cancer incidence

Beresford 200623

N = 48,835

Invasive Colorectal Cancer 

201/19,541 (0.13%)

HR 1.08 (0.90, 1.29)

Colon Cancer 153/19,541 (0.1%)

HR 1.05 (0.85, 1.30) 

Rectal cancer 50/19,541 (0.03%) 

HR 1.11 (0.77, 1.61) 

Colorectal Cancer Mortality

47 (0.03%) HR 1.26 (0.85, 

1.85)

Polyps/Adenoma Incidence: 

3,402 (2.16%) HR 0.91 (0.87,

0.95)

Total Cancer Incidence 1,946 

(1.24%) HR 0.97 (0.89, 1.05)

Total Cancer Mortality

436 (0.28%) HR 0.96 (0.90, 

1.01)

Fung 200665

N = 71,058

Breast Cancer Risk (aMED quintiles)

Q1:629 cases RR 1 

Q2: 679 RR 0.92 (0.83, 1.03)

Q3: 669 RR 0.89 (0.80, 1.00) 

Q4:750 RR 0.94 (0.84, 1.05)

Q5: 853 RR 0.98 (0.88, 1.10) 

P = .69

ER+ cases

Q1 to Q5 RR 1.05 (0.91, 1.18)

P trend = .23

ER- cases

Q1 to Q5 RR 0.79 (0.6, 1.03) 

P trend = .03

Change in risk for ER-BC with a 10% 

increase in score: 7% reduction P = .02
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Lagiou 2006 

N = 42,23763 Death from CancerTrend per 2 point increase in 

diet score:

All ages

280/42,237 MR = 0.89 (0.77, 

1.04); P trend = .2

Age <40

76/21,149 MR = 1.07 (0.79, 

1.43)

Age ≥40

204/21,068 MR = 0.84 (0.71, 

1.01) P = .184 for interaction

Score 6-9: 54/9,453 MR = 0.8 

(0.57, 1.13)

Adebamowo 200569

N = 90,638

Breast Cancer, Prudent

Q1 = 127 cases/139,864py RR 1 

Q2 = 124 cases/143,717py 

RR 0.96 (0.75, 1.23)

Q3 = 147 cases/144,021py 

RR 1.02 (0.80, 1.31)

Q4 = 169 cases/136,359py

RR 0.90 (0.68, 1.18)

P = .36
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Kim 200568

N = 42,112 

Men, Healthy pattern

Colorectal Cancer

Q4: 53/47,710py HR 0.81 (0.52, 1.24) 

P trend = .8

Colon Cancer

Q4: 36 HR 0.83 (0.49, 1.41) P trend = 

.62

Rectal cancer

Q4: 17 HR 0.76 (0.37, 1.58)

P trend = .76

Women, Healthy pattern

Colorectal Cancer

Q4: 36/52,289py HR 0.98 (0.58, 1.65)

P trend = .82

Colon Cancer

Q4: 20 HR 0.76 (0.39, 1.50) 

P trend = .68

Rectal cancer

Q4: 16 HR 1.43 (0.62, 3.28)

P trend = .34

Mannisto 200574

N = 1,598

Breast Cancer

Q4: RR 0.90 (0.67, 1.20)

Michaud 200567

N = 124,672

Pancreatic Cancer Risk, Prudent

NHS

Q5 41/239,717py RR 0.93 (0.52, 1.64)

P = .57

HPFS

Q5: 37/119,513py RR 1.88 (1.06, 3.32) 

P trend = .09

Pooled

Q5: RR 1.32 (0.66, 2.63)

P trend = .83
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Velie 200566

N = 40,559

Breast Cancer

Vegetable-fish/poultry-fruit

Q1: 341 cases RH = 1 

Q2: 391 cases RH = 1.12 (0.90, 1.3)

Q3: 378 RH 1.07 (0.92, 1.24)

Q4: 386 RH 1.07 (0.92, 1.25)

Q5: 372 RH 1.03 (0.88, 1.20)

P trend = .95

Invasive Breast Cancer

Q1: 245 RH = 1 

Q2: 290 RH 1.15 (0.97, 1.37)

Q3: 272 RH 1.06 (0.89, 1.27)

Q4: 284 RH 1.09 (0.91, 1.3)

Q5: 274 TH = 1.04 (0.87, 1.26)

P trend = .77

*No evidence of interaction with BMI 
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Dixon 200472

ATBC = 19,133

NLCS = 120,852

SMC = 61,463

Vegetable Pattern, Colorectal Cancer

ATBC: 322cases/286,967py

Linear RR 1.07 (0.95, 1.20) 

Q4 RR 1.22 (0.87, 1.73); P trend = .09

NLCS men: 660 cases/10,496py

Linear RR 1.03 (0.93, 1.15) 

Q4 RR 1.04 (0.78, 1.39); P trend = .41

NLCS women: 512 cases/11,328py

Linear RR 0.92 (0.81, 1.03)

Q4 RR 0.91 (0.65, 1.27); P trend = .78

SMC women: 586cases/749,282py

Linear RR 1.03 (0.93, 1.14)

Q4 RR 0.99 (0.77, 1.27); P trend = .9

Colon Cancer 

ATBC men: 191cases/287,375py

Linear RR 1.02 (0.87, 1.19)

Q4 RR 1.05 (0.66, 1.67); P trend = .66

NLCS men: 400cases/10,509py

Linear RR 1.02 (0.89, 1.16)

Q4 RR 0.93 (0.65, 1.32); P trend = .93

NLCS women: 360cases/11,334py

Linear RR 0.87 (0.76, 1.01)

Q4 RR 0.78 (0.54, 1.15); P trend = .29

SMC women: 396cases/749,964py

Linear RR 1.03 (0.91, 1.16)

Q4 RR 0.96 (0.71, 1.30) P trend = .87

Rectal cancer

ATBC men: 133cases /287,486py

Linear RR 1.14 (0.95, 1.36)

Q4 RR 1.48 (0.88, 2.49) P trend = .04

NLCS men: 260cases/10,525py

Linear RR 1.05 (0.91, 1.21) Q5 RR 1.23 

(0.83, 1.83) P trend = .16

NLCS women: 152cases/11,355py

Linear RR 1.01 (0.85, 1.21)

Q4 RR 1.33 (0.76, 2.35); P trend = .24

SMC women: 193cases/750,318py

Linear RR 1.06 (0.87, 1.29)

Q5 RR 1.12 (0.70, 1.79); P trend = .84
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Knoops 200471

N = 1,507

Cancer Mortality

Med Diet score ≥4 

HR 0.90 (0.70, 1.17)

233 deaths/2,152 at risk

Trichopoulou 

20034

N = 22,043

Death from Cancer

97/22,043

HR (2-pt increment in MD 

score): 0.76 (0.59, 0.98)

Terry 200173

N = 61,463

Breast Cancer, Healthy Pattern (Rate 

Ratios) 

Ages 40-76, P trend = .52

Q1: 1

Q2: 0.94 (0.79, 1.12)

Q3: 0.96 (0.80, 1.14)

Q4: 0.95 (0.79, 1.14)

Q5: 0.92 (0.76, 1.13)

Ages 40-49, P trend = .68

Q1: 1

Q2: 0.87 (0.63, 1.20) 

Q3: 1.12 (0.83, 1.53)

Q4: 0.86 (0.61, 1.20) 

