1. DREAM D iabetes RE duction A ssessment with ramipril and rosiglitazone M edication

2. DREAM 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. DREAM 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. DREAM RAS Blockade & New Diabetes (Diabetes - Not Primary Outcome) StudyN (no DM)ActiveControlRRR ACE Inhibitors HOPE5720Ramipril 10 ODPlacebo34% PEACE6174TrandolaprilPlacebo17% EUROPA10716Perindopril 8 mgPlacebo3% D-SOLVD291EnalaprilPlacebo74% Angiotensin Receptor Blockers SCOPE4368Candesartan 16/dPlacebo20% CHARM5436Candesartan 4-32/dPlacebo24% Overall Effect (HOPE, EUROPA, PEACE): 0.86 (0.78-0.95) Dagenais et al. Lancet 2006;368:581

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

8. DREAM 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 The DREAM Trial

9. DREAM 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 The DREAM Trial

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

11. DREAM Baseline Characteristics OverallRamiPlacRosiPlac N5269 2623264626352634 Age54.7 54.654.8 Females59.2% 59.758.758.360.1 IIGT (%)57.5% 57.757.357.157.9 IIFG (%)14.0% 14.014.114.0 IGT + IFG (%)28.5% 28.428.628.928.1 Hypertension43.5% 43.343.744.043.0 Smoking44.6% 44.245.143.945.3 Sedentary26.8% 27.126.526.427.2

12. DREAM Baseline Characteristics (Mean) OverallRamiPlacRosiPlac N5269 2623264626352634 SBP/DBP (mm Hg)136/83 136/84 BMI (kg/m 2 )30.9 30.831.0 Weight (kg)84.9 84.885.084.885.0 Waist/Hip (M)0.96 Waist/Hip (F)0.87 0.860.870.860.87 FPG (mM)5.8 5.835.84 5.83 2 Hr PG (mM)8.7 8.668.718.688.67

13. DREAM Results of the Ramipril Arm

14. DREAM Adherence/Adverse Effects RamiprilPlacebo On Study Drug at 1 year86.6%89.9% at 2 years81.3%84.8% at 3 years75.4%80.9% Reasons for Stopping Study Drug Participant Refusal17.4%17.7% MD advice2.3%2.5% Cough9.7%1.8% Hypotension0.8 %0.4%

15. DREAM Ramipril’s Effect on Blood Pressure Mean FinalRamiprilPlaceboP Systolic BP128.3 (17.3)132.3 (17.2)<0.0001 Diastolic BP78.0 (10.8)80.3 (10.4)<0.0001 Systolic BP Diastolic BP Ramipril Placebo Base 2 6 12 24 36 48 Final Months

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

17. DREAM Ramipril Placebo WeightBody Mass Index Ramipril’s Effect on Weight Change/yr (Slope)RamiprilPlacebo Weight (kg)0.22 (2.64)0.36 (2.61) BMI (kg/m 2 )0.09 (0.96)0.14 (0.91) Ramipril Placebo P = 0.07 P = 0.06

18. DREAM Ramipril: Primary Outcome Ramipril N=2623 Placebo N=2646 HR (95% CI)P Primary Composite 475 (18.1)517 (19.5)0.91 (0.81-1.03)0.15 Diabetes 449 (17.1)489 (18.5)0.91 (0.80-1.03)0.15 Dx by FPG/OGTT 375 (14.3)411 (15.5)0.91 (0.79-1.04)0.17 MD Diagnosed 74 (2.8)78 (3.0)0.95 (0.69-1.30)0.75 Death 31 (1.2)32 (1.2)0.98 (0.60-1.60)0.93

19. Placebo2646251022771240200 Ramipril2623249822871218194 Primary Outcome: Ramipril DREAM Ramipril Placebo Year HR 0.91 (CI 0.81-1.03); P=0.15

20. Ramipril Subgroups: Primary Outcome HR (95% CI) IFG + IGT IIGT IIFG Age < 50 Age 50-59 Age 60+ WHR <0.81 WHR 0.81-.94 WHR 0.95+ BMI < 28 kg/m 2 BMI 28-32kg/m 2 BMI 33+kg/m 2 SBP < 140 SBP > 140 P Heterogeneity 0.80 0.72 0.11 0.22

21. DREAM Regression: Ramipril Cumulative Hazard 0 1 2 3 4 Ramipril262324872060 791 127 Placebo264624942090 876 145 HR 1.16 (1.07-1.27); P=0.001 Placebo Ramipril

22. DREAM 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. DREAM Ramipril & Median Glucose Median FinalRamiprilPlacebo Fasting PG (mmol/L)5.705.74 2 Hr PG (mmol/L)7.507.80 Fasting PG (mM)2 Hour PG (mM) Ramipril Placebo Ramipril Placebo P = 0.07P = 0.01

