La Dieta Mediterrània en la
DM2. L’estudi Predimed
Dr. María-Isabel Covas Cardiovascular Risk and Nutrition Research Group
The REGICOR Study Group IMIM – Hospital del Mar Research Institut – Barcelona – Spain CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN)
V JORNADES D’ACTUALITZACIÓ EN DIABETIS GEDAPS DE LA CAMFIC Barcelona, 28 de Maig del 2013
(Primary Prevention of Cardiovascular Disease by the Mediterranean Diet)
Cardiovascular disease is the main cause of death at the onset of the XXI Century
AMI Stroke
AOLLEE Aortic aneurysm
BEST WEAPONS
AGAINST
CARDIOVASCULAR
DISEASE:
DIET AND EXERCISE
Traditional
Mediterranean Diet
high intake
Traditional
Mediterranean Diet
moderate and low intake 2010
2010
Mediterranean Food Pattern
• Rapidly increasing evidence – Increased Longevity
– Prevention of
• CV mortality
• Cancer mortality
• CVD incidence
• Metabolic syndrome
• Diabetes
• Dementia
• Depression
• Scarcity of large randomized trials
Mediterranean Diet, Risk Factors and Cardiovascular
Events after a Heart Attack: Report of the Lyon Diet
Heart Study
Design
•Randomized clinical trial on the effects of a
Mediterranean-style Diet in a sample of 605 patients
who had had a myocardial infarction.
Intervention Groups
•Mediterranean Diet supplemented with margarine
enriched with a-linolenic acid (n= 303)
•Step I Diet of the American Association of Cardiology
(n= 302)
Follow-up
• 46 months (Circulation, 1999; 99: 779-785)
The Effect of the Mediterranean Diet on the Primary Prevention of Cardiovascular Disease.The PREDIMED Study
Hospital de Álava de Vitoria
Univ Pais Vasco
Facultad de Medicina de Navarra
I.C.S.-División Primaria IMIM
IDIBAPS-Hospital Clínic Univ.de Barcelona
Hospital de Bellvitge
Facultad de Medicina de Reus
Facultad de Medicina de Valencia
Universidad de las Palmas de Gran Canaria
Centro de Salud San Pablo Instituto de la Grasa
Sevilla Facultad de Medicina de Málaga
Hospital Son Espases Univ. Illes Balears
19 Research Groups of 7 Spanish Regions
10 Recruitment Centers
Men: 55-80 yr
Women: 60-80 yr
High CV risk without CVD
type 2 diabetics
3+ risk factors
PREDIMED TRIAL: DESIGN
Random
1. Smoking
2. Hypertension
3. LDL
4. HDL
5. Overweight/obese
6. Family history CHD
PREDIMED Participants
Mediet + VOO
(n= 2543)
MeDiet + Nuts
(n=2454)
Control
(n=2450)
Age (SD) 67 (6) 67 (6) 67 (6)
Women (%) 57 54 58
Diabetes (%) 50 47 48
Hypertension (%) 82 82 84
Current smokers (%) 14 15 14
Dyslipidemia (%) 72 73 72
BMI, kg/m2 (SD) 30 (4) 30 (4) 30 (4)
Waist circumf. (SD) 100 (10) 100 (10) 101 (11)
Med Diet 0-14 pts.
(SD)
8.7 (2) 8.7 (2) 8.3 (2)
PREDIMED INTERVENTION
Strategies for behavior change
– Repeated personal contacts: every 3-mo.
– Group sessions: every 3-mo.
– Holistic approach
• Written information
• Self-monitoring
• Individualized goal-setting
• Quick feedback
• Individual motivational interviews (every 3-mo.)