Q5: 0.91 (0.63, 1.31)

Ages 50-76. P trend = .52

Q1: 1

Q2: 0.97 (0.79, 1.19)

Q3: 0.86 (0.70, 1.07)

Q4: 0.99 (0.79, 1.23)

Q5: 0.91 (0.72, 1.16)

Cognitive Impairment

Gardener 201579

N = 527

Authors’ conclusion: Higher 

baseline conformity to AusMeDi 

associated with better performance 

in executive function cognitive 

domain after 36 months in APOE 

E4 allele carriers (positive trend in 

cohort as a whole); no significant 

relationships between prudent diet 

conformity and cognitive function 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Koyama 201592

N = 2,326

Mean difference in slope of 3MS 

scores (high vs lower scores 

[points/year])

Whites: 0.09 (-0.03, 0.21), P = .14

Blacks: 0.22 (0.05, 0.39), P = .01

Valls-Pedret 201528

Group 1: MD+EVOO 

(n = 127)

Group 2: MD+nuts 

(n = 112)

Group 3: Usual care 

(n = 95)

Global Cognition 

Outcomeb

(adjusted 

change from 

baseline)

Group 1: 0.05

Group 2: -0.05

Incidence of 

MCIc

Group 1: 13.4% 

(17/127)

Group 1: 7.1% 

(8/112)

Global 

Cognition

-0.38 

(P = .005 for 

Group 1 vs 

control)

MCI

12.6%

(12/95) 

(P = .28)

MMSE 

(adjusted 

change from 

baseline)

Group 1: 

0.16 Group 

2: 

-0.07

-0.26

(P = NS)

Tangney 201490

N = 826

Rate of decline in global cognitive 

score (based on 19 cognitive tests)

MD: per one unit higher 

MedDietScore rate of decline was 

slower by 0.002 standardized units 

(P = .01)a

Only the upper tertile of 

MedDietScores was associated 

with rates of global cognitive 

change (P = .003)

No evidence of modification by age 

or sex
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Intervention (n)

Control (n)

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% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Kesse-Guyot 

201380

n = 3,083

Association between diet 

conformity and composite 

cognitive score (adjusted mean 

differences with high conformity as 

reference)

MDS:

Low conformity: -0.18 (-1.09, 0.73)

Medium conformity: 0.58 (-0.21, 

1.37)

(P = .27 with conformity as 

continuous variable)

No interaction between conformity

and sex with regard to cognitive 

performance

Martinez-Lapiscina 

201325

Group 1: MD+EVOO 

(n = 224)

Group 2: MD+nuts 

(n = 166)

Group 3: Usual care 

(n = 132)

Incidence of MCI

Group 1: 8.0% 

(18/224)

Group 2: 11.4% 

(19/166) 

Incidence of 

Dementia 

Group 1: 5.4% 

(12/224)

Group 2: 3.6% 

(6/166)

MCI 17.4% 

(23/132)

Dementia

12.9% 

(17/132)

MMSE at 

Follow-up 

(adj means)

Group 1: 27.7

Group 2: 27.7

CDR at Followup (adj means)

Group 1: 5.3

Group 2: 5.1

27.1 

(P < .05 for 

both 

groups vs 

control)

4.8

(P < .05 for 

both 

groups vs 

control)

Samieri 201384

N = 16,058

MD score not significantly 

associated with change over time 

in TICS, global cognitive score, or 

verbal memory score 

(P trends = .31, .84, and .70) 

Samieri 201383

N = 6,174

Q5 vs Q1

Global Cognition Mean Difference: 

0.02 (-0.03, 0.06), P = .63

Verbal Memory Mean Difference: 

0.03 (-0.02, 0.07); P = .44
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Wengreen 201391

N = 3,580

Participants in highest quintile of 

Med Diet Score scored 0.94 points 

higher on baseline assessment 

than did subjects in lowest quintile 

(P = .001)

Time X quintile of DASH or MD 

score not significant (difference in 

3MS scores between quintiles 

consistent over time)

Cherbuin 201276

N = 1,557

MCI: 10 new cases

OR 1.41 (0.95, 2.10)* 

CDR (0.5): 19 new cases

OR 1.18 (0.88, 1.57)*

Any MCD: 37 new cases

OR 1.20 (0.98, 1.47)*

*per one unit change in MeDi

Gardener 201278

N = 723

Correlation between baseline MD 

score and change in cognitive 

performance at 18 months (n = 

652):

MMSE: Correlation = .098, P = 

.014

Logical Memory II: Correlation = -

.011, P = .779

Delis-Kaplan Executive Function 

System: Correlation = .042, P = 

.294

California Verbal Learning Test II: 

Correlation = .029, P = .472

Kwok 201224

N = 429

Demented

22/162 (13.6%)

Worse 36/162 

(22.2%)

Demented

30/180 

(16.7%) P = 

.427

Worse 49/180 

(27.2%) P = 

.285
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Tangney 2011 89

N = 3,790

MedDiet and Med Diet Wine 

scores associated with higher 

baseline global cognitive scores 

and reduced declines in cognitive 

function (P<.001) (adjusted for 

age, gender, race, education, 

participation in cognitive activities, 

and energy)

Roberts 201082

N = 1,141

No significant association of MD 

score with incident events

HR (incident MCI or dementia):

Second tertile: 0.79 (0.51, 1.21)

Upper tertile: 0.75 (0.46, 1.21)

Féart 200977

N = 1,410

Cognitive Function

MD conformity as continuous 

variable: each additional unit of 

diet score associated with fewer 

MMSE errors, diet score X time (P

= .04)

No association with other cognitive 

tests

MD conformity as a categorical 

variable: no association with

cognitive function 

No association between MD

conformity and risk for incident 

dementia or AD

Scarmeas 200985

N = 1,880

Decrease in AD risk with 

increasing physical activity and 

diet conformity (low physical 

activity/

low MD conformity as reference) 

Adjusted (n = 1,598) 

Low activity/high MD: HR 0.77 

(0.53, 1.13)

High activity/low MD: HR 0.81 

(0.57, 1.16)

High activity/high MD: HR 0.65

(0.44, 0.96)
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Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Scarmeas 2009-287

N = 1,383

Higher MD conformity associated 

with borderline trend for lower risk 

of developing MCI

MD Continuous

Adjusted (n = 1,199) HR 0.92 

(0.85, 0.99)

MD Tertiles (Low as reference)

Middle: HR 0.83 (0.62, 1.12)

High: HR 0.72 (0.52, 1.00)

Psaltopoulou 

200881

N = 732

Multiple regression-derived 

adjusted differences in mean score 

on MMSE per specified differences 

in possible predictor variables at 

enrollment

No significant differences: gender, 

BMI, MD score (overall)

Scarmeas 200688

N = 2,226

Development of AD

MD Continuous

Adjusted (n = 1,759): HR 0.91 

(0.83, 0.98), P = .015

MD Tertiles

Adjusted (n = 1,759); low tertile 

(score 0-3) as reference

Middle tertile (score 4-5): HR 0.85 

(0.63, 1.16)

High tertile (score 6-9): HR 0.60 

(0.42, 0.87) P = .007

Significant MD X time interaction: 

higher conformity to MD 

associated with slower cognitive 

decline (Β = 0.003; P = .047)
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Study

Intervention (n)

Control (n)

