ADOPT weighs risks, benefits of 3 commonly used oral drugs to treat type 2 diabetes

In a multi-center, randomized, double-blind, controlled trial, use of rosiglitazone in patients with type 2 diabetes was found to delay the progression to monotherapy failure (fasting plasma glucose >180 mg/dL) more effectively than using metformin or glyburide.

The results from A Diabetes Outcome Progression Trial (ADOPT) were published in the New England Journal of Medicine (NEJM).

An estimated 20.8 million children and adults in the United States, or 7% of the population, have diabetes; type 2 diabetes accounts for approximately 90% to 95% of all diagnosed cases. Diabetes is the leading cause of blindness and kidney failure and is a major contributing cause of lower-extremity amputations. The total annual economic cost of diabetes in 2002 was estimated to be $132 billion, or 1out of every 10 healthcare dollars spent in the United States.

In ADOPT, 4,360 patients from 488 centers in the United States, Canada and 15 European countries, who were aged 30 to 75 years, had fasting plasma glucose levels ranging from 126 to 180 mg/dL, and who had not received previous pharmacologic treatment for recently diagnosed type 2 diabetes (ie, within 3 years) were randomly assigned to receive monotherapy with daily doses of 1 of the 3 study drugs: rosiglitazone 4 mg (n=1,456), metformin 500 mg (n=1,454), or glyburide 2.5 mg (n=1,441). For each of the 3 drugs, the dose was increased at study visits (to the maximum dose of rosiglitazone 4 mg twice daily, metformin 1 g twice daily, and glyburide 7.5 mg twice daily) if the fasting plasma glucose level was ≥140 mg/dL. The primary end point was the time to monotherapy failure defined as a fasting plasma glucose level >180 mg/dL.

After a median treatment duration of 4.0 years (maximum, 6.0) the incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. The risk of failure was reduced with rosiglitazone by 32% compared with metformin (HR=0.68; 95% CI, 0.55–0.85; P<.001) and by 63% compared with glyburide (HR=0.37; 95% CI, 0.30–0.45; P<.001). The benefit of rosiglitazone over metformin was most apparent among patients aged ≥50 years and those with a waist circumference >110 cm. Rosiglitazone was more effective than glyburide in all subgroups analyzed. In addition, 40% of patients in the rosiglitazone group had a hemoglobin A_1c level <7% (goal level) compared with 36% of metformin patients (P=.03) and 26% of glyburide patients (P<.001).

Rosiglitazone demonstrated a slower rate of loss of beta-cell function and improved insulin sensitivity to a greater extent compared with metformin or glyburide. "These complementary findings are consistent with a greater durability of glycemic control with rosiglitazone," the authors stated.

ADOPT also evaluated the long-term comparative safety of the agents, and adverse events differed markedly among the groups. Patients receiving rosiglitazone had greater increases in body weight (P<.001), were more likely to experience edema and require treatment with loop diuretics (P<.001 for both comparisons), and had significantly higher levels of low-density lipoprotein (LDL) cholesterol (P<.008) compared with patients receiving metformin and glyburide. Patients receiving rosiglitazone experienced fewer gastrointestinal side effects than those receiving metformin (P<.001), and fewer rosiglitazone patients developed hypoglycemia compared with patients receiving glyburide (P<.001).

In commenting on how the results of ADOPT should be used in daily clinical practice, the authors stressed that "the relative costs of these medications, their profiles of adverse events, and their potential risks and benefits should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes."

SOURCES

Kahn SE, Haffner SM, Heise MA, et al; for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New Engl J Med. 2006;355:2427-2443.

Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2005. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2005. Available at: http:// http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed February 23, 2007.