ADOPT: Rosiglitazone Outperforms Metformin and Glyburide as Initial Therapy

From the International Diabetes Federation5-Year Results Show Long-Term Delayed Diabetes Progression

CAPE TOWN, South Africa?In a large, long-term international trial, ?initial treatment with rosiglitazone (Avandia) for patients with type 2 diabetes reduced the risk of monotherapy failure and the progression of disease by 32% compared with metformin (Glucophage) and by 63% compared with glyburide (eg, DiaBeta, Glynase).

New England Journal of Medicine

The 5-year findings from ADOPT (A Diabetes Outcome Progression Trial) were presented at the World Diabetes Congress of the International Diabetes Federation. The study was published simultaneously in the ?(2006 Dec 4).

"As clinicians we know that after initial improvement with treatment, type 2 diabetes has remained a progressive disease with devastating side effects," said coinvestigator Giancarlo Viberti, MD, of Guy's, King's, and St. Thomas' School of Medicine, King's College, London. "In ADOPT we wanted to compare the long-term durability of response to 3 different kinds of treatments in patients who had never been treated before. Whatever index of glycemic control we looked at, rosiglitazone performed the best."

Participants were 4360 drug-na?ve patients, aged 30 to 75 years, who had been diagnosed with type 2 diabetes within the past 3 years. The trial included a screening visit, a 4-week placebo run-in, a 4- to 6-year treatment period, and an observational follow-up period of 4 to 6 years (for those who withdrew from treatment).

The patients were randomized to the recommended initial doses of rosiglitazone (4 mg/d), metformin (500 mg/d), or glyburide (2.5 mg/d). Dosages were increased to the maximum effective dose (4 mg rosiglitazone bid, 1 g metformin bid, or 7.5 mg glyburide bid).

Uptitration was required when fasting plasma glucose was ≥140 mg/dL (≥7.8 mmol/L); doses could be reduced for patients who reported adverse events.?

The primary end point was time from randomization to treatment failure, which was defined as confirmed hyperglycemia (ie, fasting plasma glucose >180 mg/dL). Patients were treated for a median of 4 years.

Monotherapy failure was reported in 143 patients receiving rosiglitazone, 207 patients in the metformin group, and 311 patients taking glyburide. At 5 years, the cumulative incidence of treatment failure was 15% for rosiglitazone, 21% for metformin, and 34% for glyburide.?

This translates into a 32% lower risk of treatment failure with rosiglitazone compared with metformin and a 63% lower risk with rosiglitazone compared with glyburide.

Dr Viberti noted that adverse events and death rates were similar across all 3 groups; however, at year 4, the rosiglitazone group had gained a median of 7 kg more than the metformin group and 2.5 kg more than the glyburide group.

"Not all fat is bad," Dr Viberti said. "We saw a gain in peripheral adipose tissue, or ?good' fat, and a reduction in visceral adipose tissue, or ?bad' fat. The weight gain among the rosiglitazone subjects did not appear to be adverse metabolically."

Commenting on these findings, David Nathan, MD, of Harvard Medical School, contends in an accompanying editorial (N Engl J Med. 2006 Dec 7), "Given the modest glycemic benefit of rosiglitazone (with the risk of fluid retention and weight gain) and higher cost (including the need for more statins and diuretics), metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes."

Responding to this comment, Dr Viberti said that physicians will have to come to their own conclusions about the data and weigh all efficacy, cost, and side-effect issues when choosing treatment. He added that the cost issue may change, "as glitazones become generically available in the not-too-distant future." He also noted that 15% to 20% of patients with type 2 diabetes cannot tolerate metformin because of gastrointestinal side effects.