Table 2

Characteristics of the included trials

First authorOriginTrial nameDesign,
masking
RegistryPublication
(journal, year)
Participants*RandomisationPrevention tierPrimary outcomeInterventionComparatorCompliance
Al Wattar58 UKESTEEMPragmatic,
Parallel,
Single blind
NCT02
218931
PLOS Med, 2019N=1252 inner-city pregnant women with metabolic risk factors (obesity, hypertension, or hypertriglyceridaemia)1:1 ratio via a password-protected on-line data management systemPrimaryMaternal composite outcome,† offspring composite outcome‡MD high in nuts, EVOO, fruits, vegetables, non-refined grains and legumes, moderate-to-high fish, low-to-moderate poultry and dairy, low intake of red/processed meat, avoidance of sugar, fast food and food rich in animal fatUsual care (dietary advice)FFQ and ESTEEM Q
Assaf-Balut59 SpainSt. Carlos GDM prevention studyParallel,
Open label
ISRCTN8
4389045
PLOS One, 2017N=1000 normoglycaemic (<92 mg/dL) pregnant women at 8±12 gestational wkStratified with permutated block randomisation, by age, pregravid BMI, ethnicity, parity, in a 1:1 ratio and 4–6 blocksPrimaryGDM incidenceMD supplemented with EVOO and pistachios (≥40 mL of EVOO and 25–30 g of pistachios each day)Standard diet with limited fat intakeMEDAS, DNCT FFQ, urine HXT and serum γ-tocopherol
Assaf-Balut60 SpainSt. Carlos GDM prevention studyParallel,
Open label
ISRCTN8
4389045
Ann Nutr Metab, 2019N=697 normoglycaemic (<92 mg/dL) pregnant women at 8±12 gestational wkStratified with permutated block randomisation, by age, pregravid BMI, ethnicity, parity, in a 1:1 ratio and 4–6 blocksPrimaryComposite maternofetal outcome§MD supplemented with EVOO and pistachios (≥40 mL of EVOO, 25–30 g of pistachios every day)Standard diet with limited fat intakeMEDAS, DNCT FFQ, urine HXT, serum γ-tocopherol
Babio61 SpainPREDIMEDParallel, single blindISRCTN3
5739639
CMAJ, 2014N=5801 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryMetS
  1. MD with EVOO (1 L/wk for the participants and families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS/9-item dietary screener (per arm)
de Lorgeril62 FranceLyon Diet Heart StudyParallel, single-blindNR Circulation, 1999N=423 consecutive patients who survived a first MI at 6 months of enrolmentNRSecondaryComposite outcome††MD: more bread, root, green vegetables and fish, less meat (beef/lamb/pork replaced by poultry), no day without fruit. Butter/cream replaced by canola margarinePrudent Western-type dietDiet ‘survey’ (MD group), plasma FA
de Lorgeril34 FranceLyon Diet Heart StudyParallel, single-blindNR Arch Intern Med, 1998N=605 consecutive patients who survived a first MI within 6 months of enrolmentNRSecondaryCV mortality, non-fatal MIMD: more bread, root, green vegetables and fish, less meat (beef/lamb/pork replaced by poultry), no day without fruit. Butter/cream replaced by canola margarinePrudent Western-type diet24 hours recall and FFQ
de Lorgeril35 36 FranceLyon Diet Heart StudyParallel, single-blindNR J Am Coll Cardiol, 1996; Lancet, 1994N=605 consecutive patients who survived a first MI within 6 months of enrolmentNRSecondaryCV mortality, non-fatal MIMD: more bread, root, green vegetables and fish, less meat (beef/lamb/pork replaced by poultry), no day without fruit. Butter/cream replaced by canola margarinePrudent Western-type diet24 hours recall and FFQ
Díaz-López37 38 SpainPREDIMEDParallel,
Single blind
ISRCTN3
5739639
Diabetes Care, 2015; Rev Esp Cardiol, 2019N=3614 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryNew-onset of diabetic retinopathy, nephropathy
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)Urine HXT and plasma ALA proportions
Esposito31 32 ItalyParallel, open-labelNCT00
725257
Diabetes Care, 2014; ; Ann Intern Med, 2009N=215 men/women (30–75 years) with newly diagnosed T2DM‘Simple’ randomisation; PC-generated random sequenceSecondaryInitiation of T2DM medicationLCMDLFDDiet diaries
Estruch18 19 SpainPREDIMEDParallel, single-blindISRCTN3
5739639
NEJM, 2018N=7447 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 sealed envelopes (pilot phase) and PC-generated random numberPrimaryComposite
CV events‡‡
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS/9-item dietary screener, urine HXT, plasma ALA
García-Gavilán33 53 SpainPREDIMEDReusParallel, single-blindISRCTN3
5739639
Clin Nutr, 2018; Am J Clin Nutr, 2018N=870 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryOsteoporotic fractures
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
García-Layana40 SpainPREDIMEDParallel, single-blindISRCTN3
5739639
Nutrients, 2017N=5802 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryOccurrence of cataract surgery
