Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
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Transcript of Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.
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DPP Research Group.Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr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