Ramón Estruch

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet

BACKGROUND Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. METHODS In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. RESULTS A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. CONCLUSIONS Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish governments Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).

Reduction in the Incidence of Type 2-Diabetes with the Mediterranean Diet: Results of the PREDIMED-Reus Nutrition Intervention Randomized Trial

OBJECTIVE To test the effects of two Mediterranean diet (MedDiet) interventions versus a low-fat diet on incidence of diabetes. RESEARCH DESIGN AND METHODS This was a three-arm randomized trial in 418 nondiabetic subjects aged 55–80 years recruited in one center (PREDIMED-Reus, northeastern Spain) of the Prevención con Dieta Mediterránea [PREDIMED] study, a large nutrition intervention trial for primary cardiovascular prevention in individuals at high cardiovascular risk. Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum, and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria. RESULTS After a median follow-up of 4.0 years, diabetes incidence was 10.1% (95% CI 5.1–15.1), 11.0% (5.9–16.1), and 17.9% (11.4–24.4) in the MedDiet with olive oil group, the MedDiet with nuts group, and the control group, respectively. Multivariable adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the MedDiet supplemented with olive oil and nuts groups, respectively, compared with the control group. When the two MedDiet groups were pooled and compared with the control group, diabetes incidence was reduced by 52% (27–86). In all study arms, increased adherence to the MedDiet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity. CONCLUSIONS MedDiets without calorie restriction seem to be effective in the prevention of diabetes in subjects at high cardiovascular risk.

Effect of a Mediterranean Diet Supplemented With Nuts on Metabolic Syndrome Status One-Year Results of the PREDIMED Randomized Trial

BACKGROUND Epidemiological studies suggest that the Mediterranean diet (MedDiet) may reduce the risk of developing the metabolic syndrome (MetS). We compared the 1-year effect of 2 behavioral interventions to implement the MedDiet vs advice on a low-fat diet on MetS status. METHODS A total of 1224 participants were recruited from the PREDIMED (Prevención con Dieta Mediterránea) Study, a multicenter, 3-arm, randomized clinical trial to determine the efficacy of the MedDiet on the primary prevention of cardiovascular disease. Participants were older subjects at high risk for cardiovascular disease. Interventions were quarterly education about the MedDiet plus provision of either 1 L/wk of virgin olive oil (MedDiet + VOO) or 30 g/d of mixed nuts (MedDiet + nuts), and advice on a low-fat diet (control diet). All diets were ad libitum, and there was no increase in physical activity for any of the interventions. Lifestyle variables and MetS features as defined by the National Cholesterol Education Program Adult Treatment Panel III criteria were assessed. RESULTS At baseline, 61.4% of participants met criteria for the MetS. One-year prevalence was reduced by 6.7%, 13.7%, and 2.0% in the MedDiet + VOO, MedDiet + nuts, and control diet groups, respectively (MedDiet + nuts vs control groups, P = .01; MedDiet + VOO vs control group, P = .18). Incident rates of the MetS were not significantly different among groups (22.9%, 17.9%, and 23.4%, respectively). After adjustment for sex, age, baseline obesity status, and weight changes, the odds ratios for reversion of MetS were 1.3 (95% confidence interval, 0.8-2.1) for the MedDiet + VOO group and 1.7 (1.1-2.6) for the MedDiet + nuts group compared with the control diet group. CONCLUSION A traditional MedDiet enriched with nuts could be a useful tool in the management of the MetS.

Olive oil and health: Summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008