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS, urine HXT and plasma ALA ratio
Gené
Huguet41
SpainPre Frail 80 StudyParallel, open-labelNR J Nutr Health Aging, 2018N=200 non-institutionalised men/women (≥80 years) fulfilling 1/2 of the Fried65 frailty criteriaRandomised list NODSecondaryReversion to robustnessMDStandard treatmentMEDAS
Greenberg57 IsraelDIRECTParallel, NRNCT001
60108
J Am Coll Nutr, 2009N=322 men/women
(40–65 years) with BMI
≥27 kg/m2/T2DM/CHD
Based on sex, age,
BMI, history of CHD/T2DM and statins use
Secondary5% BW lossHypocaloric§§ MD based on Willet.
Fat: 40% (mainly olive oil and nuts)
(1) Atkins-based LCD. CHO 20 g/d (first 2 months), ≤100 g/d thereafter.
Unlimited EI, protein, fat.
(2) Hypocaloric§§ LFD based on the AHA. Fat: 20%–30% (SFA 7%–10%, 200–300 mg cholesterol)
127-item
FFQ with 3 portion size pictures for 17 selected items
Marcos-
Forniol42
SpainParallel, open-labelISRCTN1
7382091
Eur J Prev Cardiol, 2018N=127 consecutive patients (≥70 years), with acute coronary syndrome¶¶1:1 PC allocation with random block sizes of 2SecondaryOptimal CVD risk factor control***MDStandard care9-item MD score
Martínez-González43 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
Circulation, 2014N=7447 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryIncidence of atrial fibrillation
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS, urine HXT, plasma ALA ratio
Papadaki44 63 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
Eur J Heart Fail, 2017N=7403 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryHeart failure incidence
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
Pintó52 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
J Nutr, 2019N=109 consecutive patients, men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimarySteatosis diagnosis
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
Properzi45 AustraliaParallel, single-blindACTRN1
2612000
841875
Hepatology, 2018N=56 adult patients with NAFLDIn a 1:1 fashion using randomly selected envelope-concealed allocations in blocks of 4PrimaryNAFLD resolutionMD based on foods consumed in traditional Cretan diet, altered to allow for standardisation of protein intake with the control diet. CHO: 40%, fat: 35%–40% (<10% SFA), protein:<20%LFD (based on NHMRC and AHA). CHO: 50%, fat: 30%, SFA <10%, protein: 20%Modified Burke diet history, self-assessment of food-group goals, MEDAS
Ruiz-Canela54 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
JAMA, 2014N=4991 men/women (55–80 years) PAD-free and CVD-free but with T2DM and/or ≥3 CVD risk factors¶1:1:1 ratioPrimaryNew symptomatic PAD events
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
Salas-Salvadó55 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
Arch Intern Med, 2008N=3923 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶NR but based on the PREDIMED protocol 1:1:1 PC-generated randomisation table**Primary and secondaryMetS reversion rate and incidence
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS, urine tyrosol and HXT, plasma ALA ratio
Salas-Salvadó
39 46
SpainPREDIMED ReusParallel, open-labelISRCTN3
5739639
Diabetes Care, 2011; 2018N=418 non-diabetic, CVD-free men/women with ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryDiabetes incidence
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
Salas-Salvadó
47 48
SpainPREDIMEDParallel, open-labelISRCTN3
5739639
Ann Intern Med, 2014; 2018N=3541 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryNew-onset of diabetes
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS/9-item dietary screener, urine HXT, plasma ALA
Sánchez-Villegas56 SpainPREDIMEDParallel, open-labelISRCTN3
5739639
BMC Medicine, 2013N=3923 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryDepression
  1. MD with EVOO (1 L/wk for the participant and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS
Singh49 IndiaIndo-MD Heart
Study
Parallel, single-blindNR Lancet, 2002N=1000 men/women (28–75 years) with hypercholesterolaemia, hypertension, DM, angina pectoris, previous MIBy selection of a card from a pile of an equal number of cards for each groupSecondaryTotal cardiac eventsNCEP prudent diet (fat: 30%, SFA <10%, cholesterol <300 mg/d), >400–500 g of fruit, vegetable and nuts, 400–500 g whole-grains, legumes, rice, maize, wheat, 34 serv of mustard seed/soybean oilNCEP prudent dietWeight food records and 24 hours nutrient intakes
Toledo50 SpainPREDIMEDParallel, single-blindISRCTN3
5739639
JAMA Intern Med, 2015N=4282 women (60–80 years) with T2DM and/or ≥3 CVD risk factors¶1:1:1 PC-generated randomisation table**PrimaryBreast cancer incidence
  1. MD with EVOO (1 L/wk for participants and their families)

