The Mediterranean diet:

The ideal strategy to lower CVD risk?

Emilio RosLipid ClinicEndocrinology & Nutrition ServiceHospital ClinicUniversity of BarcelonaCIBEROBN, ISCIII, Spain

Outline

• Cardioprotective dietary patterns

• North-to-South CAD mortality gradient in Europe

• The Mediterranean diet

• Evidence from epidemiological studies

• The PREDIMED trial

- Rationale

- Design, implementation, and funding

- Main results

- Conclusions

Cardioprotective dietary patterns

• Western diet

• Vegetarian diet

• Traditional Japanese diet (+ fish)

• DASH diet

• “Prudent diet” (AHEI, others)

• (Atlantic diet) (+ fish)

• Traditional Mediterranean diet (+ fish)

Plant-based

Cardioprotective dietary patterns

• Western diet – High-fat (animal)

• Vegetarian diet

• Traditional Japanese diet

• DASH diet Low-fat

• “Prudent diet” (AHEI, others)

• (Atlantic diet)

• Traditional Mediterranean diet – High-fat (vegetable)

Low-fat diet and CVD. The WHI Study

• WHI: RCT in 49.000 menopausal

women x 8 years

Low-fat diet vs usual diet

(-8% fat in active treatment group)

Advice on a diet

low in total fat:

No CV benefit

Howard BV, et al. JAMA 2006;295:655-66.

Low-fat diet, weight loss and CVD: LOOK-AHEAD

n = 5145 – all diabetics with overweightIntensive intervention with low-energy diet & physical activity vs usual careLow-fat diet stressed in the active treatment armMedian follow-up: 9.6 yrs (trial stopped because of futility)

N Engl J Med June 2013

CAD mortality in Europe, year 2000. Age groups 45-74 years, age-adjusted rates

Men Women

Müller-Nordhorn J, et al. Eur Heart J 2008;29:1316–26.

Genetic factors - improbable

Lifestyle - probable

• Mediterranean diet

• Physical activity

Psychosocial factors – possible

Factors that might explain a reducedCAD risk in Southern Europe

The true Mediterranean dietexists where olive trees grow

Beneficial effects of the Mediet

Seven Countries Study

Keys A, et al. Am J Epidemiol 1986;124:903

Harvard University

Med Diet pyramid

MUFA/SFA RATIO

4,03,02,01,00,0

CH

D D

EA

TH

RA

TE

(15

yr)

/10

,00

0

1400

1200

1000

800

600

400

200

0

JAPJAPGRE

GRE

YUG

YUG

YUG

YUG

ITA

ITAITA

HOL

FIN

FIN

US

• Ecological studies

• Olive oil as main culinary fat – unrestricted fat intake

• Abundant vegetable products

cereals (bread, pasta and rice)

fresh vegetables and fruits

legumes

tree nuts

aromatic herbs and spices

• Frequent intake of fish and shellfish

• Moderate consumption of wine with meals

meat and animal products

• Low intake of milk and milk products

simple sugars

Characteristics of the Mediterranean diet

Mente A, et al. Arch Intern Med 2009;169:659-69.

Systematic review of the evidence supportinga causal link between dietary factors and CHD

Sofi F, et al. Am J Clin Nutr 2010;92:1189-96..

Risk of mortality from or incidence of CVD associated with a 2-point increase in a 9-point score of adherence to the MeDiet

N = 534,064 subjects at risk and 8739 cases. Follow-up 4 to 10 y

Risk reduction associated with a 2-point increasein a 9-point score of adherence to the Med Diet

End point Relative risk (95% CI)

CVD incidence & mortality 0.90 (0.87 – 0.93)

Total mortality 0.92 (0.90 – 0.94)

Cancer mortality or incidence 0.94 (0.92 – 0.96)

Neurodegenerative disease 0.87 (0.81 – 0.94)

Sofi F, et al. Am J Clin Nutr 2010;92:1189-96..

The combined effect of prospective studies and clinical trials showed

that adherence to the MeDiet was associated with reduced risk of MS

and all its components.

Case-cohort study: 11,994 incident type-2 DM cases and 15,798 controls

Multiple adjusted HR of type-2 DM among individuals with high adherence

to the MeDiet: 0.88 (95% CI, 0.79–0.97) compared with low adherence.

