ADOPT

1
ADOPT

• A Diabetes Outcome Progression Trial

2
ADOPT Background and rationale

• Attaining and maintaining glycemic control
  reduces risk of long-term diabetes complications
• Despite initial efficacy with lifestyle
  pharmacologic interventions, glycemic control is
  lost over time
• Thiazolidinediones reduce insulin resistance,
  delay progression to T2DM, and have been reported
  to preserve ß-cell function

ADOPT was designed to evaluate glycemic control
in recently diagnosed T2DM patients receiving
monotherapy with rosiglitazone, metformin, or
glyburide
T2DM type 2 diabetes mellitus
Viberti G et al. Diabetes Care. 2002251737-43.
3
ADOPT Study design
Primary endpoint Time to monotherapy failure
(FPG gt180 mg/dL)
Screening
Treatment period (4 years)
Run-in period (4 weeks)
Placebo Diet/exercise
Rosiglitazone48 mg/day Metformin0.52
g/day Glyburide2.515 mg/day

• Eligible patients
• T2DM diagnosed within 3 years
• No prior oral hypoglycemic agents or insulin
  therapy
• FPG 126240 mg/dL

Non-treatment observational follow-up
Randomization baseline (visit 3) N 4360
Study end
Failure of monotherapy action point
N 6676
Uptitrate when fasting plasma glucose (FPG) 140
mg/dL at subsequent visits
Viberti G et al. Diabetes Care.
2002251737-43.Kahn SE et al. N Engl J Med.
20063552427-43.
4
ADOPT Patient enrollment and outcomes
RandomizedN 4360
Rosiglitazonen 1456
Glyburiden 1441
Metforminn 1454
Completed trialn 917
Completed trialn 807
Completed trialn 903
No significant treatment group differences in
patient characteristics in those who withdrew
from study
Kahn SE et al. N Engl J Med. 20063552427-43.
5
ADOPT Baseline characteristics
Kahn SE et al. N Engl J Med. 20063552427-43.
6
ADOPT Baseline BP, glucose, and lipid values
Homeostasis model assessment (HOMA 2)
Kahn SE et al. N Engl J Med. 20063552427-43.
7
ADOPT Treatment effect on primary outcome
N 4351
40
Hazard ratio (95 CI) Rosiglitazone vs
metformin, 0.68 (0.550.85), P lt 0.001
Rosiglitazone vs glyburide, 0.37 (0.300.45), P lt
0.001
Glyburide
30
Cumulative incidence of mono-therapy failure()
Metformin
20
Rosiglitazone
10
0
0
1
2
3
4
5
Years
Time to FPG gt180mg/dL
Kahn SE et al. N Engl J Med. 20063552427-43.
8
ADOPT Treatment effect on glucose control
8.0
160
7.6
150
7.2
140
A1C()
FPG (mg/dL)
6.8
130
6.4
120
6.0
110
0
0
0
1
2
3
4
5
5
4
3
2
1
0
Years
Years
Glyburide
Metformin
Rosiglitazone
At 4 years
Kahn SE et al. N Engl J Med. 20063552427-43.
9
ADOPT Treatment effect on insulin sensitivity
and ß-cell function
70
100
Treatment difference (95 CI) Rosiglitazone vs
metformin 12.6 (8.1 to 17.3), P lt
0.001 Rosiglitazone vs glyburide 41.2 (35.2 to
47.4), P lt 0.001
Treatment difference (95 CI) Rosiglitazone vs
metformin 5.8 (1.9 to 9.8), P
0.003 Rosiglitazone vs glyburide -0.8 (-4.7 to
3.1), P 0.67
60
90
50
80
?-Cell
Insulin sensitivity()
function
()
40
70
30
60
0
0
5
4
3
2
1
0
5
4
3
2
1
0
Years
Years
Glyburide
Metformin
Rosiglitazone
At 4 years Homeostasis model assessment (HOMA 2)
Kahn SE et al. N Engl J Med. 20063552427-43.
10
ADOPT Treatment effect on weight and waist
circumference
Treatment difference (95 CI) Rosiglitazone vs
metformin 6.9 (6.3 to 7.4), P lt
0.001 Rosiglitazone vs glyburide 2.5 (2.0 to
3.1), P lt 0.001
Treatment difference (95 CI) Rosiglitazone vs
metformin 4.11 (3.18 to 5.04), P lt
0.001 Rosiglitazone vs glyburide 0.77 (-0.21 to
1.76), P 0.12
218
42.9
213
209
42.1
Waistcircum-ference(in)
204
Weight (lbs)
200
41.3
196
40.6
191
0
0
5
4
3
2
1
0
5
4
3
2
1
0
Years
Y
ea
r
s
Glyburide
Metformin
Rosiglitazone
At 4 years
Kahn SE et al. N Engl J Med. 20063552427-43.
11
ADOPT Treatment effect on hip circumference and
waist/hip ratio
Treatment difference (95 CI) Rosiglitazone vs
metformin 5.31 (4.39 to 6.33), P lt
0.001 Rosiglitazone vs glyburide 2.42 (1.44 to
3.39), P lt 0.001
Treatment difference (95 CI) Rosiglitazone vs
metformin -0.0083 (-0.0158 to -0.0009), P
0.03 Rosiglitazone vs glyburide -0.0107 (-0.0186
to -0.0028), P 0.008
45.3
0.96
44.5
Hipcircum-ference(in)
Waist/hipratio
0.95
43.7
0.94
42.9
0
0
5
4
3
2
1
0
5
4
3
2
1
0
Years
Years
Glyburide
Metformin
Rosiglitazone
At 4 years
Kahn SE et al. N Engl J Med. 20063552427-43.
12
ADOPT Adverse events
Investigator reported Self reported
Kahn SE et al. N Engl J Med. 20063552427-43.
13
ADOPT Fracture event rate
Not part of prespecified analysis
Note added in proof P lt 0.01 vs rosiglitazone
P lt 0.05 vs rosiglitazone
Kahn SE et al. N Engl J Med. 20063552427-43.
14
ADOPT Summary

• Compared with metformin and glyburide, initial
  treatment of T2DM with rosiglitazone over 4
  years demonstrated clinical benefits
• Slowed progression to monotherapy failure (loss
  of glycemic control)
• Improved insulin sensitivity and reduced ?-cell
  function loss
• Rosiglitazone associated with
• More weight gain and edema than metformin or
  glyburide
• Fewer GI events than metformin
• Less hypoglycemia than glyburide
• Similar risk of CV events vs metformin
• Higher risk of CV events than glyburide

Kahn SE et al. N Engl J Med. 20063552427-43.
15
ADOPT Implications

• ADOPT provides long-term data on the glycemic
  durability and risks associated with
  rosiglitazone, metformin, and glyburide in the
  management of T2DM
• Risk/benefit ratios should be considered when
  guiding optimal therapy in high-risk patients

Kahn SE et al. N Engl J Med. 20063552427-43.