. 2021 Mar 9;4(1):115–131. doi: 10.1136/bmjnph-2020-000188

Table 2.

Characteristics of the included trials

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	MD with EVOO (1 L/wk for the participants and families) 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	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 Lorgeril^{35 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-López^{37 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	MD with EVOO (1 L/wk for the participant and their families) 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
Esposito^{31 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
Estruch^{18 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‡‡	MD with EVOO (1 L/wk for the participant and their families) 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-Gavilán^{33 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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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
Papadaki^{44 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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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}	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	MD with EVOO (1 L/wk for the participant and their families) 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}	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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for the participant and their families) 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	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	MD with EVOO (1 L/wk for participants and their families) 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	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 HbA_1c <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.