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DREAM
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  1. DREAM Diabetes REduction Assessment with ramipril and rosiglitazone Medication

  2. Prevention of Type 2 Diabetes • Clinical trials have shown that diet & exercise can prevent diabetes by > 50% in people with impaired glucose tolerance (IGT) • Clinical trials have also shown that drugs (e.g. metformin, acarbose) can prevent diabetes to a lesser extent in people with IGT • Growing evidence suggests that • ACE inhibitors may prevent diabetes • Thiazolidinediones may prevent diabetes

  3. Properties of ACE-Inhibitors • Inhibition of the Renin-Angiotensin system with ACE inhibitors: • Lowers BP • Reduces mortality, MI & strokes in people with • Heart failure • Previous CV events without heart failure • Diabetes plus other CV risk factors • The HOPE trial suggested that the ACE-I ramipril may also reduce DM

  4. RAS Blockade & New Diabetes(Diabetes - Not PrimaryOutcome) Overall Effect (HOPE, EUROPA, PEACE): 0.86 (0.78-0.95) Dagenais et al. Lancet 2006;368:581

  5. Do ACE-Inhibitors Prevent Diabetes? Limitations of Previous Reports • Glucose tolerance tests not done at baseline or end… may have missed prevalent diabetes at baseline & new DM on follow-up  no ability to detect regression • Different definitions of new DM were used • Participants were of high cardiovascular risk & intermediate diabetes risk (e.g. DM rate ~ 2%/year) • DM prevention was not the primary outcome

  6. Properties of Thiazolidinediones (TZDs) • Binds to PPAR gamma receptors • Increases insulin sensitivity • Reduces lipolysis • Increases preadipocytesadipocytes (SC fat) • Possible beta cell protection • Reduces glucose levels if elevated

  7. Troglitazone & New Diabetes Placebo Metformin Trog Lifestyle Placebo Troglitazone Median=30 mo; N (Trog)=133 HR = 0.45 (95%CI 0.25-0.83) Median=0.9 yrs; N (Trog)=585 HR = 0.25 (95%CI 0.14-0.43) DPP. Diabetes 2005; 1150 Buchanan et al. Diabetes 2002: 2796

  8. The DREAM Trial Aims: Does ramipril 15 mg/d prevent diabetes? Does rosiglitazone 8 mg/d prevent diabetes? Design: 2 X 2 factorial, double-blind RCT Sample: Age 30+; IGT (FPG <7 & 2 hr 7.8-11) &/or IFG (FPG 6.1-6.9) Pts: 5269 in 191 sites, 21 countries, & F/U 3 yrs Outcome: Incident DM (confirmed FPG > 7 or 2 hr > 11.1; or MD diagnosis) or death* *because undiagnosed diabetes may be more frequent in those who die than in those who do not

  9. The DREAM Trial Independent Coordination, Data Management & Analysis Population Health Research Institute McMaster University & Hamilton Health Sciences Hamilton, Ontario, Canada FundingCanadian Institutes of Health Research Sanofi-Aventis King Pharmaceuticals GlaxoSmithKline

  10. Screening & Randomization Screened 24592 Excluded: 18784 Run-in 5808 Excluded: 539 Randomized 5269 Glucose or Primary Outcome Status in 94% at study end Vital Status in 98%

  11. Baseline Characteristics

  12. Baseline Characteristics (Mean)

  13. DREAM Results of the Ramipril Arm

  14. Adherence/Adverse Effects

  15. Ramipril’s Effect on Blood Pressure Systolic BP Placebo Ramipril Diastolic BP Base 2 6 12 24 36 48 Final Months

  16. Ramipril’s Effect on ALT Placebo ALT (U/l) Ramipril P = 0.04

  17. Ramipril’s Effect on Weight Weight Body Mass Index Placebo Placebo Ramipril Ramipril P = 0.07 P = 0.06

  18. Ramipril: Primary Outcome

  19. DREAM Primary Outcome: Ramipril HR 0.91 (CI 0.81-1.03); P=0.15 Placebo Ramipril Year

  20. Ramipril Subgroups: Primary Outcome P Heterogeneity 0.80 0.11 0.72 0.80 0.22 HR (95% CI)

  21. Regression: Ramipril HR 1.16 (1.07-1.27); P=0.001 Cumulative Hazard Ramipril Placebo 0 1 2 3 4

  22. Effect on Glucose Category: Ramipril HR = 1.16; P = 0.001 HR = 1.17; P = 0.002 HR = 0.91; P = 0.15 (ADA Cutoff)

  23. Ramipril & Median Glucose Fasting PG (mM) 2 Hour PG (mM) P = 0.07 P = 0.01 Placebo Placebo Ramipril Ramipril

  24. Cardiovascular Composite: Ramipril HR 1.08 (CI 0.76-1.52); P=0.7 Cumulative Hazard • - - - Placebo • Ramipril Year

  25. Summary & Conclusions: Ramipril • Modestly improves glycemic status in IFG/IGT • A nonsignificant 9% DM reduction • Significant 16% increase in regression to normal glucose levels by at least 2 yrs • Reduced 2 hr glucose by 0.3 mM by study end • Significantly reduces BP in IGT / IFG • Small, favourable effect on liver function