Ecological (international comparisons)

Cross-sectional-

Case-control

Cohort

Randomized Trial

Study designs

High

Low

Qu

alit

y o

f e

vid

en

ce

Micronutrients: vitamin E, flavonoids, etc.,

Single macronutrients: CHO, protein, fat subtypes

Foods: fish, nuts, garlic, olive oil, etc., .

Food groups & indexes

Food patterns

Exposures in nutritional epidemiology

PREDIMED - Rationale

The Lyon Diet Heart Study. A secondary CHD prevention trial with a “peculiar” MedDiet

de Lorgeril M, et al. Final Report of the Lyon DietHeart Study.Circulation 1999;99:779-85.

Effects of a Mediterranean-type

diet on the Primary Prevention

of Cardiovascular Disease

(PREDIMED Study)

http//:predimed.es

PREDIMED - Hypothesis

Compared with usual dietary recommendations for

health (low-fat diet), the following dietary

interventions will significantly reduce the incidence of

CVD in asymptomatic high-risk individuals:

• A Mediterranean-type diet in which extra virgin olive

oil is the main culinary fat.

• A Mediterranean-type diet supplemented with tree

nuts.

Characteristics of the Mediterranean diet

• Olive oil as main culinary fat – unrestricted fat intake

• Abundant vegetable products

cereals (bread, pasta and rice)

fresh vegetables and fruits

legumes

tree nuts

aromatic herbs and spices

• Frequent intake of fish and shellfish

• Moderate consumption of wine with meals

meat and animal products

• Low intake of milk and milk products

simple sugars

• MUFA (oleic acid)

• Tocopherols

• Polyphenols

• Phytosterols

Virgin Olive Oil

Nuts: the whole is better than the parts

Unsaturated fat

Fiber

Protein (arginine)

Tocopherols

Polyphenols

Phytosterols

PREDIMED Design. Participants

Men: 55-80 y

Women: 60-80 y

High risk without CVD

with type 2 diabetes or

3+ CVD risk factors

RandomN=7447

1. Smoking

2. Hypertension

3. LDL-C

4. HDL-C

5. Overweight / obesity

6. Family history of early-onset CHD

PREDIMED – Design II. Interventions

• Control group: advice on a low-fat diet

+ non-food gifts

Med diet groups: advice on MED diet

• + EVOO: provision of OO (1 L /wk per family)

• + NUTS: provision of 30 g/d of nuts (15 g

walnuts, 7.5 g almonds, 7.5 g hazelnuts)

Intervention implemented in quarterly individual

and group sessions run by dietitians.

PREDIMED – Design IV

Primary outcomes

• Incidence of major CV events (nonfatal MI,

nonfatal stroke, or cardiovascular death –

composite score of all CV events)

Trial started October 2003, terminated July 2011

Mean follow-up ≈5 years – Results in Feb 2013

PREDIMED

Preliminary

Results

Estruch R, et al. Ann Intern Med 2006;145;1-11.

Pilot study in first 772 participants after follow-up for 3 months

• Beneficial effect of the two MeDiets on classical and emergent

cardiovascular risk factors (blood pressure, lipids, insulin

sensitivity, and inflammation / lipoprotein oxidation).

PREDIMED

Results of the

primary outcome

PREDIMED – Participants’ characteristics

Mediet + VOO

(n=2487)

MeDiet + Nuts

(n=2396)

Control

(n=2349)

Age, y (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., cm (SD) 100 (10) 100 (10) 101 (11)

MeDiet 14-p score (SD) 8.7 (2) 8.7 (2) 8.3 (2)

1. Olive oil use as main culinary fat 8. Wine ≥7 glasses/wk2. Olive oil ≥4 tbs/d 9. Legumes ≥3/wk3. Vegetables ≥2/d 10. Fish & seafood ≥3/wk4. Fruit ≥3/d 11. Cakes, sweets

PREDIMED Study – Cardiovascular diseases

Estruch R, et al. N Engl J Med 2013

PREDIMED Study – Myocardial infarction

Estruch R, et al. N Engl J Med 2013

PREDIMED Study – Stroke

Estruch R, et al. N Engl J Med 2013

PREDIMED – Secondary outcomes

Total mortality (pending extended follow-up)

Peripheral artery disease

Heart failure (under scrutiny)

Atrial fibrillation

Major cancers (some under scrutiny)

Diabetes

Dementia (under scrutiny)

Hazard Ratios (95% CI)

EVOO: 0.32 (0.19-0.56)

Nuts: 0.51 (0.32-0.83)

N = 89 cases

Follow-up 4.8 y

Ruiz-Canela M, et al. JAMA 2014;311:415-7.

