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

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Presentation on theme: "Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial."— Presentation transcript:

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. 0 20 40 60 80 100 120 140 AfricaAmericasE MeditEuropeSE Asia W Pacific Diabetes prevalence (in millions) 2000 2030  102%  160%  180%  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) Cumulative 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 and 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 Cumulative incidence of 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 years 10 15 5 1.5 Cumulative incidence of diabetes (%) Follow-up (years) 1.00.50 Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* 237 739 1568 2343n = N = 2343 at high risk of diabetes

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 (placebo-controlled trials) 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 Overall 14% RRR HR 0.86 (0.78–0.95) P = 0.0023 (all trials) *Not a prespecified end point

10 DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. DREAM: Study design Primary outcome: Diabetes or death from any cause 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 Secondary outcomes III: Glucose status Glucose levels, conversion to normoglycemia

11 Ramipril + Rosiglitazone DREAM: 2 × 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 Ramipril: 5 mg × 2 months; 10 mg × 10 months; 15 mg thereafter Rosiglitazone: 4 mg × 2 months; 8 mg thereafter

12 DREAM: Baseline characteristics Age (years) 54.7 (±10.9) Women (%)58.5 Hypertension (%)43.5 Hyperlipidemia (%)35.5 BP (mm Hg)136/83 (±18.6/11.3) BMI (kg/m 2 )30.5 (±5.1) Waist circumference (inches) Men34.3 (±10.8) Women32.6 (±11.9) Glucose FPG (mg/dL) 104 (±12.6) IFG (%)42.4 2-hour (mg/dL) 157 (±25.2) IGT (%)85.9 DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

13 DREAM: Rosiglitazone effect on primary outcome No. at risk Placebo Rosiglitazone DREAM Trial Investigators. Lancet. 2006;368:1096-1105. 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;368:1096-1105. N = 5269 *Participants may appear in both categories Hazard ratio Favors rosiglitazone Favors placebo

15 DREAM: Effect of rosiglitazone on primary outcome in key subgroups Gender Male Female Age (years) <50 60+ 50–59 Location North America South America Europe India Australia Glycemic abnormality IFG only IGT only IFG + IGT 0.6 9.9 7.6 8.4 9.5 7.7 8.8 8.0 8.6 8.7 7.2 7.0 6.1 14.0 0.09 0.14 P* Placebo (% per year) 0.20.40.60.81.01.2 Hazard ratio (95% CI) Favors rosiglitazone Favors placebo DREAM Trial Investigators. Lancet. 2006;368:1096-1105. *for heterogeneity

16 DREAM: Conversion to normoglycemia with rosiglitazone *FPG < 110 mg/dL and 2-h glucose < 140 mg/dL DREAM Trial Investigators. Lancet. 2006;368:1096-1105. 71% increase HR 1.71 (1.57  1.87) P < 0.0001 N = 5269

17 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;368:1096-1105. RosiglitazonePlacebo P < 0.0001

18 0.94 0.92 0.90 0.88 0 45.3 42.1 39.0 0 001122334455 inches WHRCircumference Rosiglitazone effect on waist and hip measurements 43.7 40.6 37.4 P < 0.0001 P = NS P < 0.0001 Waist Hip Follow-up (years) DREAM Trial Investigators. Lancet. 2006;368:1096-1105. WHR = waist-hip ratio RosiglitazonePlacebo

19 DREAM: Ramipril effect on primary outcome DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62. 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 effects on glycemic categories P = 0.006 DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.

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 –Alanine aminotransferase (ALT) levels  4.2 U/L at 1 year (P < 0.0001) Ramipril vs placebo No adverse hepatic effects –ALT levels  1.1 U/L at 1 year (P = 0.004) DREAM Trial Investigators. Lancet. 2006;368:1096-1105; N Engl J Med. 2006;355:1551-62. *Adjudicated

22 DREAM results: Summary Rosiglitazone 60% RRR in new-onset diabetes or death (P < 0.001); NNT = 7 Benefit consistent across ethnicity, gender, and age Increased conversion to normoglycemia* vs placebo (50.5% vs 30.3%) (HR 1.71, P < 0.0001)  BP vs placebo (1.7/1.4 mm Hg; P < 0.0001) Ramipril 9% RRR in new-onset diabetes or death (P = 0.15) Increased conversion to normoglycemia* vs placebo (42.5% vs 38.2%) (HR 1.16, P = 0.001)  BP vs placebo (4.3/2.4 mm Hg; P < 0.001) When ACEIs are indicated, improved glucose metabolism may be added benefit DREAM Trial Investigators. Lancet. 2006;368:1096-1105; N Engl J Med. 2006;355:1551-62. *FPG < 110 mg/dL and 2-h glucose < 140 mg/dL

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