Olive oil (OO) is the most representative food of the traditional Mediterranean Diet (MedDiet). Increasing evidence suggests that monounsaturated fatty acids (MUFA) as a nutrient, OO as a food, and the MedDiet as a food pattern are associated with a decreased risk of cardiovascular disease, obesity, metabolic syndrome, type 2 diabetes and hypertension. A MedDiet rich in OO and OO per se has been shown to improve cardiovascular risk factors, such as lipid profiles, blood pressure, postprandial hyperlipidemia, endothelial dysfunction, oxidative stress, and antithrombotic profiles. Some of these beneficial effects can be attributed to the OO minor components. Therefore, the definition of the MedDiet should include OO. Phenolic compounds in OO have shown antioxidant and anti-inflammatory properties, prevent lipoperoxidation, induce favorable changes of lipid profile, improve endothelial function, and disclose antithrombotic properties. Observational studies from Mediterranean cohorts have suggested that dietary MUFA may be protective against age-related cognitive decline and Alzheimers disease. Recent studies consistently support the concept that the OO-rich MedDiet is compatible with healthier aging and increased longevity. In countries where the population adheres to the MedDiet, such as Spain, Greece and Italy, and OO is the principal source of fat, rates of cancer incidence are lower than in northern European countries. Experimental and human cellular studies have provided new evidence on the potential protective effect of OO on cancer. Furthermore, results of case-control and cohort studies suggest that MUFA intake including OO is associated with a reduction in cancer risk (mainly breast, colorectal and prostate cancers).

A Short Screener Is Valid for Assessing Mediterranean Diet Adherence among Older Spanish Men and Women

Ensuring the accuracy of dietary assessment instruments is paramount for interpreting diet-disease relationships. The present study assessed the relative and construct validity of the 14-point Mediterranean Diet Adherence Screener (MEDAS) used in the Prevención con Dieta Mediterránea (PREDIMED) study, a primary prevention nutrition-intervention trial. A validated FFQ and the MEDAS were administered to 7146 participants of the PREDIMED study. The MEDAS-derived PREDIMED score correlated significantly with the corresponding FFQ PREDIMED score (r = 0.52; intraclass correlation coefficient = 0.51) and in the anticipated directions with the dietary intakes reported on the FFQ. Using Bland Altmans analysis, the average MEDAS Mediterranean diet score estimate was 105% of the FFQ PREDIMED score estimate. Limits of agreement ranged between 57 and 153%. Multiple linear regression analyses revealed that a higher PREDIMED score related directly (P < 0.001) to HDL-cholesterol (HDL-C) and inversely (P < 0.038) to BMI, waist circumference, TG, the TG:HDL-C ratio, fasting glucose, and the cholesterol:HDL-C ratio. The 10-y estimated coronary artery disease risk decreased as the PREDIMED score increased (P < 0.001). The MEDAS is a valid instrument for rapid estimation of adherence to the Mediterranean diet and may be useful in clinical practice.

Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial.

BACKGROUND Despite the richness in antioxidants of the Mediterranean diet, to our knowledge, no randomized controlled trials have assessed its effect on in vivo lipoprotein oxidation. METHODS A total of 372 subjects at high cardiovascular risk (210 women and 162 men; age range, 55-80 years), who were recruited into a large, multicenter, randomized, controlled, parallel-group clinical trial (the Prevención con Dieta Mediterránea [PREDIMED] Study) directed at testing the efficacy of the traditional Mediterranean diet (TMD) on the primary prevention of coronary heart disease, were assigned to a low-fat diet (n = 121) or one of 2 TMDs (TMD + virgin olive oil or TMD + nuts). The TMD participants received nutritional education and either free virgin olive oil for all the family (1 L/wk) or free nuts (30 g/d). Diets were ad libitum. Changes in oxidative stress markers were evaluated at 3 months. RESULTS After the 3-month interventions, mean (95% confidence intervals) oxidized low-density lipoprotein (LDL) levels decreased in the TMD + virgin olive oil (-10.6 U/L [-14.2 to -6.1]) and TMD + nuts (-7.3 U/L [-11.2 to -3.3]) groups, without changes in the low-fat diet group (-2.9 U/L [-7.3 to 1.5]). Change in oxidized LDL levels in the TMD + virgin olive oil group reached significance vs that of the low-fat group (P = .02). Malondialdehyde changes in mononuclear cells paralleled those of oxidized LDL. No changes in serum glutathione peroxidase activity were observed. CONCLUSIONS Individuals at high cardiovascular risk who improved their diet toward a TMD pattern showed significant reductions in cellular lipid levels and LDL oxidation. Results provide further evidence to recommend the TMD as a useful tool against risk factors for CHD. Trial Registration isrctn.org Identifier: ISRCTN35739639.

