- What Does the PREDIMED Trial Retraction & Reboot Mean for the Mediterranean Diet? | Absolutely Maybe
- The Mediterranean Diet On Trial
- The Evidence
- The Good
- The Bad
- Eat More Of These
- Avoid These
- The Expert Verdict
- That Huge Mediterranean Diet Study Was Flawed. But Was It Wrong?
- The Mediterranean Diet and Cardiovascular Health
- Is the MedDiet a Concept Promoted Mainly or Partly for Geographic-Romantic-Nostalgic Reasons?
- Is the MedDiet a Concept Vested Commercial Interests of Olive Oil and Nut Companies?
- Should Refined Cereals Be a Part of the MedDiet?
- PREDIMED Study Retraction and Republication
What Does the PREDIMED Trial Retraction & Reboot Mean for the Mediterranean Diet? | Absolutely Maybe
A very influential nutrition trial just tanked. It was retracted from the New England Journal of Medicine (NEJM) on 13 June, and re-published with new analyses and toned-down conclusions.
Both Gina Kolata, writing in the New York Times, and Alison McCook, writing at NPR, imply, at least to some extent, that it might make no difference to the evidence. But I disagree.
Here’s what’s happened to the trial, and where I think it leaves the overall evidence.
Called PREDIMED, it was a multi-center trial from Spain, with the NEJM final report published in 2013. Altogether, 7,447 people at risk of cardiovascular disease (CVD) – heart attack and stroke – were reported as randomized to one of 3 groups:
- Mediterranean diet with free olive oil provided, along with individual and group training sessions at the start, and then quarterly;
- Mediterranean diet with free nuts provided, along with individual and group training sessions at the start, and then quarterly;
- Advice to reduce fat intake, with a leaflet – but after the first 3 years, people in this control group were also offered individual and group training sessions.
The primary endpoint for the trial was a composite one of major cardiovascular events: myocardial infarction, stroke, or CVD-related death. And the trial was stopped early. More people dropped the control group than the Mediterranean diet groups.
There are several alarm bells here already, and we’ll come back to those. (For some background, I’ve written before about the care you need to take with relying on composite endpoints – here – and trials that get stopped early – here and here.)
The road to retraction of PREDIMED didn’t start with those issues, though. It began with a piece of meta-research by John Carlisle in 2017. He listed PREDIMED as an example of a trial branded “randomized”, where the data didn’t look consistent with randomization to him. NEJM followed up – and the authors dug into their data.
It turned out Carlisle was right. The authors have now reported that randomization had gone awry for 21% of the participants – 1,588 of the 7,447 people in the trial. About a third each were for one or more of these reasons:
- When more than one person in a house was recruited, instead of randomizing each, they were all assigned to the same diet;
- At one site, the randomization table hadn’t been used properly; and
- At one site, clinics were randomized instead of people.
The authors have gone to a lot of trouble to re-analyze. And they say that even without these 1,588 people, the results are much the same. They tone down their conclusion because as the trial wasn’t properly randomized, the evidence is now weaker.
Unfortunately, though, I couldn’t find data showing what the impact of these 1,588 people were on the components of the composite endpoint. (The 3 components are all secondary endpoints, but I couldn’t find a sensitivity analysis for them – let me know, please, if you see them!)
Even for the full group, there was no statistically significant difference on myocardial infarction or CVD mortality – just for stroke. And in the supplementary information, there wasn’t a difference in the Kaplan Meier analysis for stroke either.
So what have critical systematic reviewers had to say about the quality and reliability of the PREDIMED trial, even before this bad news landed? And how strong is the evidence overall for the Mediterranean diet after this retraction?
The authors list a large number of systematic reviews/meta-analyses in their supplementary information, to support their certainty that health benefits for the Mediterranean diet are established. But they don’t report the basis for selecting that list. And there are, generally, more unreliable systematic reviews than very good ones.
I looked at 2 sources of reviews for a quick check: the systematic reviews listed in PubMed as citing the 2013 paper (n = 9) and cited in the HANDI assessment of the Mediterranean diet (n = 1).
The systematic reviews listed with the trial in PubMed are those selected for PubMed Health with citations accessible. That means they are more ly to be higher quality systematic reviews – here’s a post from me of some rules of thumb on this.