Kidney Disease

% (n/N)

Cancer

% (n/N)

Cognitive Impairment

% (n/N)

Other (specify)

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Scarmeas 2006-286

N = 1,790

Risk for AD

Adjusted (n = 1,300); low tertile 

(score 0-3) as reference

Middle tertile (score 4-5): OR 0.47 

(0.29, 0.76)

High tertile (score 6-9): OR 0.32 

(0.17, 0.59) 

With all vascular variables in 

model

Adjusted (n = 1,259); low tertile 

(score 0-3) as reference

Middle tertile (score 4-5): OR 0.48 

(0.29, 0.79)

High tertile (score 6-9): OR 0.31 

(0.16, 0.58)

BC = breast cancer; CDR = Clinical Dementia Rating; CI = confidence interval; ER = estrogen receptor; HR = hazard ratio; MCD = mild cognitive disorder 

(any); MCI = mild cognitive impairment; MD = Mediterranean diet; MMSE = Mini Mental State Examination; MR = mortality ratio; MVA = multivariate 

analysis; NR = not reported; NS = not statistically significant; Q = quantile; RR = risk ratio
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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KEY QUESTION 2

Table 5. Key Question 2 – Study, Intervention, and Patient Characteristics

Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

Cancer

Yang 2015110

USA

Physicians’ Health 

Study (PHS) 

Funding: 

Department of 

Defense, National 

Institutes of 

Health, and 

Prostate Cancer 

Foundation

Cohort

Cohort: 

-men participating in PHS I or II and continued to 

be followed with annual questionnaires

-PHS I: initiated in 1982, randomized trial of 

aspirin and beta-carotene in US physicians age 

40-84

-PHS II: initiated in 1997, randomized trial of 

vitamin E, C, and a multivitamin, male US 

physicians

Included:

-diagnosed with non-metastatic prostate cancer

-completed a dietary assessment after prostate 

cancer diagnosis

Prudent Pattern: higher intake of 

legumes, vegetables, fruits, whole 

grains, garlic soy products, fish, and 

oil and vinegar

Follow-up: 9.9 years

926 men

Age (at diagnosis): 68.8

BMI <25: 46.7%

BMI 25-30: 47.3%

BMI >30: 6.1%

Population: unclear

Outcomes: low

Measurement: unclear

Confounding: low

Risk of Bias: medium

Fung 2014104

USA

NHS

Funding: National 

Institute of Health 

Cohort

Cohort:

-121,701 women, registered nurses age 30-55 at 

enrollment (1976)

-questionnaire every 2 years, diet every 4 years

Included: 

-diagnosed with stage I-III colorectal cancer 

(1986-2008) 

Excluded: 

-history of cancer within 3 years of colorectal 

cancer diagnosis

-died within first 6 months after return of first 

post-diagnosis biennial questionnaire or FFQ 

Diet assessed with first FFQ 

collected at least 6 months after 

diagnosis

aMED

a) 1 point for intake > cohort specific 

median in vegetables, legumes, 

fruits, nuts, whole grains, fish, and 

monounsaturated: saturated fat ratio

b) 1 point if intake was < median in 

meat, 

c) 1 point if alcohol intake 5-15g/day

Follow-up: 11.2 years

N = 1,201

Age (at entry to analysis): 

66.5

BMI: 25.4

Population: unclear

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Kenfield 201441

USA

HPFS

Funding: National 

Institutes of 

Health/National 

Cancer Institute 

and Prostate 

Cancer 

Foundation

Cohort:

-initiated in 1986 among US male health 

professionals age 40-75 yr

-completed FFQ for past year, updated every 4 

years

Excluded:

-reported implausible energy intake (<800 or 

>4200 kcal/d)

-missing ≥70 food items on baseline FFQ

-diagnosed with cancer, except non-melanoma 

Traditional Mediterranean diet score:

a) 1 point each for < median in dairy 

and meat intake

b) 1 point for alcohol intake of 10-50 

g/day

c) 1 point each for >median intake of 

vegetables, legumes, fruits and nuts, 

grains, fish, and the ratio of 

polyunsaturated to saturated lipids.

Follow-Up: 9 years

N = 4,538

Age (at diagnosis): 69-69.7

BMI: 25.2-26.2

Population: unclear

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

Cohort

skin cancer

-advanced cancer at diagnosis

-missing clinical stage

-no post diagnosis diet data

Vrieling 2013109

Germany

MARIE

Funding: 

Deutsche 

Krebshilife

Cohort

Cohort:

-recruited in 2002-2005

-Hamburg and Rhein-Neckar-Karlsruhe region of 

Germany

Included:

-histologically confirmed primary invasive (stage 

I-IV) or in situ breast cancer

-age 50-74 at diagnosis in 2001-2005

-FFQ referred to the year before diagnosis

Excluded:

-missing FFQ

-previous cancer

-in situ breast cancer

-energy intake in the top or bottom 1.0%

Healthy: high vegetables, fruits, 

vegetable oil, sauces/condiments, 

and soups/bouillons intake

Follow-up: 5.5 years

N = 2,522 Population: unclear

Outcomes: low

Measurement: unclear

Confounding: low

Risk of Bias: medium

Kim 2011105

USA

NHS

Funding: National 

Institutes of Health

Cohort

Cohort:

-121,701 women, registered nurses age 30-55 at 

enrollment (1976)

-questionnaire every 2 years, diet every 4 years

Included: 

-stage 1-3 breast cancer cases (1978-1998) 

Excluded: 

-stage 4 breast cancer

-4 or more positive lymph nodes without a 

complete negative metastatic work up

-missing disease stage 

-death or recurrence within 1y of breast cancer 

diagnosis

-cancer before 1978

-missing diet

-diet assessment during treatment or calculated 

recurrence date

aMED: 

a) 1 point for > median intake of 

vegetables, legumes, fruits, nuts, 

whole grains, fish, and 

monounsaturated:saturated fat ratio 

b) 1 point for < median intake of meat 

and dairy

c) 1 point for alcohol intake of 5-

15g/d.

Follow-up: 6-26 years

N = 2,729

BMI: 26 

Population: low

Outcomes: unclear

Measurement: low

Confounding: low

Risk of Bias: low

Kwan 2009107

USA

Life After Cancer 

Epidemiology 

(LACE)

Cohort:

-2280 women diagnosed with invasive breast 

cancer (1997-2000) 

Included:

-age 18-79

Prudent Diet: cruciferous vegetables, 

other vegetables, tomatoes, dark 

yellow vegetables, fruits, legumes, 

onions, leafy vegetables, fish, soups, 

whole grains, poultry (not fried), 

N = 1,901 women

Prudent:

Age: 58

BMI: 27-28

Population: low

Outcomes: low

Measurement: unclear

Confounding: low

Risk of Bias: low
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

Funding: National 

Cancer Institute, 

Utah Cancer 

Registry, and 

State of Utah 

Department of 

Health

Cohort

-diagnosis of early-stage primary breast cancer 

(stage I ≥1cm, stage II, or stage IIIA)

-enrollment 11-39 months after diagnosis

-completion of breast cancer treatment (except 

for adjuvant hormonal therapy)

-free of recurrence

-no history of other cancers in prior 5 years

Excluded:

-breast cancer recurrence

-new primary breast cancer

-death between diagnosis and 3 months after 

study enrollment

-incorrect stage

-prior breast cancer

-> 39 months since diagnosis

-incomplete demographic and medical data

-didn’t complete a dietary questionnaire at 

baseline (asked about previous yr)

-receiving treatment

-language difficulty

-extremes of dietary intake <500 or >4000kcal

-excessive number of skipped items

salad dressings (all type), rice, 

grains, plain pasta, fruit juice, low-fat 

dairy, nuts, potatoes (not fried), and 

cold cereals. 