Cohort Profile: Design and methods of the PREDIMED study

The Spanish Ministry of Health—Instituto de Salud Carlos III (ISCIII) funded the project for the period 2003–05 (RTIC G03/140). In 2006 a new funding modality was established by ISCIII through the CIBER (Centros de Investigacion Biomedica En Red). Fisiopatologia de la Obesidad y Nutricion (CIBERobn), which is providing funding for 7 of the original research groups, whereas the other 12 were funded by a new research network (RTIC RD 06/0045). Other official funds from Spanish government agencies have been obtained for subprojects related to intermediate outcomes (lipoproteins, inflammatory markers, vascular imaging, genomic and proteomic studies, etc.). Obviously, the donation by food companies of all the VOO and mixed nuts needed throughout the duration of the study is a substantial contribution.

Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers

BACKGROUND Few studies have investigated the effect of dietary polyphenols on the complex human gut microbiota, and they focused mainly on single polyphenol molecules and select bacterial populations. OBJECTIVE The objective was to evaluate the effect of a moderate intake of red wine polyphenols on select gut microbial groups implicated in host health benefits. DESIGN Ten healthy male volunteers underwent a randomized, crossover, controlled intervention study. After a washout period, all of the subjects received red wine, the equivalent amount of de-alcoholized red wine, or gin for 20 d each. Total fecal DNA was submitted to polymerase chain reaction(PCR)-denaturing gradient gel electrophoresis and real-time quantitative PCR to monitor and quantify changes in fecal microbiota. Several biochemical markers were measured. RESULTS The dominant bacterial composition did not remain constant over the different intake periods. Compared with baseline, the daily consumption of red wine polyphenol for 4 wk significantly increased the number of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, and Blautia coccoides-Eubacterium rectale groups (P < 0.05). In parallel, systolic and diastolic blood pressures and triglyceride, total cholesterol, HDL cholesterol, and C-reactive protein concentrations decreased significantly (P < 0.05). Moreover, changes in cholesterol and C-reactive protein concentrations were linked to changes in the bifidobacteria number. CONCLUSION This study showed that red wine consumption can significantly modulate the growth of select gut microbiota in humans, which suggests possible prebiotic benefits associated with the inclusion of red wine polyphenols in the diet. This trial was registered at controlled-trials.com as ISRCTN88720134.

Prevention of Diabetes With Mediterranean Diets: A Subgroup Analysis of a Randomized Trial

