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ADOPT

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ADOPT

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  1. ADOPT ADiabetes 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 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.

  3. 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.

  4. 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.

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

  6. ADOPT: Baseline BP, glucose, and lipid values *Homeostasis model assessment (HOMA 2) Kahn SE et al. N Engl J Med. 2006;355:2427-43.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  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 < 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.

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

  13. ADOPT: Fracture event rate 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.

  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. 2006;355:2427-43.

  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. 2006;355:2427-43.