1. www.unav.es/preventiva The PREDIMED trial

2. www.unav.es/preventiva

3. DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

4. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

5. www.unav.es/preventiva DOG Ecological (cross-cultural,international comparisons) Case-control Nestedcase-control Cohort Randomized Trial Evolution of designs High Low Quality of evidence

6. www.unav.es/preventiva DOG Mediterranean Food pattern  Rapidly increasing evidence Increased Longevity Prevention of  CV mortality  Cancer mortality  CVD incidence  Metabolic syndrome  Diabetes  Dementia  Depression  Highly palatable!  Scarcity of large randomized trials

7. www.unav.es/preventiva DOG Mediterranean Food pattern  Rapidly increasing evidence Increased Longevity Prevention of  CV mortality  Cancer mortality  CVD incidence  Metabolic syndrome  Diabetes  Dementia  Depression  Highly palatable!  Scarcity of large randomized trials

8. www.unav.es/preventiva DOG de Lorgeril M, Salen P, Martin JL, et al. Final Report of the Lyon Diet Heart Study. Circulation 1999;99:779-785.

9. www.unav.es/preventiva DOG Eur J Epidemiol 2004;19:9-13. What is the MeDiet? Olive oil as the main added lipid Unrestricted Total Fat MUFA-rich diet in the intervention group Low consumption of meat / meat products and what it is NOT the MeDiet Margarine, soybean oil, mustard oil...

10. de Lorgeril et al. Lyon trial. Circulation 1999;99:779-785. Diet assessed in ~30% of control ~50% of experimental No biochemical confirmation of adherence. Trial stopped after 27 months. Low number of observed endpoints (14 vs. 44).

11. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

12. www.unav.es/preventiva DOG Funding agency Network RD 06/0045 Consortium (CIBER-OBN)

13. www.unav.es/preventiva DOG Funding History 2003200420052006200720082009 1715 14171819 adhoc grant Initial Network Network RD 06/0045 Consortium ciberobn

14. www.unav.es/preventiva DOG Centers 11 RECRUITMENT GROUPS Navarra- MA Martinez-Gonzalez Valencia- D Corella Reus- J Salas-Salvado Mallorca- M Fiol Sevilla- J Lapetra Málaga- E Gomez-Gracia Barcelona-1- R Estruch Vitoria- F Aros Barcelona-2- MI Covas Las Palmas- L Serra-Majem Barcelona-3- X Pinto 8 ONLY-LAB GROUPS Barcelona-1- E Ros Sevilla- V Ruiz-Gutierrez Barcelona-2- RM Lamuela-Raventos Navarra- JA Martinez Valencia- G Saez Barcelona-3- MT Mitjavila Mallorca- JA Tur Vitoria- MP Portillo

15. www.unav.es/preventiva DOG Funded by network (RD 06/0045) 6 RECRUITMENT GROUPS Navarra- MA Martinez-Gonzalez Valencia- D Corella Reus- J Salas-Salvado Mallorca- M Fiol Sevilla- J Lapetra Málaga- E Gomez-Gracia Barcelona-1- R Estruch Vitoria- F Aros Barcelona-2- MI Covas Las Palmas- L Serra-Majem Barcelona-3- X Pinto 7 LAB-ONLY GROUPS Barcelona-1- E Ros Sevilla- V Ruiz-Gutierrez Barcelona-2- RM Lamuela-Raventos Navarra- JA Martinez Valencia- G Saez Barcelona-3- MT Mitjavila Mallorca- JA Tur Vitoria- MP Portillo

16. www.unav.es/preventiva DOG Funded by consortium (ciberobn) 5 RECRUITMENT GROUPS Navarra- MA Martinez-Gonzalez Valencia- D Corella Reus- J Salas-Salvado Mallorca- M Fiol Sevilla- J Lapetra Málaga- E Gomez-Gracia Barcelona-1- R Estruch Vitoria- F Aros Barcelona-2- MI Covas Las Palmas- L Serra-Majem Barcelona-3- X Pinto 1 LAB-ONLY GROUP Barcelona-1- E Ros Sevilla- V Ruiz-Gutierrez Barcelona-2- RM Lamuela-Raventos Navarra- JA Martinez Valencia- G Saez Barcelona-3- MT Mitjavila Mallorca- JA Tur Vitoria- MP Portillo

17. www.unav.es/preventiva DOG Food industry: only food items Provision of Olive oil ~2 000 l/wk Provision of nuts 30 kg/wk walnuts 15 kg/wk almonds

18. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

19.  Men: 55-80 yr  Women: 60-80 yr  High CV risk w ithout CVD type 2 diabetics 3+ risk factors PREDIMED TRIAL: DESIGN Random 1.Smoking 2.Hypertension 3. LDL 4. HDL 5.Overweight/obes 6.Family history

20. www.unav.es/preventiva DOG PREDIMED Participants 11 RECRUITMENT GROUPS Navarra- MA Martinez-Gonzalez Valencia- D Corella Reus- J Salas-Salvado Mallorca- M Fiol Málaga- E Gomez-Gracia Barcelona-1- R Estruch Sevilla- J Lapetra Vitoria- F Aros Barcelona-2- MI Covas Las Palmas- L Serra-Majem Barcelona-3- X Pinto

21. www.unav.es/preventiva DOG Project Leader: Dr. Ramón Estruch

22. www.unav.es/preventiva DOG PREDIMED Participants Mediet + VOO (n= 2487) MeDiet + Nuts (n=2396) Control (n=2349) Age (SD)67 (6) Women (%)575458 Diabetes (%)504748 Hypertension (%)82 84 Current smokers (%) 141514 High cholest. (%)727372 BMI (SD)30 (4) Waist (SD)100 (10) 101 (11) MeDiet 0-14 p (SD)8.7 (2) 8.3 (2)

23. www.unav.es/preventiva DOG PREDIMED: primary end-point Either: cardiovascular death myocardial infarction stroke

24. www.unav.es/preventiva DOG PREDIMED: Secondary end-points total mortality heart failure major cancers diabetes dementia We will also ascertain intermediate outcomes: blood pressure (BP) fasting blood glucose lipid profile markers of inflammation other markers of CVD

25. www.unav.es/preventiva DOG PREDIMED: intervention Introduce changes in the overall food pattern Mediterranean diet: 2 groups  Total Fat: ad libitum  High in MUFA (virgin olive oil) Fish Fruits, vegetables, legumes  Low in meats & dairy  alcohol permitted: wine Low-fat diet - Control  Reduce every fat  Increase CHO No Energy limitation tocopherols polyphenols flavonoids phytosterols

26. www.unav.es/preventiva DOG 14-point score 1.Olive oil main culinary fat8. Wine >=3 glasses/wk 2.Olive oil >=4 tablespoons/d 9. Legumes >=3/wk 3.Vegs>=2 serv./d10. Fish & seafood >=3/wk 4.Fruits>=3 serv./d11. Cakes, sweets <3/wk 5.Red meats =1/wk 6.Butter, marg, cream red meats 7.Soda drinks<1/d14. Sofrito Ann Intern Med 2006;145:1-11 Appendix, table 1 (on-line)

27. www.unav.es/preventiva DOG 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

28. www.unav.es/preventiva DOG Strategies for behavior change-2 Additional strategies Seasonal buying lists Menus and recipes Only in the 2 MeDiet groups  Provision of key food items for free

29. www.unav.es/preventiva DOG Special emphasis Negotiated goal setting  Contracted agreement  Understandable: units=servings Options for the negotiation  Serving size  Frequency of consumption  Way of cooking

30. www.unav.es/preventiva DOG Group sessions

31. www.unav.es/preventiva DOG Year% of recruitment Cum. % 2003 99 2004 2130 2005 2858 2006 1169 2007 1382 2008 1799 2009 1100 Total100 Projected follow-up = 6 years (median)

32. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

33. www.unav.es/preventiva DOG 3-mo changes Ann Intern Med 2006;145:1-11

34. www.unav.es/preventiva DOG 772 participants (55-80 yr) Randomization: 257 to a MeDiet + ( free provision of olive oil) 258 to a MeDiet + ( free provision of nuts) 257 to a LFD (control group) Follow-up: 3 months Nutrient profile and food items consumption Mediterranean score (14-point score) Classical risk factors Novel risk factors (CRP, IL6, VCAM, ICAM) 3-mo changes in RF

35. www.unav.es/preventiva DOG 3-mo changes in RF

36. www.unav.es/preventiva DOG 3-mo changes in diet

37. www.unav.es/preventiva DOG 3-mo changes

38. www.unav.es/preventiva DOG p<0.001 p=0.001 p=0.048 p=0.006 p<0.001 3-mo changes in Risk Factors

39. www.unav.es/preventiva DOG p=0.022p=0.039 p=0.017 p<0.001 3-mo changes in Risk Factors

40. www.unav.es/preventiva DOG p=0.002 p<0.001 p=0.84 p=0.37 p<0.001 3-mo changes in Risk Factors