Follow up: 5.93 years

Meyerhardt 

2007108

USA

Funding: National 

Cancer Institute 

and Pfizer 

Oncology

Cohort

Cohort:

-prospective 

-1,009 patients enrolled in randomized adjuvant 

chemotherapy trial

Included: 

-had complete surgical resection of primary 

tumor within 56 days of study entry

-had regional lymph node metastases but no 

distant metastases

-ECOG performance status of 0 to 2 

-adequate bone marrow, renal, and hepatic 

function

Dietary Assessment: based on selfadministered FFQ. 

Prudent (high fruits and vegetables, 

poultry, and fish)

Follow-up: 5.3 years

N = 1,009 Population: unclear

Outcomes: low

Measurement: unclear

Confounding: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

Kroenke 2005106

(Sub-study of Kim 

2011)

USA

NHS

Funding: National 

Cancer Institute

Cohort

Cohort:

-121,701 women, registered nurses age 30-55 at 

enrollment (1976)

-questionnaire every 2 years, diet every 4 years

Included: 

-diagnosed with invasive breast cancer (1982-

1998) 

-completed a dietary questionnaire in 1984 AND 

at least 1yr after breast cancer diagnosis

Excluded: 

in situ disease or metastatic breast cancer at 

diagnosis

-4 or more positive nodes but lacking a complete 

metastatic work-up

-previous cancer

Prudent:

a) higher amounts of fruit, 

vegetables, whole grains, low-fat 

dairy products, protein, and fiber

b) lower amounts of transunsaturated and saturated fats

c) lower glycemic load

Follow-up: 9 years

N = 2,619

BMI: 26 

Population: unclear

Outcomes: unclear

Measurement: unclear

Confounding: low

Risk of Bias: medium

Cardiovascular Disease

Tuttle 20088

USA

The Heart Institute 

of Spokane Diet 

Intervention and 

Evaluation Trial 

(THIS-DIET)

Funding: 

Washington State 

and intramural 

support from 

investigators’ 

clinical institutions

RCT

Included: 

-enrolled within 6 weeks of a first MI

Excluded: 

-NYHA class III or IV

-ventricular arrhythmias requiring medication or a 

defibrillator

-uncontrolled hypertension.

Intervention 1: low fat (AHA Step II 

diet)

Intervention 2: “Mediterranean style

diet” not otherwise described

Intervention participants received a) 

2 individual diet counselling sessions 

within first month

b) additional individual sessions at 2, 

6, 12, and 24 months

c) 6 different-content group sessions 

Controls: non-randomized, identified

through databases, met all inclusion 

and exclusion criteria, matched 1:1

with intervention patients within 6 

months after randomization, received

standard dietary advice from medical 

center dietitians

Follow-up: 46 months

Low fat (n = 50) Med (n = 

51) NR controls: (n = 101)

Age (mean) 

Low fat: 58

Med: 58

Control: 58

Gender (% male) 

Low fat: 68

Med: 80

Control: 74

BMI 

Low fat :31 

Med: 30

Control: 29

Sequence generation: 

unclear

Allocation 

concealment: unclear

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: unclear

Risk of Bias: medium 

Burr 200394

Wales

Funding: British 

Heart Foundation, 

Seven Seas Ltd, 

Novex Pharma, 

Included: 

-men<70 yr being treated for angina

Excluded: 

-awaiting CABG

-already eating oily fish twice a week

-intolerance to fish or fish oil

4 groups:

1. 2 portions of oily fish each week or 

up to 3 gm fish oil (N = 764)

2. 4-5 portions of fruits and 

vegetables, at least one glass orange 

juice, and increased oat intake (N = 

N = 3,114

Age (mean): 61

Gender (% male): 100

BMI: 28

Sequence generation: 

unclear

Allocation 

concealment: unclear

Blinding: unclear

Incomplete outcome 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

and the Fish 

Foundation

RCT

-other serious illness or likelihood of a move out 

of the area

779)

3. both intervention 1 and 2 (N = 807)

4. “sensible eating’ - nonspecific 

advice (N = 764)

Follow-up: 5 years

data: unclear

Selective outcome 

reporting: unclear

Risk of Bias: 

medium

Singh, 200298

India

Funding: Centre of 

Nutrition and 

Heart

RCT

Included: 

-≥ 1 major risk factor for coronary artery disease 

(hypertension, hypercholesterolemia, diabetes 

mellitus, angina pectoris, or previous myocardial 

infarction) 

-> 25 years old

Excluded: 

-absence of major risk factors

-cancer, chronic diarrhea or dysentery 

-a blood urea >6.6mmol/L

-arthritis

-dislike of intervention diet 

-refusal of laboratory testing

-death before randomization 

Intervention (Mediterranean-style): 

same diet and lifestyle advice as 

comparator group PLUS at least 400-

500g of fruits, vegetables, and nuts 

per day; 400-500g of whole grains, 

legumes, rice, maize, and wheat 

daily; mustard seed or soybean oil in 

3-4 servings per day

Comparator: 

a) advised to be active, take proper 

medications, not smoke or consume 

alcohol, and engage in mentally 

relaxing activities

b) suggested diet similar to NCEP 

step I prudent diet (<30% of energy 

from total fat, <10% from saturated 

fat, and <300 mg of cholesterol per 

day) 

Follow-up: 2 years

N = 1,000

IG: 499; CG: 501

Age (mean):

Intervention: 49 

Control: 48 

Gender (male)

Intervention: 91%

Control: 88%

BMI

Intervention: 24.3 

Control: 24.1 

Sequence generation: 

high

Allocation 

concealment: unclear 

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: medium

De Lorgeril 1998, 

19996,97

France

Lyon Heart Study

Funding: Institut 

National de la 

Sante et de la 

Recherche 

Medicale 

(INSERM); 

Ministry of 

Research; 

CNAMTS, 

CETIOM, and 

ONIDOL; AstraCalve BSN; and 

Foundation pour 

Included:

-<70 years 

-MI within past 6 months

Exclusion: 

-stage 3 or 4 heart failure 

-hypertension (SBP>180, DBP>110) 

-inability to complete an exercise test due to 

recurrent angina

-ventric arrhythmias or AV block

-any condition thought to limit survival or ability to 

participate in a long-term trial

Intervention:

a) more bread, more root vegetables 

and green vegetables, more fish, less 

meat (beef, lamb and pork to be 

replaced with poultry), no day without 

fruit, and butter and cream replaced 

with canola oil-based margarine 

supplied free by study

b) initial one-hour diet advice session 

followed by “further counselling at 

subsequent visits” (visit schedule: 8 

weeks then annual)

Comparator: no dietary advice apart 

from whatever they received as part 

of routine care

Follow-up: Intervention 46.7 months; 

Control 44.9 months

N = 584, Intervention 303, 

Control:302

Age (mean):

Intervention: 53.5

Control: 53.5

Gender (% male)

