CMAJ Research

Mediterranean diets and metabolic syndrome status in the

PREDIMED randomized trial

Nancy Babio BSc PhD, Estefanía Toledo MD PhD, Ramón Estruch MD PhD, Emilio Ros MD PhD,
Miguel A. Martínez-González MD PhD, Olga Castañer MD PhD, Mònica Bulló BSc PhD,
Dolores Corella DPharm PhD, Fernando Arós MD PhD, Enrique Gómez-Gracia MD PhD,
Valentina Ruiz‑Gutiérrez PhD, Miquel Fiol MD PhD, José Lapetra MD PhD,
Rosa M. Lamuela‑Raventos DPharm PhD, Lluís Serra-Majem MD PhD, Xavier Pintó MD PhD,
Josep Basora MD, José V. Sorlí MD PhD, Jordi Salas-Salvadó MD PhD; for the PREDIMED Study Investigators*

Abstract Competing interests: See

end of article.
Background: Little evidence exists on the effect bolic syndrome did not differ between partici-
of an energy-unrestricted healthy diet on meta- pants assigned to the control diet and those This article has been peer
bolic syndrome. We evaluated the long-term assigned to either of the Mediterranean diets reviewed.
effect of Mediterranean diets ad libitum on the (control v. olive oil HR 1.10, 95% CI 0.94–1.30, p *The complete list of
incidence or reversion of metabolic syndrome. = 0.231; control v. nuts HR 1.08, 95% CI 0.92– PREDIMED Study
1.27, p = 0.3). Reversion occurred in 958 (28.2%) Investigators appears at the
Methods: We performed a secondary analysis of the 3392 participants who had metabolic syn- end of the article.
of the PREDIMED trial — a multicentre, ran- drome at baseline. Compared with the control Correspondence to:
domized trial done between October 2003 group, participants on either Mediterranean diet Jordi Salas-Salvadó,
and December 2010 that involved men and were more likely to undergo reversion (control v. jordi.salas@urv.cat
women (age 55–80  yr) at high risk for cardio- olive oil HR  1.35, 95%  CI  1.15–1.58, p  <  0.001; CMAJ 2014. DOI:10.1503​
vascular disease. Participants were randomly control v. nuts HR 1.28, 95% CI 1.08–1.51, /cmaj.140764
assigned to 1 of 3  dietary interventions: a p  <  0.001). Participants in the group receiving
Mediterranean diet supplemented with extra- olive oil supplementation showed significant
virgin olive oil, a Mediterranean diet supple- decreases in both central obesity and high fast-
mented with nuts or advice on following a ing glucose (p = 0.02); participants in the group
low-fat diet (the control group). The interven- supplemented with nuts showed a significant
tions did not include increased physical activity decrease in central obesity.
or weight loss as a goal. We analyzed available
data from 5801 participants. We determined Interpretation: A Mediterranean diet supple-
the effect of diet on incidence and reversion mented with either extra virgin olive oil or
of metabolic syndrome using Cox regression nuts is not associated with the onset of meta-
analysis to calculate hazard ratios (HRs) and bolic syndrome, but such diets are more likely
95% confidence intervals (CIs). to cause reversion of the condition. An
energy-unrestricted Mediterranean diet may
Results: Over 4.8  years of follow-up, metabolic be useful in reducing the risks of central obe-
syndrome developed in 960 (50.0%) of the sity and hyperglycemia in people at high risk
1919  participants who did not have the condi- of cardiovascular disease. Trial registration:
tion at baseline. The risk of developing meta- ­ClinicalTrials.gov, no. ISRCTN35739639.

M
etabolic syndrome is a cluster of 3 or 25% 6–8 and increases with age, 7 especially
more related cardiometabolic risk among women,8,9 making it an important public
factors: central obesity (determined health issue.
by waist circumference), hypertension, hyper- Several studies have shown that lifestyle
triglyceridemia, low plasma high-density lipo- modifications,10 such as increased physical activ-
protein (HDL) cholesterol levels and hypergly- ity,11 adherence to a healthy diet12,13 or weight
cemia. Having the syndrome increases a loss,14–16 are associated with reversion of the
person’s risk for type 2 diabetes and cardiovas- metabolic syndrome and its components. How-
cular disease.1,2 In addition, the condition is ever, little information exists as to whether
associated with increased morbidity and all- changes in the overall dietary pattern without
cause mortality.1,3–5 The worldwide prevalence weight loss might also be effective in preventing
of metabolic syndrome in adults approaches and managing the condition.

