Launched in 2013 after the University of Navarra received an Advanced Grant of over €2 million from the European Research Council (ERC), PREDIMED-Plus is the largest nutrition trial ever conducted in Europe. Between 2014 and 2016, additional institutions joined the effort, bringing total funding above 15 million euros. Most of the support came from the Carlos III Health Institute (ISCIII) and the Center for Biomedical Research Network (CIBER), through its divisions on Physiopathology of Obesity and Nutrition (CIBEROBN), Epidemiology and Public Health (CIBERESP), and Diabetes and Associated Metabolic Diseases (CIBERDEM).

The study, published in Annals of Internal Medicine, followed 4,746 adults between the ages of 55 and 75 who were overweight or obese and had metabolic syndrome but no prior history of cardiovascular disease or diabetes. Over six years, researchers compared two groups. One group adopted a calorie-reduced Mediterranean diet (about 600 fewer kilocalories per day), engaged in moderate exercise such as brisk walking and strength and balance training, and received professional counseling. The other group continued a traditional Mediterranean diet without calorie limits or exercise advice.

The results revealed that the participants who followed the calorie-reduced diet and exercise plan not only reduced their diabetes risk but also lost more weight and trimmed more from their waistlines. On average, they lost 3.3 kg and 3.6 cm from their waist, compared to 0.6 kg and 0.3 cm in the control group. This translated to preventing about three new cases of type 2 diabetes for every 100 participants -- a meaningful benefit for public health.

"Diabetes is the first solid clinical outcome for which we have shown -- using the strongest available evidence -- that the Mediterranean diet with calorie reduction, physical activity and weight loss is a highly effective preventive tool," said Miguel Ángel Martínez-González, Professor of Preventive Medicine and Public Health at the University of Navarra, Adjunct Professor of Nutrition at Harvard University, and one of the principal investigators of the project. "Applied at scale in at-risk populations, these modest and sustained lifestyle changes could prevent thousands of new diagnoses every year. We hope soon to show similar evidence for other major public health challenges."

Type 2 Diabetes: A Preventable Global Epidemic

According to the International Diabetes Federation, type 2 diabetes now affects over 530 million people around the world. Its rise is fueled by urbanization (unhealthy diets, sedentary lifestyles, reduced physical activity), an aging population, and increasing rates of overweight and obesity. In Spain, an estimated 4.7 million adults live with diabetes -- mostly type 2 -- giving the country one of the highest rates in Europe, where total cases exceed 65 million. In the United States, roughly 38.5 million people have diabetes, and the disease carries some of the highest per-patient healthcare costs worldwide. Experts emphasize that prevention is crucial to slow this escalating crisis, which greatly increases the risk of heart, kidney, and metabolic complications.

"The Mediterranean diet acts synergistically to improve insulin sensitivity and reduce inflammation. With PREDIMED-Plus, we demonstrate that combining calorie control and physical activity enhances these benefits," explained Miguel Ruiz-Canela, Professor and Chair of Preventive Medicine and Public Health Department at the University of Navarra's School of Medicine and first author of the study. "It is a tasty, sustainable and culturally accepted approach that offers a practical and effective way to prevent type 2 diabetes -- a global disease that is, to a large extent, avoidable."

International Relevance and Support for a Realistic and Scalable Strategy

Annals of Internal Medicine accompanied the publication with an editorial by Sharon J. Herring and Gina L. Tripicchio, nutrition and public health experts at Temple University (Philadelphia, USA). They praised the intervention's clinical relevance and its potential as a preventive model for type 2 diabetes. Furthermore, they warn that replicating similar strategies outside the Mediterranean context -- such as in the U.S. -- requires overcoming structural barriers, including unequal access to healthy foods, the limitations of the urban environment, and the lack of professional guidance. In this scenario, they advocate strengthening public policies that promote more nutritious and more equitable environments. At a time when new drugs against obesity and diabetes are grabbing headlines, PREDIMED-Plus demonstrates that modest, sustained lifestyle changes can still deliver powerful health benefits.

