Did the PREDIMED Trial Test a Mediterranean Diet?
Lawrence J. Appel, M.D., M.P.H., and Linda Van Horn, Ph.D., R.D.
The new england journal of medicin - n engl j med 368;14 nejm.org april 4, 2013
The U.S. Dietary Guidelines recommend healthy dietary patterns — specif ically, the Dietary Ap- proaches to Stop Hypertension (DASH) diet and Mediterranean-style diets.1 A persuasive body of evidence from observational studies has docu- mented that Mediterranean-style diets are asso- ciated with a substantially reduced risk of car- diovascular disease.2 Mediterranean diets are not a single dietary pattern, but they do have common features — an emphasis on vegetables, fruits, beans, nuts, seeds, breads, unref ined grains, and olive oil (but not necessarily extra-virgin olive oil); inclusion of f ish and wine; and minimal in- take of meats and full-fat dairy products.3 Such diets are rich in total, monounsaturated, and polyunsaturated fat and are lower in saturated fat.
In this issue of the Journal, Estruch and col- leagues document that provision of extra-virgin olive oil or mixed nuts, in the context of a Medi- terranean-style diet, substantially reduced the oc- currence of cardiovascular disease.4 In brief, the Prevención con Dieta Mediterránea (PREDIMED) trial, conducted in Spain, randomly assigned 7447 persons at high risk for cardiovascular dis- ease to one of three groups: participants who received advice on a Mediterranean diet and provision of extra-virgin olive oil, those who re- ceived advice on a Mediterranean diet and pro- vision of mixed nuts, and those who received advice to reduce dietary fat (control diet). Extra- virgin olive oil is rich in polyphenols and mono- unsaturated fat, and mixed nuts are rich in polyphenols, monounsaturated fat, and poly- unsaturated fat, including alpha-linolenic acid.
The primary end point was a composite of ma- jor cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). In- terim analyses prompted early termination of the trial. As compared with the control group, the two groups that received advice on a Mediterra- nean diet reduced the risk of cardiovascular dis- ease by approximately 30%. For any therapy, in- cluding drug therapy, this magnitude of benef it is impressive; for a dietary intervention, such re- sults are truly remarkable. Still, results might be exaggerated because early termination of trials tends to spuriously inf late estimated benef it.5
Central to the interpretation of the results of the PREDIMED trial is an understanding of achieved dietary changes. Despite advice to lower fat intake and limit consumption of olive oil and nuts, the control group did not achieve a low fat intake. Indeed, the control group appeared to consume a variant of the Mediterranean diet. At the end of the trial, total fat was 37% of ener- gy intake in the control group and 41% of energy intake in the other two groups; saturated-fat in- take was low and similar in the three groups, approximately 9% of energy intake. In the group receiving extra-virgin olive oil, the additional 4 percentage points in energy intake from fat re- sulted mostly from increased monounsaturated- fat intake. In the group receiving mixed nuts, the additional 4 percentage points resulted from increases of approximately 2 percentage points in both monounsaturated and polyunsaturated fat.
The most striking differences between the randomized groups resulted from the supple- mental foods, not the dietary advice, which led to modest between-group differences (as com- pared with the control group) in legume and f ish consumption and no major differences in intake of other nutrients and food groups. The amount of extra-virgin olive oil and nuts pro- vided to participants and their households was substantial (1 liter of extra-virgin olive oil per week and 30 g of mixed nuts per day). At the end of follow-up, the average energy intake from olive oil was 22.0% in the group receiving extra- virgin olive oil (vs. 16.4% in the control group); the average energy intake from nuts was 8.2% in the group receiving mixed nuts (vs. 1.6% in the control group). Those in the group receiving extra-virgin olive oil modestly decreased con- sumption of regular olive oil but replaced it with even greater amounts of extra-virgin olive oil.
The reduction in cardiovascular disease was most evident for stroke, an outcome that is ex- ceedingly dependent on blood pressure. This re- sult is concordant with those of observational studies, which have shown that Mediterranean- style diets and olive oil are associated with reduced risk of stroke.6-8 Previously, the PREDIMED in- vestigators reported that, at 3 months after ran- domization, the group receiving extra-virgin olive oil and the group receiving mixed nuts had sub- stantially lowered blood pressure.9 Indeed, reduc- tions 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.
The impressive results of the PREDIMED trial confirm that changes in diet can have powerful, benef icial effects. But what are its policy impli- cations? The PREDIMED trial is neither a pure test of a Mediterranean-style diet nor a pure test of extra-virgin olive oil and nuts. Interpretation of the PREDIMED trial is similar in complexity to that of the Lyon Diet Heart Study, which tested provision of a margarine rich in alpha-linolenic acid, coupled with brief advice to consume a Mediterranean diet.10
Policymakers1 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. Specif ically, in the context of a Mediterranean-style diet, increased con- sumption of mixed nuts or substitution of regular olive oil with extra-virgin olive oil has bene- f icial effects on cardiovascular disease.
Still, there are many unanswered questions. Will the benef its of extra-virgin olive oil and mixed nuts accrue to persons consuming other diets? Does high consumption of extra-virgin olive oil and mixed nuts lead to weight gain? Can the benef its of extra-virgin olive oil and mixed nuts occur at lower doses?
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
From the Welch Center for Prevention, Epidemiology, and Clini- cal Research, Johns Hopkins University, Baltimore (L.J.A.); and the Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago (L.V.H.).
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DOI: 10.1056/NEJMe1301582
Copyright © 2013 Massachusetts Medical Society.
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