Effects of a Mediterranean-Style Diet on Cardiovascular Risk Factors

Context Some experts attribute a low incidence of heart disease in Mediterranean countries to dietary habits. Contribution In this multicenter, 3-group trial, investigators randomly assigned 772 adults at high risk for cardiovascular disease to a low-fat diet or to a Mediterranean diet supplemented with either virgin olive oil (1 L per week) or nuts (30 g per day). After 3 months, the Mediterranean diet groups had lower mean plasma glucose level, systolic blood pressure, and total cholesterolhigh-density lipoprotein cholesterol ratio than the low-fat diet group. Cautions The Mediterranean diet groups received more nutritional education than the low-fat diet group. Implications Mediterranean diets supplemented with olive oil or nuts may improve cardiovascular risk factors. The Editors Cardiovascular disease is the main cause of death in industrialized countries, but incidence rates have marked geographic differences. The low incidence of coronary heart disease (CHD) in Mediterranean countries has been partly ascribed to dietary habits (1-3). Recent findings from large European cohort studies (4-6) suggest that a high degree of adherence to the Mediterranean diet is associated with a reduction in mortality. In small clinical studies, the Mediterranean diet or some of its components have reduced blood pressure (7) and have improved lipid profiles (8, 9) and endothelial function (10). Moreover, a recent cross-sectional study (11) and a 2-year feeding trial (12) have shown that adherence to the Mediterranean diet is associated with reduced markers of vascular inflammation. These beneficial effects on surrogate markers of cardiovascular risk add biological plausibility to the epidemiologic evidence that supports a protective effect of the Mediterranean diet. Olive oil, a rich source of monounsaturated fatty acids, is a main component of the Mediterranean diet. Virgin olive oil retains all the lipophilic components of the fruit, -tocopherol, and phenolic compounds with strong antioxidant and anti-inflammatory properties (13, 14). Tree nuts, which are also typical in the Mediterranean diet, have a favorable fatty acid profile and are a rich source of nutrients and other bioactive compounds that may beneficially influence the risk for CHD, such as fiber, phytosterols, folic acid, and antioxidants (15). Frequent nut intake has been associated with decreased CHD rates in prospective studies (15). Walnuts differ from all other nuts through their high content of polyunsaturated fatty acids, particularly -linolenic acid, a plant n-3 fatty acid (16), which may confer additional antiatherogenic properties (17). Therefore, we designed a large-scale feeding trial in high-risk participants to assess the effects of 2 Mediterranean diets, one supplemented with virgin olive oil and the other supplemented with mixed nuts, compared with a low-fat diet on cardiovascular outcomes. We report the results of a 3-month intervention on intermediate markers of cardiovascular risk in the first 772 participants who were recruited into the trial. Supplement. Original Version (PDF) Methods Study Design The Prevencin con Dieta Mediterrnea (PREDIMED) Study is a large, parallel-group, multicenter, randomized, controlled, 4-year clinical trial that aims to assess the effects of the Mediterranean diet on the primary prevention of cardiovascular disease (www.predimed.org). An estimated 9000 high-risk participants (>5000 participants are already recruited) will be assigned to 3 interventions: Mediterranean diet with virgin olive oil, Mediterranean diet with mixed nuts, or low-fat diet. The main outcome is an aggregate of cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The anticipated completion date of the trial is December 2010. We designed our present study to assess the 3-month effects of the dietary interventions on surrogate markers of cardiovascular risk in participants entering the study during the first 6 months of recruitment. The institutional review boards of the 10 participating centers approved the study protocol. Participants and Recruitment From October 2003 to March 2004, we selected 930 potential participants in primary care centers affiliated with 10 teaching hospitals across Spain. Eligible participants were community-dwelling men, 55 to 80 years of age, and women, 60 to 80 years of age, who fulfilled at least 1 of 2 criteria: type 2 diabetes or 3 or more CHD risk factors (current smoking, hypertension [blood pressure >140/90 mm Hg or treatment with antihypertensive drugs], low-density lipoprotein [LDL] cholesterol level 4.14 mmol/L [160 mg/dL] [or treatment with hypolipidemic drugs], high-density lipoprotein [HDL] cholesterol level 1.04 mmol/L [40 mg/dL], body mass index [BMI] 25 kg/m2, or a family history of premature CHD). Exclusion criteria were history of cardiovascular disease, any severe chronic illness, drug or alcohol addiction, history of allergy or intolerance