Context Can changes in diet prevent diabetes in older adults? Contribution This subgroup analysis of a multicenter trial involved older adults with high risk for heart disease who were randomly assigned to a Mediterranean diet supplemented with either extra-virgin olive oil or mixed nuts or to a low-fat control diet. Neither energy restriction nor increased physical activity was advised. After 4 years of follow-up, fewer persons in the Mediterranean diet groups developed diabetes than in the control group. Implication Changes in dietary patterns that do not necessarily lead to weight loss or include energy restrictions could help prevent diabetes in some older adults. The Editors Type 2 diabetes mellitus represents a major health problem because worldwide prevalence has more than doubled in the past 3 decades, with nearly 347 million persons with diabetes in 2010 (1), and is a potent risk factor for cardiovascular disease (CVD), blindness, renal failure, and lower limb amputation (2). Compelling evidence shows that diabetes can be prevented with lifestyle changes. Intensive lifestyle modification promoting weight loss through energy-restricted diets together with increased physical activity can decrease incident diabetes to as low as 50% (3). Indeed, lifestyle modification has performed better than pharmacologic approaches (such as metformin or rosiglitazone) in diabetes prevention (46). Of interest, the benefit of lifestyle changes in decreasing diabetes risk seems to extend beyond the termination of active intervention (68). However, there is little information on whether changes in the overall dietary pattern, without energy restriction, increased physical activity, and ensuing weight loss, may also be effective to prevent diabetes. Prospective epidemiologic studies strongly suggest that dietary patterns characterized by high consumption of fruit, vegetables, whole grains, and fish and reduced consumption of red and processed meat, sugar-sweetened beverages, and starchy foods delay diabetes onset (9). In the last 6 years, the traditional Mediterranean diet has emerged as a healthy dietary pattern that is also associated with a decreased risk for diabetes (1012). The Mediterranean diet is moderately rich in fat (35% to 40% of energy), especially from vegetable sources (rich in olive oil and nuts), and relatively low in dairy products. Moderate consumption of alcohol, mostly wine, and frequent use of sauces with tomato, onions, garlic, and spices for meal preparation are also typical. Preliminary data from the PREDIMED (Prevencin con Dieta Mediterrnea) study (1317) showed that traditional Mediterranean diets enriched with high-fat foods of vegetable origin decreased the incidence of diabetes (18). However, that report studied participants only from 1 of the 11 PREDIMED recruiting centers. In this analysis, we provide the final results on diabetes incidence in the whole multicenter trial after a median follow-up of 4.1 years. Methods Design Overview The PREDIMED study is a parallel-group, randomized, primary cardiovascular prevention trial done in Spain in persons at high risk but without CVD at baseline. The protocol, design, objectives, and methods have been reported in detail elsewhere (13, 14). Briefly, participants were randomly assigned in a 1:1:1 ratio to 1 of 3 nutrition interventions: Mediterranean diet supplemented with extra-virgin olive oil (EVOO), Mediterranean diet supplemented with mixed nuts, or a control diet consisting of advice to reduce intake of all types of fat. A complete list of PREDIMED study investigators is available in Supplement 1. The local institutional review boards approved the protocol at each study location, and all participants provided written informed consent. Supplement. Original Version (PDF) Supplement 1. List of Prevencin con Dieta Mediterrnea Study Investigators Setting and Participants Eligible participants were community-dwelling men (aged 55 to 80 years) and women (aged 60 to 80 years) without CVD at baseline who had either type 2 diabetes or at least 3 or more cardiovascular risk factors, namely current smoking, hypertension, hypercholesterolemia, low high-density lipoprotein cholesterol levels, overweight or obesity, and family history of premature CVD. Exclusion criteria have previously been reported (13). Randomization and Intervention From October 2003 to June 2009, 7447 suitable candidates were enrolled in the trial. The study nurse from each recruiting center randomly assigned each participant to the corresponding intervention group following computer-generated random numbers for allocation contained in sealed envelopes, which were centrally prepared for each center by the coordinating unit. Four strata of randomization were built by sex and age (cutoff, 70 years) but not by baseline diabetes status. The primary care physicians did not participate in the randomization process. The study nurses were independent of the nursing staff of the primary care health centers. Therefore, they were not involved in the usual clinical care of participants, and their exclusive role was to collect data for the trial. Given the nature of the interventions (nutritional advice and provision of foods), only investigators assessing outcomes were blinded with respect to intervention assignment. This was done by providing them with coded data sets and medical records blinded with respect to the personal identity of the participant and without any information on treatment allocation. Because our main objective was to determine the effect of the 3 interventions on diabetes incidence, this report includes data only on participants who did not have diabetes at baseline and for whom we could ascertain the incidence of diabetes during follow-up (n= 3541) (Figure 1). Figure 1. Study flow diagram. EVOO = extra-virgin olive oil; MedDiet = Mediterranean diet. A behavioral intervention promoting the Mediterranean diet was implemented in the corresponding groups of the trial, as described (13). Dietitians gave personalized advice to participants about the amount and use of EVOO for cooking and dressing; weekly intake of nuts; increased consumption of vegetables, fruits, legumes, and fish; recommended intake of white meat instead of red or processed meat; avoidance of butter, fast food, sweets, pastries, or sugar-sweetened beverages; and the dressing of dishes with sofrito sauce (using tomato, garlic, onion, and spices simmered in olive oil). Reduction of alcoholic beverages other than wine was advised to all participants. Wine with meals was recommended with moderation only to habitual drinkers. At baseline and quarterly thereafter, dietitians conducted individual and group dietary training sessions to provide information on typical Mediterranean foods, seasonal shopping lists, meal plans, and recipes for each group. In each session, a 14-item questionnaire was used to assess adherence to the Mediterranean diet (13, 14) so that personalized advice could be provided to upgrade participants adherence. The same questionnaire was assessed yearly in the control group. Participants assigned to the 2 Mediterranean diet groups received allotments of either EVOO (50 mL/d) or mixed nuts (30 g/d: 15 g of walnuts, 7.5 g of almonds, and 7.5 g of hazelnuts) at no cost. Participants assigned to the control diet received recommendations to reduce intake of all types of fat (from both animal and vegetable sources) and received nonfood gifts (kitchenware, tableware, aprons, or shopping bags). Through October 2006, participants in the control group received only a leaflet describing the low-fat diet. Thereafter, participants assigned to the control diet also received personalized advice and were invited to group sessions with the same frequency and intensity as those in the Mediterranean diet groups. A separate 9-item dietary questionnaire (14) was used to assess adherence to the low-fat diet. Neither energy restriction nor increased physical activity was advised for any intervention group. At baseline examination and yearly during follow-up, we administered a 137-item validated semiquantitative food-frequency questionnaire (19); the validated Spanish version of the Minnesota Leisure-time Physical Activity Questionnaire (20); and a 47-item questionnaire about education, lifestyle, medical history, and medication use. At baseline, trained personnel performed electrocardiography and anthropometric and blood pressure measurements. Blood pressure was measured in triplicate by using a validated semiautomatic oscillometer with a 5-minute interval between measurements and the participant in a sitting position (Omron HEM-705CP, Omron, Hoofddorp, the Netherlands). Fasting blood and spot urine were sampled at baseline and follow-up years 1, 3, 5, and 7. After an overnight fast, tubes for EDTA plasma, citrate plasma, and serum and urine samples were collected and aliquots were coded and stored at 80C in the central laboratory until analysis. Serum glucose, cholesterol, and triglyceride levels were measured using standard enzymatic methods. High-density lipoprotein cholesterol was measured after precipitation with phosphotungstic acid and magnesium chloride. Biomarkers of adherence to the supplemental foods, including urine hydroxytyrosol levels and plasma -linolenic acid proportions, which are reliable biomarkers of EVOO and walnut intake, respectively, were measured in random subsamples of participants during the first 5 years of follow-up (by gas chromatographymass spectrometry and by gas chromatography, respectively). Laboratory technicians were blinded to intervention group. Outcomes and Follow-up Diabetes was a prespecified secondary outcome of the PREDIMED trial. IT was considered to be present at baseline by clinical diagnosis or use of antidiabetic medication. New-onset diabetes during follow-up was diagnosed using the American Diabetes Association criteria, namely fasting plasma glucose levels of 7.0 mmol/L or g