(Disclosure: In a previous role, I had recommended the providers of systematic reviews included in PubMed Health.)
those 10 reviews, 6 of them were directly relevant and of acceptable quality. Only 1 of them was included in the PREDIMED paper’s list of systematic reviews/meta-analyses. (You can see a summary of all 10 reviews below this post.)
I think the strongest and most recent of these reviews were from organizations that specialize in systematic reviews: 2 from the Cochrane Collaboration and 1 from NICE. The 2 Cochrane reviews rejected the PREDIMED trial from consideration, even before these revelations, primarily because of taking issue with the control group.
The reviewers from NICE assessed the PREDIMED trial as at “serious” risk of bias for individual CVD outcomes, with “low or very low quality” data – and underpowered for mortality outcomes (even at the full complement). In addition, they wrote, the trial
was difficult to interpret because the control group was advised to reduce their fat intake and to follow some of the components of the Mediterranean diet.
Even before this retraction, the evidence base for the Mediterranean diet wasn’t really a slam dunk. There have been several trials, but they are riddled with problems – and what’s called “the Mediterranean diet” varies a lot.
So how does this evidence apply to you? Keep in mind, these people were at relatively high risk of CVD, with the men 55 and older, and the women 60 and older. So if you’re at less risk than that, these results don’t necessarily apply anyway. And we don’t really know what aspects of a Mediterranean diet might make a health difference to people from other countries.
If you are keen on trying to stick to a Mediterranean diet, HANDI has a guide here.
It’s not lots of pasta and pizza and red wine! And speaking of red wine, check out this article by Julia Belluz in Vox, on the shifting evidence about even moderate alcohol use.
If there does turn out to be an adverse effect to the popularization of the Mediterranean diet, it could be in the idea that the best diet includes regular red wine.
The Mediterranean-food-and-red-wine hypothesis is really appealing – at least to some social groups. But that could be a problem. If we’re not particularly careful with health claims that are attractive to us, there’s a good chance we’re going to be disappointed.
Disclosure: I don’t believe I have any critical conflict of interest about the Mediterranean diet – other than a personal bias towards the health of Asian diets. I do eat pasta frequently, though, so I would be delighted if that was good for me!
The cartoons are my own (CC BY-NC-ND license).(More cartoons at Statistically Funny and on Tumblr.) I borrowed the notion of there being no use crying over spilled milk, to represent the damaged trial, not just the trial. Here’s a piece on the interesting history of the spilled milk analogy.
[CORRECTION] The original version of this post mistakenly described the control group as participating in the same training sessions as the experimental groups after the first three years. However, they were only of the “same frequency and intensity”. Thank you to Angeliki Papadaki for pointing out the error.
The systematic reviews I assessed are listed below: * indicates the systematic review is directly relevant and of acceptable quality.
Listed in PubMed as systematic reviews citing 2013 PREDIMED trial:
- Kane (2017) (not listed in PREDIMED): cognitive outcomes, not CVD.
- Palmer (2017 – Cochrane) (not listed in PREDIMED): kidney disease, not CVD.
- * Bloomfield (2015 – VA) (not listed in PREDIMED): Mediterranean diet compared to other diets. For CVD mortality, they rated PREDIMED as “overall low risk of bias. Consistency is unknown and there was imprecision”. For overall mortality, “There is large imprecision and inconsistency, and overall risk of bias is medium”.
- * Hooper (2015 – Cochrane) (not listed in PREDIMED): diets low in saturated fats, CVD: excluded PREDIMED because “Total fat goals in the low-fat arm were unclear and authors confirmed that aims were non-specific (if aims < 30%E this study would be included)”.
- NICE (2014) (not listed in PREDIMED): obesity, not DVD.
- * NICE (2014) (not listed in PREDIMED): lipids, CVD: PREDIMED assessed as “serious” risk of bias for individual CVD outcomes – all included studies categorized as under-powered for mortality, with “low or very low quality” data. In addition, “The most up to date study from Spain that examined ‘Mediterranean diet’ was difficult to interpret because the control group was advised to reduce their fat intake and to follow some of the components of the Mediterranean diet”. There was, they concluded, critical differences in what constituted a Mediterranean diet in included studies.
- * Lara (2014) (not listed in PREDIMED): people “of retirement age” (54 to 70 years), used Cochrane risk of bias tool, but did not report individual results or take data quality into account in drawing conclusions. However, authors reported “None of the studies satisfied all of the criteria of the quality assessment tool”. Concluded evidence of effectiveness for the Mediterranean diet.
