1. ClinicalTrialsResults.org “DREAM Trial TZDS without ACE inhibitors” Jeffrey L. Probstfield, MD, FACP, FACC, FAHA, FESC Director, Clinical Trials Service Unit Professor of Medicine (Cardiology) University of Washington School of Medicine Adjunct Professor of Epidemiology University of Washington School of Public Health and Community Medicine

2. CDC. www.cdc.gov. Parallel epidemics of diabetes and obesity Diabetes Obesity (BMI ≥30 kg/m 2 ) <4%4%–4.9%5%–5.9%>6% 10%–14%15%–19%20%– 24%>25% 20041994

3. DO YOU SEE THE TSUNAMI HEADED TOWARD US? OBESITY, ATTENDENT DIABETES AND CHD/CVD

4. Numbers of People with Diabetes 2000-2030 Wild S et al: Diabetes Care 27:1047-1053; 2004 33.0 66.8 102% Numbers are millions 33.3 50.0 44% 15.2 35.9 136% 7.0 18.2 160% 46.9 119.5 155% 35.8 71.0 99% World 2000 = 171 million 2030 = 366 million Increase 114%

5. Fasting Plasma Glucose 100 mg/dL Normal 2-Hour PG on OGTT 140 mg/dL Impaired Fasting Glucose Impaired Glucose Tolerance Normal 126 mg/dL Diabetes Mellitus 200 mg/dL Diabetes Mellitus Glucose Tolerance Categories

6. Macrovascular disease risk Microvascular disease risk Natural History of T2DM and Risk for Complications DeFronzo R. Diabetes Care. 1992;15:318-368. Haffner S, et al. Diabetes Care. 1999;22:562-568. Haffner S, et al. N Engl J Med. 1998;339:229-234. American Diabetes Association. Diabetes Care. 2003;26:S33-S50. Meets ADA diagnostic criteria for T2DM Post-meal glucose Fasting glucose Time (years) PG 200 mg/dL PG 126 mg/dL Insulin Resistance Beta-cell Function

7. 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

8. 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.

9. 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 *Withdrawn from study after 1.5 yr Diabetes Prevention Program 10 15 5 1.5 Cumulative incidence of diabetes (%) Years 1.00.50 Placebo Metformin 850 mg bid Lifestyle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

10. 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

11. DREAM: Background and study objective Previous studies have shown evidence for  new-onset diabetes with RAAS and PPAR agonists Does treatment with ramipril and/or rosiglitazone prevent or delay the development of diabetes in persons with IGT or IFG and no diabetes? DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. Diabetes REduction Assessment with ramipril and rosiglitazone Medication

12. 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

13. 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

14. DREAM: Baseline glucose status Isolated IGT 1835 (35%) Isolated IFG* 739 (14%) IGT and IFG* 2692 (51%) FPG (mean) 104 2-hr plasma glucose (mean) 157 DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. *Based on 100 mg/dL threshold n mg/dL

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

16. 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.

17. 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%

18. 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

19. 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

20. 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

21. 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

22. Details of Heart Failure All cases centrally adjudicated No cases of fatal CHF Similar risk with/without ramipril Distributed throughout follow-up period Peripheral edema did not predict CHF Therapies given: Oral Loop Diuretics57% ACE-I24% IV Diuretics38% CPAP29% Other Diuretics38% Hospital81% Digoxin29%

23. Different Manifestations of Fluid Retention in TZD Users and Non-Users Pulmonary Edema Jugular Venous Distension AscitesPeripheral Edema 95% 80% 18% 63% 0 20 40 60 80 100 11% 32% 0% TZD (n=19) Non-TZD (n=80) % of Patients Tang WHW et al: J Am Coll Cardiol 41:1394-1398; 2003

24. 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

25. Independent Effects of Rami + Rosi HR Rosi + Rosi - Rosi + Rosi - Rami + Rami - Rami + Rami - Ramipril Rosiglitazone New Diabetes Regression Favours Rosiglitazone

26. 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

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

28. Independent Effects of Rami + Rosi HR Rosi + Rosi - Rosi + Rosi - Rami + Rami - Rami + Rami - Ramipril Rosiglitazone New Diabetes Regression Favours Ramipril

29. DREAM: Safety Rosiglitazone vs placebo Increased incidence of HF* (0.5% vs 0.1%, P = 0.01: 14 vs 2) –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%: 12 vs 4) 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

30. 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

31. Washout Period Study drugs were stopped at last visit Participants switched to single blind placebo 2-3 mo later, return for –local FPG & HbA1c if DM diagnosed during study –local FPG & OGTT (2 hr PG) & HbA1c if no prior dx To assess if DM was prevented or masked, the FPG & OGTT criteria for possible DM will be used To assess the effect of drugs, analyze both as continuous variables

32. 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

33. Clinical Implications It is possible to slow the development of type 2 diabetes with lifestyle intervention. Medications (metformin, acarbose, TZDs) also slow development, with rosiglitazone being about as effective as intensive lifestyle. Lifestyle change has to be the primary approach to reduce the risk of type 2 diabetes. In those who are at high risk, but in whom lifestyle intervention is not feasible, individualized consideration can be given to the use of medication understanding the risk-benefit ratio.

35. 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

36. 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