Long-Term Immunomodulatory Effects of a Mediterranean Diet in Adults at High Risk of Cardiovascular Disease in the PREvención con DIeta MEDiterránea (PREDIMED) Randomized Controlled Trial

J Nutr. 2016 Sep;146(9):1684-93. doi: 10.3945/jn.115.229476. Epub 2016 Jul 20.


Background: The Mediterranean diet (MedDiet) has demonstrated short-term anti-inflammatory effects, but little is known about its long-term immunomodulatory properties.

Objective: Our goal was to assess the long-term effects of the MedDiet on inflammatory markers related to atherogenesis in adults at high risk of cardiovascular disease (CVD) compared with the effects of a low-fat diet (LFD).

Methods: We randomly assigned 165 high-risk participants (one-half men; mean age: 66 y) without overt CVD to 1 of 3 diets: a MedDiet supplemented with extra-virgin olive oil, a MedDiet supplemented with nuts, or an LFD. Follow-up data were collected at 3 and 5 y. Repeated-measures ANOVA, adjusted for potential confounding variables, was used to evaluate changes in diet adherence, CVD risk factors, and inflammatory variables.

Results: The 2 MedDiet groups achieved a high degree of adherence to the intervention, and the LFD group had reduced energy intake from fat by 13% by 5 y. Compared with baseline, at 3 and 5 y, both MedDiet groups had significant reductions of ≥16% in plasma concentrations of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor α, and monocyte chemoattractant protein 1 (P ≤ 0.04), whereas there were no significant changes in the LFD group. The reductions in CD49d and CD40 expressions in T lymphocytes and monocytes at 3 y were ≥16% greater in both MedDiet groups than were the changes in the LFD group (P < 0.001) at 3 y. Compared with baseline, at 3 y, the MedDiet groups had increased HDL-cholesterol (≥8%) and decreased blood pressure (>4%) and total cholesterol, LDL-cholesterol, and triglyceride (≥8%) concentrations. At 5 y, concentrations of glucose (13%) and glycated hemoglobin (8%) had increased with the LFD.

Conclusions: The MedDiet participants had lower cellular and plasma concentrations of inflammatory markers related to atherosclerosis at 3 and 5 y. This anti-inflammatory role of the MedDiet could explain in part the long-term cardioprotective effect of the MedDiet against CVD. This trial was registered at controlled-trials.com as ISRCTN35739639.

Keywords: Mediterranean diet; adhesion molecules; cardiovascular disease; inflammation; long-term; peripheral blood mononuclear cells.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Blood Pressure
  • C-Reactive Protein / metabolism
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / prevention & control*
  • Diet, Fat-Restricted
  • Diet, Mediterranean*
  • Energy Intake
  • Exercise
  • Female
  • Follow-Up Studies
  • Glycated Hemoglobin / metabolism
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Nuts
  • Olive Oil / administration & dosage
  • Risk Factors
  • Single-Blind Method
  • Treatment Outcome


  • Biomarkers
  • Blood Glucose
  • Glycated Hemoglobin A
  • Olive Oil
  • C-Reactive Protein

Associated data

  • ISRCTN/ISRCTN35739639