ADOPT: Risk for failure of monotherapy may be lower with rosiglitazone

CAPE TOWN, South Africa — Fasting plasma glucose and HbA1c increases occurred less rapidly among patients receiving rosiglitazone, according to a presentation of the ADOPT study at the International Diabetes Federation 2006 19th World Diabetes Congress.

ADOPT (A Diabetes Outcome Progression Trial) included 4,351 patients (52% North America, 48% Europe) randomized 1–1–1 to rosiglitazone (Avandia, GlaxoSmithKline), metformin or glyburide. The study goal was to compare the durability of glycemic control with rosiglitazone vs. metformin or glyburide as initial monotherapy in patients with recently diagnosed type 2 diabetes.

At baseline, the patients (mean age 57 years; mean BMI 32.2) had diabetes for a duration of three years or less. They were drug naive, with FPG levels of 126 mg/dL to 180 mg/dL after a four-week run-in. Pre-ADOPT treatment included diet and lifestyle modification only.

All patients received diet and exercise reinforcement and periodic clinic visits (bi-annually in the first year, quarterly thereafter) during the treatment period of four to six years.

The primary endpoint was monotherapy failure defined as FPG >180 mg/dL. Steven Kahn, MD, professor at the University of Washington School of Medicine, Seattle, who presented the ADOPT results, pointed out that FPG was chosen as the primary endpoint rather than HbA1c because at the inception of the study, guidelines focused on FPG; HbA1c was a secondary ADOPT endpoint.

Risk for monotherapy failure

After five years, the risk for monotherapy failure was 32% lower for rosiglitazone vs. metformin (P<.001) and 63% lower for rosiglitazone vs. glyburide (P<.001). At four years, mean FPG was 9.8 mg/dL lower with rosiglitazone vs. metformin and 17.4 mg/dL lower vs. glyburide (P<.001 for both).

Similarly, HbA1c levels were lower with rosiglitazone (–0.13 vs. metformin; P=.002; –0.42 vs. glyburide; P<.001). Glycemic control, defined as HbA1c <7%, was maintained longer in the rosiglitazone group at a mean of 60 months compared with 45 months and 33 months for metformin and glyburide, respectively.

Weight gain at four years was higher in the rosiglitazone group compared with metformin (6.9 kg; P<.001) and glyburide (2.5 kg; P<.001). Adverse events (92% for all), hospitalizations (11%) and all-cause deaths (2.2%) were similar between groups.

Congestive heart failure-related events were lower (0.6%; P<.05) in the glyburide group than in the rosiglitazone group (1.5%), as were HF-related serious adverse events (0.2% glyburide, 0.8% for rosiglitazone and metformin; P<.05).

Gastrointestinal adverse events were more common in the metformin group than with rosiglitazone (38% vs. 23%; P<.05). Hypoglycemia was reported more commonly in the glyburide group (39% vs. 10% for rosiglitazone; P<.05). Edema with rosiglitazone at 14% was higher than with metformin (7%) or glyburide (9%; P<.05 for both). Fractures among women were also more common in the rosiglitazone group (9.3% vs. 5.1% and 3.5% for metformin and glyburide, respectively; P<.05). Kahn emphasized, however, that the excess in fractures in the rosiglitazone group occurred in hands and feet and not in the hip or spine.

Kahn concluded that initial monotherapy with rosiglitazone slowed progression of hyperglycemia compared with metformin or glyburide.

“This is the first study to show that the progressive loss of glucose control in early type 2 diabetes can be slowed,” he said. The greater efficacy of rosiglitazone, he added, was likely attributable to its positive effects on both insulin sensitivity and beta-cell function. “Use of rosiglitazone early in the course of the disease is preferable to the use of glyburide.” – by Walter Alexander

This article also appeared in Endocrine Today, a SLACK Incorporated publication.

For more information:

• Kahn S. Presented at: International Diabetes Federation 2006 19th World Diabetes Congress; December 3-7, 2006; Cape Town, South Africa.
• Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. New Engl J Med. 2006;355:2427-2443.