– adapted to the patient’s features
• clinical condition
• preferences
• beliefs
– expressed in servings/d to improve understanding
– Additional strategies
– Seasonal buying lists
– Menus and recipes
– Only in the 2 MeDiet groups
• Provision of key food items for free
PREDIMED INTERVENTION
Strategies for behavior change
Control Group: Small gifts non-related with food
MeDiet (both groups)*
Control
Results-Adherence to Mediterranean Diet
Adherence to MedDiet plus Virgin Olive Oil intervention
Adherence to the MedDiet plus nuts Intervention
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6
Odds ratio (95% confidence interval)
Metabolic syndrome
development
Metabolic syndrome
regression
Control group MedDiet + VOO MedDiet + Nuts
Odds ratios (ORs) and 95% confidence intervals (CIs) of 1-year reversion among
MetS participants and incidence among participants who did not have MetS at
baseline (bottom) in the PREDIMED Study (n = 1224)
Salas-Salvadó et al. Arch Int Med, 2008
180 Italians with Metabolic Syndrome. 2 years-Intervention study.
Evidence pro the Mediterranean type Diet Effect of a Mediterranean-Style Diet, on Endothelial Dysfunction,
Vascular Inflammation in the metabolic Syndrome.
Esposito K , Marfella R, Ciotola M, et al. JAMA 2004;292:1440-1446
Components
of Met S%
Intervention (MedDiet)
2 years Change
Control
2 years Change
P
between
groups
3 31 (34) -43 59 (66) -17 <0.001
4 10 (11) -8 12 (13) -4
5 1(1) -7 7 (8) -1
After 2 years,in the intervention group (n=82),only 40 could be
classified as Met S. In control group (n=82), 78 patients
remained as Met S
Cumulative diabetes free-survival by group of intervention (n =418 non-diabetic participants)
Salas-Salvadó J et al. Dia Care 2011;34:14-19
Copyright © 2011 American Diabetes Association, Inc.
MedDiet+ VOO
MedDiet+Nuts
Low fat diet
Reduction in the Incidence of Type 2 Diabetes With the Mediterranean Diet
Adjusted by sex, age, baseline energy intake, BMI, waist circumference, physical activity, smoking status, fasting serum glucose, use of lipid-lowering drugs, MedDiet Score, and weight change during the study
MedDiet + VOO =0.49 (0.25-0.97)
MedDiet + Nuts = 0.48 (0.24-0.96)
215 overweight people with newly diagnosed type 2 diabetes who were never
treated with antihyperglycemic drugs .4years-Intervention study.
Evidence pro the Mediterranean type Diet Effects of a Mediterranean-style diet on the need for antihyperglycemic drug
therapy in patients with newly diagnosed type 2 diabetes: a randomized trial.
Esposito K , et al. Ann Int Med 2009
After 4 years, 44% of patients in the
Mediterranean-style diet group and 70% in
the low-fat diet group required treatment
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Recruitm.
1 yr
2 yr
3 yr
4 yr
5 yr
6 yr
Year % of recruitment
Cum. %
2003 9 9 2004 21 30 2005 28 58 2006 11 69 2007 13 82 2008 17 99 2009 1 100
Total 100
Projected follow-up = 6 years (median)
Interim Analyses with Data until Dec 2010
PREDIMED Independent Data and Safety Monitoring Board Xavier Pi-Sunyer (chair). Columbia University. USA Carlos A. González. Institut Catalá d’Oncologia (ICO), Spain Frank B. Hu. Harvard University, USA Joan Sabaté. Loma Linda University, CA, USA
PREDIMED Steering Committee R. Estruch (chair); D. Corella; M.I. Covas; M.A. Martínez-Gonzalez; E. Ros;J. Salas-Salvadó
Median Follow-up: 4.8 (2.8 to 5.8)
Participants: 7447
Intention-to-treat-analyses
PRIMARY END-POINT
Composite of:
• Cardiovascular death
• Non-fatal myocardial infarction
• Non-fatal stroke
SECONDARY END-POINTS
• Cardiovascular death
• Non-fatal myocardial infarction
• Non-fatal stroke
• Death from any cause
• Angina leading to revascularization procedure
• Heart failure
Kaplan-Meier Estimates of the Incidence of the Primary End-point
109 96 83
Events
Inci
de
nce
of
the
Co
mp
osi
te
The PREDIMED Study. Subgroup analyses
The PREDIMED Study. Subgroup analyses
Mechanisms by which the
Mediterranean Diet
could exert protective effects
Glucose, mg/dL
Insulin, pmol/L
Homa index (x10)
-35
-30
-25
-20
-15
-10
-5
0
TMD+VOO TMD+Nuts Control
* *
* *
*
Changes in fasting glucose, insulin, and HOMA index after 3-
months (n =305 non dibetic participants). The PREDIMED Study.