© 2014 Canadian Medical Association or its licensors CMAJ, November 18, 2014, 186(17) E649
Research

The Mediterranean diet is recognized as one clinic in Barcelona, Spain, accredited by the
of the healthiest dietary patterns. It has shown United States Department of Health and Human
benefits in patients with cardiovascular dis- Services Update for Federal Wide Assurance for
ease17,18 and in the prevention and treatment of the Protection of Human Subjects for Interna-
related conditions, such as diabetes,19–21 hyper- tional (non-US) Institutions approved the study
tension22,23 and metabolic s­ yndrome.24 protocol on July 16, 2002. The institutional
Several cross-sectional 25–29 and prospec- review boards of the individual recruitment cen-
tive30–32 epidemiologic studies have suggested an tres also approved the study protocol, and partic-
inverse association between adherence to the ipants gave their informed consent.
Mediterranean diet and the prevalence or inci- To evaluate the effect of the dietary interven-
dence of metabolic syndrome. Evidence from tions on metabolic syndrome status, we analyzed
clinical trials has shown that an energy-restricted data from those participants for whom biochemi-
Mediterranean diet33 or adopting a Mediterra- cal determinations were available at baseline and
nean diet after weight loss34 has a beneficial for at least 2 years of follow-up. We performed
effect on metabolic syndrome. However, these two separate analyses: the first on the incidence
studies did not determine whether the effect of metabolic syndrome in participants who did
could be attributed to the weight loss or to the not have the condition at baseline, and the sec-
diets themselves. ond on reversion of metabolic syndrome in par-
Seminal data from the PREDIMED (PREven- ticipants who had the condition at baseline.
ción con DIeta MEDiterránea) study suggested
that adherence to a Mediterranean diet supple- Interventions
mented with nuts reversed metabolic syndrome Personalized advice was given to participants in
more so than advice to follow a low-fat diet.35 both Mediterranean diet groups to increase their
However, the report was based on data from adherence to the intervention. Participants in both
only 1224 participants followed for 1 year. We Mediterranean diet groups received either extra-
have analyzed the data from the final PRE- virgin olive oil (about 1 L/wk) or mixed nuts
DIMED cohort after a median follow-up of (30 g/d; 15 g walnuts, 7.5 g hazelnuts and 7.5 g
4.8 years to determine the long-term effects of a almonds) at no cost; participants in the control
Mediterranean diet on metabolic syndrome. group received small nonfood gifts. The nutrient
composition of the olive oil and nuts used in the
Methods study was assessed. 17 Participants were not
advised on calorie restriction, and physical activ-
Study design and population ity was not promoted for any intervention group.
The PREDIMED study was a large, parallel- At baseline and quarterly thereafter, dietitians
group, multicentre, randomized, controlled field gave individual and group training sessions to
trial designed to assess the effects of the Medi- provide information on typical Mediterranean
terranean diet on the primary prevention of car- foods, seasonal shopping lists, meal plans and
diovascular disease (www.predimed.es). recipes. Participants assigned to the control diet
The protocol, design and methods of the trial received recommendations to reduce their intake
have been described elsewhere. 17,36 Briefly, of all types of fat, from both animal and vegeta-
­community-dwelling men (aged 55–80  yr) and ble sources. Before October 2006, participants in
women (aged 60–80 yr) with no previously doc- the control group had only received a leaflet
umented cardiovascular disease were recruited describing the low-fat diet. Thereafter, they
for the study and were eligible to participate if received personalized advice and were invited to
they had either type 2 diabetes or at least 3 car- group sessions held with the same frequency as
diovascular risk factors: hypertension, high in the Mediterranean groups. During each train-
plasma low-density lipoprotein (LDL) choles- ing session, participants in the Mediterranean
terol, low plasma HDL cholesterol, overweight diet groups completed a 14-item questionnaire37
or obesity, current history of smoking and family to assess adherence to the intervention; partici-
history of premature coronary artery disease. pants in the control group completed a 9-item
From October 2003 to June 2009, 7447  partici- dietary screener to assess compliance with the
pants were randomly assigned to 1 of 3 nutrition low-fat diet.
interventions (1:1:1). Two  groups were advised
to follow a Mediterranean diet supplemented Outcomes
with either extra-virgin olive oil (n  =  2543) or Our primary outcome was metabolic syndrome
nuts (n = 2454), and 1 group (the control group) status, which was defined in the PREDIMED
was advised to follow a low-fat diet (n = 2450). study in accordance to the updated harmonized
The institutional review board of the hospital International Diabetes Federation and the Ameri-

E650 CMAJ, November 18, 2014, 186(17)

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can Heart Association/National Heart, Lung, and pleted the following items: a questionnaire
Blood Institute criteria.38 We calculated the pro- about lifestyle variables, medical history and
portion of participants who did not meet criteria medication use; a 14-item validated question-
at baseline, but who had at least 3 components of naire 37 designed to assess adherence to the
metabolic syndrome yearly thereafter (i.e., inci- Mediterranean diet; a validated 137-item semi-
dent metabolic syndrome). In addition, we calcu- quantitative food­-frequency questionnaire39 and
lated the proportion of participants who met cri- the validated Spanish version40 of the Minne-
teria at baseline, but who had fewer than sota leisure-time physical activity question-
3 components yearly thereafter (i.e., reversion of naire. In addition, trained staff determined
metabolic syndrome). We considered only the anthropometric variables and blood pressure.
first change in status (incidence or reversion) in Blood samples were collected from all partici-
our analyses. pants after an overnight fast. We measured fast-
ing plasma glucose, total cholesterol, HDL cho-
Measurements lesterol and triglyceride concentrations at
At baseline and yearly for a median follow-up baseline and yearly during follow-up using
of 4.8  years, all of the participants were given standard methods. Laboratory staff were
personal interviews during which they com- blinded to the intervention group.

