IDF: Avandia Delays Therapy Failure in Type 2 Diabetes

CAPE TOWN, South Africa, Dec. 4 -- The thiazolidinedione Avandia (rosiglitazone) has a more durable response than two older oral type 2 diabetes agents, but it was more expensive and had more side effects, researchers reported here.

In a large, randomized controlled trial, Avandia was better than either Glucophage (metformin) or Diabeta (Glyburide) at slowing progression to monotherapy failure in patients with type 2 diabetes, reported Steven E. Kahn, M.B., Ch.B., of the University of Washington in Seattle, on behalf of colleagues in the ADOPT (A Diabetes Outcome Progression Trial) study.

Results of the ADOPT trial, sponsored by GlaxoSmithKline, the maker of Avandia, were presented today at the International Diabetes Federation Congress here, and were published online simultaneously by the New England Journal of Medicine, in advance of the Dec. 4 issue.

But in an editorial accompanying the published NEJM study, a diabetes authority who was not involved in the trial pointed out that the primary end point of time to monotherapy failure was based on fasting plasma glucose, rather than the currently accepted standard of glycosylated hemoglobin (HbA1c).

"Despite the reduction in time to failure, according to the primary outcome, the glycated hemoglobin results suggest a clinically less impressive effect," wrote David M. Nathan, M.D., of Harvard and director the Diabetes Center at Massachusetts General Hospital.

"Although these differences are statistically significant, the relatively small difference in glycated hemoglobin levels achieved over four years in the rosiglitazone group as compared with the metformin group is of questionable clinical significance," Dr. Nathan wrote. "The benefits of rosiglitazone over glyburide, which is often not recommended for older patients because of its increased risk of hypoglycemia, are more convincing."

The primary goal of the ADOPT study was to determine whether the thiazolidinedione agent could help patients with type 2 diabetes achieve long-term glycemic control, compared with the older oral diabetes drugs Glucophage and Diabeta.

To that end, the investigators conducted a multicenter double-blind, randomized, controlled trial in 4,360 patients with recently diagnosed type 2 diabetes.

To be eligible for the study, the patients had to be 30 to 75 years old, and have fasting plasma glucose levels ranging from 126 to 180 mg/dL (7.0 to 10.0 mmol/L) on lifestyle management only.

The patients were randomly assigned to be started on daily doses of Avandia at 4 mg, Glucophage at 500 mg, or Diabeta at 2.5 mg. The drug doses were increased according to the protocol to the maximum effective dose of 4 mg twice daily for Avandia, 1 gram twice daily for Glucophage, and 7.5 mg twice daily for Diabeta.

Dose increases were required at each visit if the fasting plasma glucose level was 140 mg/dL or greater. Dose reductions were allowed if the patient had an adverse event. Median treatment was for 4.0 years.

The primary study outcome was time to monotherapy failure, which the investigators defined as a confirmed level of fasting plasma glucose of more than 180 mg/dL (10.0 mmol/L) for Avandia, compared with the other drugs.

Secondary endpoint outcomes were levels of fasting plasma glucose and HbA1c, hemoglobin, insulin sensitivity, and ?-cell function.

Monotherapy failed in 143 patients on Avandia (2.9 per 100 patient-years), 207 on Glucophage (4.3 per 100 patient-years), and 311 on Diabeta (7.5 per 100 patient-years).

Using Kaplan-Meier analysis, the investigators determined that the cumulative incidence at five years was 15% with Avandia, 21% with Glucophage, and 34% with Diabeta. Compared with Glucophage, Avandia reduced the risk for monotherapy failure by 32 (95% confidence interval 15% to 45%, P<0.001), and compared with Diabeta, Avandia reduced the risk by 63% (95% CI 55%-70%, P<0.001).

The difference in the durability of the treatment effect was greater between Avandia and Diabeta than between Avandia and Glucophage, the authors noted.

"The durability of glycemic control in the rosiglitazone group was robust in comparison with that in the glyburide group; however, it was modest in comparison with the durability in the metformin group," Dr. Nathan noted in his editorial. "Such findings must be tempered by the surprisingly high proportion of patients who withdrew from the study; only about 60% of the cohort completed the study. The loss of so many patients, which required an expansion in the number of patients evaluated and the duration of follow-up, weakens the results, since the outcomes in the entire randomized population cannot be ascertained."

The number of deaths from all causes was similar among the three groups. Avandia was associated with a significantly higher risk for congestive heart failure compared with Diabeta (hazard ratio 2.20, 95% CI, 1.01 to 4.79; P= 0.05), but not compared with Glucophage (hazard ratio 1.22 95% CI, 0.66 to 2.26; P=0.52).

Avandia was associated more frequently associated with edema and the use of loop diuretics than were either of the other two drugs (P<0.001 for both comparisons), but was associated less frequently with gastrointestinal side effects than Glucophage (P<0.001). In addition, fewer patients in the Avandia group than in the Diabeta group had hypoglycemic episodes (P<0.001).

At four years, patients on Avandia had gained a mean 2.5 kg (5.5 pounds) more than patients on Diabeta, and 6.9 kg (15.8 pounds) more than patients on Glucophage. Dr. Nathan suggested that some of the weight gain associated with Avandia could have been due to fluid retention.

In an addendum to their report, the ADOPT investigators noted that patients in the Avandia group had significantly more fractures than patients in the other two groups; they described the finding as an unexpected event that was discovered in a subsequent analysis, and was not included in the original pre-specified analysis.

"Taken together, the data from our study document the glycemic durability and risks associated with three commonly used drugs in the initial management of type 2 diabetes," the ADOPT trialists wrote. "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."

Dr. Nathan, however, said that the weight of evidence falls in favor or Glucophage.

"The hope that thiazolidinediones may affect the underlying pathophysiology of type 2 diabetes by protecting ?-cell function and may alter the course of the disease is only weakly supported by ADOPT," he wrote. "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."

Four of the co-authors are employees of GlaxoSmithKline, and most of the others have received honoraria, research support, lecture fees and other compensation from the company, as well as other diabetes drug makers.

Dr. Nathan has also received financial support from GlaxoSnithKline for an educational program.