- Benatar (2013) (not listed in PREDIMED): dairy food, PREDIMED cited but not included.
- * Rees (2013 – Cochrane) (listed in PREDIMED): Mediterranean diet to prevent CVD. PREDIMED “did not meet our strict inclusion criteria as the comparison group was not minimal”…. “Low-fat diet arm had face-to-face nutritional advice as well as leaflets, therefore, not a minimal control”.
Cited in HANDI:
- * Nordmann (2011) (not listed in PREDIMED): Mediterranean to low-fat diets, CVD. An author of PREDIMED is one of these reviewers, although did not participate in quality assessment. However, as PREDIMED was subsequently terminated early for benefit, the completed trial would not have met this review’s inclusion criteria. The authors concluded that “None of the included trials was powered to detect any differences in clinical outcomes between the 2 diets”. Quality assessment identified some problems. PREDIMED was classified as concealing allocation, but not reporting on whether outcome assessment was blinded; there was
The Mediterranean Diet On Trial
The catch-all name for the traditional diet eaten by the populations of Italy, Greece and southern France and Spain. Obviously, the cuisine varies by region, but it usually includes vegetables, fruits, nuts, beans, cereal grains, olive oil and fish, along with moderate amounts of red wine and limited sugar.
Solid. This one’s been around for a while.
A 2011 review of studies found that the Mediterranean diet is probably more effective than a low-fat diet in lowering LDL (“bad”) cholesterol and blood pressure, while a 2015 study found that adherence to the diet lowers your overall stroke risk. If your main concern is fat loss, though, you might want to look elsewhere: a 2016 review found that it’s no more successful than other diets.
It’s not a difficult diet to follow, and the food recommendations still allow for social eating with minimal hardship.
It also shares a few similarities with the currently popular Sirt diet, which suggests that the protective effects of red wine and olive oil (among other things) are actually related to a little-researched class of proteins called sirtuins, discovered only in 2005. Put it this way: you’re unly to do yourself any harm following this one, even though the mechanisms aren’t clear.
Though there’s a decent amount of evidence to support the diet, some studies are confounded by lifestyle factors.
There’s an argument that the benefits arise from actually living in Mediterranean countries, which comes with more social support and less stress than the typical British office-worker grind.
You might also need to be picky about your olive oil and greens: the traditional kind are grown in the mountains and tend to be very antioxidant-heavy, which might complicate matters.
Eat More Of These
The Mediterranean diet isn’t very prescriptive, especially as there is a great range in the kind of foods eaten around the Med, but for a start you’ll want to up the amount of fruit and vegetables you eat. No need to get fancy with the types involved – just make sure you have a portion with every meal.
You should also up your intake of seafood, especially oily fish, and legumes beans and lentils. Nuts and seeds, wholegrain carbs and tubers sweet potatoes should all also feature regularly on your menu, and make sure everything is drizzled with olive oil. OK, maybe not everything.
Nothing is explicitly outlawed with the Mediterranean diet but when it comes to meat you should aim for poultry and fish over red meat, and all meat should be eaten in moderation. The same goes for dairy and eggs, and you should avoid added sugars and processed foods where possible.
The Expert Verdict
The Mediterranean diet ticks all the right boxes for dietitian Chloe Miles of the British Dietetic Association. “The diet encourages plenty of fruit and vegetables, beans and pulses, fish, wholegrain cereals, and modest amounts of olive oil and low-fat dairy. It has been found to reduce the risk of heart disease and stroke, and it may also help you maintain a healthy weight.”
That Huge Mediterranean Diet Study Was Flawed. But Was It Wrong?
Continue reading the main storyImageAn olive farm in Tuscany. Participants in a study of the Mediterranean diet were not always assigned at random to test various diets, the investigators conceded.Credit…
Giulio Piscitelli for The New York Times
But now that trial, published in the New England Journal of Medicine in 2013, has come under fire.
The authors retracted their original paper on Wednesday and published an unusual “re-analysis” of their data in the same journal.
Despite serious problems in the way the study was conducted, their conclusions are the same: A Mediterranean diet can cut the risk of heart attacks and strokes by about 30 percent in those at high risk.