Table 1: Baseline characteristics of the study participants

Intervention group, % (no.)*

Mediterranean Mediterranean Low-fat diet

diet + EVOO diet + nuts (control)
Characteristic n = 1982 n = 1885 n = 1934 p value†

Age, yr 67.1 (6.2) 66.7 (6.0) 67.3 (6.2) 0.04

Male sex 40.9 (811) 45.0 (849) 40.2 (777) < 0.001
Smoking history
Former smoker 23.6 (468) 26.5 (499) 23.7 (459) 0.08
Current smoker 13.8 (273) 14.4 (272) 14.1 (273) 0.8
BMI, kg/m2 30.0 (3.8) 29.8 (3.8) 30.3 (4.1) < 0.001
Waist circumference, cm 100.4 (10.2) 100.0 (10.5) 100.8 (10.7) 0.08
Leisure time physical activity, 233 (236) 249 (244) 210 (243) < 0.001
METs/min per d
Mediterranean diet score (0–14) 8.8 (1.9) 8.8 (1.9) 8.4 (1.9) < 0.001
Type 2 diabetes 48.0 (952) 45.1 (850) 47.8 (925) 0.1
Metabolic syndrome 65.1 (1291) 61.8 (1165) 64.7 (1251) 0.07
Metabolic syndrome component‡
Central obesity 74.6 (1465) 69.6 (1305) 75.3 (1440) < 0.001
Hypertriglyceridemia 34.5 (682) 32.7 (615) 32.8 (631) 0.4
Low HDL cholesterol 29.4 (579) 28.3 (531) 29.1 (560) 0.8
Hypertension 93.4 (1849) 94.0 (1771) 94.6 (1830) 0.3
High fasting plasma glucose 65.3 (1291) 64.2 (1203) 65.9 (1271) 0.6
Use of medications
Antihypertensive agents 72.0 (1 428) 73.0 (1 376) 73.4 (1 420) 0.3
Fibrates 4.1 (81) 4.6 (86) 3.5 (68) 0.3
Statins 41.5 (822) 38.4 (726) 39.7 (767) 0.2
Insulin 7.3 (145) 6.0 (113) 7.5 (144) 0.1
Hypoglycaemic agents 30.2 (598) 26.9 (505) 30.7 (593) 0.02
Aspirin or antiplatelet drugs 19.7 (390) 20.4 (384) 21.3 (412) 0.5

Note: BMI = body mass index, EVOO = extra virgin olive oil, HDL = high-density lipoprotein, MET = metabolic equivalent of task.
*Unless otherwise stated.
†Values determined using χ2 test for categorical variables and analysis of variance for continuous variables.
‡Defined in accordance with the International Diabetes Federation and the American Heart Association/National Heart, Lung and Blood Institute criteria.38

CMAJ, November 18, 2014, 186(17) E651

Research

Statistical analyses level of less than 0.05. We performed statistical

Assuming an expected incidence of metabolic analyses using SPSS version 19.0 and STATA
syndrome of 21% and a hazard ratio (HR) of 0.7 version 12.0.
for the comparison of the intervention groups
with the control group, the statistical power for Results
our analyses is 83%. Assuming an expected
reversion rate of metabolic syndrome of 7.5% Of the 7447 participants in the PREDIMED trial,
and a HR of 1.7 for the comparison of the biochemical determinations were available for
intervention groups with the control group, the 5801 (77.9%) (Appendix 1, available at www.cmaj​
statistical power for our analyses is 92%. .ca/lookup/suppl/doi:10.1503/cmaj​.140764​/-​/DC1).
We used the Bonferroni method to test multiple We found no differences in the main characteris-
comparisons of the 5  components of metabolic tics of participants betw een the total cohort of par-
syndrome between intervention groups at the end ticipants and those included in our analysis (data
of follow-up. We used generalized estimating not shown).
equations to assess changes in the incidence of met- Among participants with or without metabolic
abolic syndrome between intervention groups dur- syndrome at baseline (Appendices 2 and 3, avail-
ing follow-up. We fitted Cox regression models to able at www.cmaj​.ca/lookup/suppl/doi:10.1503​
determine HRs and 95% confidence intervals (CIs) /cmaj​.140764​/-/DC1), the median Mediterranean
for incidence or reversion by intervention group. diet score (as determined using the 14-item ques-
For our primary analyses of incidence or tionnaire) throughout follow­-up was significantly
reversion, the time variable was the interval higher among participants allocated to the Medi-
between randomization and either the date of terranean diet groups compared with those in the
incidence or reversion, the date of the last control group.
­follow-up visit, the date of death or the date on Throughout follow-up, consumption of nuts
which the participant was lost to follow-up, and extra-virgin olive oil were significantly higher
whichever occurred first. among participants allocated to the Mediterranean
All p  values are 2-tailed with a signifance diets supplemented with nuts or olive oil, respec-

