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. www.who.org.

33

15

33

47

36

18

67

4248

120

71

7

0

20

40

60

80

100

120

140

Africa Americas E Medit Europe SE Asia W Pacific

Diabetes prevalence(in millions)

2000 2030

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)

Mortalityhazard

(%)

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 EuropeN = 25,364 aged ≥30 years

20

10

00 2 4 6 8 10

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.

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

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DPP Research Group.Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr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

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

BradykininAngiotension II

Nitric oxideSkeletal muscle blood flow

Glucose metabolism

HOPE, EUROPA, PEACE: Reduction in new-onset diabetes

0

2

4

6

8

10

12

14

HOPE EUROPA PEACE Pooled data

New-onset diabetes

(%)

Placebo ACEI

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

14% RRRRR 0.86 (0.78–0.95)P = 0.0023

(all trials)

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

Ramipril + Rosiglitazone

DREAM: 2 x 2 factorial design

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.

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

Rosiglitazone effect on weight and BMI

200

196

191

187

182

0

32

31

30

00 01 12 23 34 45 5

Follow-up (years)

lbs kg/m2

Weight BMI

DREAM Trial Investigators. Lancet. 2006.

Rosiglitazone Placebo

P < 0.0001 P < 0.0001

0.94

0.92

0.90

0.88

0

115

107

99

00 01 12 23 34 45 5

cm

WHR Circumference

Rosiglitazone effect on waist and hip measurements

111

103

95

P < 0.0001

P = NS

P < 0.0001

Waist

Hip

Follow-up (years)

DREAM Trial Investigators. Lancet. 2006.WHR = Waist-hip ratio

Rosiglitazone Placebo

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

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.

DREAM: SafetyRosiglitazone 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 – 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%)

• 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