Not everyone is convinced. “Nothing they have done in this re-analyzed paper makes me more confident,” said Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute.
For decades, researchers have noted that people living in some Mediterranean countries have lower rates of heart disease and cancer. Scientists have long suspected that the regional diet — rich in fruits, vegetables, nuts and olive oil, with moderate levels of fat — played a protective role.
But the idea has been hard to prove. It is very difficult to test any diet in a clinical trial. Participants may be reluctant to stick to the prescribed meal plan, for instance, and it can be difficult to monitor them over months or years.
The original study was conducted in Spain by Dr. Miguel A. Martínez-González of the University of Navarra and his colleagues. The trial enrolled 7,447 participants aged 55 to 80 who were assigned one of three diets: a Mediterranean diet with at least four tablespoons a day of extra virgin olive oil; the same diet with an ounce of mixed nuts; or a traditional low-fat diet.
The participants were followed for a median of nearly five years. Dr. Martínez-González and his colleagues reported that there were fewer cardiovascular events in the groups consuming olive oil and nuts.
“That was the first hint that there could have been some imperfection,” Dr. Martínez-González said in an interview.
A statistician at the New England Journal of Medicine suggested the researchers look at the methods at each center that recruited participants.
The idea of a randomized trial is to assign treatments — in this case, diets — to participants with the statistical equivalent of a coin toss. That way, the groups being compared should be equivalent, with no group healthier or sicker, or older or younger, than another on average.
If subjects are not assigned at random, the investigators cannot be sure that the effects they see result from the treatment. And attempts to correct statistically after the fact are fraught with difficulty.
On re-evaluating their data, the scientists running the Mediterranean diet study soon found what Dr. Martínez-González said were “small problems affecting 10 percent of participants.”
Some investigators would assign one person in a household — the wife, for example — to one arm of the study — say, to the group consuming olive oil. Then they would ask other members of the household to share that diet, including them as though they had been randomly assigned to it.
“We realized we had never reported that,” Dr. Martínez-González said.
Dr. Miguel A. Martínez-GonzálezCredit…via Wikimedia Commons
An omission that erodes the randomized nature of the trial. Family members are ly to share more than just a diet: If a husband and wife both dodge heart disease, it’s difficult to say that their diet is the only reason.
In their re-analysis, the investigators statistically adjusted data on 390 people who happened to be household members but whose diets were not randomly assigned.
Then the investigators discovered another problem.
A researcher at one of the 11 clinical centers in the trial worked in small villages. Participants there complained that some neighbors were receiving free olive oil, while they got only nuts or inexpensive gifts.
So the investigator decided to give everyone in each village the same diet. He never told the leaders of the study what he had done.
“He did not think it was important,” Dr. Martínez-González said.
But the decision meant that participants were not truly randomized and forced Dr. Martínez-González and his colleagues to make another statistical adjustment to data on 652 people in the trial.
The investigators spent a year working on the re-analysis in collaboration with Dr. Miguel Hernan of the Harvard T.H. Chan School of Public Health.
In the end, they concluded that the original findings were still accurate.
“You cannot imagine what it has been ,” Dr. Martínez-González said, adding that he and his team worked through vacations and weekends — and swallowed considerable professional embarrassment.
Randomized trials are difficult, other experts agreed, and randomized diet studies so perilous they are seldom attempted.
“These people were naïve,” said Donald Berry, a statistician at MD Anderson Cancer Center in Houston. “They were sloppy and didn’t know they were being sloppy.”
Dr. Berry said he wants to believe the results. He loves nuts and has taken to cooking with extra virgin olive oil.
But he remains unconvinced, because the re-analysis did not solve the study’s problems, he said.
Dr. Bradley Efron, a statistics professor at Stanford University, also was skeptical. The revamped results “wouldn’t convince me to be on a Mediterranean diet,” he said.
But Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, is persuaded and plans to continue advising patients to go on the Mediterranean diet.
When the initial paper was published, he said, “I was thrilled to see what seemed to be an impeccable trial.”
Although it was “sobering” to learn of the errors, “I was reassured that the conclusions are correct,” he said.
Dr. Martínez-González shares the sentiment. “After all this long work, I am more convinced than ever” by the study’s data.
“Seldom has a trial undergone more scrutiny,” he added.
