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DREAM. D iabetes RE duction A ssessment with ramipril and rosiglitazone M edication. Prevention of Type 2 Diabetes. Clinical trials have shown that diet & exercise can prevent diabetes by > 50% in people with impaired glucose tolerance (IGT)

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dream

DREAM

Diabetes REduction Assessment with ramipril and rosiglitazone Medication

prevention of type 2 diabetes
Prevention of Type 2 Diabetes
  • Clinical trials have shown that diet & exercise can prevent diabetes by > 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
properties of ace inhibitors
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
ras blockade new diabetes diabetes not primary outcome
RAS Blockade & New Diabetes(Diabetes - Not PrimaryOutcome)

Overall Effect (HOPE, EUROPA, PEACE): 0.86 (0.78-0.95)

Dagenais et al. Lancet 2006;368:581

do ace inhibitors prevent diabetes limitations of previous reports
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
properties of thiazolidinediones tzds
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
troglitazone new diabetes
Troglitazone & New Diabetes

Placebo

Metformin

Trog

Lifestyle

Placebo

Troglitazone

Median=30 mo; N (Trog)=133

HR = 0.45 (95%CI 0.25-0.83)

Median=0.9 yrs; N (Trog)=585

HR = 0.25 (95%CI 0.14-0.43)

DPP. Diabetes 2005; 1150

Buchanan et al. Diabetes 2002: 2796

the dream trial
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 <7 & 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 > 7 or 2 hr > 11.1; or MD diagnosis) or death*

*because undiagnosed diabetes may be more frequent in those who die than in those who do not

the dream trial1
The DREAM Trial

Independent Coordination, Data Management & Analysis

Population Health Research Institute

McMaster University & Hamilton Health Sciences

Hamilton, Ontario, Canada

FundingCanadian Institutes of Health Research

Sanofi-Aventis

King Pharmaceuticals

GlaxoSmithKline

slide10

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%

dream1

DREAM

Results of the Ramipril Arm

ramipril s effect on blood pressure
Ramipril’s Effect on Blood Pressure

Systolic BP

Placebo

Ramipril

Diastolic BP

Base 2 6 12 24 36 48 Final

Months

ramipril s effect on alt
Ramipril’s Effect on ALT

Placebo

ALT (U/l)

Ramipril

P = 0.04

slide17

Ramipril’s Effect on Weight

Weight

Body Mass Index

Placebo

Placebo

Ramipril

Ramipril

P = 0.07

P = 0.06

primary outcome ramipril

DREAM

Primary Outcome: Ramipril

HR 0.91 (CI 0.81-1.03); P=0.15

Placebo

Ramipril

Year

ramipril subgroups primary outcome
Ramipril Subgroups: Primary Outcome

P Heterogeneity

0.80

0.11

0.72

0.80

0.22

HR (95% CI)

slide21

Regression: Ramipril

HR 1.16 (1.07-1.27); P=0.001

Cumulative Hazard

Ramipril

Placebo

0 1 2 3 4

slide22

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)

slide23

Ramipril & Median Glucose

Fasting PG (mM)

2 Hour PG (mM)

P = 0.07

P = 0.01

Placebo

Placebo

Ramipril

Ramipril

cardiovascular composite ramipril
Cardiovascular Composite: Ramipril

HR 1.08 (CI 0.76-1.52); P=0.7

Cumulative Hazard

  • - - - Placebo
  • Ramipril

Year

summary conclusions ramipril
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
dream vs previous trials
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)
summary conclusions ramipril1
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
dream2

DREAM

Results of the Rosiglitazone Arm

slide30

Rosiglitazone’s Effect on ALT

Placebo

ALT (U/l)

P <0.0001

Rosiglitazone

Months

slide31

Rosiglitazone’s Effect on BP

Systolic BP

P=0.0001

Placebo

Rosiglit

P<0.0001

Diastolic BP

Base 2 6 12 24 36 48 Final

slide32

Rosiglitazone & Weight, BMI

Weight (Kg)

BMI (Kg/m2)

Rosiglitazone

Rosiglitazone

Placebo

Placebo

P < 0.0001

P < 0.0001

slide33

Rosiglitazone & Waist, Hip

Waist / Hip

Hip (cm)

P<0.0001

Waist (cm)

P<0.0001

P=NS

slide35

Primary Outcome: Rosiglitazone

HR = 0.40 (0.35-0.46); P<0.0001

Placebo

Rosiglitazone

DREAM

Year

slide36

Effect on Glucose Category: Rosiglitazone

HR 1.71; P < 0.0001

HR 1.83; P < 0.0001

HR 0.38; P < 0.0001

slide37

Rosiglitazone & Median Glucose

Fasting PG (mM)

2 Hour PG (mM)

Placebo

Placebo

Rosiglitazone

Rosiglitazone

slide38

Rosiglitazone Subgroups: Primary

Overall

P (Heterogeneity)

0.6

0.09

0.09

0.14

Favours Rosiglitazone

Favours Placebo

slide39

Rosiglitazone Subgroups: Primary

Overall

P (Heterogeneity)

0.002

0.0004

0.009

0.0002

0.03

Favours Rosiglitazone

Favours Placebo

cardiovascular outcomes rosiglitazone
Cardiovascular Outcomes: Rosiglitazone

HR 1.37 (0.97-1.94): P=0.08

14 (0.5%) vs. 2 (0.1%); P=0.01

LOG HR (95% CI)

summary conclusions rosiglitazone
Summary & Conclusions: Rosiglitazone
  • A dose of 8 mg/day reduces new DM by > 60% in people with IGT or IFG
  • Promotes regression to normal FPG & 2 hr PG by >70%
  • 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
summary conclusions rosiglitazone1
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

conclusions of the dream trial
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

dream team
DREAM TEAM

International Leaders

S. Anand

A. Avezum

A. Budaj

J. Chiasson

I. Conget

G. Dagenais

H.C. Gerstein S. Yusuf

R. Holman J. Bosch

F. Lanas

E. Lonn

M. McQueen

V.Mohan

A. Phillips

L. Piegas

V. Pirags

J. Probstfield

I. Schmid

J. Shaw

K. Teo

P. Zimmet

B. Zinman

M. Davis

R. Diaz

N. Dinccag

M. Enjalbert

A. Escalante

G. Fodor

M. Hanefeld

T. Hedner

B. Hoogwerf

K. Jolly

M. Keltai

M. Laakso

Statisticians: P. Sheridan, J. Pogue

D. Sackett; D. Altman; C. Clark; P. Bennett;

R. Hamman; L. Ryden

TMC: