ADOPTA Diabetes Outcome Progression Trial

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

Viberti G et al. Diabetes Care. 2002;25:1737-43.

ADOPT was designed to evaluate glycemic control in recently diagnosed T2DM patients receiving monotherapy with

rosiglitazone, metformin, or glyburide

T2DM = type 2 diabetes mellitus

ADOPT: Study design

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

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

Eligible patients:• T2DM diagnosed within 3 years• No prior oral hypoglycemic

agents or insulin therapy• FPG: 126–240 mg/dL

Placebo + Diet/exercise

Rosiglitazone4–8 mg/day*

Metformin0.5–2 g/day*

Glyburide2.5–15 mg/day*

Non-treatment observational follow-up

Randomization baseline (visit 3)

N = 4360

Study endFailure of monotherapy action point

N = 6676

Screening Treatment period(4 years)

Run-in period(4 weeks)

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

ADOPT: Patient enrollment and outcomes

RandomizedN = 4360

Rosiglitazonen = 1456

Glyburiden = 1441

Completed trialn = 917

Completed trialn = 807

Metforminn = 1454

Completed trialn = 903

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

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

ADOPT: Baseline characteristics

Rosiglitazone(n = 1456)

Metformin (n = 1454)

Glyburide (n = 1441)

Age (years) 56.3 57.9 56.4

Male (%) 55.7 59.4 58.0

Race/ethnicity (%) White Black Asian Hispanic Other

87.24.22.75.20.7

89.13.72.43.81.0

89.04.22.24.20.3

Weight (lbs) 203.3 203.6 204.4

Body mass index (kg/m2) 32.2 32.1 32.2

Waist circumference (in) 41.5 41.6 41.6

Hip circumference (in) 43.9 43.8 44.0

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

ADOPT: Baseline BP, glucose, and lipid values

Rosiglitazone(n = 1456)

Metformin (n = 1454)

Glyburide (n = 1441)

BP (mm Hg)Antihypertensive therapy (%)

133/80 51.1

133/80 50.7

133/79 52.3

FPG (mg/dL) 151.5 151.3 152.4

A1C (%) 7.36 7.36 7.35

Fasting insulin (pmol/L) 149.9 151.8 150.4

Insulin sensitivity (%)* 33.8 33.3 33.1

β-cell function (%)* 68.0 69.5 67.9

Total-C (mg/dL) 205 204 202

LDL-C (mg/dL) 121 120 119

HDL-C (mg/dL) 46.9 46.5 47.3

Triglycerides (mg/dL)

Lipid lowering therapy (%)

163

26.0

165

25.9

156

25.7

Kahn SE et al. N Engl J Med. 2006;355:2427-43.*Homeostasis model assessment (HOMA 2)

ADOPT: Treatment effect on primary outcome

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

40

30

20

10

0

Glyburide

Metformin

Rosiglitazone

0 1 2 3 4 5

Years

Cumulative incidence of mono-therapy failure*

(%)

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

N = 4351

*Time to FPG >180mg/dL

ADOPT: Treatment effect on glucose control

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

A1C(%)

7.2

7.6

6.8

6.4

6.0

00 1 2 3 4 5

8.0

0110

120

130

140

150

160

543210Years

FPG (mg/dL)

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

GlyburideMetforminRosiglitazone

Years

*At 4 years

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

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

*At 4 years†Homeostasis model assessment (HOMA 2)

Insulinsensitivity†

(%)

50

60

40

30

0

Years

70

-Cell function†

(%)

80

90

70

60

0

Years

100

543210

GlyburideMetforminRosiglitazone

Treatment difference* (95% CI)

Rosiglitazone vs metformin12.6 (8.1 to 17.3), P < 0.001

Rosiglitazone vs glyburide41.2 (35.2 to 47.4), P < 0.001

Treatment difference* (95% CI)

Rosiglitazone vs metformin5.8 (1.9 to 9.8), P = 0.003

Rosiglitazone vs glyburide-0.8 (-4.7 to 3.1), P = 0.67

543210

ADOPT: Treatment effect on weight and waist circumference

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

0

40.6

41.3

42.1

543210Years

Waistcircum-ference

(in)

42.9

Years

0

191

196

200

204

209

543210

Weight (lbs)

213

GlyburideMetforminRosiglitazone

Treatment difference* (95% CI)

Rosiglitazone vs metformin6.9 (6.3 to 7.4), P < 0.001

Rosiglitazone vs glyburide2.5 (2.0 to 3.1), P < 0.001

Treatment difference* (95% CI)

Rosiglitazone vs metformin4.11 (3.18 to 5.04), P < 0.001

Rosiglitazone vs glyburide0.77 (-0.21 to 1.76), P = 0.12

218

*At 4 years

ADOPT: Treatment effect on hip circumference and waist/hip ratio

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

GlyburideMetforminRosiglitazone

44.5

45.3

43.7

42.9

0

Years

Waist/hip

ratio

0.96

0.95

0.94

0

Years

Treatment difference* (95% CI)

Rosiglitazone vs metformin5.31 (4.39 to 6.33), P < 0.001

Rosiglitazone vs glyburide2.42 (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

Hipcircum-ference

(in)

543210543210

*At 4 years

ADOPT: Adverse events

Total events (%)Rosiglitazone

(n = 1456)Metformin (n = 1454)

Glyburide (n = 1441)

Cardiovascular diseaseFatal MINonfatal MICHF*Stroke

0.11.71.51.1

0.11.41.31.3

0.21.00.61.2

Peripheral vascular disease 2.5 1.9 2.2

Gastrointestinal (GI)NauseaVomitingDiarrheaAbdominal discomfort

7.74.08.911.1

11.75.8

23.715.4

6.93.19.911.3

Hypoglycemia† 9.8 11.6 38.7

Weight gain 6.9 1.2 3.3

Edema 14.1 7.2 8.5

*Investigator reported; †Self reported Kahn SE et al. N Engl J Med. 2006;355:2427-43.

ADOPT: Fracture event rate

Rosiglitazone(n = 1456)

Metformin (n = 1454)

Glyburide (n = 1441)

Men (%) 4.0 3.4 3.4

Women (%) Upper limb Lower limb Hip Spine

9.33.45.60.30.2

5.1*1.73.1†

0.30.2

3.5*1.5†

1.3*0.00.2

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

Note added in proof*P < 0.01 vs rosiglitazone; †P < 0.05 vs rosiglitazone

Not part of prespecified analysis

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. 2006;355:2427-43.

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. 2006;355:2427-43.