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The Mediterranean Diet and Cardiovascular Health
The Mediterranean diet (MedDiet), abundant in minimally processed plant-based foods, rich in monounsaturated fat from olive oil, but lower in saturated fat, meats, and dairy products, seems an ideal nutritional model for cardiovascular health.
Methodological aspects of Mediterranean intervention trials, limitations in the quality of some meta-analyses, and other issues may have raised recent controversies. It remains unclear whether such limitations are important enough as to attenuate the postulated cardiovascular benefits of the MedDiet.
We aimed to critically review current evidence on the role of the MedDiet in cardiovascular health. We systematically searched observational prospective cohorts and randomized controlled trials which explicitly reported to assess the effect of the MedDiet on hard cardiovascular end points.
We critically assessed all the original cohorts and randomized controlled trials included in the 5 most comprehensive meta-analyses published between 2014 and 2018 and additional prospective studies not included in these meta-analyses, totaling 45 reports of prospective studies (including 4 randomized controlled trials and 32 independent observational cohorts). We addressed the existing controversies on methodology and other issues. Some departures from individual randomization in a subsample of the landmark Spanish trial (PREDIMED [Prevención con Dieta Mediterránea]) did not represent any clinically meaningful attenuation in the strength of its findings and the results of PREDIMED were robust in a wide range of sensitivity analyses. The criteria for causality were met and potential sources of controversies did not represent any reason to compromise the main findings of the available observational studies and randomized controlled trials. The available evidence is large, strong, and consistent. Better conformity with the traditional MedDiet is associated with better cardiovascular health outcomes, including clinically meaningful reductions in rates of coronary heart disease, ischemic stroke, and total cardiovascular disease.
Diet has been traditionally considered as a main determinant of cardiovascular health. In fact, one of the 7 cardiovascular health metrics proposed in 2010 by the American Heart Association (Life’s simple 7) directly corresponds to a healthy diet.
1 But also, other 4 of the remaining 6 proposed health metrics (body mass index, blood pressure, total cholesterol, and blood glucose) are closely determined by dietary habits. Moreover, an additional health metric, physical activity, represents just the other side of the energy balance equation and it is indirectly related to dietary energy intake.
Therefore, a healthy diet is essential to meet most of the goals of Life’s simple 7 and to ensure cardiovascular health.
In this context, the overall quality of the whole food pattern may be more important and more interpretable than analyses focused on single nutrients or foods.
The study of overall food patterns represents the current state of the art in the investigation of the nutritional determinants of cardiovascular health.
2,3 This approach is advantageous because it limits confounding by individual dietary factors and it captures the synergistic effects of individual foods and nutrients.
It may also provide a more powerful tool to assess the effect of dietary habits on cardiovascular health because the effect of a single dietary element is ly to be too small as to be detected in epidemiological studies or randomized controlled trials (RCTs). In contrast, it seems logical that the cumulative effect of many different aspects of diet is ly to be considerably larger.4
The Mediterranean diet (MedDiet) represents a salient overall dietary pattern in nutritional epidemiology that has been extensively studied, especially during the last 2 decades.
The MedDiet is defined as a traditional eating pattern found among populations living in the Mediterranean Basin during the 50s and 60s of the 20th century, but, unfortunately, not today.
5 The main characteristics of the MedDiet at those times were a low consumption of meat and meat products, with very low consumption of red meat (beef, pork, and lamb were reserved only for special occasions), very low or null consumption of processed meats, butter, ice creams, or other whole-fat dairy products (only fermented dairy products, cheese and yogurt, were consumed in moderate amounts). It presented a relatively fat-rich profile because of the abundant consumption of olive oil, together with a high consumption of minimally processed, locally grown, vegetables, fruits, nuts, legumes, and cereals (mainly unrefined).6 An important source of protein was a moderate consumption of fish and shellfish, that was variable depending on the proximity to the sea. The main sources of fat and alcohol among persons in the traditional MedDiet are primarily extra-virgin olive oil (EVOO) and red wine, respectively. The abundant use of olive oil, through salads, traditionally cooked vegetables, and legumes, together with the moderate consumption of red wine during meals makes this diet highly nutritious and palatable. Red wine and EVOO contain several bioactive polyphenols (hydroxytyrosol and tyrosol, oleocanthal, and resveratrol) with postulated anti-inflammatory properties.7 Postulated antiatherogenic properties of olive oil were supposedly attributed to its high content of monounsaturated fat (MUFA; oleic acid),8 and some more recent investigations also suggest that bioactive polyphenols, only present in the EVOO, but not in the refined-common variety of olive oil, may contribute to these cardioprotective actions.9 EVOO is the product from the first pressing of the ripe olive fruit and contains many antioxidants (polyphenols, tocopherols, and phytosterols).10 Lower-quality oils (refined or common olive oils) are believed to be devoid of most of these antioxidant, anti-inflammatory, or pleiotropic capacities because they are obtained by physical and chemical procedures that keep the fat but lead to the loss of most bioactive elements.