  26. DREAM vs. Previous Trials • Diabetes was the primary outcome in DREAM • People with undiagnosed diabetes were excluded • Regression was a predefined secondary outcome • People were low vs. high CV risk so: • may have had a less activated RAS • controls were less likely on drugs that raise glucose • there was low power to detect differences in CVD events (short duration, low risk participants)

  27. Summary & Conclusions: Ramipril • The DREAM results provide the best estimate of the effect of ACE-Is on diabetes prevention in people with IFG / IGT & no previous CV disease • Ramipril cannot currently be recommended for DM prevention • However, in people in whom there is an indication for ACE inhibitors (high BP, CHF, vascular disease, high risk DM) the favourable effects on glucose may be of added benefit

  28. DREAM Results of the Rosiglitazone Arm

  29. Adherence/Adverse Effects

  30. Rosiglitazone’s Effect on ALT Placebo ALT (U/l) P <0.0001 Rosiglitazone Months

  31. Rosiglitazone’s Effect on BP Systolic BP P=0.0001 Placebo Rosiglit P<0.0001 Diastolic BP Base 2 6 12 24 36 48 Final

  32. Rosiglitazone & Weight, BMI Weight (Kg) BMI (Kg/m2) Rosiglitazone Rosiglitazone Placebo Placebo P < 0.0001 P < 0.0001

  33. Rosiglitazone & Waist, Hip Waist / Hip Hip (cm) P<0.0001 Waist (cm) P<0.0001 P=NS

  34. Rosiglitazone & Primary Outcome

  35. Primary Outcome: Rosiglitazone HR = 0.40 (0.35-0.46); P<0.0001 Placebo Rosiglitazone DREAM Year

  36. Effect on Glucose Category: Rosiglitazone HR 1.71; P < 0.0001 HR 1.83; P < 0.0001 HR 0.38; P < 0.0001

  37. Rosiglitazone & Median Glucose Fasting PG (mM) 2 Hour PG (mM) Placebo Placebo Rosiglitazone Rosiglitazone

  38. Rosiglitazone Subgroups: Primary Overall P (Heterogeneity) 0.6 0.09 0.09 0.14 Favours Rosiglitazone Favours Placebo

  39. Rosiglitazone Subgroups: Primary Overall P (Heterogeneity) 0.002 0.0004 0.009 0.0002 0.03 Favours Rosiglitazone Favours Placebo

  40. Cardiovascular Outcomes: Rosiglitazone HR 1.37 (0.97-1.94): P=0.08 14 (0.5%) vs. 2 (0.1%); P=0.01 LOG HR (95% CI)

  41. Summary & Conclusions: Rosiglitazone • A dose of 8 mg/day reduces new DM by > 60% in people with IGT or IFG • Promotes regression to normal FPG & 2 hr PG by >70% • Effective in all regions of the world • Eliminates the gradient of DM risk with increasing weight • ~ 3% increase in body weight, but a favourable effect on waist/hip ratio • Reduces ALT

  42. Summary & Conclusions: Rosiglitazone • Modestly lowers systolic BP & diastolic BP • Increases the risk of CHF • Too few events to draw any conclusions re the effect on other CV events or death For every 1000 people treated with rosiglitazone for ~ 3 years, 144 cases of DM will be prevented with an excess of ~ 4 cases of CHF

  43. Conclusions of the DREAM Trial • Rosiglitazone has a substantial benefit on prevention of diabetes & regression to normoglycaemia • Ramipril has a modest benefit on regression to normoglycaemia • The durability of the glycaemic effect of these drugs is being assessed in a washout phase DREAM Slides: www.phri.ca/dream 2 DREAM Papers:NEJM & Lancet - online

  44. DREAM TEAM International Leaders S. Anand A. Avezum A. Budaj J. Chiasson I. Conget G. Dagenais H.C. Gerstein S. Yusuf R. Holman J. Bosch F. Lanas E. Lonn M. McQueen V.Mohan A. Phillips L. Piegas V. Pirags J. Probstfield I. Schmid J. Shaw K. Teo P. Zimmet B. Zinman M. Davis R. Diaz N. Dinccag M. Enjalbert A. Escalante G. Fodor M. Hanefeld T. Hedner B. Hoogwerf K. Jolly M. Keltai M. Laakso Statisticians: P. Sheridan, J. Pogue D. Sackett; D. Altman; C. Clark; P. Bennett; R. Hamman; L. Ryden TMC: