ClinicalTrialsResults.org

“DREAM Trial TZDS without ACE inhibitors”

Jeffrey L. Probstfield, MD, FACP, FACC, FAHA, FESC

Director, Clinical Trials Service UnitProfessor of Medicine (Cardiology)

University of Washington School of MedicineAdjunct Professor of Epidemiology

University of Washington School of Public Health and Community Medicine

CDC. www.cdc.gov.

Parallel epidemics of diabetes and obesity

Diabetes

Obesity(BMI ≥30 kg/m2)

<4% 4%–4.9% 5%–5.9% >6%

10%–14% 15%–19% 20%– 24% >25%

2004 1994

DO YOU SEE THE TSUNAMI HEADED

TOWARD US?

OBESITY, ATTENDENT DIABETES AND CHD/CVD

Numbers of People with Diabetes 2000-2030

Wild S et al: Diabetes Care 27:1047-1053; 2004

33.066.8102%

Numbers are millions

33.350.044%

15.235.9136%

7.018.2160%

46.9119.5155%

35.871.099%

World2000 = 171 million

2030 = 366 millionIncrease 114%

Fasting Plasma Glucose

100 mg/dL

Normal

2-Hour PGon OGTT

140 mg/dL

Impaired FastingGlucose

Impaired GlucoseTolerance

Normal

126 mg/dL

Diabetes Mellitus

200 mg/dL

Diabetes Mellitus

Glucose Tolerance CategoriesGlucose Tolerance Categories

Macrovascular disease risk

Microvascular disease risk

Natural History of T2DM and Risk for Natural History of T2DM and Risk for ComplicationsComplications

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.

Meets ADA diagnostic criteriafor T2DM

Post-meal glucoseFasting glucose

Time (years)

PG 200 mg/dL

PG 126 mg/dL

InsulinResistance

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;346:393-403.

Years

N = 3234 with IFG/IGT without diabetes

0

0

10

20

30

40

1.0 2.0 3.0 4.0

Placebo

Metformin

Lifestyle

Cumulativeincidence

of diabetes(%)

31%

58%

P*

< 0.001

< 0.001

*vs placeboIFG = 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;287.360-72.

0

TZDs blunt diabetes progression

DPP Research Group.Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr

Diabetes Prevention Program

10

15

5

1.5

Cumulativeincidence

of diabetes(%)

Years

1.00.50

Placebo

Metformin850 mg bid

Lifestyle

Troglitazone400 mg/d*

23773915682343n =

75% vs placeboP < 0.001

TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetesTRoglitazone In Prevention Of Diabetesn = 236 Hispanic women with gestational diabetes

60

40

20

0

New-onset diabetes

(%)

Follow-up (months)

0 12 24 36 48 60

Buchanan TA et al. Diabetes. 2002;51:2796-803.

Placebo

Troglitazone 400 mg

12.1%

5.4%

Annual incidence

55% RRRHR 0.45 (0.25–0.83)*

P = 0.009

*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;47:1519-27.

Diabetes REduction Assessment with ramipril and rosiglitazone Medication

Primary outcome:Diabetes or death from any cause

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

DREAM: Study design

Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina,

ventricular arrhythmia

Secondary outcomes II: Renal eventsProgression to micro- or

macroalbuminuria, or 30% CrCl

Ramipril 15 mg/d vs placeboAND

Rosiglitazone 8 mg/d vs placebo

Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease

Follow-up: 3–5 years

Excluded: 18784Excluded: 18784

Screened24592

Screened24592

Randomized5269

Randomized5269

Run-in5808

Run-in5808

Excluded: 539Excluded: 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) 104

• 2-hr plasma glucose (mean) 157

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27. *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;47:1519-27.

N = 5269 with IFG and/or IGT

Ramipril

Rosiglitazone Placebo

Ramipril + Placebo

PlaceboRosiglitazone +

PlaceboPlacebo +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/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.

Adherence/Adverse Effects

Rosiglitazone Placebo

On Study Drug at 1 year 88.4% 91.3%

at 2 years 83.7% 87.7%

at 3 years 79.5% 84.0%

Reasons for Stopping Study Drug

Participant Refusal 19.1% 16.7%

Edema 4.8% 1.6%

MD advice 1.9% 1.5%

Weight Gain 1.9% 0.6%

DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death

No. at riskPlaceboRosiglitazone

DREAM Trial Investigators. Lancet. 2006.

