Diabetes Care NOVEMBER 02, 2018

PREDIMED-Plus: A Randomized Trial of an Energy-Restricted Mediterranean Diet and Lifestyle Intervention

Jordi Salas-Salvadó, Miguel Á. Martínez-González, et al.

Bottom Line

The PREDIMED-Plus trial is a large-scale, multicenter study evaluating the long-term impact of an intensive lifestyle intervention—combining an energy-restricted Mediterranean diet, increased physical activity, and behavioral support—on cardiovascular outcomes and weight maintenance in older adults with metabolic syndrome.

Key Findings

1. In a 1-year interim analysis, the intensive intervention group achieved significant weight loss (mean reduction of 3.2 kg) compared to the control group (0.7 kg), resulting in a mean between-group difference of -2.5 kg (95% CI -3.1 to -1.9 kg; P < 0.001).

2. Clinical markers significantly improved in the intervention group, including reductions in waist circumference, fasting glucose, triglycerides, and improvements in HDL cholesterol (P < 0.002 for all comparisons).

3. A secondary analysis conducted after a median follow-up of approximately 7 years demonstrated that the intensive lifestyle intervention was associated with a 31% lower relative risk for incident type 2 diabetes compared to the ad libitum Mediterranean diet control group.

Study Design

Design

RCT

Single-Blind

Sample

6,874

Patients

Duration

6-8 yr

Median

Setting

Multicenter, Spain

Population Community-dwelling men (55-75 years) and women (60-75 years) with overweight or obesity (BMI 27-40 kg/m2) and metabolic syndrome.

Intervention Intensive weight loss program: energy-restricted Mediterranean diet (30% calorie deficit), physical activity promotion (walking 45 min/day), and intensive behavioral support.

Comparator Usual care: energy-unrestricted Mediterranean diet (similar to PREDIMED study) without calorie restriction, exercise goals, or intensive behavioral support.

Outcome A composite of hard cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), and long-term weight loss maintenance.

Study Limitations

• The trial was designed primarily for hard cardiovascular endpoints, while findings such as diabetes incidence were secondary or exploratory analyses, which may limit the certainty of the conclusions.

• The intervention is behavioral in nature, making it impossible to blind participants to their assigned group, which introduces the potential for performance and reporting bias.

• While the study provides strong evidence for metabolic and weight-related improvements, the final long-term assessment of major adverse cardiovascular events is ongoing, limiting conclusions regarding hard clinical outcomes like myocardial infarction and stroke.

Clinical Significance

The PREDIMED-Plus trial reinforces the clinical utility of combining dietary structure, physical activity, and behavioral modification to address the components of metabolic syndrome, providing a scalable, non-pharmacological strategy for the prevention of type 2 diabetes and potentially reducing cardiovascular risk in high-risk populations.

Historical Context

PREDIMED-Plus builds directly upon the original PREDIMED trial (2003–2010), which established that an ad libitum Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the risk of cardiovascular events by 30%. PREDIMED-Plus evolves this framework by testing whether adding caloric restriction, structured exercise, and intensive behavioral coaching yields superior outcomes for weight maintenance and long-term metabolic health.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Beyond simple calorie counting, what specific biochemical mechanisms allow the Mediterranean diet's high intake of monounsaturated fatty acids (MUFAs) and polyphenols to improve insulin sensitivity in patients with metabolic syndrome?

Key Response

The Mediterranean diet is rich in olive oil (high in oleic acid) and antioxidants. These components modulate gene expression (e.g., activating PPAR-gamma) and reduce systemic inflammation by lowering C-reactive protein and pro-inflammatory cytokines, which directly combats the pathophysiology of insulin resistance central to metabolic syndrome.

Resident

A 68-year-old patient with obesity and metabolic syndrome asks if they should follow the 'standard' Mediterranean diet from the original PREDIMED study or the 'Plus' version. Based on the PREDIMED-Plus trial design, what is the primary clinical advantage of the 'Plus' intervention for this specific patient population?

Key Response

While the original PREDIMED trial focused on a non-restrictive Mediterranean diet, PREDIMED-Plus adds intensive energy restriction and physical activity. For patients with obesity and metabolic syndrome, this addition is designed to achieve significant weight loss and greater reductions in waist circumference and HbA1c, which were not primary targets in the first trial.