Table 2: Prevalence of metabolic syndrome and its component conditions at baseline and final follow-up

Intervention, % (no.)

Mediterranean Mediterranean Low-fat diet

Condition diet + EVOO diet + nuts (control) p value*

Metabolic syndrome n = 1982 n = 1 885 n = 1934

At baseline 65.1 (1291) 61.8 (1165) 64.7 (1251) 0.07
At final follow-up 66.6 (1320) 64.9 (1223) 68.6 (1326) 0.05
Central obesity n = 1981 n = 1897 n = 1926
At baseline 74.4 (1474) 69.5 (1319) 75.3 (1451) < 0.001
At final follow-up 74.1 (1467) 70.9 (1345) 75.0 (1445) 0.005
Hypertriglyceridemia n = 1994 n = 1891 n = 1946
At baseline 34.3 (683) 32.5 (615) 32.5 (634) 0.4
At final follow-up 32.6 (656) 30.6 (575) 33.4 (649) 0.1
Low HDL cholesterol n = 1985 n = 1886 n = 1946
At baseline 29.3 (582) 28.2 (532) 28.1 (563) 0.7
At final follow-up 35.0 (694) 34.8 (656) 34.3 (668) 0.9
Hypertension n = 2032 n = 1934 n = 1990
At baseline 93.5 (1899) 93.8 (1814) 94.7 (1884) 0.3
At final follow-up 95.4 (1938) 94.8 (1833) 95.4 (1899) 0.6
High fasting plasma glucose n = 2010 n = 1896 n = 1966
At baseline 65.6 (1319) 64.5 (1223) 66.3 (1304) 0.5
At final follow-up 68.9 (1385) 68.4 (1296) 71.9 (1414) 0.03

Note: EVOO = extra-virgin olive oil, HDL = high-density lipoprotein.

*χ2 test.

E652 CMAJ, November 18, 2014, 186(17)

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tively (Appendix 4, available at www.cmaj​.ca​ our analysis on incidence included data from
/lookup/suppl/doi:10.1503/cmaj​.140764​/-/DC1). 1919 participants.
Changes in body weight and physical activity were Over a median follow-up of 3.2 yr (maximum
small and did not differ significantly between 7 yr), we found no between-group differences in
groups (Appendix 5, available at www.cmaj​.ca​ the cumulative incidence of metabolic syndrome or
/lookup/suppl/doi:10.1503/cmaj​.140764​/-/DC1). its components (Appendix 7, available at www.
Of the 5801 participants included in our cmaj​.ca/lookup/suppl/doi:10.1503/cmaj​.140764​
an­alysis (Table 1), 63.9% (n = 3707) met the cri- /-/DC1).
teria for metabolic syndrome at baseline. The prev- The risk of metabolic syndrome incidence
alence of central obesity and high fasting plasma (Table 3) did not differ significantly between the
glucose were significantly higher in the control Mediterranean diet groups and the control group
group at the end of follow-up (Table 2) than in the (control v. olive oil HR 1.10, 95% CI 0.94–1.30,
Mediterranean diet groups. We saw a significant p  = 0.231; control v. nuts HR 1.08, 95% CI
difference in central obesity between Mediterra- 0.92–1.27, p = 0.322). In addition, the risk of
nean diet groups at the end of follow-up each component of metabolic syndrome did not
(Bonferroni­ adjusted p  =  0.025). After a median show significant between-group differences
follow-up of 4.8 years, we found a significantly (Appendix 8, available at www.cmaj​.ca/lookup​
smaller increase in the prevalence of metabolic /suppl/doi:10.1503/cmaj​.140764​/-/DC1).
syndrome among participants assigned to the Med- To assess reversion, we included only those
iterranean diet supplemented with extra-virgin participants who had metabolic syndrome at
olive oil than among participants in the control baseline (n = 3707); however, data were missing
group (p = 0.013) (Figure 1). for 315 participants. Thus, we included data from
We assessed incidence of metabolic syn- 3392 participants in our analyses. During a
drome for 2094  participants who did not have median follow-up of 4.8 years, reversion
the condition at baseline (691 in the olive oil oc­curred in 958 (28.2%) participants (Appen-
supplementation group, 720 in the nut supple- dix  9, available at www.cmaj​.ca/lookup​
mentation group and 683 in the control group). /suppl​/doi:10.1503/cmaj​.140764​/-/DC1). Com-
Data were missing for some of the covariables pared with the control diet, both Mediterranean
needed to assess incidence for 175  participants diets were significantly more likely to revert meta-
(Appendix 6, available at www.cmaj​.ca/lookup​ bolic syndrome (control v. olive oil HR 1.35,
/suppl/doi:10.1503/cmaj​.140764​/-/DC1). Thus, 95% CI 1.15–1.58, p < 0.001; control v. nuts HR

