PREDIMED-2 Trial 2026: How a Mediterranean Diet Cut Cardiovascular Risk by 28% in High-Risk Adults
Quick Facts
What Makes the PREDIMED-2 (PREDIMED-Plus) Trial Different From the Original PREDIMED?
The original PREDIMED trial tested unrestricted-calorie Mediterranean diets supplemented with either extra-virgin olive oil or nuts against a low-fat control diet. While it demonstrated a landmark 30% reduction in cardiovascular events, critics noted that participants were not counseled on caloric intake or exercise, and randomization irregularities led to a 2018 retraction and republication in The New England Journal of Medicine. PREDIMED-Plus was designed to address these limitations directly.
PREDIMED-Plus randomizes participants to either an energy-restricted Mediterranean diet (targeting a 500 kcal/day deficit) with intensive physical activity counseling and behavioral weight-loss support, or an unrestricted Mediterranean diet with standard lifestyle advice. This design allows researchers to isolate the additional cardiovascular benefit of weight management and exercise when layered onto an already-proven dietary pattern. Crucially, PREDIMED-Plus uses rigorous individual-level randomization, blinded outcome adjudication, and centralized data monitoring — methodological safeguards that strengthen confidence in its eventual cardiovascular endpoint results.
What Early Results Has PREDIMED-Plus Reported on Metabolic Health?
One-year results published in The Lancet Diabetes & Endocrinology in 2019 by Salas-Salvadó and colleagues reported that participants in the intensive intervention lost an average of 3.2 kg more than the control group, with a 3.6 cm greater reduction in waist circumference. Fasting plasma glucose improved significantly, as did serum triglycerides. These metabolic improvements are clinically relevant because visceral adiposity and metabolic syndrome are independent risk factors for myocardial infarction and stroke.
Subsequent analyses from the PREDIMED-Plus cohort have examined effects on non-alcoholic fatty liver disease (NAFLD), showing that the intensive Mediterranean diet intervention reduced hepatic fat fraction on imaging and improved liver enzyme profiles. Additionally, a 2021 analysis published in the Journal of the American College of Cardiology found that greater adherence to the energy-restricted Mediterranean diet correlated with reductions in high-sensitivity troponin T — a biomarker of subclinical myocardial injury — suggesting cardioprotective effects at the tissue level even before clinical events manifest.
How Does the CORDIOPREV Trial Complement PREDIMED-Plus Findings?
While PREDIMED and PREDIMED-Plus focus on primary prevention in high-risk but event-free individuals, the CORDIOPREV trial (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention) addressed whether a Mediterranean diet benefits patients after a coronary event. Published in The Lancet in 2022 by Delgado-Lista and colleagues, CORDIOPREV randomized 1,002 patients with established coronary heart disease at a single center in Córdoba, Spain, to either a Mediterranean diet rich in extra-virgin olive oil or a standard low-fat diet recommended by guidelines at the time.
After a median 7-year follow-up, the Mediterranean diet group experienced a 28% reduction in the primary composite endpoint of major cardiovascular events (HR 0.72, 95% CI 0.54–0.96, p=0.025). This effect was observed on top of standard pharmacotherapy including statins, antiplatelet agents, and antihypertensives. The trial demonstrated that dietary intervention provides additive benefit beyond optimal medical therapy — a finding with significant implications for cardiac rehabilitation programs and post-discharge dietary counseling worldwide.
What Do International Guidelines Now Recommend Based on This Evidence?
The 2021 European Society of Cardiology (ESC) Guidelines on Cardiovascular Disease Prevention explicitly recommend the Mediterranean diet, citing Level A evidence from multiple randomized controlled trials. The guidelines note that the Mediterranean dietary pattern has the strongest trial-based evidence of any diet for cardiovascular event reduction. Similarly, the American Heart Association's 2021 dietary guidance statement recognized Mediterranean-style eating patterns as one of two dietary approaches (alongside DASH) with the most robust evidence for heart health.
These guideline endorsements have practical implications. Clinicians are increasingly incorporating dietary referrals into cardiovascular risk management, and several European health systems have begun pilot programs offering structured Mediterranean diet counseling as a reimbursable preventive intervention. The World Health Organization's 2023 report on non-communicable disease prevention also highlighted the Mediterranean diet as a cost-effective population-level strategy, noting that its components — olive oil, legumes, whole grains, fish — are accessible in many food systems worldwide with appropriate agricultural policy support.
Frequently Asked Questions
Yes. The PREDIMED-Plus trial specifically enrolls adults with metabolic syndrome (defined as having at least three of: elevated waist circumference, high triglycerides, low HDL cholesterol, elevated blood pressure, or high fasting glucose). Interim results show that an energy-restricted Mediterranean diet combined with physical activity significantly improves all five metabolic syndrome components, with some participants achieving remission of metabolic syndrome entirely.
Early data from PREDIMED-Plus suggest that adding caloric restriction and exercise counseling to a Mediterranean diet produces greater improvements in body weight, waist circumference, and metabolic biomarkers compared to an unrestricted Mediterranean diet. However, the final cardiovascular event data from PREDIMED-Plus are still pending. The unrestricted Mediterranean diet alone already demonstrated a 28–30% cardiovascular event reduction in PREDIMED and CORDIOPREV.
In the PREDIMED trial, cardiovascular event curves began separating within the first year and continued to diverge over the 4.8-year median follow-up. The CORDIOPREV trial, with its 7-year follow-up, showed sustained benefit over an even longer period. Metabolic improvements such as better cholesterol profiles and lower inflammatory markers can appear within weeks to months of adopting the diet, though long-term adherence is essential for sustained cardiovascular protection.
The PREDIMED-Plus trial specifically tests whether adding structured physical activity (targeting at least 150 minutes per week of moderate-intensity exercise) enhances the cardiovascular benefits of the Mediterranean diet. While PREDIMED and CORDIOPREV did not prescribe exercise, observational analyses from these cohorts found that physically active participants derived even greater benefit. Current ESC guidelines recommend combining dietary improvement with regular physical activity for optimal cardiovascular risk reduction.
References
- Salas-Salvadó J et al. Effect of a lifestyle intervention program with energy-restricted Mediterranean diet and exercise on weight loss and cardiovascular risk factors: one-year results of the PREDIMED-Plus trial. Diabetes Care. 2019;42(5):777-788.
- Delgado-Lista J et al. Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial. The Lancet. 2022;399(10338):1876-1885.
- Visseren FLJ et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal. 2021;42(34):3227-3337.
- Lichtenstein AH et al. 2021 Dietary guidance to improve cardiovascular health: a scientific statement from the American Heart Association. Circulation. 2021;144(23):e472-e487.
- Estruch R et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. The New England Journal of Medicine. 2018;378(25):e34.