Level 2: Mid-level evidence

Before rosiglitazone was linked to increases in heart disease, researchers for A Diabetes Outcome Progression Trial (ADOPT) compared the efficacy of rosiglitazone (Avandia) vs. metformin (Glucophage, Fortamet) vs. glyburide (Diabeta, Glynase, Micronase) for glycemic control in 4,360 patients aged 30-75 years with type 2 diabetes (N Engl J Med. 2006;355:2427-2443). Patients were randomized to rosiglitazone 4 mg daily initially (increased up to 4 mg twice daily if needed) vs. metformin 500 mg daily initially (increased up to 1 g twice daily if needed) vs. glyburide 2.5 mg daily initially (increased up to 7.5 mg twice daily if needed) for a median of four years. Only 2,627 patients (60%) completed the study; dropout rates were 37% with rosiglitazone, 38% with metformin, and 44% with glyburide.

Treatment failure was defined as fasting plasma glucose >180 mg/dL on consecutive testing after maximum-tolerated dose. Comparing rosiglitazone vs. metformin vs. glyburide, the five-year cumulative incidence of treatment failure was 15% vs. 21% vs. 34%. The rate of hemoglobin A1c (HbA1c) <7% at four years was 40% vs. 36% vs. 26%. Mean weight change over five years was +4.8 kg (+10.6 lb) vs. -2.9 kg (-6.4 lb) vs. +1.6 kg (+3.5 lb). Congestive heart failure events were reported in 1.5% vs. 1.3% vs. 0.6% of patients.

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Based on a subgroup analysis of ADOPT, rosiglitazone was associated with higher fracture rates of the upper arm, hand, or foot in women (FDA MedWatch. 2007 Feb 20; full-text available online free of charge at: www.fda.gov/medwatch/safety/2007/safety07.htm. Accessed September 11, 2007). Among 2,511 men, fractures occurred in 3.95% of rosiglitazone vs. 3.36% of metformin vs. 3.35% of glyburide patients. Among 1,840 women, fractures occurred in 9.3% of rosiglitazone vs. 5.09% of metformin vs. 3.47% of glyburide patients; fractures were attributable to foot fractures in 22 (3.41%) vs. 7 (1.19%) vs. 4 (0.66%), hand fractures in 8 (1.24%) vs. 4 (0.68%) vs. 1 (0.17%), and humerus fractures in 5 (0.78%) vs. 0 vs. 0.