41. www.unav.es/preventiva DOG 3-mo changes in Risk Factors

42. www.unav.es/preventiva DOG 3-mo changes in Risk Factors

43. www.unav.es/preventiva DOG 3-mo changes in Risk Factors

44. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

45. www.unav.es/preventiva DOG Salas-Salvado et al, Eur J Clin Nutr 2008;62:651-9

46. www.unav.es/preventiva DOG 339 men and 433 women (55-80 yr) Exposure: Food groups (137-item FFQ) MeDiet adherence (14-point score) Outcomes: hs-C Reactive protein interleukin-6 (IL-6) intracellular adhesion molecule-1 (ICAM-1) vascular cell adhesion molecule-1 (VCAM-1) Salas-Salvado et al, Eur J Clin Nutr 2008;62:651-9

47. www.unav.es/preventiva DOG Change (p value*) CRPIL6 VCAM1ICAM1 Cereals  (0.005) Fruits  (0.008) Nuts  (0.003) Virgin Olive Oil  (0.02) MeDiet**  (0.14)  (0.49)  (0.09) *Adjusted for age, gender, diabetes, smoking, BMI, educational level, use of statins, NSAID, and aspirin. **Test for linear trend (multivariate adjusted) Salas-Salvado et al, Eur J Clin Nutr 2008;62:651-9

48. www.unav.es/preventiva DOG 3.51 3.18 3.59 0 1 2 3 4 5 6 7 8 <77 to 10>10 MeDiet score (0-14) IL-6 (pg/ml) CRP (mg/l) Salas-Salvado et al, Eur J Clin Nutr 2008;62:651-9

49. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oMeDiet & inflammatory markers ( Eur J Clin Nutr 2007 ) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

50. 3204 participants Exposure: MeDiet (14-point score) Adherence: Above Median (9) in the score Ordered categories (5) in the score Outcomes: Diabetes Hypertension Obesity Hypercholesterolemia All of them together Sánchez-Tainta, et al. Eur J Cardiovasc Prev Rehabil. 2008;15:589-93.

51. www.unav.es/preventiva DOG Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), educational level (4 categories), and BMI (3 categories, except when using obesity as outcome). MeDiet (>Median) and prevalence of Risk Factors Sánchez-Tainta, et al. Eur J Cardiovasc Prev Rehabil. 2008;15:589-93.

52. www.unav.es/preventiva DOG Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), educational level (4 categories), and BMI (3 categories). Adherence to MeDiet and prevalence of diabetes

53. www.unav.es/preventiva DOG Adjusted for age, gender, leisure-time physical activity (tertiles), smoking (5 categories), marital status (4 categories), and educational level (4 categories). p<0.001 for linear trend Adherence to MeDiet & prevalence of all 4 RF Sánchez-Tainta, et al. Eur J Cardiovasc Prev Rehabil. 2008;15:589-93.

54. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

55. Fitó for the PREDIMED group. Arch Inter Med 2007;167:1195-1203. n = 372 Mediet+VOO=123 Mediet+nuts=128control=121

56. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

57. www.unav.es/preventiva DOG Zazpe et al for the PREDIMED group, J Am Diet Assoc 2008;108:1134-44 1-yr changes in diet

58. www.unav.es/preventiva DOG 1-yr changes in diet n= 1551 in 3 groups: MeDiet +VOO: 533 MeDiet +Nuts: 533 Control: 485 Assessment of changes from baseline

59. Baseline characteristics of the 3 randomized groups

61. www.unav.es/preventiva DOG 1-yr within-group changes in VIRGIN OLIVE OIL (VOO) consumption * *

62. www.unav.es/preventiva DOG 1-yr within-group changes in REFINED OLIVE OIL consumption * *

63. www.unav.es/preventiva DOG 1-yr within-group changes TOTAL NUTS * *

64. www.unav.es/preventiva DOG 1-yr within-group changes VEGETABLES * *

65. www.unav.es/preventiva DOG 1-yr within-group changes FRUITS * * *

66. www.unav.es/preventiva DOG 1-yr within-group changes CEREALS * * Between-group: non-significant

67. www.unav.es/preventiva DOG 1-yr within-group changes LEGUMES * *

68. www.unav.es/preventiva DOG 1-yr within-group changes FISH / SEAFOOD Between-group: non-significant

69. www.unav.es/preventiva DOG 1-yr within-group changes MEAT / MEAT PRODUCTS * ** Between-group: non-significant

70. www.unav.es/preventiva DOG 1-yr within-group changes DAIRY Between-group: non-significant

