Prevention is Cheaper than Cure

1. Harry de Koning (Erasmus University Medical Center, Netherlands)

2. Olle Melander (Lund University, Sweden)

3. Estefania Toledo (University of Navarra, Spain)

Vaida Bankauskaite (Maria Siomos) (ERC)

27 July 2016: 3:45-5 pm, Exchange 11

Prevention is cheaper than cure

Olle Melander, MD, PhD, Professor of Internal Medicine

Lund University and Skåne University Hospital, Malmö,

Sweden

ERC StG-282255 “CARDIOPREVENT”

WHAT IS IT IN DIABETES THAT CAUSES

CARDIOVASCULAR DISEASE?

Vasopressinexcess

CARDIOMETABOLIC DISEASE?

Neurotensinexcess

Satiety hormone-

Fat sensitive

Osmolality hormone-

Water sensitive

CARDIoGRAM (2011): Total of 25 loci for CAD

SORT1 = Neurotensin receptor 3

Nature, 2010;465:714-721

Neurotensin

SORT1

Lipoprotein sorting GLUT4 translocation

CVD Diabetes

JAMA 2012;308:1469-75

NTSR1

G-coupled

NTSR2 NTSR3

G-coupled Not G-coupled=SORT1

*GUT (N-CELLS) AND BRAIN

*FAT INTAKE TRIGGERS RELEASE

*CANCER INITIATION / GROWTH

Odds ratio (95% confidence interval)

N / N cases Pro-NT

Quartile 1

Pro-NT

Quartile 2

Pro-NT

Quartile 3

Pro-NT

Quartile 4

P for

trend

Prevalent

Obesity* 4626 / 604 1.0 (ref) 1.00

(0.78-1.29)

1.13

(0.88-1.45)

1.34

(1.05-1.70)

0.01

Prevalent

Abdominal

Obesity*

4625 / 1769 1.0 (ref) 1.07

(0.90-1.27)

1.23

(1.04-1.46)

1.30

(1.09-1.54)

0.001

Prevalent

Insulin

Resistance*

4468 / 1140 1.0 (ref) 1.30

(1.06-1.59)

1.43

(1.17-1.74)

1.70

(1.39-2.06)

<0.0001

New-Onset

Obesity** 2594 / 333 1.0 (ref) 1.41

(0.95-2.10)

1.79

(1.21-2.65)

2.05

(1.38-3.06)

<0.0001

Proneurotensin is high in obesity/insulin resistance and

predicts future development of obesity on non-obese

subjects (Malmö Diet and Cancer / re-exam)

*Adjusted for age and sex

**Adjusted for age, sex and BMI Nature, May 11th 2016

NT+/+ NT-/- NT+/+ NT-/-

Nature, May 11th 2016

Nature, May 11th 2016

Neurotensin

OBESITY, DIABETES, CARDIOVASCULAR

DISEASE AND PREMATURE DEATH

SORT1

*Low fat intake

*Neurotensin blockade

NEUROTENSIN- ”DANGEROUSLY EFFECTIVE” AND

”OLD FASHIONED” WAY TO CONSERVE ENERGY (FAT)

Vasopressinexcess

CARDIOMETABOLIC DISEASE?

Neurotensinexcess

Satiety hormone-

Fat sensitive

Osmolality hormone-

Water sensitive

Major MinorMinor Homeostasis

WATER REABSORPTION

AVP

VASOPRESSIN: FRIEND OR ENEMY?

ABDOMINAL OBESITY

INSULIN RESISTANCE

HYPERTENSION

DIABETES&

CARDIOVASCULAR

DISEASE

DYSLIPIDEMIA

CUSHINGS SYNDROME

AUTONOMOUS OVERPRODUCTION OF CORTISOL

AVP STIMULATES ACTH SECRETION THROUGH PITUITARY V1B RECEPTORS

--- AN EFFECT WHICH LACKS A NEGATIVE FEEDBACK LOOP

Gillies et al, Nature 1982 & Tanoue et al, J Clin Invest 2004

++

Circulation 2010;121:2102-2108

J Clin Endocrinol Metab 2011;96:E1065-E1072

HR 95% CI P* HR 95% CI P

MACE 1.33 (1.04-1.69) 0.02 1.02 (0.90-1.15) 0.78

CVD 1.28 (1.03-1.60) 0.03 1.04 (0.94-1.15) 0.44

Death 1.38 (1.09-1.74) 0.007 1.04 (0.95-1.13) 0.40

CVD death 1.34 (0.93-1.92) 0.12 1.04 (0.88-1.22) 0.64

HF 1.62 (1.09-2.41) 0.02 1.19 (0.92-1.55) 0.18

DIABETES PATIENTS NORMOGLYCEMIC

copeptin x diabetes: P for interaction=0.006

Mean age 70 years

5.6 years of follow-up

WHICH IS THE EASIEST AND MOST

EFFICIENT WAY TO LOWER

VASOPRESSIN?

