The New England Journal of Medicine June 21, 2018

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts

Ramón Estruch, Emilio Ros, Jordi Salas-Salvadó, et al.

Bottom Line

In patients at high cardiovascular risk, adherence to a Mediterranean diet supplemented with extra-virgin olive oil or mixed nuts significantly reduced the incidence of major cardiovascular events compared to a reduced-fat diet.

Key Findings

1. A primary endpoint event (myocardial infarction, stroke, or cardiovascular death) occurred in 288 participants: 96 (3.8%) in the extra-virgin olive oil (EVOO) group, 83 (3.4%) in the mixed nuts group, and 109 (4.4%) in the control group.

2. In the intention-to-treat analysis adjusting for baseline characteristics and propensity scores, the Mediterranean diet supplemented with EVOO reduced the risk of major cardiovascular events by 31% compared to control (HR 0.69; 95% CI, 0.53 to 0.91).

3. The Mediterranean diet supplemented with mixed nuts reduced the risk of major cardiovascular events by 28% compared to control (HR 0.72; 95% CI, 0.54 to 0.95).

4. The statistically significant cardiovascular benefit persisted even after the omission of 1,588 participants whose randomization was known or suspected to have departed from the protocol.

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

7,447

Patients

Duration

Median 4.8 years

Median

Setting

Multicenter, Spain

Population Men aged 55 to 80 years and women aged 60 to 80 years with no cardiovascular disease at enrollment, who had either type 2 diabetes mellitus or at least three major cardiovascular risk factors (smoking, hypertension, elevated LDL, low HDL, overweight/obesity, or family history of premature CHD).

Intervention Participants were assigned to one of two intervention arms: a Mediterranean diet supplemented with extra-virgin olive oil (approximately 1 liter per week provided) or a Mediterranean diet supplemented with mixed nuts (30 g/day: 15 g walnuts, 7.5 g hazelnuts, and 7.5 g almonds). Both groups received regular educational sessions.

Comparator A control diet emphasizing advice to reduce overall dietary fat (both animal and plant-based fats), supported by educational sessions.

Outcome A composite of major cardiovascular events, defined as myocardial infarction, stroke, or death from cardiovascular causes.

Study Limitations

• Protocol deviations occurred during the trial, including the enrollment of household members without randomization and cluster-assignment at specific clinics, requiring a retraction and republication of the data with corrected statistical methodology.

• The trial was stopped early after a median follow-up of 4.8 years (instead of the planned 6 years) due to early evidence of benefit, which carries a risk of overestimating the true effect size.

• The dietary interventions were inherently open-label, which could introduce behavioral bias, though clinical endpoints were adjudicated by a blinded committee.

• The control group experienced higher dropout rates and received less intense dietary intervention during the first few years of the trial (which was later amended).

Clinical Significance

The PREDIMED trial provides robust, randomized evidence that a Mediterranean diet—specifically one rich in unsaturated fats from extra-virgin olive oil or nuts—is superior to a generalized low-fat diet for the primary prevention of cardiovascular events in high-risk individuals. It catalyzed a paradigm shift in preventative cardiology away from strict total fat restriction and toward optimizing dietary fat quality.

Historical Context

For decades, the Mediterranean diet was supported primarily by observational studies (dating back to Ancel Keys' Seven Countries Study) and secondary prevention trials like the Lyon Diet Heart Study. The original PREDIMED trial, published in 2013, was hailed as a landmark achievement for proving its efficacy in a large-scale primary prevention RCT. In 2018, following external scrutiny that revealed randomization irregularities, the original paper was famously retracted and simultaneously republished with rigorous re-analyses. The corrected data yielded nearly identical hazard ratios, reaffirming the diet's cardiovascular benefits and setting a new standard for statistical transparency in nutrition science.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the proposed physiological mechanisms by which the Mediterranean diet, specifically when supplemented with extra-virgin olive oil or mixed nuts, reduces cardiovascular risk compared to a standard low-fat diet?

Key Response

This question teaches basic science concepts. Extra-virgin olive oil (rich in oleic acid and polyphenols) and nuts (rich in alpha-linolenic acid, L-arginine, and fiber) improve endothelial function, reduce oxidative stress, lower systemic inflammation, and improve lipid profiles (higher HDL, lower LDL oxidation) compared to simple carbohydrate replacement often seen in low-fat diets.

Resident

How should the results of the PREDIMED trial alter your dietary counseling for a patient with type 2 diabetes and hypertension who currently follows a strict low-fat, high-carbohydrate diet?