71. www.unav.es/preventiva DOG 1-yr within-group changes ALCOHOL * * * Between-group: non-significant

72. www.unav.es/preventiva DOG 1-yr within-group changes 14-unit Score * * *

73. www.unav.es/preventiva DOG Baseline vs. 1-yr 14-unit Score

74. www.unav.es/preventiva DOG 1-yr within-group changes Nutrient profile * * * * * *

75. www.unav.es/preventiva DOG

76. www.unav.es/preventiva DOG 1-yr within-group changes Types of Fat * * ** ** * Between-group: non-significant for SFA

77. www.unav.es/preventiva DOG Urine tyrosol (μg/L): baseline vs. 1-yr

78. www.unav.es/preventiva DOG Plasma alpha-linolenic acid (%): baseline vs. 1-yr

79. www.unav.es/preventiva DOG Intervention vs. control  Significant between-group changes in food groups VOO & nuts (+) Vegetables (+) Fruits (+) Legumes (+) 14-unit MeDiet score (+)  Significant between-group changes in nutrient intake Energy (+) Carbohydrates (-) Fiber (+) Total fat (+) MUFA, MUFA/SFA (+) PUFA (+) alpha-Linolenic acid (+) Marine n-3 fatty acids (+)

80. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

81. www.unav.es/preventiva DOG  1224 participants 409 VOO 411 Nuts 404 Control  Changes in the prevalence of MetS ATP-III: 3 out of five  Waist  TG  HDL  Glucose  BP

82. www.unav.es/preventiva DOG

84. www.unav.es/preventiva DOG Rationale Funding sources Methods and intervention protocol Pilot study: Risk Factors at 3-mo (Ann Intern Med 2006) Cross-sectional assessments: oDiet & inflammatory markers (Eur J Clin Nutr 2007) oMeDiet & risk factors (Eur J CV Prev 2008) 3-mo changes in oxLDL (Arch Intern Med 2008) 1-yr changes in diet (J Am Diet Assoc 2008) 1-yr changes in MetS (Arch Intern Med 2008) Other nested sub-studies PREDIMED TRIAL

85. www.unav.es/preventiva DOG Main trial 1 2 3 4 5 6 7... n Nested substudies

86. www.unav.es/preventiva DOG

87. www.unav.es/preventiva www. predimed.es

88. www.unav.es/preventiva DOG Thank you very much

89. www.unav.es/preventiva DOG

90. www.unav.es/preventiva DOG de reserva

91. www.unav.es/preventiva DOG Effects of Mediterranean diet on the primary prevention of cardiovascular disease http://www.controlled-trials.com/ISRCTN35739639

92. www.unav.es/preventiva DOG Effects of Mediterranean diet on the primary prevention of cardiovascular disease http://www.controlled-trials.com/ISRCTN35739639

93. www.unav.es/preventiva DOG Effects of Mediterranean diet on the primary prevention of cardiovascular disease http://www.controlled-trials.com/ISRCTN35739639

94. www.unav.es/preventiva DOG Dietary changes at 1-yr & 2-yr follow-up NutrientMD+VOOMD+nutsControl Prot 1yr 2 yr -0.1 -0.6* -0.3* -0.5* +0.1 +0.3 CHO 1yr 2 yr -1.3* -1.4* -2.1* -0.7* +1.0* +2.5* Fat 1yr 2 yr +1.8* +2,6* +2.7* +1,5* -1.0* -2,5* SFA 1yr 2 yr -0.6* -0,6* -0.7* -0,8* -0.4* -1,0*

95. www.unav.es/preventiva DOG Dietary changes at 1-yr & 2-yr follow-up NutrientMD+VOOMD+nutsControl MUFA 1yr 2 yr +2.1* +2.5* +1.6* +1.8* -0.3 -1.0* PUFA 1yr 2 yr +0.2 +0.7* +1.8 +0.7* -0.3* -0.4* Fibre1yr 2 yr +2.2* +2.9* +3.1* +3.3* -0.5 MD1yr 14p2 yr +1.9* +2.4* +2.3* +2.2* +0.5* +0.8*

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103. www.unav.es/preventiva DOG  The data from the PREDIMED trial will be analyzed at 5 intervals (4 interim analyses and the final analysis).  The 4 interim analyses to decide on the continuation of the PREDIMED trial will be conducted after 2, 3, 4 and 5 years of median follow-up.  The 2-sided p-values for stopping the trial at each interim analysis are YrBenefitHarm 25*10-69*10-5 30.0010.005 40.0090.02 5 0.05 Apr 08 Jun 09 Jul 10 Jun 11