Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279-1290. Epub 2013 Feb 25.
A multicenter trial in Spain randomly assigned participants who were at high risk for cardiovascular disease (CVD) but had no CVD at enrollment to 1 of 3 diets: a Mediterranean diet supplemented with 4 T per day of extra-virgin olive oil, a Mediterranean diet supplemented with 30 g per day of a mixture of nuts (50% walnuts, 25% almonds, 25% hazelnuts), or a low-fat control diet. The participants in the Mediterranean diet arms of the study were supplied with free extra virgin olive oil or nuts depending on their assigned group. The control group on the low-fat diet was given nonfood gifts.
A total of 7447 persons were enrolled in the study; 57% were women, and mean age was approximately 67 years. As mentioned, study participants were at high risk for CVD: about half were taking ACE inhibitors, one-fifth were taking diuretics, slightly more than one-fourth were taking other antihypertensive agents, two-fifths were taking a statin lipid lowering drug, and over one-third were taking an oral hypoglycemic agent or insulin. The olive oil group started with 2543 participants, the nut group 2454, and the control group 2450.
Study Medication and Dosage
Participants in the 2 Mediterranean diet groups received dietary counseling individually and via group sessions at their first visit and then every 3 months. They were given, without charge, 1 L of extra virgin olive oil each week (approximately 2 oz per day) or 30 g mixed nuts per day (15 g walnuts and 7.5 g each of almonds and hazelnuts). The control group received small nonfood gifts. The Mediterranean diet groups were encouraged using dietary screening to adhere to a Mediterranean diet. The control group was encouraged to follow a low-fat diet. The control group initially did not have regular counseling with dieticians, though they did receive regular mailings encouraging compliance. Three years into the study, this was seen as a methodological weakness and moving forward, the control group was also counseled by a dietician.
The primary endpoint 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. A primary endpoint occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI]: 0.54-0.92) 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, vs the control group (109 events). Relative risk for CVD was reduced by approximately 30% among a group of people who had been at very high risk for disease.
The study has been hailed as definitive evidence that a Mediterranean diet prevents cardiovascular disease. As Gina Kolata reported in the New York Times, “The magnitude of the diet’s benefits startled experts. The study ended early, after almost five years, because the results were so clear it was considered unethical to continue.”1
A careful reading of this paper fails to fully support Kolata’s conclusion. There are still valuable lessons to be learned from these data, including strong evidence that dietary supplementation with nuts or extra virgin olive oil provides significant protection against cardiovascular events.
This is the first report on the findings of the PREDIMED Trial, a large multicenter trial was conducted in Spain. Location of the study is relevant because all of the participants at baseline were eating close to the ideal Mediterranean diet.
Most of the past evidence in support of the Mediterranean diet has been garnered from epidemiological studies, not randomized controlled trials. The Lyon Heart Study published in 1999 is the one exception; it reported that following a Mediterranean diet reduced rate of a recurrence in individuals who had suffered a first myocardial infarction.2
A Problem in the Details
This sounds as if the Mediterranean diet works, at least until one reads through the study details more carefully. In reality, the study is more about the extra virgin olive oil and nut interventions than dietary changes.
Dietary Counseling Did Little
The most important message hidden in this data is how difficult it is to change a patient’s diet. Recall that these study participants were at high risk for disease, most were already on medications to lower cholesterol, blood pressure, and/or blood sugar. They should have been “motivated.” Estruch and colleagues employed all the tools they could to encourage dietary changes. They write,
dietary intervention followed a behavioral strategy focused on modifying the way an individual views the dietary pattern, appraises its meaning, and makes informed choices. We applied common cognitive behavioral techniques, including goal setting, self-monitoring, feedback and reinforcement, self-efficacy enhancement, incentives, problem solving, relapse prevention, and motivational interviewing in quarterly individual and group sessions throughout the duration of the trial. Measurable realistic goals easily identifiable by the participant and attainable in specified time frames were set.
Just because study participants were encouraged to follow particular diets doesn’t mean they did. In fact, these study participants changed their diets very little, even with quarterly counseling sessions and encouragement from dieticians. Over the nearly 5years of the trial, the only significant changes made by the 2 Mediterranean diet groups were in fish and legume consumption: fish consumption increased by 0.3 servings per week and legumes by 0.4 servings per week in comparison to the control group. No other changes reached statistical significance, except for extra virgin olive oil or nut consumption.
Few of us would believe that eating one-third of a serving of fish and less than half a serving of beans per week more would be enough to have an impact on CVD. Belin reported in 2011 that 5 servings of fish per week were required to see a similar 30% decrease in CVD risk as reported in the current study.3
Low Fat Wasn’t Low Fat
The diet of the control group counseled to follow a low-fat diet did not change significantly. The percentage of total energy in the diet from fat dropped from 39% to 37%, a nonsignificant decrease of 1.96%, over the course of the trial. No conclusions can be drawn about the impact of switching to a low-fat diet from this study’s data, as no one appears to have really done so.
Type of Oil Mattered and Any Nuts Make a Difference
No conclusion about olive oil consumption in general can be warranted from these data. One year into the study, nearly 92% of the “low-fat diet” control group reported that olive oil was the primary culinary fat in their diets. After 5 years, this consumption level had increased to more than 96%. More than 58% of the control group on the low-fat diet reported consuming more than 4 T of olive oil per day. Any difference in CVD risk between groups was probably from the type of olive oil, “regular” vs extra virgin.