In the Spanish landmark PREDIMED trial (Prevención con Dieta Mediterránea), with 7447 high-risk participants initially free of cardiovascular disease (CVD), a 5-year intervention with a MedDiet significantly reduced the incidence of a composite major CVD end point that included nonfatal stroke, nonfatal coronary heart disease (CHD), and all fatal CVD events. However, the results of that trial were recently retracted by the authors and simultaneously republished in the same journal.11 They included many new analyses and comprehensively addressed some small departures from individual randomization. Notwithstanding, many questions remain as to whether the MedDiet can confer benefits for cardiovascular health in both Mediterranean and non-Mediterranean populations. It is also uncertain how variations in the components of the MedDiet indices used in different studies may influence this association. In addition, other potential sources of bias should be adequately addressed.
In the first sections of this article, we will discuss some potential concerns about the beneficial cardiovascular effects of the MedDiet. In the following sections, we will address issues related to these concerns. The currently available evidence strongly supports the MedDiet as an ideal approach for cardiovascular health.
Is the MedDiet a Concept Promoted Mainly or Partly for Geographic-Romantic-Nostalgic Reasons?
Many of the investigators who are currently strong supporters of the MedDiet have born, live, or have an ancestry in Mediterranean countries.
6,12 This might represent a reason of concern because they may be biased when selecting the pieces of evidence that best fit in the picture of their preconceptions about what should be a healthy diet.
13 They are ly to include those aspects of their diet that they have loved since childhood and even they learnt from their grandparents or ancestors.
14 It is easy to think that there might be a sort of mixture of scientific and nonscientific reasons, some of them probably unconscious, in this group of investigators and these mixed motives may have contributed to the adoption of their strong positions and opinions on the cardiovascular benefits of the MedDiet. As discussed below, this assertion is not supported by the fact that numerous studies conducted in non-Mediterranean populations have found similar benefits of Mediterranean-type dietary patterns on CVD risk.
Is the MedDiet a Concept Vested Commercial Interests of Olive Oil and Nut Companies?
The potential biases in biomedical investigation related to research funding by the pharmaceutical industry have been largely studied and documented. It is well-known that there is a significant association between industry sponsorship and pro-industry conclusions. But similar biases related to research funding by food industry have been only recently documented.
Pro-industry bias in pharmaceutical research might have adverse health effects on millions of patients receiving medications, but pro-industry bias in nutrition research will have adverse health effects for absolutely everyone, with a substantially higher harm for public health. In addition, regulations are tighter for pharmaceutical research than for nutritional research.
In the jungle of academic-industry interactions scientific truth—nothing more, nothing less—should be the primary aim that all should pursue.16 This statement has been frequently repeated in the scientific environments surrounding investigators on nutrition and cardiovascular health.
The primary interests of multinational food companies are to increase their profits, and consequently, to make easier the most profitable food choices. In contrast, the primary interest of public health is to make easier the healthiest choices. There is a clear clash of interests.
Many published studies, particularly small trials with soft end points and reviews or commentaries, on the benefits of the MedDiet for cardiovascular health have been funded by food industries or were written after their presentation in an industry-funded meeting.
Although not to the same extent than for sugar-sweetened beverages,17 this potential conflict of interest has been specifically criticized in relationship with the very concept of the MedDiet.
Richard Smith, the former editor of the BMJ, wrote “a combination of vested interests, including the International Olive Oil Council and a public relations company Oldways, which promoted the diet, has—together with the natural seductiveness of the Mediterranean region—made the diet popular”.18 These criticisms, however, do not hold water the fact that the vast majority of evidence on MedDiet has been funded publicly. We will discuss this issue in a later section.