Key Response

Residents must translate evidence into actionable counseling. A low-fat diet was historically recommended, but PREDIMED showed that replacing fats with healthy fats (monounsaturated and polyunsaturated) rather than restricting total fat (which often inadvertently increases refined carbohydrate intake) is superior for primary cardiovascular prevention in high-risk patients.

Fellow

The primary composite endpoint in the PREDIMED trial was significantly reduced, but looking at the individual components, which specific cardiovascular event drove this outcome, and how does this influence your preventive cardiology strategy?

Key Response

Fellows need to look beyond the composite endpoint. The cardiovascular benefit in PREDIMED was driven almost entirely by a reduction in stroke, with no statistically significant difference in myocardial infarction or cardiovascular death. This highlights the specific neuroprotective and anti-atherothrombotic effects of the diet, which is particularly relevant for tailoring cerebrovascular risk reduction.

Attending

Given the challenges of sustained dietary adherence in clinical practice, how can we pragmatically implement the 'food as medicine' approach validated by PREDIMED without relying solely on the intensive dietician support and free food provisions utilized in the trial?

Key Response

Attendings focus on systems-based practice and feasibility. The trial used intense, frequent dietary counseling and provided free olive oil or nuts. Replicating this in a standard 15-minute visit requires multidisciplinary teams, leveraging community resources, and focusing on simple, actionable food substitutions rather than complex macronutrient tracking.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PREDIMED trial underwent a highly publicized retraction and republication due to irregularities in the randomization process. How did these departures from individual randomization occur, and what statistical methods were required in the re-analysis to salvage the trial's validity?

Key Response

This addresses essential PhD-level trial methodology. Some study sites randomized participants by clinic or household rather than individually, introducing cluster effects and selection bias. The re-analysis excluded these individuals or used robust variance estimators adjusting for clustering, yielding similar results, but serving as a massive cautionary tale for trial oversight and randomization auditing.

Journal Editor

As a peer reviewer, how would you evaluate the control group's intervention in PREDIMED, considering that the low-fat diet group received less intensive dietary counseling in the first few years of the study compared to the Mediterranean diet groups?

Key Response

Editors look for systemic biases. Early in the trial, the control group received only an annual leaflet, while the intervention groups had quarterly sessions. Although this was corrected later, the difference in 'attention' (performance bias) could account for some of the behavioral changes and outcomes, separate from the nutritional differences.

Guideline Committee

How do the findings of PREDIMED inform the ACC/AHA guidelines on primary prevention regarding dietary fat composition, and does this data warrant a Class I recommendation for the Mediterranean diet over other established dietary patterns like DASH?

Key Response

This evaluates evidence synthesis. ACC/AHA guidelines (e.g., 2019 Primary Prevention) give a Class I (Level of Evidence B-R) recommendation for a diet emphasizing vegetables, fruits, legumes, nuts, whole grains, and fish. While PREDIMED strongly supports the Mediterranean diet, guidelines group it with DASH and vegetarian diets because head-to-head mortality data among these specific healthy patterns is limited, though PREDIMED provides the strongest RCT data for specific healthy fat supplementation.

Clinical Landscape

Noteworthy Related Trials

1999

Lyon Diet Heart Study

n = 605 · Circulation

Tested

Mediterranean-type diet (rich in alpha-linolenic acid)

Population

Patients surviving a first myocardial infarction

Comparator

Prudent Western-type diet

Endpoint

Cardiovascular death and non-fatal myocardial infarction

Key result: The Mediterranean diet significantly reduced the rate of cardiovascular recurrence by over 70 percent compared to the control diet.

2006

WHI Dietary Modification Trial

n = 48,835 · JAMA

Tested

Low-fat dietary pattern (reduced fat, increased fruits, vegetables, and grains)

Population

Postmenopausal women aged 50 to 79 years

Comparator

Usual diet

Endpoint

Coronary heart disease and stroke

Key result: A low-fat dietary pattern did not significantly reduce the risk of coronary heart disease, stroke, or overall cardiovascular disease over an 8.1-year follow-up.

2022

CORDIOPREV Trial

n = 1,002 · Lancet

Tested

Mediterranean diet rich in extra-virgin olive oil

Population

Patients with established coronary heart disease

Comparator

Low-fat diet

Endpoint

Composite of cardiovascular death, myocardial infarction, stroke, or revascularization

Key result: The Mediterranean diet was superior to a low-fat diet in preventing major cardiovascular events among patients with coronary heart disease.

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