There were significant differences in nut consumption between the experimental and control groups. At the end of the trial, nearly 91% of the nut group reported eating 3 or more servings of nuts a week while less than 17% of the control group ate that many. What the data from this study really tell us is about switching from regular olive oil to extra virgin olive oil or eating a lot more nuts; this was not a comparison of a Mediterranean diet vs a low-fat diet.
Better Use of Our Time
Simply switching to extra virgin from regular olive oil lowered cardiovascular events by nearly a third. Eating 3 more servings of nuts a week did nearly the same. This study may not say much about a Mediterranean diet, but it certainly provides us with therapeutic options. Perhaps we should skip trying to get patients to switch to a Mediterranean diet—our efforts might be better focused on encouraging consumption of extra virgin olive oil and nuts.
Try as we might, it is often hard to change a patient’s diet for the long term. . . We may get both better compliance and greater impact by attempting to add a specific food to a patient’s diet.
The current study isn’t the first report that adding nuts to the diet might benefit heart health. In a 2011 paper, Sánchez-Villegas et al reported that a similar protocol encouraging consumption of supplemental nuts along with adherence to a Mediterranean diet over a 3-year period significantly reduced plasma brain-derived neurotrophic factor (BDNF) levels by 78%.4
Estruch conducted an earlier smaller version of this new trial. Published in 2006, it divided 772 people into the same 3 groups, had them follow similar protocols as in the current study for 3 months, and tracked biomarkers of CVD risk. Those following the Mediterranean diet with olive oil or with nuts had significant decreases in plasma glucose, systolic blood pressure, total cholesterol/ high-density lipoprotein (HDL) ratio, and the olive oil group alone had decreased c-reactive protein levels.5 In 2012 Urpi-Sarda reported similar results, telling us that adding virgin olive oil or nuts improved many of the inflammatory biomakers related to atherosclerosis. Both Mediterranean diets had an antiinflammatory effect reducing serum C-reactive protein, interleukin-6, and endothelial and monocytary adhesion molecules and chemokines (P<0.05; all). In those participants following a low-fat diet, all of these parameters increased.6
Two Decades of Nuts
Numerous studies over the last 2 decades have suggested that eating nuts might protect against CVD. In 1992, Fraser and colleagues reported that among 31,208 California Seventh Day Adventists, those who ate nuts more than 4 times per week experienced significantly fewer fatal CVD events and nonfatal myocardial infarctions compared with those who ate nuts less than once per week.7 These reductions in risk do not differ greatly from those seen in Estruch’s current study if one factors in the relatively greater risk for disease of the current participants.
In May 2010, Sabaté and colleagues reported the results from a meta-analysis of intervention trials on nuts and blood lipids. They pooled individual primary data from 25 nut consumption trials conducted in 7 countries among 583 men and women with normal lipids and hypercholesterolemia. Mean nut consumption was slightly more than twice that reported in the present study, 67 g per day instead of 30 g. Total cholesterol concentration decreased by 5.1%. Low-density lipoprotein (LDL) cholesterol decreased by 7.4%. The LDL/HDL ratio decreased 8.3%, and total cholesterol/HDL ratio dropped by 5.6%. Triglyceride levels decreased by 10.2% in participants whose levels were greater than 150 mg/dL.8
The Bottom Line
The conclusion that we can draw from Estruch’s current study is that supplementing with nuts or extra virgin olive oil has a positive impact. We can’t associate any effect of dietary counseling with the reduced risk of CVD events, even though it’s tempting to do so. The only real nutrient changes in these 2 Mediterranean diet groups resulted from the free foods given to the participants.
Try as we might, it is often hard to change a patient’s diet for the long term. In this study, even with quarterly meetings with a dietician, the average person ate the same way for 5 years. We may get both better compliance and greater impact by attempting to add a specific food to a patient’s diet.
Adding extra virgin olive oil or nuts to the diet clearly lowered cardiovascular disease risk to a degree that can be clinically significant. Whether or not following a Mediterranean diet will do the same remains a still unanswered question.
- Kolata G. Mediterranean diet shown to ward off heart attack and stroke. New York Times. February 25, 2013. Available at: http://www.nytimes.com/2013/02/26/health/mediterranean-diet-can-cut-heart-disease-study-finds.html?pagewanted=all&module=Search&mabReward=relbias%3Aw&_r=0. Accessed September 25, 2014.
- de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. 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(6):779-785.
- Belin RJ, Greenland P, Martin L, et al. Fish intake and the risk of incident heart failure: the Women’s Health Initiative. Circ Heart Fail. 2011;4(4):404-413.
- Sánchez-Villegas A, Galbete C, Martinez-González MA, et al. The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: the PREDIMED-NAVARRA randomized trial. Nutr Neurosci. 2011;14(5):195-201.
- Estruch R, Martínez-González MA, Corella D, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006;145(1):1-11.
- Urpi-Sarda M, Casas R, Chiva-Blanch G, et al. Virgin olive oil and nuts as key foods of the Mediterranean diet effects on inflammatory biomakers related to atherosclerosis. Pharmacol Res. 2012;65(6):577-583.
- Fraser GE, Sabaté J, Beeson WL, Strahan TM. A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern Med. 1992;152(7):1416-1424.
- Sabaté J, Oda K, Ros E. Nut consumption and blood lipid levels: a pooled analysis of 25 intervention trials. Arch Intern Med. 2010;170(9):821-827.