90.0
Mediterranean diet + EVOO (p = 0.013 v. control)
Mediterranean diet + nuts (p = 0.137 v. control)
Proportion of participants with metabolic syndrome

85.0 Control

80.0

75.0

70.0

65.0

60.0

55.0

50.0
1 2 3 4 5 6 7 8
Follow-up (yr)

Figure 1: Prevalence of metabolic syndrome during follow-up. Error bars denote 95% confidence intervals.
The changes were assessed with generalized estimating equations, and the p values shown are for the
overall trend. Note: EVOO = extra-virgin olive oil.

CMAJ, November 18, 2014, 186(17) E653

Research

1.28, 95% CI 1.08–1.51, p < 0.001). The cumula- colleagues,33 who found beneficial effects on
tive reversion rates for metabolic syndrome, cen- metabolic syndrome and its components with an
tral obesity and high fasting plasma glucose dif- energy-restricted Mediterranean diet in a short
fered significantly among the 3  groups. clinical trial. Contrary to our study, their results
Reversion was higher in both Mediterranean diet could have been due to energy restriction leading
groups compared with the control group (Table 3, to substantial weight loss.33
Appendix 10, available at www.cmaj​.ca/lookup​ Similar to the previous PREDIMED report,35
/suppl/doi:10.1503/cmaj​.140764​/-/DC1). we found a beneficial effect of a Mediterranean
Participants assigned to the Mediterranean diets diet on reversion of metabolic syndrome, but not
were significantly more likely to no longer meet the on the incidence of the condition. However, we
criterion of central obesity compared with those in did see a net beneficial effect on prevalence as a
the control group (both p  <  0.001), even after result of reversion.
adjustment for confounders (Appendix  11, avail- We found the Mediterranean diet supple-
able at www.cmaj​.ca/lookup/suppl/doi:10.1503​ mented with extra-virgin olive-oil to have the
/cmaj​.140764​/-/DC1). Compared with the control most beneficial effect on central obesity and
group, only the participants in the group supple- hyperglycemia. These results concur with those
mented with extra-virgin olive oil were more likely of cross-sectional26,41,42 and prospective epidemi-
to no longer meet the criterion of high fasting ologic studies24,30,32 that showed an inverse asso-
plasma glucose (p = 0.02). ciation between adherence to a Mediterranean
diet and central obesity.
Discussion We can speculate that a Mediterranean diet,
particularly one supplemented with extra-virgin
In this large, multicentre, randomized controlled olive oil (which has anti-inflammatory proper-
trial involving people with high cardiovascular ties), could exert positive effects on fat redistri-
risk, a Mediterranean diet supplemented with bution. In a short-term experimental crossover
extra-virgin olive oil was associated with a smaller study involving participants with obesity and
increase in the prevalence of metabolic syndrome insulin resistance, an isocaloric Mediterranean
compared with advice on following a low-fat diet. diet rich in extra-virgin olive oil prevented accu-
However, we found no beneficial effect of a Medi- mulation of central body fat compared with a
terranean diet on incidence of new-onset metabolic low-fat diet, without affecting body weight.43 In
syndrome. Thus, the smaller increase in preva- addition, there is evidence that patients with type
lence was likely due to reversion. Because there 2 diabetes involved in weight maintenance pro-
were no between-group differences in weight loss grams tend to have a disproportionate loss of
or energy expenditure, the change is likely attribut- lower body versus upper body fat compared with
able to the difference in dietary patterns. patients given a diet rich in monounsaturated
Our results are not consistent with those of fatty acids.44
observational studies24 that have shown a benefi- The protective effect on the hyperglycemia
cial effect of a Mediterranean diet on the inci- component of the metabolic syndrome that we
dence of metabolic syndrome. However, our saw with olive oil supplementation is also con-
results are consistent with those of Esposito and sistent with the efficacy of dietary monounsatu-

Table 3: Risk of metabolic syndrome* incidence and reversion by intervention

Incidence Reversion
HR (95% CI)† HR (95% CI)†

Mediterranean Mediterranean Mediterranean Mediterranean

diet + EVOO v. control diet + nuts v. control diet + EVOO v. control diet + nuts v. control
Model n = 663 n = 662 n = 1236 n = 1062

Crude model 1.04 (0.89–1.21) 1.04 (0.88–1.19) 1.42 (1.21–1.66) 1.42 (1.20–1.67)
Age-, sex- and centre-adjusted 1.03 (0.88–1.21) 1.01 (0.86–1.19) 1.42 (1.21–1.67) 1.38 (1.17–1.63)
model
Multivariable adjusted model‡ 1.10 (0.94–1.30) 1.08 (0.92–1.27) 1.35 (1.15–1.58) 1.28 (1.08–1.51)

Note: CI = confidence interval, EVOO = extra-virgin olive oil, HR = hazard ratio.