PREDIMED Study – Peripheral Artery Disease

Martinez-Gonzalez MA, et al. Circulation. published online April 30, 2014

PREDIMED Study – Atrial Fibrillation

PREDIMED Study - Incident diabetes

Salas-Salvadó J, et al. Ann Intern Med 2014;160:1-10.

↓18%

↓40%

2-year changes in ICA IMT and plaque height with two MeDiets

vs. a control diet in 164 PREDIMED participants

control EVOO NUTS-0.3

-0.2

-0.1

-0.0

0.1

0.2

0.3

p = 0.024

Control Diet

MedDiet + EVOO

MedDiet + nuts

Ch

an

ge I

CA

-IM

Tm

ean,

mm

control EVOO NUTS-0.3

-0.2

-0.1

-0.0

0.1

0.2

0.3 p = 0.047

Control Diet

MedDiet + EVOO

MedDiet + nuts

Ch

an

ge P

laq

ue

max,

mm

MedDiet+EVOO MedDiet+Nuts Control diet-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

24-h BP

Daytime BP

Nighttime BP

Basal 127 (124 to131) 125 (122 to 128) 123 (120 to 126)

1 year 124 (121 to 127) 123 (120 to 126) 125 (122 to 128)

Basal 131 (127 to 134) 129 (126 to 132) 126 (123 to129)

1 year 128 (125 to 131) 126 (123 to 129) 129 (126 to 132)

Basal 118 (114 to 122) 117 (114 to 120) 114 (111 to 117)

Change 115 (112 to 119) 115 (112 to 119) 116 (112 to 119)

aa

b

aa

b

a ab

b

Ch

an

ge o

f S

ysto

lic B

lod

d p

resu

re (

mm

Hg

)

Adjusted for sex, age, Mediterranean diet score, energy intake, body mass index, physical activity, smoking and antidiabetic drugs other than insulin.

Babio N, et al. CMAJ 2014;186:E649-57.

METABOLC SYNDROMEPREDIMED. Metabolic syndrome

MetS incidence MetS reversion

1.10 1.08

1.351.28

P value MeDiet+EVOO vs control:

Mechanisms of CVD prevention

In older subjects at high cardiovascular risk, non–energy-restricted

MeDiets enriched in EVOO (MUFA)* or tree nuts (MUFA + PUFA)* :

• Reduce blood pressure

• Improve the lipid profile

• Decrease insulin resistance

• Reduce oxidation and inflammation

• Induce regression of carotid atherosclerosis

• Prevent metabolic syndrome and diabetes

• REDUCE INCIDENCE OF CARDIOVASCULAR DISEASES

without weight gain

*plus bioactive molecules in these foods

HR= 0.72 (0.55-0.94)HR= 0.47 (0.35-0.65)

Q1

Q2-3

Q4-5

Hazard ratios (95% CI) for incident CVD by quintile

distribution of the baseline 14-item PREDIMED score

Schroder H, et al. JAMA Intern Med 2014;174:1690-2.

Of the 14 items of the PREDIMED screener, only baseline consumption of

vegetables and nuts related independently to reduced CVD risk

Nuts

EVOO

Legumes

Cereals

Vegs.& fruit

Unsaturated Fatty Acids

Complex CHO

Fiber

Low GI

Vegetable protein

Phytosterols

Polyphenols

Minerals (K, Mg, Ca)

↓ TC & TG

↑ Glycemiccontrol

↓ Blood pressure

↓ Oxidation↓ Inflammation

↓ CVD & diabetes

DMED

↓ Adiposity

Wine

Alcohol

↑ HDL-C

Main Conclusions

The MeDiet, a plant-based, high-fat, high-unsaturated

fat dietary pattern, appears to be optimal for CV health.

Small changes in dietary habits make a big difference

in CV risk reduction, illustrating the great power of

(healthy) foods to effect cardiometabolic pathways.

It appears that it is never too late to change dietary

habits to improve health.

The MeDiet is an evidence-based lifestyle intervention

for CV risk reduction.