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

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 AfricaAmericasE MeditEuropeSE Asia W Pacific Diabetes prevalence (in millions)  102%  160%  180%  44%  155%  99%

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: *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

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: Years N = 3234 with IFG and IGT, without diabetes Placebo Metformin Lifestyle Cumulative incidence of diabetes (%)  31%  58% P* <0.001 *vs placebo IFG = impaired fasting glucose

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:

TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes TRoglitazone In Prevention Of Diabetes N = 236 Hispanic women with gestational diabetes Cumulative incidence of new-onset diabetes (%) Follow-up (months) Buchanan TA et al. Diabetes. 2002;51: Placebo Troglitazone 400 mg 12.1% 5.4% Annual incidence 55% RRR HR 0.45 (0.25–0.83)* P = *Unadjusted

0 TZDs blunt diabetes progression DPP Research Group. Diabetes. 2005;54: *Withdrawn from study after 1.5 years Cumulative incidence of diabetes (%) Follow-up (years) Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* n = N = 2343 at high risk of diabetes

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

HOPE, EUROPA, PEACE: Reduction in new-onset diabetes (placebo-controlled trials) Dagenais GR et al. Lancet. 2006;368: 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 = (all trials) *Not a prespecified end point

DREAM Trial Investigators. Diabetologia. 2004;47: 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

Ramipril + Rosiglitazone DREAM: 2 × 2 factorial design DREAM Trial Investigators. Diabetologia. 2004;47: 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

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 (%) hour (mg/dL) 157 (±25.2) IGT (%)85.9 DREAM Trial Investigators. Diabetologia. 2004;47:

DREAM: Rosiglitazone effect on primary outcome No. at risk Placebo Rosiglitazone DREAM Trial Investigators. Lancet. 2006;368: Follow-up (years) Rosiglitazone Placebo 60% RRR HR 0.40 (0.35–0.46) P < Cumulative hazard rate

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) P < < DREAM Trial Investigators. Lancet. 2006;368: N = 5269 *Participants may appear in both categories Hazard ratio Favors rosiglitazone Favors placebo

DREAM: Effect of rosiglitazone on primary outcome in key subgroups Gender Male Female Age (years) < –59 Location North America South America Europe India Australia Glycemic abnormality IFG only IGT only IFG + IGT P* Placebo (% per year) Hazard ratio (95% CI) Favors rosiglitazone Favors placebo DREAM Trial Investigators. Lancet. 2006;368: *for heterogeneity

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

Rosiglitazone effect on weight and BMI Follow-up (years) lbskg/m 2 WeightBMI DREAM Trial Investigators. Lancet. 2006;368: RosiglitazonePlacebo P <

inches WHRCircumference Rosiglitazone effect on waist and hip measurements P < P = NS P < Waist Hip Follow-up (years) DREAM Trial Investigators. Lancet. 2006;368: WHR = waist-hip ratio RosiglitazonePlacebo

DREAM: Ramipril effect on primary outcome DREAM Trial Investigators. N Engl J Med. 2006;355: Placebo Ramipril No. at risk Placebo Ramipril Follow-up (years) % RRR HR 0.91 (0.81–1.03) P = 0.15 Cumulative hazard rate

DREAM: Ramipril effects on glycemic categories P = DREAM Trial Investigators. N Engl J Med. 2006;355:

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 < ) –Increased hip circumference (  0.71 in, P < ) –No difference in waist circumference –Decreased waist-hip ratio (P < ) No adverse hepatic effects –Alanine aminotransferase (ALT) levels  4.2 U/L at 1 year (P < ) 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: ; N Engl J Med. 2006;355: *Adjudicated

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 < )  BP vs placebo (1.7/1.4 mm Hg; P < ) 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: ; N Engl J Med. 2006;355: *FPG < 110 mg/dL and 2-h glucose < 140 mg/dL