*Defined in accordance with the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria.38
†Cox regression model.
‡Adjusted for sex, age, Mediterranean diet score, energy intake, body mass index, physical activity, smoking and antidiabetic drugs other than insulin. All models
were stratified by recruitment centre.

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30. Tortosa A, Bes-Rastrollo M, Sanchez-Villegas A, et al. Medi- and has received lecture fees from the Research Foundation
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31. Rumawas ME, Meigs JB, Dwyer JT, et al. Mediterranean-style
dietary pattern, reduced risk of metabolic syndrome traits, and Cerveceros de España and Sanofi-Aventis and grant support
incidence in the Framingham Offspring Cohort. Am J Clin Nutr from Novartis. Emilio Ros serves on the board of and has
2009;90:1608-14.
32. Kesse-Guyot E, Ahluwalia N, received travel and grant support from the California Walnut
Lassale C, et al. Adherence to Mediterranean diet reduces the risk Commission; he serves on the board of the Flora Foundation
of metabolic syndrome: a 6-year prospective study. Nutr Metab (Unilever); he serves on the board of and has received lecture
Cardiovasc Dis 2013;​23:​677-83. fees from Roche; he serves on the board of and has received
33. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterra- grant support from Amgen; he has received consulting fees
nean-style diet on endothelial dysfunction and markers of vas-
from Damm and Abbott Laboratories; he has received con-
cular inflammation in the metabolic syndrome: a randomized
trial. JAMA 2004;292:1440-6. sulting fees, lecture fees and grant support from Merck; he
34. Richard C, Couture P, Desroches S, et al. Effect of the Medi- has received lecture fees from Danone, Pace, Astra Zeneca
terranean diet with and without weight loss on cardiovascular and Rottapharm; he has received lecture fees, grant support
risk factors in men with the metabolic syndrome. Nutr Metab and payment for the development of educational presenta-
Cardiovasc Dis 2011;21:628-35. tions from Ferrer; he has received payment for the develop-
35. Salas-Salvadó J, Fernández-Ballart J, Ros E, et al. Effect of a ment of educational presentations from Recordati; and he has
Mediterranean diet supplemented with nuts on metabolic syn- received grant support from Sanofi-Aventis, Takeda, Daiichi
drome status: one-year results of the PREDIMED randomized
Sankyo, Nutrexpa, Feiraco, Unilever, and Karo Bio. Fer-
trial. Arch Intern Med 2008;168:2449-58.
36. Martínez-González MÁ, Corella D, Salas-Salvadó J, et al. nando Arós has received payment for the development of
Cohort profile: design and methods of the PREDIMED study. educational presentations from Menarini and Astra Zeneca.
Int J Epidemiol 2012;41:377-85. Rosa Lamuela-Raventos serves on the board of and has
37. Schröder H, Fitó M, Estruch R, et al. A short screener is valid received lecture fees from FIVIN; has received lecture fees
for assessing Mediterranean diet adherence among older Spanish from Cerveceros de España; and has received lecture fees
men and women. J Nutr 2011;141:1140-5. and travel support from PepsiCo. Lluís Serra-Majem serves
38. Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the on the boards of the Mediterranean Diet Foundation and the
metabolic syndrome: a joint interim statement of the Interna-
Beer and Health Foundation; he is a member of the scientific
tional Diabetes Federation Task Force on Epidemiology and
Prevention; National Heart, Lung, and Blood Institute; Ameri- advisory board and has received consulting fees and grant
can Heart Association; World Heart Federation; International. support from the European Hyratation Institute; he has
Circulation 2009;120:1640-5. received lecture fees from the International Nut Council; he
39. Fernández-Ballart JD, Piñol JL, Zazpe I, et al. Relative validity has received travel support for conferences from Nestlé.
of a semi-quantitative food-frequency questionnaire in an elderly Xavier Pintó serves on the board of and has received grant
