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