Intervention: 89.4

Control: 92.1

BMI

Intervention: 25.8

Control: 25.8

Sequence generation: 

unclear

Allocation 

concealment: low

Blinding: low

Incomplete outcome 

data: unclear

Selective outcome 

reporting: low

Risk of Bias: medium
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

la Recherche 

Medicale

RCT

De Lorgeril, 1994, 

199695,96

France

Lyon Heart Study

Funding: see De

Lorgeril 1998, 

1999 (above)

RCT 

See above See above

Follow-up: Intervention 26.9 months, 

Control 27.1 months

N = 605, Intervention 303, 

Control 302

Age (mean) 

Intervention: 53.5

Control: 53.5

Gender (% male)

Intervention: 89.4

Control: 92.1

BMI 

Intervention: 25.8

Control: 25.8

Sequence generation: 

unclear

Allocation 

concealment: low

Blinding: low

Incomplete outcome 

data: unclear

Selective outcome 

reporting: low

Risk of Bias: medium

Singh, 199299

India

Funding: Not 

reported

RCT

Included: 

-admission to hospital in previous 24 hours for 

acute MI or unstable angina

Excluded: 

-patient refusal 

-cancer, diarrhea, or dysentery

-death before randomization

-BUN > 400mg/l

-non-cardiac chest pain

Intervention (indo-Mediterranean): a) 

meat, eggs, hydrogenated oils, 

butter, and clarified butter replaced 

with vegetarian meat substitutes and 

soya bean, sunflower, and ground 

nut oils

b) advice to eat fruits, vegetables, 

pulses, nuts, and fish plus general 

health advice (regularly reinforced)

Comparator (Step 1 NCEP): 

a) meat, eggs, hydrogenated oils, 

butter, and clarified butter replaced 

with vegetarian meat substitutes and 

soya bean, sunflower, and ground 

nut oils 

b) general health advice that was 

NOT reinforced

Follow-up: 1 year 

N = 406/505 Intervention:

204, Control: 202

Age (mean) 

Intervention: 50.5

Control: 52.0

Gender (% male)

Intervention:(88%

Control: 92%

BMI 

Intervention: 24.3

Control: 23.3

Sequence generation: 

unclear

Allocation 

concealment: unclear

Blinding: low

Incomplete outcome 

data: unclear

Selective outcome 

reporting: unclear

Risk of Bias: Medium

*An article published in 

BMJ 2005 331 (7511) 

outlines serious doubts 

about Singh and this 

paper in particular and 

whether results are 

true or fabricated. A 

check of the raw data 

didn’t match the 

figures published and 

some methods have 

been questioned. 

Singh 1991100

India

Funding: Not 

Included: 

-responded to ads in local newspapers, clubs, 

and clinics

Intervention: 

a) meat and eggs replaced with fish 

or protein and fat-rich cereals and 

N = 463

Intervention: N = 228

Age (mean): 45.2

Sequence generation: 

unclear

Allocation 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

reported

RCT 

Excluded: 

-respondents with cancer, chronic renal failure, 

diarrhea, or dysentery 

-those who did not like diet protocol

cottage cheese

b) low in saturated fat; many fruits, 

vegetables, cereals, peas, beans, 

nuts, and soybean/sunflower oils*

c) follow-up at 1-4-wk intervals

d) counseling sessions with dietitian 

and one of the physicians, “the 

dietitian also made home visits to 

educate housewives regarding the 

maintenance of dietary compliance”

Control: usual care/diet

*Diets for obese and hyperlipidemic 

individuals lower in fat content and 

had same ratio of polyunsaturated to 

saturated fatty acids

Follow-up: 1 year

Gender (% male): 91

Obese: 36%

Control: N = 230

Age (mean): 47.5

Gender (% male): 90, 

Obese: 34%

concealment: low

Blinding: low

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: low

Cognitive

Scarmeas 200987

USA 

Washington 

Heights-Inwood 

Columbia Aging 

Project (WHICAP) 

Funding: National 

Institute on Aging

Cohort

Cohort: 

-WHICAP 1992, WHICAP 1999

-identified from probability sample of Medicare 

beneficiaries 

-residing in area of 3 contiguous census tracts in 

northern Manhattan

Included:

-diagnosis of MCI defined as 1) subjective 

memory complaint, 2) objective impairment in at 

least one cognitive domain (memory, executive, 

language, visuospatial), 3) essentially preserved 

activities of daily living, 4) no diagnosis of 

dementia 

Excluded: 

-missing or incomplete dietary information 

-insufficient data for MCI diagnosis

Semi-quantitative FFQ (61 items) 

used to determine MD score (0 = 

minimal conformity, 9 = maximum) 

a) 1 point for >median consumption 

of fruits, vegetables, legumes, 

cereals, and fish

b) 1 point for < median consumption 

of meat and dairy

c) 1 point for > median ratio of 

MUFA:SFA

d) 1 point for alcohol 0-30gm/d

Follow-up: 4.3 years 

N = 482 with MCI at 

baseline

Age (mean): 78

Gender (% male): 32

BMI: 27.2

Population: low

Outcomes: low

Measurement: low

Confounding: low

Risk of Bias: low

Rheumatoid Arthritis

McKellar 2007101

United Kingdom

Funding: Scottish 

Society of 

Physicians 

Cohort:

-recruitment aimed at residents from Social 

Inclusion Partnership areas in Glasgow (areas of 

social deprivation)

Included: 

-female

Intervention (n = 75): 

a) 6 week (2 hrs/wk) “hands-on” 

cookery course with emphasis on 

Mediterranean-type diet

b) written information on diet 

including recipes

N = 130

Age (mean): 54

Gender (% male): 0

BMI: 27.3

Disease duration: 9.4 years

Sequence generation: 

high

Allocation 

concealment: unclear

Blinding: unclear 

Incomplete outcome 
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Author, year

Country

Study name

Funding Source

Study type

Inclusion/Exclusion Criteria

Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

RCT -age 30-70 years 

Excluded: NR

c) information about food hygiene, 

nutrition, and local accessibility of 

affordable ingredients (fruits, 

vegetables, legumes, MUFA>SFA, 

olive oil)

Comparator (n = 55): received readily 

available written information on 

healthy eating

Follow-up: 6 months

data: low 

Selective outcome 

reporting: low 

Risk of Bias: medium

Sköldstam 2003102

Sweden

Funding: Faculty 

of Social Sciences 

(Umea University), 

Swedish 

Foundation for 

Health Care 

Sciences and 

Allergy Research, 

Health Research 

Council, and other 

foundations

RCT

Cohort:

-recruited from Kalmar in SE Sweden

Included: 

-RA (per 1987 American College of 

Rheumatology criteria) 

-disease duration ≥ 2 years

-disease clinically stable and under adequate 

control (per patient’s rheumatology specialist)

-disease modifying anti-rheumatic drugs 

unchanged for ≥3 months 

-corticosteroids unchanged for ≥4 weeks, and 

NSAIDs unchanged for ≥10 days before starting 

trial

Excluded:

-daily dose of oral corticosteroids (Prednisolone) 

>12.5 mg 

-DAS28 > 2.0 (active disease) 