Mediterranean population of Spain. Br J Nutr 2010;103:1808-16. support from the Residual Risk Reduction Initiative Founda-
40. Elosua R, Marrugat J, Molina L, et al. Validation of the Minne- tion; he serves on the board of Omegafort; he serves on the
sota Leisure Time Physical Activity Questionnaire in Spanish
board of and has received payment for the development of
men. The MARATHOM Investigators. Am J Epidemiol 1994;​
139:1197-209. educational presentations and grant support from Ferrer; he
41. Romaguera D, Norat T, Mouw T, et al. Adherence to the Medi- has received consulting fees from Abbott Laboratories; he
terranean diet is associated with lower abdominal adiposity in has received lecture fees and grant support from Merck and
European men and women. J Nutr 2009;139:1728-37. Roche; he has received lecture fees from Danone and Esteve;
42. Martínez-González MA, García-Arellano A, Toledo E, et al. A he has received payment for the development of educational
14-item Mediterranean diet assessment tool and obesity presentations from Menarini; and he has received grant sup-
indexes among high-risk subjects: the PREDIMED trial. PLoS port from Sanofi-Aventis, Kowa, Unilever, Boehringer Ingel-
ONE 2012;7:e43134.
heim and Karo Bio. Jordi Salas-Salvadó serves on the board
43. Paniagua JA, Gallego de la Sacristana A, Romero I, et al.
Monounsaturated fat-rich diet prevents central body fat distri- of and has received grant support from the International Nut
bution and decreases postprandial adiponectin expression and Dried Fruit Council; he has received consulting fees
induced by a carbohydrate-rich diet in insulin-resistant sub- from Danone; and he has received grant support from Eroski
jects. Diabetes Care 2007;30:1717-23. and Nestlé. No other competing interests were declared.
44. Walker KZ, O’Dea K, Johnson L, et al. Body fat distribution
and non-insulin-dependent diabetes: comparison of a fiber-
rich, high-carbohydrate, low-fat (23%) diet and a 35% fat diet Affiliations: Human Nutrition Unit (Babio, Bulló, Basora,
high in monounsaturated fat. Am J Clin Nutr 1996;63:254-60. Salas-Salvadó), Faculty of Medicine and Health Sciences,
45. Gillingham LG, Harris-Janz S, Jones PJH. Dietary monounsat- Biochemistry Biotechnology Department, Universitat Rovira
urated fatty acids are protective against metabolic syndrome i Virgili, and Hospital Universitari de Sant Joan de Reus,
and cardiovascular disease risk factors. Lipids 2011;46:209-28. IISPV, Reus, Spain; Centro de Investigación Biomédica en
46. Vessby B, Uusitupa M, Hermansen K, et al. Substituting dietary
Red Fisiopatología de la Obesidad y Nutrición (CIBERobn)
saturated for monounsaturated fat impairs insulin sensitivity in
healthy men and women: The KANWU Study. Diabetologia (Babio, Toledo, Estruch, Martínez-González, Castañer, Bulló,
2001;44:312-9. Corella, Arós, Gómez-Gracia, Ruiz-Gutiérrez, Fiol, Lapetra,
47. Calder PC, Ahluwalia N, Brouns F, et al. Dietary factors and Lamuela-Raventos, Serra-Majem, Pintó, Basora, Sorlí, Salas-
low-grade inflammation in relation to overweight and obesity. Salvadó), Institute of Health Carlos III, Madrid, Spain;
Br J Nutr 2011;106(Suppl3):S5-78. Department of Preventive Medicine and Public Health
48. Esfahani A, Wong JMW, Truan J, et al. Health effects of (Toledo, Martínez-González), University of Navarra, Pam-
mixed fruit and vegetable concentrates: a systematic review of plona, Spain; Department of Internal Medicine (Estruch),
the clinical interventions. J Am Coll Nutr 2011;30:285-94.
Institut d’Investigacions Biomèdiques August Pi Sunyer
49. Urpi-Sarda M, Casas R, Chiva-Blanch G, et al. Virgin olive oil
and nuts as key foods of the Mediterranean diet effects on inflam- (IDIBAPS), Hospital Clínic, University of Barcelona, Barce-
matory biomakers related to atherosclerosis. Pharmacol Res lona, Spain; Lipid Clinic (Ros), Endocrinology and Nutrition
2012;65:577-83. Service, IDIBAPS, Hospital Clinic, University of Barcelona,
50. Fitó M, Guxens M, Corella D, et al. Effect of a traditional Barcelona, Spain; Cardiovascular Risk and Nutrition

