DREAM

1
DREAM

• Diabetes REduction Assessment with ramipril and
  rosiglitazone Medication

2
Prevention of Type 2 Diabetes

• Clinical trials have shown that diet exercise
  can prevent diabetes by gt 50 in people with
  impaired glucose tolerance (IGT)
• Clinical trials have also shown that drugs (e.g.
  metformin, acarbose) can prevent diabetes to a
  lesser extent in people with IGT
• Growing evidence suggests that
• ACE inhibitors may prevent diabetes
• Thiazolidinediones may prevent diabetes

3
Properties of ACE-Inhibitors

• Inhibition of the Renin-Angiotensin system with
  ACE inhibitors
• Lowers BP
• Reduces mortality, MI strokes in people with
• Heart failure
• Previous CV events without heart failure
• Diabetes plus other CV risk factors
• The HOPE trial suggested that the ACE-I ramipril
  may also reduce DM

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RAS Blockade New Diabetes (Diabetes - Not
Primary Outcome)
Overall Effect (HOPE, EUROPA, PEACE) 0.86
(0.78-0.95) Dagenais et al. Lancet 2006368581
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Do ACE-Inhibitors Prevent Diabetes? Limitations
of Previous Reports

• Glucose tolerance tests not done at baseline or
  end
• ?may have missed prevalent diabetes at baseline
  new DM on follow-up
• ? no ability to detect regression
• Different definitions of new DM were used
• Participants were of high cardiovascular risk
  intermediate diabetes risk (e.g. DM rate
  2/year)
• DM prevention was not the primary outcome

6
Properties of Thiazolidinediones (TZDs)

• Binds to PPAR gamma receptors
• Increases insulin sensitivity
• Reduces lipolysis
• Increases preadipocytes?adipocytes (SC fat)
• Possible beta cell protection
• Reduces glucose levels if elevated

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Troglitazone New Diabetes
Placebo
Metformin
Trog
Lifestyle
Placebo
Troglitazone
Median30 mo N (Trog)133 HR 0.45 (95CI
0.25-0.83)
Median0.9 yrs N (Trog)585 HR 0.25 (95CI
0.14-0.43)
DPP. Diabetes 2005 1150
Buchanan et al. Diabetes 2002 2796
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The DREAM Trial

• Aims Does ramipril 15 mg/d prevent diabetes?
• Does rosiglitazone 8 mg/d prevent diabetes?
• Design 2 X 2 factorial, double-blind RCT
• Sample Age 30 IGT (FPG lt7 2 hr 7.8-11) /or
  IFG (FPG 6.1-6.9)
• Pts 5269 in 191 sites, 21 countries, F/U 3
  yrs
• Outcome Incident DM (confirmed FPG gt 7 or 2
  hr gt 11.1 or MD diagnosis) or death

because undiagnosed diabetes may be more
frequent in those who die than in those who do
not
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The DREAM Trial

• Independent Coordination, Data Management
  Analysis
• Population Health Research Institute
• McMaster University Hamilton Health Sciences
• Hamilton, Ontario, Canada
• Funding Canadian Institutes of Health Research
• Sanofi-Aventis
• King Pharmaceuticals
• GlaxoSmithKline

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Screening Randomization
Screened 24592
Excluded 18784
Run-in 5808
Excluded 539
Randomized 5269
Glucose or Primary Outcome Status in 94 at study
end Vital Status in 98
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Baseline Characteristics
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Baseline Characteristics (Mean)
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DREAM

• Results of the Ramipril Arm

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Adherence/Adverse Effects
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Ramiprils Effect on Blood Pressure
Systolic BP
Placebo
Ramipril
Diastolic BP
Base 2 6 12 24
36 48 Final
Months
16
Ramiprils Effect on ALT
Placebo
ALT (U/l)
Ramipril
P 0.04
17
Ramiprils Effect on Weight
Weight
Body Mass Index
Placebo
Placebo
Ramipril
Ramipril
P 0.07
P 0.06
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Ramipril Primary Outcome
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Primary Outcome Ramipril
HR 0.91 (CI 0.81-1.03) P0.15
Placebo
Ramipril
Year
20
Ramipril Subgroups Primary Outcome
P Heterogeneity
0.80
0.11
0.72
0.80
0.22
HR (95 CI)
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Regression Ramipril
HR 1.16 (1.07-1.27) P0.001
Cumulative Hazard
Ramipril
Placebo
0 1 2 3
4
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Effect on Glucose Category Ramipril
HR 1.16 P 0.001
HR 1.17 P 0.002
HR 0.91 P 0.15
(ADA Cutoff)
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Ramipril Median Glucose
Fasting PG (mM)
2 Hour PG (mM)
P 0.07
P 0.01
Placebo
Placebo
Ramipril
Ramipril
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Cardiovascular Composite Ramipril
HR 1.08 (CI 0.76-1.52) P0.7
Cumulative Hazard

• - - - Placebo
• Ramipril

Year
25
Summary Conclusions Ramipril

• Modestly improves glycemic status in IFG/IGT
• A nonsignificant 9 DM reduction
• Significant 16 increase in regression to normal
  glucose levels by at least 2 yrs
• Reduced 2 hr glucose by 0.3 mM by study end
• Significantly reduces BP in IGT / IFG
• Small, favourable effect on liver function

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DREAM vs. Previous Trials

• Diabetes was the primary outcome in DREAM
• People with undiagnosed diabetes were excluded
• Regression was a predefined secondary outcome
• People were low vs. high CV risk so
• may have had a less activated RAS
• controls were less likely on drugs that raise
  glucose
• there was low power to detect differences in CVD
  events (short duration, low risk participants)

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Summary Conclusions Ramipril

• The DREAM results provide the best estimate of
  the effect of ACE-Is on diabetes prevention in
  people with IFG / IGT no previous CV disease
• Ramipril cannot currently be recommended for DM
  prevention
• However, in people in whom there is an indication
  for ACE inhibitors (high BP, CHF, vascular
  disease, high risk DM) the favourable effects on
  glucose may be of added benefit

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DREAM

• Results of the Rosiglitazone Arm

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Adherence/Adverse Effects
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Rosiglitazones Effect on ALT
Placebo
ALT (U/l)
P lt0.0001
Rosiglitazone
Months
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Rosiglitazones Effect on BP
Systolic BP
P0.0001
Placebo
Rosiglit
Plt0.0001
Diastolic BP
Base 2 6 12 24 36 48
Final
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Rosiglitazone Weight, BMI
Weight (Kg)
BMI (Kg/m2)
Rosiglitazone
Rosiglitazone
Placebo
Placebo
P lt 0.0001
P lt 0.0001
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Rosiglitazone Waist, Hip
Waist / Hip
Hip (cm)
Plt0.0001
Waist (cm)
Plt0.0001
PNS
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Rosiglitazone Primary Outcome
35
(No Transcript)
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Effect on Glucose Category Rosiglitazone
HR 1.71 P lt 0.0001
HR 1.83 P lt 0.0001
HR 0.38 P lt 0.0001
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Rosiglitazone Median Glucose
Fasting PG (mM)
2 Hour PG (mM)
Placebo
Placebo
Rosiglitazone
Rosiglitazone
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Rosiglitazone Subgroups Primary
P (Heterogeneity)
Overall
0.6
0.09
0.09
0.14
Favours Rosiglitazone
Favours Placebo
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Rosiglitazone Subgroups Primary
P (Heterogeneity)
Overall
0.002
0.0004
0.009
0.0002
0.03
Favours Rosiglitazone
Favours Placebo
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Cardiovascular Outcomes Rosiglitazone
HR 1.37 (0.97-1.94) P0.08
14 (0.5) vs. 2 (0.1) P0.01
LOG HR (95 CI)
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Summary Conclusions Rosiglitazone

• A dose of 8 mg/day reduces new DM by gt 60 in
  people with IGT or IFG
• Promotes regression to normal FPG 2 hr PG by
  gt70
• Effective in all regions of the world
• Eliminates the gradient of DM risk with
  increasing weight
• 3 increase in body weight, but a favourable
  effect on waist/hip ratio
• Reduces ALT

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Summary Conclusions Rosiglitazone

• Modestly lowers systolic BP diastolic BP
• Increases the risk of CHF
• Too few events to draw any conclusions re the
  effect on other CV events or death
• For every 1000 people treated with rosiglitazone
  for 3 years, 144 cases of DM will be prevented
  with an excess of 4 cases of CHF

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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

DREAM Slides www.phri.ca/dream 2 DREAM Papers
NEJM Lancet - online
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DREAM TEAM
International Leaders
H.C. Gerstein S. Yusuf R. Holman J. Bosch
F. Lanas E. Lonn M. McQueen V.Mohan A. Phillips L.
Piegas

• S. Anand
• A. Avezum
• A. Budaj
• J. Chiasson
• I. Conget
• G. Dagenais

M. Hanefeld T. Hedner B. Hoogwerf K. Jolly M. Kelt
ai M. Laakso
M. Davis R. Diaz N. Dinccag M. Enjalbert A.
Escalante G. Fodor
V. Pirags J. Probstfield I. Schmid J. Shaw K. Teo
P. Zimmet B. Zinman
Statisticians P. Sheridan, J. Pogue
D. Sackett D. Altman C. Clark P. Bennett
R. Hamman L. Ryden
TMC