1. Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial

2. Worldwide prevalence of diabetes expected to increase Diabetes prevalence >171 million in 2000 ~366 million in 2030 World Health Organization, 2000 vs 2030 World Health Organization. www.who.org. 33 15 33 47 36 18 67 42 48 120 71 7 0 20 40 60 80 100 120 140 AfricaAmericasE MeditEuropeSE Asia W Pacific Diabetes prevalence (in millions) 2000 2030  102%  160%  181%  44%  155%  99%

3. DECODE: IGT increases mortality risk Diagnosed diabetes (n = 1275) Undiagnosed diabetes (n = 3071) Impaired glucose tolerance (n = 2766)* Normal glucose tolerance (n = 18,252)* Follow-up (years) Mortality hazard (%) DECODE Study Group. Lancet. 1999;354:617-21. *2-hour oral glucose tolerance test (OGTT) IGT = impaired glucose tolerance Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe N = 25,364 aged ≥30 years 20 10 0 02468

4. DPP: Benefit of diet + exercise or metformin on diabetes prevention in at-risk patients Diabetes Prevention Program (DPP) Research Group. N Engl J Med. 2002;346:393-403. Years N = 3234 with IFG/IGT without diabetes 0 0 10 20 30 40 1.02.03.04.0 Placebo Metformin Lifestyle Cumulative incidence of diabetes (%)  31%  58% P* < 0.001 *vs placebo IFG = impaired fasting glucose

5. TZDs: Focus on PPAR  activation Reduces insulin resistance Preserves pancreatic β-cell function Improves CV risk profile –Improves dyslipidemia (  HDL,  LDL density,  or  TG) –  Renal microalbumin excretion –  Blood pressure –  VSMC proliferation/migration in arterial wall –  PAI-1 levels –  C-reactive protein levels –  Adiponectin –  Free fatty acids Inzucchi SE. JAMA. 2002;287.360-72.

6. TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes TRoglitazone In Prevention Of Diabetes n = 236 Hispanic women with gestational diabetes 60 40 20 0 New-onset diabetes (%) Follow-up (months) 01224364860 Buchanan TA et al. Diabetes. 2002;51:2796-803. Placebo Troglitazone 400 mg 12.1% 5.4% Annual incidence 55% RRR HR 0.45 (0.25–0.83)* P = 0.009 *Unadjusted

7. 0 TZDs blunt diabetes progression DPP Research Group. Diabetes. 2005;54:1150-6. *Withdrawn from study after 1.5 yr Diabetes Prevention Program 10 15 5 1.5 Cumulative incidence of diabetes (%) Years 1.00.50 Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* 237 739 1568 2343n =  75% vs placebo P < 0.001

8. Potential antidiabetic mechanisms of ACE inhibition Henriksen EJ et al. J Cell Physiol. 2003;196:171-9. ACE/ Kininase II ACE Inhibitor Angiotension I Angiotension II Bradykinin Degradation products  Bradykinin  Angiotension II  Nitric oxide  Skeletal muscle blood flow  Glucose metabolism

9. HOPE, EUROPA, PEACE: Reduction in new-onset diabetes Dagenais GR et al. Lancet. 2006;368:581-8. N = 23,340 free from diabetes at baseline Ramipril 10 mg Perindopril 8 mg Trandolapril 4 mg 14% RRR RR 0.86 (0.78–0.95) P = 0.0023 (all trials)

10. Primary outcome: Diabetes or death from any cause DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. DREAM: Study design Secondary outcomes I: CV events Combined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomes II: Renal events Progression to micro- or macroalbuminuria, or  30% CrCl Ramipril 15 mg/d vs placebo AND Rosiglitazone 8 mg/d vs placebo Randomized, double-blind 2 × 2 factorial design N = 5269 with IFG and/or IGT, free from CV disease Follow-up: 3–5 years

11. Ramipril + Rosiglitazone DREAM: 2 x 2 factorial design DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. N = 5269 with IFG and/or IGT Ramipril RosiglitazonePlacebo Ramipril + Placebo Placebo Rosiglitazone + Placebo Placebo + Placebo