-no condition other than RA that demanded 

active medical attention 

-vegetarian

-already living on Mediterranean-like diet

Intervention (n = 26): Cretan MD*

a) olive and canola oil for food 

preparation, baking, and salad 

dressings; canola oil margarine for 

cooking and as a spread

b) 6 diet lessons (plus consultations if 

needed)

c) written instructions and recipes 

d) some food supplied free (oils, 

margarine, frozen vegetables, and 

tea)

Comparator (n = 25): usual diet

NOTES: 

1) both groups participated in 3-week 

outpatient rehabilitation program (8 

hrs/day, 5 days/wk); lunch and dinner 

provided (either MD or usual diet, as 

randomized); study continued for 9 

additional weeks with participants 

preparing their own meals

2) daily doses of anti-rheumatic 

drugs, corticosteroids, and 

supplementary prescriptions

remained constant throughout study; 

NSAID doses could be adjusted

Follow-up: 3 months

*dairy and alcohol components 

modified for Swedish subjects

N = 51

Age (mean): 58

Gender (% male): 20%

Race: NR

BMI: 27*

Disease duration: 13.6 

years* 

*Intervention group 

participants had 

significantly higher BMI and 

longer disease duration

Sequence generation: 

unclear

Allocation 

concealment: unclear

Blinding: unclear

Incomplete outcome 

data: low

Selective outcome 

reporting: low 

Risk of Bias: low

AD = Alzheimer’s disease; aMED = alternative Mediterranean diet score; BMI = body mass index; FFQ = food frequency questionnaire; MCI = mild cognitive 

impairment; MD = Mediterranean diet; MUF = monounsaturated fat; NR = not reported; NSAID = non-steroidal anti-inflammatory; SF = saturated fat
Benefits and Harms of the Mediterranean Diet Compared to Other Diets Evidence-based Synthesis Program

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Table 6. Key Question 2 – Outcomes for Populations with Diabetes, Heart Disease, Kidney Disease, and/or Hypertension (Part 

1) 

Study

Intervention (n)

Control (n)

All-cause Mortality

% (n/N)

Quality of Life 

(describe)

Patients with any

Adverse Event % (n/N)

Adverse Events Related 

to Diet (describe) % (n/N) Other (describe)

Intervention Control Intervention Control Intervention Control Intervention Control Intervention Control

Cardiovascular Disease

Tuttle 20088

N = 101

Med Diet: 

0/51

Low fat 

diet: 0/50

P = 1.0

None 

described 

Cardiac Death 

Med Diet

0/51

Cardiac 

Death LowFat diet

0/50

P = 1.0

Burr 200394

N = 3,114

1. 18.4% 

(141/764) 

2. 17.1% 

(133/779) 

3. 17/6% 

(142/807) 

14/3% 

(109/764) 

Cardiac 

Deaths

Fish+Fruit 

10.7% 

(86/807)

Cardiac 

Deaths 

Sensible 

eating 

8.8% 

(67/764)

Singh 200298

N = 1,000

5% (24/299) 8% 

(38/501)

P = .064

Total cardiac 

endpoints:

7.8% 

(39/499)

Total 

cardiac 

endpoints

: 

15.2% 

(76/501)

ARR 0.48 

(0.33, 

0.71)

Suspected 

cardiac deaths

0.4% (2/499) 

Suspected 

cardiac 

deaths

0.2% 

(1/501) 

P = .56

De Lorgeril 

1998,19996,97

N = 605

4.6% 

(14/302) 

7.9% 

(24/303) 

RR 0.44 

(0.21, 

0.94)

Cardiac 

Deaths

2.0% (6/302) 

Cardiac 

deaths

6.3% 

(19/303) 

RR 0.35 

(0.15, 0.83)

De Lorgeril 1994, 

199695,96

N = 605

2.6% (8/302) 6.6% 

(20/303) 

HR 0.30 

(0.11, 

0.82)

2 pts reported 

“margarine 

related side 

effects”: 

“colitis” and 

“diarrhea”
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Study

Intervention (n)

Control (n)

All-cause Mortality

% (n/N)

Quality of Life 

(describe)

Patients with any

Adverse Event % (n/N)

Adverse Events Related 

to Diet (describe) % (n/N) Other (describe)

Intervention Control Intervention Control Intervention Control Intervention Control Intervention Control

Singh 1992 99

N = 406

10% 

(21/204) 

19% 

(38/202)

RR 0.55

(0.34, 

0.75)

“mild belching 

and fullness 

in a few 

patients”

Total Cardiac 

Mortality

9.8% (20/204) 

Total 

Cardiac 

Mortality 

16.8% 

(34/202)

RR 0.58 

(0.34, 0.83)

Singh 1991100

N = 458

3.5% (8/228) 4.8% 

(11/230)

NS

Complications

Angina: 12

Resistant 

HTN: 5 

Total: 101 

Angina:

28

HTN: 10

Total: 165

P<.02-

total

CI = confidence interval; HR = hazard ratio; HTN = hypertension; MD = Mediterranean diet; NR = not reported; NS = not statistically significant; RR = risk 

ratio
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Table 7. Key Question 2 – Outcomes for Populations with Diabetes, Heart Disease, Kidney Disease, and/or Hypertension (Part 

2) 

Study

Intervention (n)

Control (n)

New MI

% (n/N)

New Stroke

% (n/N)

New Revascularization 

Procedure % (n/N)

New Amputation

% (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Cardiovascular Disease

Tuttle 20088

N = 101

Med Diet

2% (1/51) 

Low-fat

6% (3/50) 

P = .36

Med Diet

6% (3/51) 

Low-fat

2% (1/50) 

P = .62

Med Diet

22% (11/51) 

Low-fat

16% (8/50) 

Singh 200298

N = 1,000

33/499 

(6.6%)

Non-fatal:

21/499 

(4.2%)

Adj RR 0.47 

(0.28, 0.79)

Fatal:

12/499 

(2.4%)

Adj RR 0.67

(0.31, 1.42)

60/501 (12%)

Non-fatal:

43/501 

(8.6%)

Fatal: 

17/501 

(3.4%)

*adjusted for 

age, gender, 

BMI, 

cholesterol, 

and blood 

pressure

7/499 (1.4%)

Stroke death:

2/499 (0.4%)

13/501 (2.6%) 

P = .17

Stroke death:

3/501 (0.6%)

CABG or 

angioplasty

6/499 (1.2%)

CABG or 

angioplasty

16/501 

(3.2%)

P = .03

De Lorgeril 19996

N = 605

Nonfatal MI:

2.6% (8/302) 

Nonfatal MI:

8.3% 

(25/303)

De Lorgeril 1994, 

199695,96

N = 605

Nonfatal MI:

1.6% (5/302) 

Nonfatal MI:

5.6% 

(17/303)

0/302 3/303 10% (31/302) 14% (41/303)

Singh 1992 99

N = 406

21% (43/204)

RR 0.62 

(-0.42, 0.83)

33% (67/202)

Singh 1991100

N = 458

12.3% 

(28/228)

20.0% 

(46/230)

0.4% (1/228) 1.3% (3/230)

CABG = coronary artery bypass graft; RR = risk ratio
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Table 8. Key Question 2 – Outcomes for Populations with Diabetes, Heart Disease, Kidney Disease, and/or Hypertension (Part 

3) 

Study

Intervention (n)

Control (n)

Development of Retinopathy

% (n/N)

Development of Neuropathy

% (n/N)

Development of End-stage 

Renal Disease % (n/N)