Should Refined Cereals Be a Part of the MedDiet?
The currently available epidemiological evidence consistently supports the recommendation to consume less refined grains and replace them by whole grains. This replacement will reduce the risks of type 2 diabetes mellitus and CVD.
19–21 However, in the most frequently used operational definition of the MedDiet,22 all cereals are included as a single positive item. No difference is made between refined and whole grain cereals.
The assumption that all grains, including refined grains, provide cardiovascular protection might be against the current scientific evidence. Fung et al23 modified the score developed by Trichopoulou and included only whole grain products in the alternative Mediterranean diet (aMedDiet) score.
Similarly, Panagiotakos et al24 gave the greater adherence to the MedDiet to the highest consumption of whole grains (Table 1). This modification seems more consistent with current mainstream findings in nutrition science.
The PREDIMED trial did not include the consumption of cereals in the MedDiet adherence screener.25 This difference might cast doubts on the reliability of some MedDiet scores to capture a dietary pattern with the largest potential for cardiovascular health.
|Positively weighted components||Monounsaturated/saturated*||Monounsaturated/saturated†||Olive oil in cooking‡||Olive oil as main culinary fat|
|Vegetables*||Vegetables†||Vegetables‡||≥4 tablespoon§/d olive oil|
|Fruits and nuts*||Fruits†||Fruits‡||≥2 servings/wk olive oil sauce with tomato, garlic, onion, or leek (sofrito)|
|Legumes*||Nuts†||Legumes‡||≥2 servings/d vegetables|
|Fish*||Legumes†||Fish‡||≥3 servings/d fruits|
|Cereals*||Fish†||Whole grains‡||≥3 servings/wk nuts|
|Whole grains†||≥3 servings/wk legumes|
|≥3 servings/wk fish|
|Preference for poultry (chicken, turkey, or rabbit) > red meats (beef, pork, hamburgers, or sausages)|
|Negatively weighted components||Meat/meat products‖||Red and processed meat¶||Red and processed meat‡|
PREDIMED Study Retraction and Republication
On June 13, 2018, the New England Journal of Medicine (NEJM) retracted the 2013 study, “Primary Prevention of Cardiovascular Diseases with a Mediterranean Diet,”  as a result of error in randomization procedures affecting a portion of participants in the PREDIMED (Prevención con Dieta Mediterránea) trial. Concurrently, NEJM published a corrected version of the study with reanalyzed data, “Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts.” 
- The number of participants included in the analysis:
- The original study included 7447 participants at high cardiovascular risk 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). 
- The republished study disclosed several issues related to the randomization process: enrollment of household members without randomization; allocation of several clinics instead of individual patients at 1 of 11 study sites; and apparent inconsistent use of randomization tables at another study site.
- The authors re-ran the analyses by statistically correcting for correlations within families or clinics. They also re-ran the analyses omitting 1588 participants whose trial-group assignments were known or suspected to have departed from proper randomization protocol. 
What Didn’t Change?
- Despite these revelations, there was no significant change in the results of the trial when researchers reanalyzed the data:
- In both the original and republished study, the incidence of cardiovascular disease in the Mediterranean diet groups was lowered by approximately 30% when compared to the control diet. [1,2]
- The overall conclusion remains largely unchanged: “In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet.” 
- To date, PREDIMED remains the largest dietary intervention trial to assess the effects of the Mediterranean diet on cardiovascular disease prevention.
The Big Picture
As a randomized clinical trial, results from PREDIMED remain a significant contribution to the scientific literature on a traditional Mediterranean diet.
That said, it is only a portion of the large body of evidence indicating the healthfulness of this dietary pattern.
The bottom line remains that strong evidence supports the use of the traditional Mediterranean diet as a healthy eating pattern for the prevention of cardiovascular diseases, increasing lifespan, and healthy aging.
Furthermore, the discussion surrounding the retraction and republication of this landmark research study is an important reminder that solid science is not any single study, but the result of sustained and critically evaluated research by multiple investigators through many studies, over many years.
Diet Review: Mediterranean Diet
What should I Eat?
Preventing Heart Disease
- Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM. Primary prevention of cardiovascular disease with a Mediterranean diet. New England Journal of Medicine. 2013 Apr 4;368(14):1279-90.
- Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM. Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts. New England Journal of Medicine. 2018 Jun 13.