Components of the mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease

Objective:To evaluate associations between components of the Mediterranean diet and circulating markers of inflammation in a large cohort of asymptomatic subjects at high risk for cardiovascular disease.Subjects/Methods:A total of 339 men and 433 women aged between 55 and 80 years at high cardiovascular risk because of presence of diabetes or at least three classical cardiovascular risk factors, food consumption was determined by a semi-quantitative food frequency questionnaire. Serum concentrations of high-sensitivity C-reactive protein (CRP) were measured by immunonephelometry and those of interleukin-6 (IL-6), intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by enzyme-linked immunosorbent assay.Results:After adjusting for age, gender, body mass index, diabetes, smoking, use of statins, non-steroidal antiinflammatory drugs and aspirin, a higher consumption of fruits and cereals was associated with lower concentrations of IL-6 (P for trend 0.005;both). Subjects with the highest consumption of nuts and virgin olive oil showed the lowest concentrations of VCAM-1, ICAM-1, IL-6 and CRP; albeit only for ICAM-1 was this difference statistically significant in the case of nuts (for trend 0.003) and for VCAM-1 in the case of virgin olive oil (P for trend 0.02). Participants with higher adherence to the Mediterranean-type diet did not show significantly lower concentrations of inflammatory markers (P<0.1 for VCAM-1 and ICAM-1).Conclusions:The consumption of some typical Mediterranean foods (fruits, cereals, virgin olive oil and nuts) was associated with lower serum concentrations of inflammatory markers especially those related to endothelial function, in subjects with high cardiovascular risk living in a Mediterranean country.