Development of Congestive 

Heart Failure % (n/N)

Intervention Control Intervention Control Intervention Control Intervention Control

Cardiovascular Disease 

Tuttle 20088

N = 101

0/51 0/50

P = 1.0

Singh 200298

N = 1,000

Heart Failure:

2.2% 

(11/499)

Heart Failure:

7% (35/501) P 

= .0003

De Lorgeril 19996

N = 605

2.0% (6/302) 3.6% (11/303)

De Lorgeril 1994, 

199695,96

N = 605

0.7% (2/302) 2.6% (8/303)

Singh 1991100

N = 458

0.9% (2/228) 0.9% (2/230)
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Table 9. Key Question 2 – Outcomes for Populations with Cancer

Study

Intervention 

(n)

Control (n)

Cancer-specific 

Mortality

% (n/N)

Quality of Life

(specify)

Cancer Progression

% (n/N)

Cancer Recurrence

% (n/N)

Adverse Events

% (n/N)

Interventio

n

Control Interventio

n

Control Interventio

n

Control Interventio

n

Control Intervention Control

Yang 2015110

N = 926

Prostate Cancer Mortality

Q4: 10 events/213

HR 0.46 (0.17, 1.24) 

P trend = .11

Fung 2014104

N = 1,201

Colorectal Cancer Mortality

aMED (P = .19)

Q1:39 RR 1 

Q2:32 RR 1.18 (0.73, 1.91)

Q3:32 RR 0.96 (0.58, 1.56)

Q4:23 RR 0.73 (0.42, 1.28)

Q5:36 RR 0.84 (0.50, 1.42)

Prudent (P = .16)

Q1:39 RR 1 

Q2:26 RR 0.67 (0.40, 1.12)

Q3: 30 RR 0.62 (0.37, 1.05)

Q4:35 RR 0.91 (0.53, 1.55)

Q5: 32 RR 0.67 (0.37, 1.22)

Kenfield 201441

N = 4,538

Fatal Prostate Cancer

6-9: 85 cases HR 1.01 (0.75, 

1.38) P = .95

Vrieling 

2013109

N = 2,522

Breast Cancer Mortality –

Healthy Diet Pattern

Q1: 72/614

Q2: 46/616 HR 0.76 

(0.51, 1.14)

Q3: 55/617 HR 0.83 

(0.56, 1.23)

Q4: 50/609 HR 0.89 

(0.59, 1.35)

P = .25

Breast Cancer 

Recurrence – Healthy

Diet Pattern

Q1: 67 recurrences/517 

(stage I-IIIa)

Q2: 56/542 HR 0.84 

(0.58, 1.21)

Q3: 61/543 HR 0.77 

(0.54, 1.12)

Q4: 55/533 HR 0.71 

(0.48, 1.06) 

P = .02
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Study

Intervention 

(n)

Control (n)

Cancer-specific 

Mortality

% (n/N)

Quality of Life

(specify)

Cancer Progression

% (n/N)

Cancer Recurrence

% (n/N)

Adverse Events

% (n/N)

Interventio

n

Control Interventio

n

Control Interventio

n

Control Interventio

n

Control Intervention Control

Kim 2011105

N = 2,729

Breast Cancer Deaths 

aMED 

Q1: 51 RR 1 

Q2: 48 RR 0.97 (0.63, 1.50)

Q3: 56 RR 0.72 (0.47, 1.10)

Q4: 73 RR 1.25 (0.83, 1.89)

Q5: 75 RR 1.15 (0.74, 1.77)

P = .21 

Pre-diagnosis diet not 

associated with mortality

Kwan 2009107

N = 1,901 

Death from Breast Cancer

Prudent

Q1: 34/451

Q2: 27/449 HR 0.78 

(0.46, 1.32)

Q3: 34/456 HR 0.94 

(0.57, 1.57)

Q4: 26/454 HR 0.79 

(0.43, 1.43)

P trend = .57

Breast Cancer 

Recurrence

Prudent

Q1: 62/451

Q2: 60/449 HR 0.95 

(0.66, 1.37)

Q3: 71/456 HR 1.09 

(0.76, 1.56)

Q4: 63/454 HR 0.95 

(0.63, 1.43)

P trend = .94

Meyerhardt 

2007108

N = 1,009

Colon Cancer 

Recurrence

1.13 (0.77, 1.67)

Kroenke 

2005106

(Sub-study of 

Kim 2011)

N = 2,619

Breast Cancer Deaths

Q1: 38 RR 1 

Q2: 38 RR 0.85 (0.53, 1.34)

Q3: 53 RR 1.17 (0.74, 1.84)

Q4: 56 RR 1.18 (0.75, 1.87)

Q5: 57 RR 1.07 (0.66, 1.73)

P = .57

aMed = alternative Mediterranean diet score; HR = hazard ratio; Q = quantile; RR = relative risk
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Table 10. Key Question 2 – Outcomes for Populations with Rheumatoid Arthritis 

Study

Intervention (n)

Control (n)

Pain (specify)

% (n/N) Quality of Life (specify) Functional Status (specify) Adverse Events% (n/N)

Intervention Control Intervention Intervention Control Control Intervention Control

McKellar 2007101

N = 130

Global pain 

score (VAS 0-

100) (median)

Baseline: 50

6 months: 50

Baseline: 55

6 months: 63

(P = .049)

DAS28 

(median)

Baseline: 4.7

6 months: 4.4

HAQ (median)

Baseline: 1.75

6 months: 1.63

Baseline: 5.0

6 months: 4.8

(P = NR; 

change reflects 

“no response”)

Baseline: 1.75

6 months: 1.88 

(P = NR at 6m)

Sköldstam 2003102

N = 51

Pain score 

(VAS 0-100) 

(mean)

Baseline: 32

12 weeks: 20

Baseline: 31

12 weeks: 34

(P = .006 for 

difference 

between 

groups for 

change from 

baseline to 12 

weeks) 

SF-36 

Significant 

change from 

baseline to 12 

weeks for 1 of 8 

dimensions 

(Vitality)

No significant 

changes from 

baseline to 12 

weeks

DAS28 (mean 

(SD))

Baseline: 4.4 

(1.2)

12 weeks: 3.9 

(1.2)

HAQ (mean 

(SD))

Baseline: 0.7 

(0.5)

12 weeks: 0.6 

(0.4)

Baseline: 4.3 

(1.4) (n = 23)

12 weeks: 4.3 

(1.5) (n = 23)

(P = .047 for 

difference 

between 

groups for 

change from 

baseline to 12 

weeks) 

Baseline: 0.8 

(0.6) (n = 23)

12 weeks: 0.8 

(0.6) (n = 23)

(P = .012 for 

difference 

between 

groups for 

change from 

baseline to 12 

weeks)

2 

withdrawals: 

1 due to 

dyspepsia 

(diet related); 

1 relapse of 

rheumatoid 

pleuritis (not 

diet-related, 

required 

increased 

prednisolone)

None reported

DAS = Disease Activity Score; HAQ = Health Assessment Questionnaire; NR = not reported; SD = standard deviation; SF – 36 = Short Form – 36; VAS = 

visual analog scale
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Table 11. Key Question 2 – Outcomes for Populations with Cognitive Impairment 

Study

Intervention (n)

Control (n) 

