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

CDC. 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%

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

Numbers of People with Diabetes Wild S et al: Diabetes Care 27: ; % Numbers are millions % % % % % World 2000 = 171 million 2030 = 366 million Increase 114%

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

Macrovascular disease risk Microvascular disease risk Natural History of T2DM and Risk for Complications DeFronzo R. Diabetes Care. 1992;15: Haffner S, et al. Diabetes Care. 1999;22: Haffner S, et al. N Engl J Med. 1998;339: 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

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;

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 Diabetes. 2005;54: *Withdrawn from study after 1.5 yr Diabetes Prevention Program Cumulative incidence of diabetes (%) Years Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d* n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

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

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: Diabetes REduction Assessment with ramipril and rosiglitazone Medication

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

Excluded: Screened Screened 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

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

Ramipril + Rosiglitazone DREAM: 2 x 2 factorial design-main effects analysis 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:

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%

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

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 ( ): P=0.08

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%

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

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

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

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

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

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 < ) –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%: 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 *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

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

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

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.

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