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  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. Parallel epidemics of diabetes and obesity <4% 4%–4.9% 5%–5.9% >6% 10%–14% 15%–19% 20%–24% >25% 1994 2004 Diabetes Obesity (BMI ≥30 kg/m2) CDC. www.cdc.gov.

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

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

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

  6. Post-meal glucose Fasting glucose Macrovascular disease risk Insulin Resistance Microvascular disease risk Beta-cell Function Natural History of T2DM and Risk for Complications PG 200 mg/dL Meets ADA diagnostic criteria for T2DM PG 126 mg/dL Time (years) 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.

  7. DPP: Benefit of diet + exercise or metformin on diabetes prevention in at-risk patients N = 3234 with IFG/IGT without diabetes 40 Placebo P* 30 Metformin < 0.001 31% Cumulative incidence of diabetes (%) 20 Lifestyle 58% < 0.001 10 0 0 1.0 2.0 3.0 4.0 Years *vs placebo IFG = impaired fasting glucose Diabetes Prevention Program (DPP) Research Group. N Engl J Med. 2002;346:393-403.

  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. TZDs blunt diabetes progression Diabetes Prevention Program 15 Placebo Metformin 850 mg bid Cumulative incidence of diabetes (%) 10 Lifestyle 75% vs placeboP < 0.001 Troglitazone400 mg/d* 5 0 0 0.5 1.0 1.5 Years 1568 n = 2343 237 739 DPP Research Group.Diabetes. 2005;54:1150-6. *Withdrawn from study after 1.5 yr

  10. TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes 12.1% 5.4% TRoglitazone In Prevention Of Diabetesn = 236 Hispanic women with gestational diabetes Annual incidence 60 55% RRR HR 0.45 (0.25–0.83)*P = 0.009 40 New-onset diabetes (%) Placebo 20 Troglitazone 400 mg 0 0 12 24 36 48 60 Follow-up (months) *Unadjusted Buchanan TA et al. Diabetes. 2002;51:2796-803.

  11. DREAM: Background and study objective Diabetes REduction Assessment with ramipril and rosiglitazone Medication • 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.

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

  13. 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%

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

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

  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/m2) 30.5 kg/m2 (±5.1) Waist circumference (inches) Men 34.3 (±10.8) Women 32.6 (±11.9) Glucose (mg/dL) FPG 104 (±12.6) 2-hour 157 (±25.2) DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  17. Adherence/Adverse Effects

  18. DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death 0.6 Placebo 60% RRR HR 0.40 (0.35–0.46) P < 0.0001 0.5 0.4 Cumulative hazard rate 0.3 0.2 Rosiglitazone 0.1 0.0 0 1 2 3 4 Follow-up (years) No. at riskPlaceboRosiglitazone 26342635 24702538 21502414 11481310 177217 DREAM Trial Investigators. Lancet. 2006.

  19. DREAM: Rosiglitazone decreases new-onset diabetes or death N = 5269 Favorsrosiglitazone Favorsplacebo P <0.0001 <0.0001 0.70 0.25 1 1.75 Hazard ratio *Participants may appear in both categories DREAM Trial Investigators. Lancet. 2006.

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

  21. 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)

  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:

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

  24. DREAM: Rosiglitazone and hepatic enzymes Effect on ALT 30 Placebo 28 P <0.0001 ALT (U/L) 26 24 Rosiglitazone 0 Baseline 2 4 6 8 10 12 Follow-up (months) ALT = alanine aminotransferase DREAM Trial Investigators. Lancet. 2006.

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

  26. DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death 0.6 9% RRRHR 0.91 (0.81–1.03) P = 0.15 0.5 Placebo 0.4 Cumulative hazard rate 0.3 0.2 Ramipril 0.1 0.0 0 1 2 3 4 Follow-up (years) 26462623 25102498 22772287 12401218 200194 No. at riskPlaceboRamipril DREAM Trial Investigators. N Engl J Med. 2006.

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

  28. Ramipril Ramipril Rosi + Rosi + Rosi - Rosi - Rosiglitazone Rosiglitazone Rami + Rami + Rami - Rami - HR HR Independent Effects of Rami + Rosi Regression New Diabetes Favours Ramipril 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) *Adjudicated DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.

  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) *FPG < 110 mg/dL and 2-h glucose < 141 mg/dL DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.

  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.