* P < 0.05 versus control
TMD, traditional Mediterranean Diet; VOO, virgin olive oil
Estruch R et al. Ann Int Med 2006
*
Glucose
Cholesterol
Triglycerides
HDL - cholesterol
127±44
220±39
137±62
44±9
121±42
215±37
133±66
126±38
213±39
139±63
45±10
122±38
209±37
132±63
46±11
133±49
219±40
147±70
47±10
137±48
221±42
151±80
47±11
TMD+VOO
TMD+ Nuts Low-fat
Changes in Glucose and Lipid Profile after 3-months
(n =772).The PREDIMED Study
LDL - cholesterol 147±35 141±36 140±35 136±33 144±34 145±34
47±10
p<0.05
LDL / HDL 3.4+1.0 3.1+0.9 3.0+1.0 3.2+1.0 3.1+0.9 3.1+0.9
TMD, traditional Mediterranean Diet; VOO, virgin olive oil
Estruch R et al. Ann Int Med, 2006
-6
-5
-4
-3
-2
-1
0
% d
e C
am
bio
MD+ VOO MD + Nuts Low Fat
SBP
DBP
Changes in Blood Pressure at 3-month Interventions, (mmHg,
N =772). The PREDIMED Study
*¥ * ¥ * ¥ * ¥
* P < 0.01, 3 mo vs baseline
¥ P < 0.001, versus low-fat changes
Ch
an
ge (
%)
Estruch R et al. Ann Int Med, 2006
Fitó for the PREDIMED group. Arch Inter Med 2007;167:1195-1203.
n = 372
Mediet+VOO=123 Mediet+nuts=128 control=121
Changes from baseline in plasma inflammatory biomarkers. The PREDIMED Study (n =772)
Estruch et al. Ann Int Med, 2006.
-1.25
-1.00
-0.75
-0.50
-0.25
0.00
0.25
0.50
0.75
1.00
1.25
**
Ch
an
ges
in
CR
P (
mg
/L)
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
** * C
ha
ng
es i
n I
L-6
(p
g/m
L)
-100
-75
-50
-25
0
25
50
75
** **
*
Ch
an
ges
in
IC
AM
-1 (
ng
/mL
)
-250
-200
-150
-100
-50
0
50
100
150
200
** **
*
Ch
an
ges
in
VC
AM
-1 (
ng
/mL
)
MedDiet + VOO
MedD + nuts
Low fat diet
The protocol for the control group was changed halfway through the trial (October 2006). A lower intensity of dietary intervention for the control group during the first few years
might have caused a bias toward a benefit in the Mediet groups, since the participants in these groups received a more
intensive intervention during that time.
However, we found no significant interaction between the period of trial enrollment (before vs. after the protocol
change) and the benefit in the Mediet groups.
Limitations
The generalizability of our findings is limited because all the
study participants lived in a Mediterranean country and
were at high cardiovascular risk.
Whether the results can be generalized to persons at lower
risk or to other settings requires further research.
Limitations
1. Among individuals at cardiovascular risk, a traditional Mediterranean diet supplemented with Extra Virgin Olive Oil or with Nuts promoted:
1.1 A 52% reduction of diabetes incidence at a
median follow-up of 4 years 1.2 A 30% reduction in the incidence of major
cardiovascular events at a median follow-up of 4.8 years
Conclusions
2. Results of the PREDIMED Study provide first level
evidence on the benefits of the traditional
Mediterranean diet on the primary prevention of
diabetes and cardiovascular disease.
