First author | Origin | Trial name | Design, masking | Registry | Publication (journal, year) | Participants* | Randomisation | Prevention tier | Primary outcome | Intervention | Comparator | Compliance |
Al Wattar58 | UK | ESTEEM | Pragmatic, Parallel, Single blind | NCT02 218931 | PLOS Med, 2019 | N=1252 inner-city pregnant women with metabolic risk factors (obesity, hypertension, or hypertriglyceridaemia) | 1:1 ratio via a password-protected on-line data management system | Primary | Maternal 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 fat | Usual care (dietary advice) | FFQ and ESTEEM Q |
Assaf-Balut59 | Spain | St. Carlos GDM prevention study | Parallel, Open label | ISRCTN8 4389045 | PLOS One, 2017 | N=1000 normoglycaemic (<92 mg/dL) pregnant women at 8±12 gestational wk | Stratified with permutated block randomisation, by age, pregravid BMI, ethnicity, parity, in a 1:1 ratio and 4–6 blocks | Primary | GDM incidence | MD supplemented with EVOO and pistachios (≥40 mL of EVOO and 25–30 g of pistachios each day) | Standard diet with limited fat intake | MEDAS, DNCT FFQ, urine HXT and serum γ-tocopherol |
Assaf-Balut60 | Spain | St. Carlos GDM prevention study | Parallel, Open label | ISRCTN8 4389045 | Ann Nutr Metab, 2019 | N=697 normoglycaemic (<92 mg/dL) pregnant women at 8±12 gestational wk | Stratified with permutated block randomisation, by age, pregravid BMI, ethnicity, parity, in a 1:1 ratio and 4–6 blocks | Primary | Composite maternofetal outcome§ | MD supplemented with EVOO and pistachios (≥40 mL of EVOO, 25–30 g of pistachios every day) | Standard diet with limited fat intake | MEDAS, DNCT FFQ, urine HXT, serum γ-tocopherol |
Babio61 | Spain | PREDIMED | Parallel, single blind | ISRCTN3 5739639 | CMAJ, 2014 | N=5801 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | MetS |
| Control diet (advice to reduce dietary fat) | MEDAS/9-item dietary screener (per arm) |
de Lorgeril62 | France | Lyon Diet Heart Study | Parallel, single-blind | NR | Circulation, 1999 | N=423 consecutive patients who survived a first MI at 6 months of enrolment | NR | Secondary | Composite 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 margarine | Prudent Western-type diet | Diet ‘survey’ (MD group), plasma FA |
de Lorgeril34 | France | Lyon Diet Heart Study | Parallel, single-blind | NR | Arch Intern Med, 1998 | N=605 consecutive patients who survived a first MI within 6 months of enrolment | NR | Secondary | CV mortality, non-fatal MI | 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 margarine | Prudent Western-type diet | 24 hours recall and FFQ |
de Lorgeril35 36 | France | Lyon Diet Heart Study | Parallel, single-blind | NR | J Am Coll Cardiol, 1996; Lancet, 1994 | N=605 consecutive patients who survived a first MI within 6 months of enrolment | NR | Secondary | CV mortality, non-fatal MI | 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 margarine | Prudent Western-type diet | 24 hours recall and FFQ |
Díaz-López37 38 | Spain | PREDIMED | Parallel, Single blind | ISRCTN3 5739639 | Diabetes Care, 2015; Rev Esp Cardiol, 2019 | N=3614 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | New-onset of diabetic retinopathy, nephropathy |
| Control diet (advice to reduce dietary fat) | Urine HXT and plasma ALA proportions |
Esposito31 32 | Italy | – | Parallel, open-label | NCT00 725257 | Diabetes Care, 2014; ; Ann Intern Med, 2009 | N=215 men/women (30–75 years) with newly diagnosed T2DM | ‘Simple’ randomisation; PC-generated random sequence | Secondary | Initiation of T2DM medication | LCMD | LFD | Diet diaries |
Estruch18 19 | Spain | PREDIMED | Parallel, single-blind | ISRCTN3 5739639 | NEJM, 2018 | N=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 number | Primary | Composite CV events‡‡ |
| Control diet (advice to reduce dietary fat) | MEDAS/9-item dietary screener, urine HXT, plasma ALA |
García-Gavilán33 53 | Spain | PREDIMEDReus | Parallel, single-blind | ISRCTN3 5739639 | Clin Nutr, 2018; Am J Clin Nutr, 2018 | N=870 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Osteoporotic fractures |
| Control diet (advice to reduce dietary fat) | MEDAS |
García-Layana40 | Spain | PREDIMED | Parallel, single-blind | ISRCTN3 5739639 | Nutrients, 2017 | N=5802 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Occurrence of cataract surgery |
