A Diabetes Outcome Progression Trial

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Presentation transcript:

A Diabetes Outcome Progression Trial 4/24/2017 8:14 PM ADOPT A Diabetes Outcome Progression Trial

ADOPT: Background and rationale 4/24/2017 8:14 PM 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.

ADOPT: Study design 4/24/2017 8:14 PM Primary endpoint: Time to monotherapy failure (FPG >180 mg/dL) Screening Run-in period (4 weeks) Treatment period (4 years) Placebo + Diet/exercise Rosiglitazone 4–8 mg/day* Metformin 0.5–2 g/day* Glyburide 2.5–15 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.

ADOPT: Patient enrollment and outcomes 4/24/2017 8:14 PM Randomized N = 4360 Rosiglitazone n = 1456 Metformin n = 1454 Glyburide n = 1441 Completed trial n = 917 Completed trial n = 903 Completed trial n = 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.

ADOPT: Baseline characteristics 4/24/2017 8:14 PM 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 87.2 4.2 2.7 5.2 0.7 89.1 3.7 2.4 3.8 1.0 89.0 4.2 2.2 4.2 0.3 Weight (lbs) 203.3 203.6 204.4 Body mass index (kg/m2) 32.2 32.1 Waist circumference (in) 41.5 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 4/24/2017 8:14 PM 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 7.35 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 *Homeostasis model assessment (HOMA 2) Kahn SE et al. N Engl J Med. 2006;355:2427-43.

ADOPT: Treatment effect on primary outcome 4/24/2017 8:14 PM 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 1 2 3 4 5 Years *Time to FPG >180mg/dL Kahn SE et al. N Engl J Med. 2006;355:2427-43.

ADOPT: Treatment effect on glucose control 4/24/2017 8:14 PM 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 (%) 6.8 130 120 6.4 6.0 110 1 2 3 4 5 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.

ADOPT: Treatment effect on insulin sensitivity and β-cell function 4/24/2017 8:14 PM 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 Insulin sensitivity† (%) -Cell function† (%) 40 70 30 60 1 2 3 4 5 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.

ADOPT: Treatment effect on weight and waist circumference 4/24/2017 8:14 PM 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 Waist circumference (in) 42.1 204 Weight (lbs) 200 41.3 196 191 40.6 1 2 3 4 5 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.

ADOPT: Treatment effect on hip circumference and waist/hip ratio 4/24/2017 8:14 PM 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 Hip circumference (in) 44.5 Waist/ hip ratio 0.95 43.7 0.94 42.9 1 2 3 4 5 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.

ADOPT: Adverse events Total events (%) Rosiglitazone (n = 1456) 4/24/2017 8:14 PM Total events (%) Rosiglitazone (n = 1456) Metformin (n = 1454) Glyburide (n = 1441) Cardiovascular disease Fatal MI Nonfatal MI CHF* Stroke 0.1 1.7 1.5 1.1 0.1 1.4 1.3 1.3 0.2 1.0 0.6 1.2 Peripheral vascular disease 2.5 1.9 2.2 Gastrointestinal (GI) Nausea Vomiting Diarrhea Abdominal discomfort 7.7 4.0 8.9 11.1 11.7 5.8 23.7 15.4 6.9 3.1 9.9 11.3 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 4/24/2017 8:14 PM Not part of prespecified analysis Rosiglitazone (n = 1456) Metformin (n = 1454) Glyburide (n = 1441) Men (%) 4.0 3.4 Women (%) Upper limb Lower limb Hip Spine 9.3 3.4 5.6 0.3 0.2 5.1* 1.7 3.1† 0.3 0.2 3.5* 1.5† 1.3* 0.0 0.2 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.

ADOPT: Summary 4/24/2017 8:14 PM 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 4/24/2017 8:14 PM 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.