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ADOPT. A D iabetes O utcome P rogression T rial. 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

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Adopt l.jpg

ADOPT

ADiabetes Outcome Progression Trial


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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 β-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. 2002;25:1737-43.


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ADOPT: Study design

Primary endpoint: Time to monotherapy failure (FPG >180 mg/dL)

Screening

Run-in period

(4 weeks)

Treatment period

(4 years)

Placebo + Diet/exercise

Rosiglitazone4–8 mg/day*

Metformin0.5–2 g/day*

Glyburide2.5–15 mg/day*

  • Eligible patients:

  • T2DM diagnosed within 3 years

  • No prior oral hypoglycemic agents or insulin therapy

  • FPG: 126–240 mg/dL

Non-treatment observational follow-up

N = 6676

Randomization baseline (visit 3)

N = 4360

Failure of monotherapy action point

Study end

*Uptitrate when fasting plasma glucose (FPG) ≥140 mg/dL at subsequent visits

Viberti G et al. Diabetes Care. 2002;25:1737-43.Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Patient enrollment and outcomes

RandomizedN = 4360

Rosiglitazonen = 1456

Metforminn = 1454

Glyburiden = 1441

Completed trialn = 917

Completed trialn = 903

Completed trialn = 807

No significant treatment group differences in patient characteristics in those who withdrew from study

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Baseline characteristics

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Baseline BP, glucose, and lipid values

*Homeostasis model assessment (HOMA 2)

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Treatment effect on primary outcome

N = 4351

40

Hazard ratio (95% CI)

Rosiglitazone vs metformin, 0.68 (0.55–0.85), P < 0.001

Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P < 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 >180mg/dL

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Treatment effect on glucose control

Treatment difference* (95% CI)

Rosiglitazone vs metformin

-9.8 (-12.7 to -7.0), P < 0.001

Rosiglitazone vs glyburide

-17.4 (-20.4 to -14.5), P < 0.001

Treatment difference* (95% CI)

Rosiglitazone vs metformin

-0.13 (-0.22 to -0.05), P = 0.002

Rosiglitazone vs glyburide

-0.42 (-0.50 to -0.33), P < 0.001

8.0

160

7.6

150

7.2

140

FPG (mg/dL)

A1C(%)

6.8

130

6.4

120

6.0

110

0

0

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

Rosiglitazone

Metformin

Glyburide

*At 4 years

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Treatment effect on insulin sensitivity and β-cell function

70

100

Treatment difference* (95% CI)

Rosiglitazone vs metformin

12.6 (8.1 to 17.3), P < 0.001

Rosiglitazone vs glyburide

41.2 (35.2 to 47.4), P < 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

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

Rosiglitazone

Metformin

Glyburide

*At 4 years

†Homeostasis model assessment (HOMA 2)

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Treatment effect on weight and waist circumference

Treatment difference* (95% CI)

Rosiglitazone vs metformin

6.9 (6.3 to 7.4), P < 0.001

Rosiglitazone vs glyburide

2.5 (2.0 to 3.1), P < 0.001

Treatment difference* (95% CI)

Rosiglitazone vs metformin

4.11 (3.18 to 5.04), P < 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

191

40.6

0

0

0

1

2

3

4

5

0

1

2

3

4

5

Years

Y

ea

r

s

Rosiglitazone

Metformin

Glyburide

*At 4 years

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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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 < 0.001

Rosiglitazone vs glyburide

2.42 (1.44 to 3.39), P < 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

0

1

2

3

4

5

0

1

2

3

4

5

Years

Years

Rosiglitazone

Metformin

Glyburide

*At 4 years

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Adverse events ratio

*Investigator reported; †Self reported

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Fracture event rate ratio

Not part of prespecified analysis

Note added in proof

*P < 0.01 vs rosiglitazone; †P < 0.05 vs rosiglitazone

Kahn SE et al. N Engl J Med. 2006;355:2427-43.


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ADOPT: Summary ratio

  • 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. 2006;355:2427-43.


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ADOPT: Implications ratio

  • 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. 2006;355:2427-43.


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