Fellow

How does the PREDIMED-Plus intervention attempt to overcome the 'Look AHEAD' trial's failure to show a significant reduction in cardiovascular events despite successful weight loss in patients with Type 2 Diabetes?

Key Response

Unlike Look AHEAD, which used a standard low-fat approach for the intervention, PREDIMED-Plus utilizes the Mediterranean diet as the baseline for energy restriction. This addresses the 'quality vs. quantity' of nutrients, aiming to synergize the cardiovascular benefits of Mediterranean-style fats and phytonutrients with the metabolic benefits of weight loss.

Attending

The PREDIMED-Plus trial utilizes a high frequency of behavioral support, including monthly individual interviews and group sessions. How does this intensive delivery model challenge our current outpatient management of metabolic syndrome, and what are the implications for long-term adherence?

Key Response

The trial highlights that dietary quality changes are difficult to maintain without frequent behavioral reinforcement. For attendings, this serves as a teaching point on 'implementation science'—clinical success depends less on the specific diet and more on the infrastructure of behavioral support, which is often under-reimbursed and under-utilized in standard practice.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

PREDIMED-Plus is a multicomponent intervention (diet, exercise, behavioral therapy). What statistical or study design strategies could be employed to perform a 'decomposition analysis' to determine which component is the primary driver of the observed metabolic improvements?

Key Response

In multicomponent trials, identifying the 'active ingredient' is challenging. Researchers could use mediation analysis or a factorial design (if pre-planned) to isolate effects. Understanding whether weight loss (energy restriction) or nutrient composition (Mediterranean diet) is the independent driver of CVD risk reduction is critical for refining future lifestyle interventions.

Journal Editor

Given the history of the original PREDIMED trial (which required a major retraction/republication due to randomization errors), what specific safeguards in the PREDIMED-Plus methodology should be scrutinized to ensure the integrity of the multicenter randomization process?

Key Response

A critical reviewer would look for central randomization protocols, concealment of allocation, and evidence that participants from the same household or clinic cluster were handled appropriately. Editors would also flag whether the control group (receiving general Mediterranean diet advice) was sufficiently 'active' to avoid the Hawthorne effect while still allowing for a measurable difference against the intensive intervention.

Guideline Committee

If PREDIMED-Plus demonstrates superior CVD outcomes compared to the original PREDIMED, should guidelines be updated to move away from 'ad libitum' Mediterranean diet recommendations toward 'energy-restricted' versions for all patients with metabolic syndrome?

Key Response

Current AHA/ACC guidelines recommend calorie-controlled diets for weight loss but are often neutral on the specific dietary pattern. If PREDIMED-Plus shows that the *combination* of energy restriction and Mediterranean patterns is superior to the 'non-restrictive' MedDiet seen in the original PREDIMED (Grade B/C evidence currently), it could lead to a Grade A recommendation specifying the Mediterranean diet as the preferred vehicle for caloric restriction in high-risk metabolic patients.

Clinical Landscape

Noteworthy Related Trials

2008

DIRECT Trial

n = 322 · NEJM

Tested

Low-carbohydrate, Mediterranean, or low-fat diets

Population

Moderately obese subjects

Comparator

Other dietary interventions

Endpoint

Changes in weight and cardiovascular risk factors

Key result: The Mediterranean diet was as effective as a low-carbohydrate diet for weight loss and offered superior improvements in glycemic control and lipid profiles.

2013

PREDIMED Trial

n = 7,447 · NEJM

Tested

Mediterranean diet supplemented with extra-virgin olive oil or nuts

Population

Persons at high cardiovascular risk

Comparator

Reduced-fat diet

Endpoint

Composite of myocardial infarction, stroke, or cardiovascular death

Key result: The Mediterranean diet reduced the incidence of major cardiovascular events by approximately 30% in high-risk individuals.

2013

Look AHEAD Trial

n = 5,145 · NEJM

Tested

Intensive lifestyle intervention for weight loss

Population

Overweight or obese adults with type 2 diabetes

Comparator

Diabetes support and education

Endpoint

Composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalized angina

Key result: Despite successful weight loss and improved glycemic control, the intensive lifestyle intervention did not reduce the rate of cardiovascular events compared to standard care.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis