adopt a diabetes outcome progression trial. adopt: background and rationale attaining and...
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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.