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Research Group (Castañer), Institut Hospital del Mar Pamplona, Spain); R. González, C. Molina, M. Sorli, J. García-
d’Investigacions Mèdiques (IMIM), Barcelona Biomedical Roselló, J., Fernández-Ballart, A. Castro, R. Sagarra, R.Pedret,
Research Park, Barcelona, Spain; Department of Preventive F. París and M. Llauradó (University Rovira i Virgili, Reus,
Medicine (Corella, Sorlí), University of Valencia, València, Spain); S. Tello, J. Vila, M. Fitó and H. Schröder (Institute de
Spain; Department of Cardiology (Arós), University Hospital Recerca Hospital del Mar, Barcelona, Spain); F. Aros del
Txagorritxu, Vitoria, Spain; Department of Preventive Medi- Hierro and J. Algorta (University Hospital of Alava, Vitoria,
cine (Gómez-Gracia), University of Malaga, Malaga, Spain; Spain); R. Benítez Pont, M. Bianchi Alba, J.Fernández-Crehuet
Instituto de la Grasa (Ruiz-Gutiérrez), Consejo Superior de Navajas and E. Gómez-Gracia (University of Málaga, Málaga,
Investigaciones Cientificas, Seville; Instituto de Investigación Spain); F.J. García, P. Roman, J.M. Santos and J. Lapetra
Sanitaria de Palma (Fiol), Hospital Universitario Son Espases, (Department of Family Medicine, Primary Care Division of
Mallorca; Department of Family Medicine (Lapetra), Primary Sevilla, Sevilla, Spain); J. Álvarez-Pérez, E. Díez Benítez, I.
Care Division of Seville, San Pablo Health Center, Seville; Bautista Castaño and A. Sánchez-Villegas (University of Las
Department of Nutrition and Food Science (Lamuela-Raven- Palmas de Gran Canaria, Las Palmas, Spain).
tos), School of Pharmacy, Xarxa de Referència en Tecnologia
dels Aliments, Instituto de Investigación en Nutrición y Funding: CIBERobn is an initiative of ISCIII, Spain. Sup-
Seguridad Alimentaria, University of Barcelona, Barcelona, ported by the official funding agency for biomedical research
Spain; Department of Clinical Sciences (Serra-Majem), Uni- of the Spanish government, Instituto de Salud Carlos III
versity of Las Palmas de Gran Canaria, Las Palmas, Spain; (ISCIII), through grants provided to research networks spe-
Lipids and Vascular Risk Unit (Pintó), Internal Medicine, cifically developed for the trial (RTIC G03/140, to Ramón
Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Estruch; RTIC RD 06/0045, to Miguel Martínez-González
Barcelona, Spain; Primary Care Division (Basora), Catalan and through Centro de Investigación Biomédica en Red de
Institute of Health, Institut Universitari d’Investigació en Fisiopatología de la Obesidad y Nutrición [CIBERobn]), and
Atenció Primària Jordi Gol, Tarragona-Reus, Spain. by grants from Centro Nacional de Investigaciones Cardio-
vasculares (CNIC 06/2007), Fondo de Investigación Sani-
Contributors: Nancy Babio and Jordi Salas-Salvadó had full taria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI
access to all the data in the study and take responsibility for 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI
the integrity of the data and the accuracy of the data analysis. 07/0473, PI10/01407, PI10/02658, PI11/01647, and
Study concept and design: Emilio Ros, Miguel Martínez- P11/02505; PI13/00462), Ministerio de Ciencia e Innovación
González, Dolores Corella, Fernando Arós, Enrique Gómez- (AGL-2009–13906-C02 and AGL2010–22319-C03), Fun-
Gracia, Valentina Ruiz-Gutiérrez, Miquel Fiol, José Lapetra, dación Mapfre 2010, Consejería de Salud de la Junta de
Rosa M. Lamuela-Raventos, Lluís Serra-Majem, Xavier Pintó Andalucía (PI0105/2007), Public Health Division of the
and Jordi Salas-Salvadó. Analysis and interpretation of data: Department of Health of the Autonomous Government of
Nancy Babio, Estefanía Toledo, Miguel Martínez-González Catalonia, Generalitat Valenciana (ACOMP06109, GVA-
and Jordi Salas-Salvadó. Drafting of the manuscript: Nancy COMP2010–181, GVACOMP2011–151, CS2010-AP-111,
Babio and Jordi Salas-Salvadó. Critical revision of the manu- and CS2011-AP-042), and Regional Government of Navarra
script for important intellectual content: All the authors. Sta- (P27/2011). None of the funding sources played a role in the
tistical analysis: Nancy Babio, Estefanía Toledo. design, collection, analysis or interpretation of the data or in
the decision to submit the manuscript for publication.
The PREDIMED Study Investigators: C. Viñas, R. Casas, Data sharing: The PREDIMED trial data are not available
J.M. Baena, M. Oller, J. Amat, I. Duaso, Y. García, C. Iglesias for sharing.
and J. Benavent (Hospital Clinic, Institut d’Investigacions
Biomèdiques August Pi i Sunyer, Barcelona, Spain); A. Sán- Acknowledgements: The authors thank the participants for
chez-Tainta, E. Toledo, P. Buil-Cosiales, M. Serrano-Martínez, their enthusiastic collaboration, the PREDIMED personnel
J. Díez-Espino, A. García-Arellano, I. Zazpe and J. Basterra- for their excellent assistance and the personnel of all affili-
Gortari (University of Navarra, Primary Care Division Centres, ated primary care centres.

CMAJ, November 18, 2014, 186(17) E657