26342635

24702538

21502414

11481310

177217

0.6

0.5

0 1 2 3 4

Follow-up (years)

0.4

0.3

0.2

0.1

0.0

Rosiglitazone

Placebo60% RRR HR 0.40 (0.35–0.46) P < 0.0001

Cumulative hazard rate

DREAM: Rosiglitazone decreases new-onset diabetes or death

Rosiglitazone group(n) (%)

Placebo group(n) (%)

Primary outcome composite 306 (11.6%) 686 (26.0%)

Diabetes* 280 (10.6%) 658 (25.0%)

Death* 30 (1.1%) 33 (1.3%)

0.25 1 1.75

P

<0.0001

0.70

<0.0001

DREAM Trial Investigators. Lancet. 2006.

N = 5269

*Participants may appear in both categories

Hazard ratio

Favorsrosiglitazone

Favorsplacebo

DREAM: Regression to normoglycemia with rosiglitazone

26.0

43.7

30.3

11.6

37.9

50.5

0

10

20

30

40

50

60

Diabetes IFG and/or IGT Normal*

Participants (%)

Placebo Rosiglitazone

*FPG < 110 mg/dL DREAM Trial Investigators. Lancet. 2006.

71% increaseHR 1.71 (1.571.87)P < 0.0001

N = 5269

0.5 1.0 2.0 4.0 10.0 20.0 90.0

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 (0.97-1.94): 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 Diuretics 57% ACE-I 24%

IV Diuretics 38% CPAP 29%

Other Diuretics 38% Hospital 81%

Digoxin 29%

Different Manifestations of Fluid Retention in TZD Users

and Non-Users

PulmonaryEdema

JugularVenous

Distension

Ascites PeripheralEdema

95%

80%80%

18%

63%

0

20

40

60

80

100

11%

32%

0%

TZD (n=19)Non-TZD (n=80)

% ofPatients

Tang WHW et al: J Am Coll Cardiol 41:1394-1398; 2003

Rosiglitazone

Placebo

Follow-up (months)

ALT (U/L)P <0.0001

Effect on ALT

0

24

26

28

30

Baseline 2 4 6 8 10 12

DREAM: Rosiglitazone and hepatic enzymes

DREAM Trial Investigators. Lancet. 2006.ALT = alanine aminotransferase

Independent Effects of Rami + Rosi

0.25 0.50 0.75 1.00 1.25

Effect of Ramipril

Rosi +

Rosi -

Effect of Rosiglitazone

Rami +

Rami -

0.75 1.00 1.25 1.50 1.75 2.00

Effect of Ramipril

Rosi +

Rosi -

Effect of Rosiglitazone

Rami +

Rami -

HR HR

Rosi +

Rosi -

Rosi +

Rosi -

Rami +

Rami -

Rami +

Rami -

Ramipril Ramipril

Rosiglitazone Rosiglitazone

New Diabetes Regression

Favours Rosiglitazone Favours Rosiglitazone

DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death

DREAM Trial Investigators. N Engl J Med. 2006.

Placebo

Ramipril

No. at riskPlaceboRamipril

Follow-up (years)

0.6

0.5

0.4

0.3

0.2

0.1

0.00 1 2 3 4

26462623

25102498

22772287

12401218

200194

9% RRRHR 0.91 (0.81–1.03)

P = 0.15

Cumulative hazard rate

DREAM: Ramipril effect on glycemic categories

18.5

43.3

38.2

17.1

40.342.6

0

5

10

15

20

25

30

35

40

45

Diabetes IGT or IFG Normoglycemia

Patients (%)

Placebo Ramipril

P = 0.006

DREAM Trial Investigators. N Engl J Med. 2006.

Independent Effects of Rami + Rosi

0.25 0.50 0.75 1.00 1.25

Effect of Ramipril

Rosi +

Rosi -

Effect of Rosiglitazone

Rami +

Rami -

0.75 1.00 1.25 1.50 1.75 2.00

Effect of Ramipril

Rosi +

Rosi -

Effect of Rosiglitazone

Rami +

Rami -

HR HR

Rosi +

Rosi -

Rosi +

Rosi -

Rami +

Rami -

Rami +

Rami -

Ramipril Ramipril

Rosiglitazone RosiglitazoneNew Diabetes Regression

Favours Ramipril Favours Ramipril

DREAM: SafetyRosiglitazone 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)

DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006. *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 < 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)

DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.

*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.