to olive oil or nuts, or low predicted likelihood of changing dietary habits according to the stages-of-change model (18). The primary care physicians based participants' eligibility on review of clinical records and a screening visit. They obtained a list of candidates from computer-based records of patients who attended each participating center and reviewed their clinical records to exclude those who did not meet eligibility criteria. They then invited suitable candidates by telephone to attend a screening visit. The visit included an interview with administration of a 26-item questionnaire to inquire about medical conditions and risk factors related to eligibility. Of the eligible candidates who met entry requirements, 95% agreed to participate and provided informed consent. Randomization and Intervention After the screening visit, each center randomly assigned eligible participants to 1 of 3 diet groups by using a computer-generated random-number sequence. The coordinating center constructed the randomization table, and participants were randomly assigned into blocks of 50 participants balanced by center, sex, and age group (<70 years and 70 years). We concealed allocation into the intervention groups by using closed envelopes with correlative numbers by prespecified subgroups of sex and age. The baseline examination included the administration of a 14-item questionnaire, an extension of a previously validated questionnaire (19), that assessed the degree of adherence to the traditional Mediterranean diet. We assigned values of 0 or 1 to each item (Appendix Table 1). We also administered a 137-item validated food frequency questionnaire (20); the validated Spanish version (21) of the Minnesota Leisure Time Physical Activity Questionnaire; and a 47-item questionnaire about education, lifestyle, history of illnesses, and medication use. We performed anthropometric and blood pressure measurements and obtained samples of fasting blood and spot urine. We repeated all examinations at 3 months. The same dietitian delivered the interventions to the 3 randomized groups in each center. On the basis of the assessment of individual Mediterranean diet scores, the dietitian gave personalized dietary advice during a 30-minute session to each participant, with recommendations on the desired frequency of intake of specific foods. We advised participants who were allocated to the low-fat diet to reduce intake of all types of fat, and we gave them a leaflet with written recommendations according to the American Heart Association guidelines (22). For total fat intake, these recommendations were opposite to those given to participants in the 2 Mediterranean diet groups, who received instructions intended to increase the 14-item Mediterranean diet score, including increased consumption of vegetable fats and oils. We did not suggest any energy restriction. While the participants who were allocated to the low-fat diet did not receive further intervention, those assigned the 2 Mediterranean diet groups had access to more intense intervention in 2 ways. First, they were given a free provision of typical Mediterranean fatty foods (olive oil or nuts). Depending on group assignment, participants were given either free virgin olive oil (15 L [1 L/wk] for 3 months) or free sachets of walnuts, hazelnuts, and almonds (1350 g of walnuts [15 g/d], 675 g of hazelnuts [7.5 g/d], and 675 g of almonds [7.5 g/d] for 3 months). To improve adherence and account for family needs, participants in the corresponding Mediterranean diet groups were given excess olive oil or additional 1000-g packets of nuts. We analyzed the nutrient composition of the olive oil and nuts used in the study by standard methods in a reference laboratory (Appendix Table 2)). Second, 1 week after inclusion, the dietitian delivered a 1-hour group session with up to 20 participants, with separate sessions for each Mediterranean diet group. Each group session consisted of informative talks and provision of written materials with elaborate descriptions of typical Mediterranean foods and seasonal shopping lists, meal plans, and cooking recipes. Throughout the study, all participants had free and continuous access to their center dietitian for advice and consultation. Measurements Trained personnel measured weight and height by using calibrated scales and a wall-mounted stadiometer, respectively; waist circumference midway between the lowest rib and the iliac crest by using an anthropometric tape; and blood pressure in triplicate with a validated semiautomatic oscillometer (Omron HEM-705CP, Hoofddorp, the Netherlands). We calculated energy and nutrient intake from Spanish food composition tables (23). At the 3-month visit and when consulted by participants, dietitians assessed any adverse effects from the interventions by administering a checklist of symptoms and gave advice on how to remedy them. The checklist included mouth symptoms; bloating, fullness, or indigestion; altered bowel hab