Conclusions
Primary Prevention by the Mediterranean Diet The PREDIMED Study
Hospital de Álava de Vitoria
Univ Pais Vasco
Facultad de Medicina de Navarra
I.C.S.-División Primaria IDIBAPS-Hospital Clínic
IMIM Univ.de Barcelona
Hospital de Bellvitge
Facultad de Medicina de Reus
Facultad de Medicina de Valencia
Universidad de las Palmas de Gran Canaria
Centro de Salud San Pablo Instituto de la Grasa
Sevilla Facultad de Medicina de Málaga
Hospital Son Espases Univ. Illes Balears
We thank the participants in the trial for their
enthusiastic and sustained collaboration and
Joan Vila from Institut Municipal
d’Investigació Mèdica, Barcelona, for expert
assessment in the statistical analyses.
ACKNOWLEDGEMENTS
Centro de Investigación Biomédica En Red
Fisiopatología de la Obesidad y Nutrición
Centro de Investigación Biomédica En Red
Fisiopatología de la Obesidad y Nutrición
Centro de Investigaciones Biomédicas en Red
Physiopathology of Obesity and Nutrition.
CIBERobn CB06/03 is an initiative of the Instituto de
Salud Carlos III.
Ministry of Science and Innovation
“Spanish Network G03/140
AGL2005-05597; AGL2006-14228-C03-02/01
AGL2007-66638-C02-01;
RETICS RD06/0045/0003
Programa INGENIO CONSOLIDER 2010, FUN-C-
FOOD (CSD2007-063)
THANK YOU FOR YOUR ATTENTION
Encuesta de 14 puntos
Forest plot of the association between a 2-point increase of adherence score to the Mediterranean diet and the risk of
all-cause mortality.
Sofi F et al. Am J Clin Nutr 2010;92:1189-1196 ©2010 by American Society for Nutrition
Forest plot of the association between a 2-point increase of adherence score to the Mediterranean diet and the risk of
all-cause mortality.
Sofi F et al. Am J Clin Nutr 2010;92:1189-1196 ©2010 by American Society for Nutrition
Encuesta de 14 puntos
∫ Stratified by recruiting Center and adjusted by age, sex, family history of CHD, and
smoking
¶ Additionally adjusted by BMI, Waist-to height, and hypertension, dyslipidemia and diabetes at baseline
Stratified by recruiting Center and adjusted by age, sex, family history of CHD, smoking,
BMI, Waist-to height, and hypertension, dyslipidemia and diabetes at baseline
Kaplan-Meier Estimates of the Incidence of Total Mortality MeDiet+EVOO MedDiet+Nuts Low-Fat No. of events: 118 116 114
Crude rate/1000 person-yr (95% CI): 10.0 (8.2–11.9) 11.2 (9.3–13.4) 11.7 (9.6–14.0)
Low Medium High 140
145
150
155
160
165 S
BP
,
mm
Hg
Low Medium High 80
82
84
86
88
DB
P,
mm
Hg
Tertiles of oxLDL
P = 0.004 for linear trend
P = 0.001 for linear trend
¥
† *
Systolic and diastolic blood pressure (mean ± s.e.) according to tertiles of in vivo
circulating oxidized low density lipoproteins (oxLDL) in the PREDIMED population
(N=1130)
*P value < 0.01,†P value < 0.01 and ¥ P value < 0.01 vs. low tertile.
Guxens M, et al. Am J Hypertens 2009
Metabolic syndrome and Diabetes are associated with elevated circulating
oxidized LDL
Metabolic
Syndrome
Oxidized
LDL
+
Abdominal Obesity
Impaired glucose
homeostasis
Hypertriglyceridemia
Low HDL cholesterol
High Blood Pressure
-
-
+
-
-
-
Holvoet P et al. Futur Lipidol, 2008
Mediterranean
Diet
-
Inflammation
-
X
X
X
X
X
X
X
X
X
0
X
X
X
X
X
X
X
1
X
X
X
X
X
X
X
2
X
X
X
X
X
X
X
3
X
X
X
X
X
X
X
4 Years
Measurements
Eligilibilty questionnaire
General questionnaire
Follow-up questionnaire
Food Freq. questionnaire
14 item score of Med diet
Physical activity ques.
EKG, BP, and Anthropometric
Blood samples
Fresh urine sample
Toenail sample
*
*
Urinary tyrosol and hydroxytyrosol Plasma fatty acid composition (oleic and -linolenic acids)
* Specific measurements Intervention compliance assessment
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