Diabetes REduction Assessment
with ramipril and rosiglitazone
Medication (DREAM) trial
Worldwide prevalence of diabetes
expected to increase
World Health Organization, 2000 vs 2030
Diabetes prevalence
140 155%
>171 million in 2000
120
120 ~366 million in 2030
100
102% 99%
Diabetes 80
prevalence 67 71
(in millions) 181% 44%
60
48 47
42
40 36
160% 33 33
20 18 15
7
0
Africa Americas E Medit Europe SE Asia W Pacific
2000 2030
World Health Organization. www.who.org.
DECODE: IGT increases mortality risk
Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe
N = 25,364 aged ≥30 years
20 Diagnosed diabetes (n = 1275)
Undiagnosed diabetes (n = 3071)
Impaired glucose tolerance (n = 2766)*
Normal glucose tolerance (n = 18,252)*
Mortality
hazard 10
(%)
0
0 2 4 6 8 10
Follow-up (years)
*2-hour oral glucose tolerance test (OGTT)
IGT = impaired glucose tolerance DECODE Study Group. Lancet. 1999;354:617-21.
DPP: Benefit of diet + exercise or metformin
on diabetes prevention in at-risk patients
N = 3234 with IFG/IGT without diabetes
40 Placebo
P*
30 Metformin
31% < 0.001
Cumulative
incidence
of diabetes 20 Lifestyle
(%) 58% < 0.001
10
0
0 1.0 2.0 3.0 4.0
Years
*vs placebo Diabetes Prevention Program (DPP) Research Group.
IFG = impaired fasting glucose N Engl J Med. 2002;346:393-403.
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 diabetes
TRoglitazone In Prevention Of Diabetes
n = 236 Hispanic women with gestational diabetes
Annual
60
incidence
55% RRR 12.1%
HR 0.45 (0.25–0.83)*
40 P = 0.009
New-onset
diabetes Placebo
(%)
20 5.4%
Troglitazone
400 mg
0
0 12 24 36 48 60
Follow-up (months)
*Unadjusted Buchanan TA et al. Diabetes. 2002;51:2796-803.
TZDs blunt diabetes progression
Diabetes Prevention Program
15 Placebo
Metformin
850 mg bid
Cumulative 10
incidence Lifestyle
of diabetes 75% vs
Troglitazone
(%) 5 placebo
400 mg/d*
P < 0.001
0
0 0.5 1.0 1.5
Years
n= 2343 1568 739 237
DPP Research Group.
*Withdrawn from study after 1.5 yr Diabetes. 2005;54:1150-6.
Potential antidiabetic mechanisms
of ACE inhibition
Angiotension I Bradykinin
ACE/
Kininase II
Angiotension II Degradation
products
ACE Inhibitor
Angiotension II Bradykinin
Nitric oxide
Skeletal muscle
blood flow
Glucose metabolism
Henriksen EJ et al. J Cell Physiol. 2003;196:171-9.
HOPE, EUROPA, PEACE: Reduction in new-onset
diabetes
N = 23,340 free from diabetes at baseline
14 14% RRR
RR 0.86 (0.78–0.95)
12 P = 0.0023
10
New-onset 8
diabetes
(%) 6
4
2
0
HOPE EUROPA PEACE Pooled data
Ramipril Perindopril Trandolapril (all trials)
10 mg 8 mg 4 mg
Placebo ACEI
Dagenais GR et al. Lancet. 2006;368:581-8.
DREAM: Study design
Randomized, double-blind 2 × 2 factorial design
N = 5269 with IFG and/or IGT, free from CV disease
Ramipril 15 mg/d vs placebo
AND
Rosiglitazone 8 mg/d vs placebo
Primary outcome:
Diabetes or death from any cause
Secondary outcomes I: CV events Secondary outcomes II: Renal events
Combined MI, stroke, CV death, Progression to micro- or
revascularization, HF, angina, macroalbuminuria,
ventricular arrhythmia or 30% CrCl
Follow-up: 3–5 years
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
DREAM: 2 x 2 factorial design
N = 5269 with IFG and/or IGT
Rosiglitazone Placebo
Ramipril + Ramipril +
Ramipril
Rosiglitazone Placebo
Rosiglitazone + Placebo +
Placebo
Placebo Placebo
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
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
0.6
60% RRR Placebo
0.5
HR 0.40 (0.35–0.46)
0.4 P < 0.0001
Cumulative
0.3
hazard rate
0.2
Rosiglitazone
0.1
0.0
0 1 2 3 4
No. at risk Follow-up (years)
Placebo 2634 2470 2150 1148 177
Rosiglitazone 2635 2538 2414 1310 217
DREAM Trial Investigators. Lancet. 2006.
DREAM: Rosiglitazone decreases new-onset
diabetes or death
N = 5269
Rosiglitazone
group Placebo group Favors Favors
(n) (%) (n) (%) rosiglitazone placebo P
Primary outcome
composite 306 (11.6%) 686 (26.0%) <0.0001
Diabetes* 280 (10.6%) 658 (25.0%) <0.0001
Death* 30 (1.1%) 33 (1.3%) 0.70
0.25 1 1.75
Hazard ratio
*Participants may appear in both categories DREAM Trial Investigators. Lancet. 2006.
DREAM: Regression to normoglycemia
with rosiglitazone
N = 5269
71% increase
HR 1.71 (1.571.87)
P < 0.0001
60
50.5
50 43.7
40 37.9
Participants 30.3
30 26.0
(%)
20
11.6
10
0
Diabetes IFG and/or IGT Normal*
Placebo Rosiglitazone
*FPG < 110 mg/dL DREAM Trial Investigators. Lancet. 2006.
Rosiglitazone effect on weight and BMI
Weight BMI
200 32
196
191 31
lbs kg/m2
187
P < 0.0001 30 P < 0.0001
182
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Follow-up (years)
Rosiglitazone Placebo
DREAM Trial Investigators. Lancet. 2006.
Rosiglitazone effect on waist and hip
measurements
WHR Circumference
0.94 115
Hip
111
0.92
107 P < 0.0001
cm
103 Waist
0.90
P < 0.0001 99
P = NS
0.88 95
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Follow-up (years)
Rosiglitazone Placebo
WHR = Waist-hip ratio DREAM Trial Investigators. Lancet. 2006.
DREAM: Rosiglitazone and hepatic enzymes
Effect on ALT
30
Placebo
28
P <0.0001
ALT (U/L) 26
24
Rosiglitazone
0
Baseline 2 4 6 8 10 12
Follow-up (months)
ALT = alanine aminotransferase DREAM Trial Investigators. Lancet. 2006.
DREAM: Ramipril demonstrates neutral effect on
new-onset diabetes or death
0.6
9% RRR
0.5 HR 0.91 (0.81–1.03)
P = 0.15
0.4 Placebo
Cumulative
0.3
hazard rate
0.2
Ramipril
0.1
0.0
0 1 2 3 4
Follow-up (years)
No. at risk
Placebo 2646 2510 2277 1240 200
Ramipril 2623 2498 2287 1218 194
DREAM Trial Investigators. N Engl J Med. 2006.
DREAM: Ramipril effect on glycemic categories
P = 0.006
45 43.3 42.6
40.3
40 38.2
35
30
Patients 25
(%) 20 18.5 17.1
15
10
5
0
Diabetes IGT or IFG Normoglycemia
Placebo Ramipril
DREAM Trial Investigators. N Engl J Med. 2006.
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 < 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)
*Adjudicated DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.
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)
*FPG < 110 mg/dL and
2-h glucose < 141 mg/dL DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.