24. DREAM Cumulative Hazard Cardiovascular Composite: Ramipril Placebo2646261525711485271 Ramipril26232577254414853253 HR 1.08 (CI 0.76-1.52); P=0.7 - - - -Placebo Ramipril Year

25. DREAM 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 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: a)may have had a less activated RAS b)controls were less likely on drugs that raise glucose c)there was low power to detect differences in CVD events (short duration, low risk participants)

27. DREAM 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. DREAM Adherence/Adverse Effects RosiglitazonePlacebo On Study Drug at 1 year88.4%91.3% at 2 years83.7%87.7% at 3 years79.5%84.0% Reasons for Stopping Study Drug Participant Refusal19.1%16.7% Edema4.8%1.6% MD advice1.9%1.5% Weight Gain1.9%0.6%

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

31. Rosiglitazone’s Effect on BP Systolic BP Diastolic BP Rosiglit Placebo Mean FinalRosiglitazonePlaceboP Systolic BP (mm)129.4 (17.0)131.1 (17.5)0.0001 Diastolic BP (mm)78.4 (10.7)79.8 (10.5)<0.0001 Base 2 6 12 24 36 48 Final P=0.0001 P<0.0001

32. DREAM Rosiglitazone Placebo Weight (Kg) BMI (Kg/m 2 ) Rosiglitazone & Weight, BMI Change/yr (Slope)RosiglitazonePlacebo Weight (kg)0.67(2.77)-0.09 (2.41) BMI (kg/m 2 )0.25 (1.01)-0.01 (0.84) Rosiglitazone Placebo P < 0.0001

33. DREAM P<0.0001 P=NS Hip (cm) Waist (cm) Change/Yr (Slope)RosiglitazonePlaceboP Waist / Hip-0.00002 (0.03)0.004 (0.04)<0.0001 Waist0.70 (3.49)0.60 (3.91)0.4 Hip0.84 (3.46)0.17 (3.01)<0.0001 Rosiglitazone & Waist, Hip Waist / Hip

34. DREAM Rosiglitazone & Primary Outcome Rosi N=2635 Placebo N=2634 HR (95% CI)P Primary Composite 306 (11.6)686 (26.0)0.40 (0.35-0.46)<0.0001 Diabetes 280 (10.6)658 (25.0)0.38 (0.33-0.44)<0.0001 Dx by FPG/OGTT 231 (8.8)555 (21.1)0.38 (0.33-0.44)<0.0001 MD Diagnosed 49 (1.9)103 (3.9)0.47 (0.33-0.66)<0.0001 Death 30 (1.1)33 (1.3)0.91 (0.55-1.49)0.70

35. DREAM Primary Outcome: Rosiglitazone HR = 0.40 (0.35-0.46); P<0.0001 Year Rosiglitazone Placebo 2634247021501148177 Rosiglita2635253824141310217

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

37. DREAM Rosiglitazone & Median Glucose Median FinalRosiglitazonePlaceboP Fasting PG (mmol/L)5.56.0<0.0001 2 Hr PG (mmol/L)6.98.5<0.0001 Fasting PG (mM)2 Hour PG (mM) Rosiglitazone Placebo Rosiglitazone Placebo

38. Favours Rosiglitazone Favours Placebo Male Female Age < 50 Age 50-59 Age 60+ N. America S. America Europe India Australia IIFG IIGT IFG + IGT 0.14 0.09 0.6 0.09 P (Heterogeneity)Overall Rosiglitazone Subgroups: Primary

39. Weight <75 kg Weight 75-91 kg Weight 92+ Kg BMI < 28 kg/m 2 BMI 28-32kg/m 2 BMI 33+kg/m 2 WHR <0.81 WHR 0.81-.94 WHR 0.95+ Waist < 91.5 cm Waist 91.5-103 Waist 104+ cm Hip < 103 cm Hip 103-112 cm Hip 113+ cm PlaceboRosiglitazone (%/yr) 6.43.8 8.23.8 10.83.8 6.54.2 8.63.3 10.23.7 6.23.7 9.13.7 10.44.0 6.13.9 8.73.9 10.83.6 7.24.1 8.73.4 9.73.9 0.03 0.0002 0.009 0.0004 0.002 Rosiglitazone Subgroups: Primary P (Heterogeneity)Overall Favours Rosiglitazone Favours Placebo

40. DREAM Cardiovascular Outcomes: Rosiglitazone LOG HR (95% CI) 14 (0.5%) vs. 2 (0.1%); P=0.01 Composite MI Stroke CV Death CHF New Angina Revascularized HR 1.37 (0.97-1.94): P=0.08

41. DREAM 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. DREAM 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 Summary & Conclusions: Rosiglitazone

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