Obese Low-VP

A

Lean

Obese Norm-VP Obese High-VP

Taveau et al. Diabetologia 2015

Liver steatosis is prevented by high water intake (=low VP)

Drinking 500 ml water in healthy humans produces a

rapid and sustained suppression of vasopressin

(copeptin) in plasma

0-240 minutes post 1L water

P<0.0001

In preparation 2016

RANDOMISED CONTROLLED TRIAL OF WATER SUPPLEMENTATION

FOR IMPROVEMENT IN GLUCOSE TOLERANCE

SCAPIS-Malmö

N=5.000Malmö Offspring Study

N=5.000

Big3

N=10.000

Measurement of copeptin (vasopressin):

>6.1 pmol/L in females / >10.7 pmol/L in males

25% of population 50-65y

Inclusion /Exclusion criteria

Invitation, informed consent

Randomisation

Diet and life style advise

+ 1.5 L water/day

N=500

Diet and life style advise

N=500

12 months follow-up including coaching,

dose adjustment based on 24-h osmolarity

EpiHealth

N=7.000

Vasopressinexcess

HYPERTENSION, DIABETES, ABDOMINAL OBESITY,CARDIOVASCULAR DISEASE

Neurotensinexcess

SORT1 V1R

*Low fat intake

*Neurotensin blockade

*High water intake

*VP rec blockade

Two key hormones involved in ”cardiometabolic disease”

Bo Hedblad

Peter Nilsson

Gunnar Engström

Sofia Enhörning

Celine Fernandez

Cristiano Fava

Malin Svensson

Widet Tas

Peter Almgren

Marketa Sjögren

Margaretha Persson

Gerd Östling

Philippe Burri

Klas Gränsbo

Gustav Smith

Martin Magnusson

Patrik Svensson

Viktor Hamrefors

Jonas Dahlberg

Marju Orho-Melander

ACKNOWLEDGEMENTS:

ERC StG-282255 “CARDIOPREVENT”

Prevention is cheaper than cure

The PREDIMED Plus trial

Estefanía Toledo, MD, MPH, PhD

University of Navarra

No conflicts of interest.

2. Dietary

patterns3. Observational

studies1. NCD/CVD

5. PREDIMED4. Association

or causality?

6. Predimed-

PLUS

2. Dietary

patterns3. Observational

studies1. NCD/CVD

5. PREDIMED4. Association

or causality?

6. Predimed-

PLUS

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Lancet 2012; 380: 2197–223

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Lancet 2012; 380: 2197–223

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

McKinlay J. A case for refocussing upstream: the political economy of illness.

In: Proceedings of American Heart Association Conference.

Washington: June 1974.

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Ideal CV Health METRICS (7)1.2.3.4.5.6.7.

Circulation. 2010;121:586-613

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Ideal CV Health METRICS (7)1. Never smoking2. BMI < 25 kg/m2

3. Physical activity >149 min/wk4. Healthy eating >3/55. Total cholesterol < 200 mg/dl6. Blood pressure <120/80 mmHg7. Fasting glucose < 100 mg/dl

Circulation. 2010;121:586-613

JAMA. 2012;307:1273-83

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns3. Observational

studies1. NCD/CVD

5. PREDIMED4. Association

or causality?

6. Predimed-

PLUS

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

g/d USA The Netherlands Greece (Crete)

Fish/Seafood 3 12 18

Legumes 1 2 30

Bread 97 227 380

Fruit 233 82 464

Olive Oil 0 0 95

Meats 273 138 35

Butter 26 21 0

Margarine 4 56 0

MUFA/SFA RATIO

4,03,02,01,00,0

CH

D D

EA

TH

RA

TE

(1

5 y

r)/1

0,0

00

1400

1200

1000

800

600

400

200

0

JAPJAPGRE

GRE

YUG

YUG

YUG

YUG

ITA

ITAITA

HOL

FIN

FIN

US

Keys et al

Am J Epidemiol 1986;124:903

2. Dietary

patterns

3.

Observational

studies

1. NCD/CVD

5. PREDIMED4. Association

or causality?

6. Predimed-

PLUS

•1 point if >= sex-specific Median1. MUFA/SFA ratio

2. Fruits & nuts

3. Vegetables

4. Cereals

5. Legumes

6. Fish

•1 point if <= sex-specific Median7. Meat/meat products

8. Dairy

9. Alcohol: 1 point if•Men: between 10-50 g/d•Women: between 5-25 g/d

9-item2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

When studies using only fatal cases

were removed, the heterogeneity disappearedand the risk

reduction for every

+2 points was 13%

Martinez-Gonzalez MA, Bes-Rastrollo M. Curr Opin Lipidol 2014;25:20-6.

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

For each + 2 points

2. Dietary

patterns

3.

