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%  181%  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) 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/IGT without diabetes Placebo Metformin Lifestyle Cumulative incidence of diabetes (%)  31%  58% P* < *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;

TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes TRoglitazone In Prevention Of Diabetes n = 236 Hispanic women with gestational diabetes 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 Diabetes. 2005;54: *Withdrawn from study after 1.5 yr Diabetes Prevention Program Cumulative incidence of diabetes (%) Years Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* n =  75% vs placebo P < 0.001

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 Dagenais GR et al. Lancet. 2006;368: 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 = (all trials)

Primary outcome: Diabetes or death from any cause DREAM Trial Investigators. Diabetologia. 2004;47: 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

Ramipril + Rosiglitazone DREAM: 2 x 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

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:

DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death No. at risk Placebo Rosiglitazone DREAM Trial Investigators. Lancet 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 N = 5269 *Participants may appear in both categories Hazard ratio Favors rosiglitazone Favors placebo

DREAM: Regression to normoglycemia with rosiglitazone *FPG < 110 mg/dL DREAM Trial Investigators. Lancet % 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 RosiglitazonePlacebo P <

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

Rosiglitazone Placebo Follow-up (months) ALT (U/L) P < Effect on ALT Baseline DREAM: Rosiglitazone and hepatic enzymes DREAM Trial Investigators. Lancet ALT = alanine aminotransferase

DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death DREAM Trial Investigators. N Engl J Med 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 effect on glycemic categories P = DREAM Trial Investigators. N Engl J Med

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 –ALT levels  4.2 U/L at 1 year (P < ) 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 *Adjudicated

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 < ) 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 *FPG < 110 mg/dL and 2-h glucose < 141 mg/dL