Diagnosis of Dementia 

(specify) % (n/N) Quality of Life (specify) Functional Status (specify) Adverse Events% (n/N)

Intervention Control Intervention Intervention Control Control Interventio

n

Control

Scarmeas 2009-287

N = 482

Higher conformity to MD 

associated with lower risk of 

developing AD

MD Continuous

Adjusted (n = 406) HR 0.89 

(0.78, 1.02)

MD Tertiles (Low as reference)

Middle: HR 0.55 (0.34, 0.90)

High: HR 0.52 (0.30, 0.91)

Results similar for patients with 

MCI without memory 

impairment

No significant association for 

subjects with MCI with memory 

impairment

AD = Alzheimer’s disease; HR = hazard ratio; MCI = mild cognitive impairment; MD = Mediterranean diet
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KEY QUESTION 3

Table 12. Key Question 3 – Study, Intervention, and Patient Characteristics

Author, year

Country

Study name

Funding Source

Inclusion/Exclusion Criteria Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

Elmer 2006111

USA

PREMIER

Funding: 

National Heart, 

Lung and Blood

Institute

RCT

Included: 

-generally healthy adults

-25y or older 

-prehypertension or stage 1 hypertension and 

met Joint National Committee VI criteria for a 

6-month trial of non-pharmacologic therapy 

-not taking antihypertensive medication and 

blood pressure of 120-159/80-95 mmHg

Excluded: 

-BMI <18.5 or >45 

-use of antihypertensive drugs or other drugs 

that affect blood pressure 

-JNC VI risk category C (target organ damage 

or diabetes)

-use of prescription weight loss medications

-previous cardiovascular event, congestive 

heart failure, angina, or cancer 

-consumption of > 21 alcoholic drinks per 

week

Established (comparator): 

a) goals included weight loss of at 

least 15 lbs if BMI >25, at least 180 

min/wk week of moderate physical 

activity, reduced sodium 

(<100mmol/day), and no more than 

30 (men) or15 (women) ml of 

alcohol

b) attended 14 group sessions and 

4 individual during first 6 months; 

monthly group sessions and 3 

individual for remaining year 

Established + DASH (intervention): 

a) everything from established 

intervention (above)

b) counseling on DASH diet with 

goals for increased consumption of 

fruits and vegetables (9-12 

servings/day) and low-fat dairy 

products (2-3 s/d) and reduced 

consumption of saturated fat (≤7%) 

and total fat (≤ 25%)

Advice Only:

advised to follow National ‘High 

Blood Pressure Education program 

lifestyle recommendations for 

blood pressure control (outcomes 

not extracted for this group)

Follow-up: 1.5 years

N = 810, all middle aged

Gender (% male): 38

Race: 34% African 

American

BMI: 33

Sequence generation:

low

Allocation concealment:

low

Blinding: low

Incomplete outcome 

data: low

Selective Outcome 

reporting: unclear

Risk of Bias: low
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Author, year

Country

Study name

Funding Source

Inclusion/Exclusion Criteria Intervention

Comparator

Follow-up

Patient Characteristics Risk of Bias

WHI Study 

Group 2004113

Beresford 200623

USA

WHI-DM

Funding: 

National Heart, 

Lung, and Blood 

Institute and 

Department of 

Health and 

Human Services

Included:

-postmenopausal women

-age 50-79 years 

-interested in one or more components of the 

clinical trials

-willing to be randomized to an intervention or 

comparison group

Excluded: 

-baseline diet estimated to have less than 32% 

of energy from fat

Intervention: intensive behavioral 

modification program using 18 

group sessions in first year and 

then quarterly sessions

a) decrease total fat intake to 20% 

or less of energy

b) consume 5 or more servings per 

day of vegetables and fruits and 6 

or more servings per day of grains 

Comparison: received US 

Department of Health and Human 

Services Dietary Guidelines for 

Americans

Follow-up: 5 years

Intervention, n = 19,542

Control, n = 29,294

1yr post randomization:

50-54: 13.8%

55-59: 22.4%

60-64: 26.1%

65-69: 21%

70-74: 12.3%

75-79: 4.4% 

BMI <25: 25.9%

25-29.9: 36.2%

30-34.9: 22.9%

≥35: 15%

Sequence generation:

unclear

Allocation concealment: 

unclear

Blinding: unclear

Incomplete outcome 

data: low

Selective outcome 

reporting: low

Risk of Bias: medium

BMI = body mass index

Table 13. Key Question 3 – Adherence

Study

Intervention (n)

Control (n) 

Adherence to Diet

(describe)

Intervention Control

Elmer 2006111

N = 537

Change at 18 months, mean servings/day

Fruit and vegetable intake: 2.8 (SD 3.4)

Dairy intake: 0.4 (1.5)

Change at 18m, mean saturated fat (%): -2.9% (3.4)

Change at 18 months, mean servings/day

Fruit and vegetable intake: 0.1 (2.7)

Dairy intake: -0.2 (1.5)

Change at 18m, mean saturated fat (%): -1.1% (3.7)

WHI 2004113

Beresford 200623

N = 48,836

Difference between control and intervention (C-I)

Fat intake: Year 1 10.9%, Year 5 9%

Saturated Fat: Year 1 4%, Year 5 3.5%

Servings of fruits and vegetables: Year 1 -1.2, Year 5 -1.3

Servings per day of grains: Year 1 -0.8, Year 5 -0.5

All P<.001

Mean difference (intervention - comparison) in change in consumption at year 3 (Beresford 200623) 

Red meat: -20.2% (-25.5, -14.8)

Fish: -3.9% (-13.1, 5.2)

Poultry: 2.3% (-4.9, 9.5)

Vegetables and fruits: 47.4% (42.5, 52.2)

Grains: 17.6% (12.7, 22.4)
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APPENDIX D. LITERATURE FLOW

Figure 1. Literature Flow Key Questions 1 and 2 Randomized Controlled Trials

Hand Search:

2 papers

Excluded: 127 papers

Diet: 19 papers

Study Design, Size, or Follow up: 52 

papers

Outcomes: 56 papers

Search Results

Ovid: 3,167 abstracts

Cochrane: 1052 abstracts

CINAHL: 77 abstracts

Total: 4,296 abstracts

Excluded:

4,150 abstracts

Full Text Review:

146 papers

Included:

21 papers on 11 studies
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151

Figure 2. Literature Flow Key Questions 1 and 2 Cohort Studies (Cancer, RA, Cognitive)

Hand Search:

10 papers

Excluded: 91 papers

Population: 1 paper

Diet: 14 papers

Study Design, Size, or 

Follow-up: 55 papers

Outcomes: 21 papers

Search Results

Ovid: 3,463 abstracts

Cochrane: 216 abstracts

CINAHL: 32 abstracts

Total: 3,711 abstracts

Excluded:

3,561 abstracts

Full Text Review:

150 papers

Included:

69 papers on 43 studies
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Figure 3. Literature Flow Key Question 3

Excluded: 10 papers

Diet: 1 paper

Study Design, Size, or Follow-up: 

4 papers

Outcomes: 3 papers

Setting: 2 papers

Search Results

Ovid: 1,042 abstracts

Cochrane: 531 abstracts

CINAHL: 22 abstracts

Total: 1,595 abstracts

Excluded:

1,591 abstracts

Full Text Review:

13 papers

Included:

3 papers on 2 studies

KQ1-2:

9 papers