12. DREAM: Baseline characteristics Age (years)54.7 (±10.9) Hypertension (%)43.5 Hyperlipidemia (%)35.5 BP (mm Hg)136/83 (±18.6/11.3) BMI (kg/m 2 )30.5 kg/m 2 (±5.1) Waist circumference (inches) Men34.3 (±10.8) Women32.6 (±11.9) Glucose (mg/dL) FPG104 (±12.6) 2-hour157 (±25.2) DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

13. DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death No. at risk Placebo Rosiglitazone DREAM Trial Investigators. Lancet. 2006. 2634 2635 2470 2538 2150 2414 1148 1310 177 217 0.6 0.5 01234 Follow-up (years) 0.4 0.3 0.2 0.1 0.0 Rosiglitazone Placebo 60% RRR HR 0.40 (0.35–0.46) P < 0.0001 Cumulative hazard rate

14. DREAM: Rosiglitazone decreases new-onset diabetes or death Rosiglitazone group (n) (%) Placebo group (n) (%) Primary outcome composite306 (11.6%)686 (26.0%) Diabetes*280 (10.6%)658 (25.0%) Death*30 (1.1%)33 (1.3%) 0.2511.75 P <0.0001 0.70 <0.0001 DREAM Trial Investigators. Lancet. 2006. N = 5269 *Participants may appear in both categories Hazard ratio Favors rosiglitazone Favors placebo

15. DREAM: Regression to normoglycemia with rosiglitazone *FPG < 110 mg/dL DREAM Trial Investigators. Lancet. 2006. 71% increase HR 1.71 (1.57  1.87) P < 0.0001 N = 5269

16. Rosiglitazone effect on weight and BMI 200 196 191 187 182 0 32 31 30 0 001122334455 Follow-up (years) lbskg/m 2 WeightBMI DREAM Trial Investigators. Lancet. 2006. RosiglitazonePlacebo P < 0.0001

17. 0.94 0.92 0.90 0.88 0 115 107 99 0 001122334455 cm WHRCircumference Rosiglitazone effect on waist and hip measurements 111 103 95 P < 0.0001 P = NS P < 0.0001 Waist Hip Follow-up (years) DREAM Trial Investigators. Lancet. 2006. WHR = Waist-hip ratio RosiglitazonePlacebo

18. Rosiglitazone Placebo Follow-up (months) ALT (U/L) P <0.0001 Effect on ALT 0 24 26 28 30 Baseline24681012 DREAM: Rosiglitazone and hepatic enzymes DREAM Trial Investigators. Lancet. 2006. ALT = alanine aminotransferase

19. DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death DREAM Trial Investigators. N Engl J Med. 2006. Placebo Ramipril No. at risk Placebo Ramipril Follow-up (years) 0.6 0.5 0.4 0.3 0.2 0.1 0.0 01234 2646 2623 2510 2498 2277 2287 1240 1218 200 194 9% RRR HR 0.91 (0.81–1.03) P = 0.15 Cumulative hazard rate

20. DREAM: Ramipril effect on glycemic categories P = 0.006 DREAM Trial Investigators. N Engl J Med. 2006.

21. DREAM: Safety Rosiglitazone vs placebo Increased incidence of HF* (0.5% vs 0.1%, P = 0.01) –No cases of fatal HF –No difference for other CV events Increased incidence of peripheral edema (6.8% vs 4.9%, P = 0.003) 4.9-lb weight gain (P < 0.0001) –Increased hip circumference (  0.71 in, P < 0.0001) –No difference in waist circumference –Decreased waist-hip ratio (P < 0.0001) No adverse hepatic effects –ALT levels  4.2 U/L at 1 year (P < 0.0001) Ramipril vs placebo Increased incidence of confirmed HF* (0.5% vs 0.2%) No adverse hepatic effects –ALT levels  1.1 U/L at 1 year (P = 0.004) DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006. *Adjudicated

22. DREAM results: Summary Rosiglitazone 60% RRR in new-onset diabetes or death (P < 0.001) NNT = 7 Benefit observed regardless of ethnicity, sex, age, weight, and fat distribution Increased regression to normoglycemia* vs placebo (50.5% vs 30.3%) (HR 1.71, P < 0.0001) Ramipril 9% RRR in new-onset diabetes or death (nonsignificant) Increased regression to normoglycemia* vs placebo (42.6% vs 38.2%) (HR 1.16, P = 0.001) DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006. *FPG < 110 mg/dL and 2-h glucose < 141 mg/dL