The PREDIMED-Plus project (2013-2024), which involves different patients, is a continuation of the PREDIMED study (2003-2010). This study demonstrated that following a Mediterranean diet enriched with extra-virgin olive oil or nuts reduces the risk of cardiovascular disease by 30%. Researchers emphasize that primary care providers can integrate the new intervention as a sustainable, cost-efficient strategy to prevent type 2 diabetes on a large scale.

Participating Institutions

The PREDIMED-Plus trial has assembled a broad network of investigators from across Spain. In order of the number of participants, the study included researchers from the following institutions: the University of Navarra and the Navarra Health Service (2 centers), Hospital Clínic de Barcelona (2 centers), University of Valencia, Rovira i Virgili University (Reus), IMIM-Hospital del Mar, Miguel Hernández University (Alicante), Son Espases Hospital (Palma de Mallorca), University of Malaga, Reina Sofía Hospital (Córdoba) and University of Granada. In addition, Bioaraba and the UPV/EHU (Vitoria), the University of the Balearic Islands, the Hospital Virgen de la Victoria (Malaga), the University of Las Palmas de Gran Canaria, the University of Leon, the Primary Health Care District of Seville, the Fundación Jiménez Díaz (Madrid), the Hospital de Bellvitge, the Hospital Clínico San Carlos (Madrid), the University of Jaen, and the IMDEA Food Institute (Madrid) have also participated.

The project also benefited from international collaboration with the Harvard T.H. Chan School of Public Health (USA). Most of the participating researchers are affiliated with the CIBEROBN, CIBERESP, or CIBERDEM research networks.

Over a seven-year period, researchers followed 5,794 adults who participated in the Netherlands Epidemiology of Obesity (NEO) Study. None of the participants had diabetes or cardiovascular disease when the study began. Each person completed a detailed questionnaire assessing depressive symptoms. Based on these responses, the researchers identified two main types of depression: one characterized by "melancholic" features (including early morning awakening and loss of appetite) and another defined by "atypical/energy-related" features (such as fatigue, increased sleep, and higher appetite).

During the study, about 8% of participants developed a cardiometabolic disorder. The specific illness that appeared, however, depended on the kind of depression they had. Individuals with "atypical/energy-related" depression were roughly 2.7 times more likely to develop Type 2 diabetes than those without depressive symptoms, but they did not face a higher risk of cardiovascular disease.

By contrast, participants with "melancholic" depression were about 1.5 times more likely to experience cardiovascular disease (including heart attack or stroke) than those without depression, but they did not have a significantly greater risk of Type 2 diabetes.

Lead researcher Dr. Yuri Milaneschi (Amsterdam UNC) explained:

"Further metabolic analysis revealed that patients with the atypical/energy-related symptoms showed disruptions in inflammatory and metabolic processes linked to cardiometabolic health. This biological signature was not seen in those with "melancholic" symptoms, suggesting biochemical differences in the way that different types of depression link to cardiovascular health.

We already knew that not all depressions are the same, but this means that we may need to consider how the type of depression someone has impacts different areas of their physical health. It very much pushes us towards the idea of precision psychiatry -- the idea that we need to look for physical associations with mental health profiles, so that we can better treat mental illness. To treat sufferers individually."

Commenting, Dr. Chiara Fabbri (of the University of Bologna) said:

"The prevention and treatment of physical diseases in people with depression are not less important than the treatment of depression. These physical conditions are common and expected to raise, for example the number of people with diabetes (66 million) in the EUR Region will see a 10% increase by 2050 according to the International Diabetes Federation. It is a health care priority to prevent cardiometabolic diseases, diagnose them early, and continue to improve monitoring and treatment. This study on the NEO cohort provides highly valuable data on how to do this better for people suffering from depressive symptoms."

Dr. Fabbri was not involved in this work; this is an independent comment.