Editor's Note: Commentary based on Estruch R, Ros E, Salas-Salvadó J; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.

Background

Multiple observational cohort studies and one secondary prevention trial have documented that Mediterranean-style diets are associated with a substantially reduced risk of cardiovascular disease (CVD). Although there is no uniform definition of a Mediterranean diet, it generally consists of:

• Olive oil as main culinary fat – unrestricted fat intake
• Abundant vegetable products
• cereals (bread, pasta and rice)
• fresh vegetables and fruits
• legumes
• tree nuts
• aromatic herbs and spices
• Frequent intake of fish and shellfish
• Moderate consumption of wine with meals
• Low intake of meat and animal products, milk and milk products, simple sugars

The aim of this randomized trial was to examine whether adherence to a Mediterranean diet led to the prevention of cardiovascular events (myocardial infarction, stroke or death from cardiovascular causes).

Methods

The PREDIMED trial inducted 7447 persons (57% women) at high risk for CVD age 55-80 yrs in 11 centers in Spain. Subjects were randomized to three groups and were advised to follow:
    Group 1. Mediterranean diet (MeD Diet) plus provided extra-virgin olive oil (EVOO) 1L/week/family) (50 g/day rich in poly-phenols and monounsaturated fat).

    Group 2. Mediterranean diet (MeD Diet) plus provided 30 gm/day of unsalted mixed nuts including walnuts 15 g/d, almonds 7.5 g/day and hazelnuts 7.5 g/day [rich in poly-phenols, monounsaturated fatty acids (MUFA) & polyunsaturated fatty acids (PUFA) such as alpha-linolenic acid (ALA)].

    Group 3. Control group (advised to reduce dietary fat)

Both intervention groups 1 and 2 received quarterly individual and group educational sessions with the registered dietitians for 4.8 years. The Control group received only annual sessions with the registered dietitians for the first three years, then quarterly during the next 1.8 years.

The primary end point was to measure the rate of major CV events (MI, stroke or death from CV causes).

Figure: Kaplan-Meier Estimate of the incidence of Stroke events in the Total Study Population. Hazard ratios were stratified according to center (Cox model with robust variance estimators), CI denotes confidence interval, EVOO extra virgin olive oil, and Med Mediterranean. Ros, E. (2013). Primary Prevention of Cardiovascular Disease with a Mediterranean Diet [PowerPoint slides]. Retrieved from the Academy of Nutrition & Dietetics.

Results

Interim analyses prompted early termination of the trial at 4.8 years. Both MeD diet groups adhered to the intervention per self-reported intake and biomarker test results. As compared with control group, the two groups that received advice on a MeD diet plus EV olive oil or nuts reduced the risk of CVD by approximately 30% & stroke 50%. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [(CI), 0.54 to 0.92] with extra virgin olive oil (96 events) and 0.72 (95% CI, 0.54 to 0.96) for the Med Diet Group with nuts (83 events) versus the control group (109 events). At three months after randomization, both Mediterranean Diet groups (extra-virgin olive oil & the mixed nuts) significantly lowered blood pressure.

Conclusion

In older subjects at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events in the absence of weight gain.

Commentary/Perspective

The reduction in CVD was most evident for stroke, an outcome associated with reduction in blood pressure. This study confirmed that unsaturated fats such as extra virgin olive oil or mixed nuts when added to an otherwise cardio-protective diet reduced the incidence of major cardiovascular events in the absence of weight gain. In 2006 Estruch et al. had shown that at three months follow up both intervention groups had a significant reduction in blood pressure compared to the control group.

Saturated-fat intake was similar in all three groups, approximately 9% of energy intake. In the extra-virgin olive oil supplemented group, monounsaturated fats (n-9) contributed the additional four percentage points. In the mixed nuts supplemented group, two percentage points were derived from monounsaturated (n-9) fats and two percentage points from polyunsaturated fats (n-3 and n-6). To improve adherence to dietary intervention, group 1 and 2 participants were provided extra virgin olive oil and nuts respectively. Since all three groups consumed a high fat diet, it is possible that supplementation with extra virgin olive oil and nuts and additional dietary counseling sessions with the registered dietitians were responsible for the outcomes. Dietary advice was also associated with a modest increase in legume and fish consumption in both intervention groups. No other major differences were noted in nutrient intake or food groups between the intervention and control groups.

Limitations of this study include 1) Discrepancy in the protocol on the number of counseling sessions provided by registered dietitians to the two treatment groups versus control group. While the two MeD diet groups received quarterly individualized and group interventions from registered dietitians throughout the study period (4.8 years), the low fat diet control group received only one session per year for the first three years. This lower intensity of dietary intervention in the control group could have led to a bias toward a benefit in the two Mediterranean diet groups, 2) A higher drop-out rate was noted in the control group possibly because they did not receive the same intensity of counseling and support as the two intervention groups, 3) Study results cannot be generalized to the entire world population as the study participants were living in a Mediterranean region and were therefore already following a Mediterranean dietary pattern, and 4) Despite advice to lower fat intake and limit consumption of olive oil and nuts, the total fat consumption in the control group was also high (37% of energy intake) versus 41% in the two intervention groups.

Observational studies have shown that Mediterranean-style diets and olive oil are associated with reduced risk of stroke. An accompanying commentary by Appel and Vanhorn stated "Reductions in blood pressure probably contributed to observed reductions in cardiovascular disease. However, the effects of the interventions on known blood-pressure determinants (i.e., weight and dietary sodium and potassium intake) are unknown. Policymakers already recommend consumption of a Mediterranean-style diet on the basis of a persuasive body of evidence from observational studies. Our sense is that the policy implications of the PREDIMED trial relate primarily to the supplemental foods. A Mediterranean-style diet with increased consumption of mixed nuts or substitution of regular olive oil with extra-virgin olive oil has beneficial effects on cardiovascular disease". However, many unanswered questions remain such as 1) Will the benefits of extra-virgin olive oil and mixed nuts accrue to persons consuming other diets?, 2) Does high consumption of extra-virgin olive oil and mixed nuts lead to weight gain?, and 3) Can the benefits of extra-virgin olive oil and mixed nuts occur at lower doses?

References

1. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999; 99:779–785.
2. Kris-Etherton PM, Eckel RH, Howard BV et al. AHA Science Advisory Lyon Diet Heart Study. Benefits of a Mediterranean-Style, National Cholesterol Education Program/American Heart Association Step I Dietary Pattern on Cardiovascular Disease Circulation 2001; 103: 1823-1825.
3. Estruch R, Martinez-Gonzalez MA, Corella D, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006;145:1-11.
4. Supplement to: Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013. DOI: 10.1056/NEJMoa1200303
5. Did the PREDIMED Trial Test a Mediterranean Diet? Appel LJ & Van Horn L. N Engl J Med 2013; 368:1353-1354.

Keywords: Cardiovascular Diseases, Diet