  2. MD with mixed nuts (30 g/d: 15 g walnuts, 7.5 g hazelnuts, 7.5 g almonds)

Control diet (advice to reduce dietary fat)MEDAS/9-item dietary screener (per group)
Tuttle51 USATHIS-DIETParallel, open-label
(blind PI)
Am J Cardiol, 2008N=101 MI survivorsSealed envelopes with the allocation sequence, prepared by a PI, placed in a locked drawerPrimaryFree survival†††MD with fat: 30%–40% (<7% SFA), CHO: 50%, protein: 10%–20%LFD (AHA step II). Fat:<30%, protein: 10%–20%, SFA <7%, CHO: 55%–60%Self-reported 3-d food diaries, verified by plasma FA
  • *Number of initially randomised participants or in the secondary analyses of the Prevención con Dieta Mediterránea (PREDIMED) study, the number of initially randomised participants as stated in the respective papers.

  • †Maternal composite outcome: gestational diabetes mellitus (GDM) or preeclampsia.67

  • ‡Offspring composite outcome: stillbirth, small-for-gestational age (SGA), or admission to neonatal care unit.67

  • §Emergency caesarean section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational age, and SGA.

  • ¶Smoking, hypertension, elevated low-density lipoprotein (LDL) level, low high-density lipoprotein level, overweight/obesity, or family history of premature coronary heart disease (CHD).

  • **Concerns regarding randomisation rose post publication.

  • ††cardiac death and non-fatal myocardial infarction (MI).

  • ‡‡MI, stroke, or death from cardiovascular (CV) causes.

  • §§Hypocaloric, 1200–1500 kcal/day for women and 1500–1800 kcal/day for men.

  • ¶¶ST-elevation MI, non-ST elevation MI and unstable angina.

  • ***Achievement of ≥5 risk factor goals: blood pressure <140/90 mm Hg, LDL <2.6 mmol/L, smoking cessation, body mass index (BMI) <25 kg/m2, physical activity of moderate intensity >30 min/day, 3 days/week (≥6 MET h/wk) and HbA1c <7% in patients with diabetes.

  • †††Composite of all-cause and cardiac deaths, MI, hospital admissions for heart failure, unstable angina pectoris or stroke.

  • ‡‡‡MI, stroke, or CV death.

  • AHA, American Heart Association; ALA, α-linolenic acid; BW, body weight; CHO, carbohydrate; CVD, cardiovascular disease; DIRECT, dietary intervention randomised controlled trial; DM, diabetes mellitus; DNCT, diabetes nutrition and complications trial; EI, energy intake; ESTEEM, Effect of Simple, Targeted Diet in Pregnant Women With Metabolic Risk Factors on Pregnancy Outcomes; EVOO, extra-virgin olive oil; FA, fatty acid; FFQ, food frequency questionnaire; HXT, hydroxytysosol; LCD, low-carbohydrate diet; LCMD, low-carbohydrate MD; LFD, low-fat diet; MD, Mediterranean diet; MEDAS, Mediterranean Diet Adherence Screener66; MET, metabolic equivalents; MetS, metabolic syndrome; NAFLD, non-alcoholic fatty liver disease; NCEP, National Cholesterol Education Program; NHMRC, National Health and Medical Research Council; NOD, not-other defined; NR, not reported; PAD, peripheral artery disease; PC, personal computer; PI, principle investigator; ESTEEM Q, ESTEEM questionnaire67; SFA, saturated fatty acids; ST, sinus tachycardia; T2DM, type 2 diabetes mellitus; THIS-DIET, The Heart Institute of Spokane Diet Intervention and Evaluation Trial.