| Control diet (advice to reduce dietary fat) | MEDAS, urine HXT and plasma ALA ratio |
Gené Huguet41 | Spain | Pre Frail 80 Study | Parallel, open-label | NR | J Nutr Health Aging, 2018 | N=200 non-institutionalised men/women (≥80 years) fulfilling 1/2 of the Fried65 frailty criteria | Randomised list NOD | Secondary | Reversion to robustness | MD | Standard treatment | MEDAS |
Greenberg57 | Israel | DIRECT | Parallel, NR | NCT001 60108 | J Am Coll Nutr, 2009 | N=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 | Secondary | 5% BW loss | Hypocaloric§§ 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 | Spain | – | Parallel, open-label | ISRCTN1 7382091 | Eur J Prev Cardiol, 2018 | N=127 consecutive patients (≥70 years), with acute coronary syndrome¶¶ | 1:1 PC allocation with random block sizes of 2 | Secondary | Optimal CVD risk factor control*** | MD | Standard care | 9-item MD score |
Martínez-González43 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | Circulation, 2014 | N=7447 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Incidence of atrial fibrillation |
| Control diet (advice to reduce dietary fat) | MEDAS, urine HXT, plasma ALA ratio |
Papadaki44 63 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | Eur J Heart Fail, 2017 | N=7403 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Heart failure incidence |
| Control diet (advice to reduce dietary fat) | MEDAS |
Pintó52 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | J Nutr, 2019 | N=109 consecutive patients, men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Steatosis diagnosis |
| Control diet (advice to reduce dietary fat) | MEDAS |
Properzi45 | Australia | – | Parallel, single-blind | ACTRN1 2612000 841875 | Hepatology, 2018 | N=56 adult patients with NAFLD | In a 1:1 fashion using randomly selected envelope-concealed allocations in blocks of 4 | Primary | NAFLD resolution | MD 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 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | JAMA, 2014 | N=4991 men/women (55–80 years) PAD-free and CVD-free but with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 ratio | Primary | New symptomatic PAD events |
| Control diet (advice to reduce dietary fat) | MEDAS |
Salas-Salvadó55 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | Arch Intern Med, 2008 | N=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 secondary | MetS reversion rate and incidence |
| Control diet (advice to reduce dietary fat) | MEDAS, urine tyrosol and HXT, plasma ALA ratio |
Salas-Salvadó 39 46 | Spain | PREDIMED Reus | Parallel, open-label | ISRCTN3 5739639 | Diabetes Care, 2011; 2018 | N=418 non-diabetic, CVD-free men/women with ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Diabetes incidence |
| Control diet (advice to reduce dietary fat) | MEDAS |
Salas-Salvadó 47 48 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | Ann Intern Med, 2014; 2018 | N=3541 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | New-onset of diabetes |
| Control diet (advice to reduce dietary fat) | MEDAS/9-item dietary screener, urine HXT, plasma ALA |
Sánchez-Villegas56 | Spain | PREDIMED | Parallel, open-label | ISRCTN3 5739639 | BMC Medicine, 2013 | N=3923 men/women (55–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Depression |
| Control diet (advice to reduce dietary fat) | MEDAS |
Singh49 | India | Indo-MD Heart Study | Parallel, single-blind | NR | Lancet, 2002 | N=1000 men/women (28–75 years) with hypercholesterolaemia, hypertension, DM, angina pectoris, previous MI | By selection of a card from a pile of an equal number of cards for each group | Secondary | Total cardiac events | NCEP 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 oil | NCEP prudent diet | Weight food records and 24 hours nutrient intakes |
Toledo50 | Spain | PREDIMED | Parallel, single-blind | ISRCTN3 5739639 | JAMA Intern Med, 2015 | N=4282 women (60–80 years) with T2DM and/or ≥3 CVD risk factors¶ | 1:1:1 PC-generated randomisation table** | Primary | Breast cancer incidence |
| Control diet (advice to reduce dietary fat) | MEDAS/9-item dietary screener (per group) |
Tuttle51 | USA | THIS-DIET | Parallel, open-label (blind PI) | – | Am J Cardiol, 2008 | N=101 MI survivors | Sealed envelopes with the allocation sequence, prepared by a PI, placed in a locked drawer | Primary | Free 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.