Observational

studies

1. NCD/CVD

5. PREDIMED4. Association

or causality?6. Predimed-

PLUS

Strength of association

Temporal sequence

Graduality

Consistency

Coherence

Biological plausibility

Specificity

Analogy

Experimental evidence

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Arch Intern Med 2009;169:659-669

We used the Bradford Hill guidelines to derive acausation score based on 4 criteria (strength, consistency, temporality, and coherence) for each dietary exposure in cohort studies and examined for consistency with the findings of randomized trials.

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3.

Observational

studies

1. NCD/CVD

5. PREDIMED4. Association

or causality?6. Predimed-

PLUS

Ros et al.

Adv Nutr.

2014;5:330S-6S

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

14-point score

1. Olive oil main culinary fat 8. Wine >=7 glasses/wk2. Olive oil >=4 tablespoons/d 9. Legumes >=3/wk3. Vegs>=2 serv./d 10. Fish & seafood >=3/wk4. Fruits>=3 serv./d 11. Cakes, sweets <2/wk5. Red meats<1/d 12. Nuts >=3/wk6. Butter, marg, cream<1/d 13. Poultry > red meats7. Soda drinks<1/d 14. Sofrito

Zazpe et al for the PREDIMED group,

J Am Diet Assoc 2008;108:1134-44

www.predimed.es

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Stopped for early evidence of benefitafter 4.8-y median follow-up

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Estruch R, et al. N Engl J Med 2013

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

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.

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Peripheral artery disease

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

253 cases

Follow-up 4.7 y

Martínez-González MA, et al. Circulation 2014;130:18-26

Atrial fibrillation

Toledo E, et al. JAMA Intern Med 2015;175:1752-60.

38%

62%

Breast cancer2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3.

Observational

studies

1. NCD/CVD

5. PREDIMED4. Association

or causality?

6. Predimed-

PLUS

Rationale for the trial

Low-fat

MedDiet+ E. restriction+ physical activity+ behavioral intervention

Predimed 1

MedDiet

Predimed plus

Weight loss long-term maintenance CVD

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Primary endpoint:

1. AMI, non-fatal stroke or CV mortality

www.predimedplus.com

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

DietitiansINTENSIVE INTERVENTION

Month -1 to 0: run in (2 visits + phone call)RANDOMIZATION

Months 1-12: 1 group + 1 indiv. + 1 phone call

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

DietitiansINTENSIVE INTERVENTION

Month -1 to 0: run in (2 visits + phone call)RANDOMIZATION

Months 1-12: 1 group + 1 indiv. + 1 phone callYears 2-6: monthly 1 group + 1 indiv. (P each 3 mo/Phone)

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

1. Olive oil main culinary fat

2. Vegetables ≥ 2 /d

3. Fruits ≥ 3 /d

4. Red/processed meats ≤ 1 /wk

5. Butter, margarine, cream < 1/wk

6. Sugary beverages < 1 /wk

7. Legumes ≥ 3 /wk

8. Fish / seafood ≥ 3 /wk

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

9. Bakery, cookies, sweets < 3 /wk

10. Tree nuts ≥ 3 /wk

11. Poultry > red-processed meats

12. Sofrito ≥ 2 /wk

13. Not adding sugar to beverages

14. White bread ≤ 1 /d

15. Whole grains ≥ 5 /wk

16. Refined grains-rice-pasta < 3 /wk

17. Wine glasses: men 2-3 /d women 1-2 /d

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

Traditional Mediterranean eating patterns: PREDIMED 14-item screener Minimal intervention by dietitiansWritten recommendations from the PREDIMED-1 (leaflet, brochures, recipes, menus, shopping lists)

Total energy intake: ad libitumNo specific recommendation on physical activityNo weight /waist/PA self-monitoringNo aims for weight loss

2 gr. sessions/y- incentive free VOO (12 l/y) + nuts (6 kg/y)

Low-intensity control group2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

n=2229

n=1473

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

n=2341

n=1509

p<.001

p<.001

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

n=2290

n=1466

p<.001

p<.001

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

n=1445

n=776

n=776

p=0.01

p<.001

2. Dietary

patterns

3. Observational

studies

1. NCD/CVD

5. PREDIMED

4. Association

or causality?

6. PREDIMED

Plus

n=2179

n=1383

p=0.020

p=0.02

In summary

• A 14-item assessment tool can validly • appraise adherence to MedDiet• predict future incidence of CVD• be used for immediate feedback in intervention studies

• No other dietary pattern has such a strong evidence to support its benefits on CVD

• er-MedDiet: probably the most sensible option to combat obesity, T2D & CVD (the huge XXI epidemic)

A clever person solves a problem,

a wise person avoids it.

Prevention is cheaper than cure

The PREDIMED Plus trial

Estefanía Toledo, MD, MPH, PhD

University of Navarra