Rosiglitazone has lower treatment failure rate

A multinational study showing that rosiglitazone monotherapy was associated with a lower treatment failure rate at 5 years than either metformin or glyburide has fueled debate over whether thiazolidinediones should be considered for first-line therapy in type 2 diabetes.

The results of A Diabetes Outcome Progression Trial (ADOPT), sponsored by rosiglitazone manufacturer GlaxoSmithKline, also showed that rosiglitazone was associated with a higher incidence of cardiovascular adverse events than metformin or glyburide. The study, released early to coincide with a presentation at the International Diabetes Federation Congress in Cape Town, South Africa, was published in the New England Journal of Medicine. 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. 

But in an accompanying editorial 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. Doctors criticized the choice of fasting blood glucose rather than glycated hemoglobin as the primary end point “anachronistic,” and noted that even though the differences in glycated hemoglobin also were statistically significant. They were of “questionable clinical significance.” He also said that the “surprisingly high” withdrawal rate “weakens the results, since the outcomes in the entire randomized population cannot be ascertained.” And, he noted, the decreased risk of cardiovascular events shown in a previous trial with another thiazolidinedione, pioglitazone, was not supported by ADOPT.

The president-elect of medicine and science for the American Diabetes Association, agreed that although ADOPT is clearly positive toward delaying the progression of diabetes, at the same time there were more cardiovascular events. And fundamentally, that’s what kills people with diabetes. Past president of the American Association of Clinical Endocrinologists (AACE), took a different view of the study. The results of ADOPT add to the evidence-based support for considering TZDs as first-line therapy for some patients with type 2 diabetes, keeping in mind the adverse events associated with this class of drugs. However, the adverse events are generally detectable and manageable in most cases. in ADOPT, a total of 4,360 drug-naïve adults who had been diagnosed with type 2 diabetes within the previous 3 years were randomly assigned to receive initial daily dosages of 4 mg rosiglitazone, 500 mg metformin, or 2.5 mg glyburide. For each drug, the dosage was increased if fasting blood glucose levels reached or exceeded 140 mg/dL, up to twice-daily dosages each of 4 mg rosiglitazone, 1,000 mg metformin, and 7.5 mg glyburide.

Dosages were reduced if adverse events occurred. The primary outcome was time form randomization to treatment failure, defined as a fasting plasma glucose (FPG) level greater than 180 mg/dL on consecutive testing after at least 6 weeks of treatment at maximum dosage. The median duration of treatment was 4.0 years for rosiglitazone and metformin and 3.3 years for glyburide. Monotherapy failed in 143 rosiglitazone patients, 207 taking metformin, and 311 on glyburide. At 5 years, the cumulative incidence of monotherapy failure was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide.

FPG levels fell in all treatment groups within the first 6 months, with glyburide having the greatest effect. But after 6 months, glyburide showed the greatest annual rate of increase in both FPG (5.6 mg/dL per year) and glycated hemoglobin (0.24% per year), compared with 2.7 mg/dL and 0.14%, respectively, for metformin and 0.7 mg/dL and 0.07% for rosiglitazone.

At the 4-year evaluation, 40% of the 1,456 patients in the rosiglitazone group had a glycated hemoglobin level of less than 7%, compared with 36% of 1,454 patients in the metformin group and 26% of the 1,441 glyburide patients. Insulin sensitivity rose more in the rosiglitazone  group than in the metformin patients during the first 6 months, improved similarly in both groups thereafter, and remained significantly different at 4 years.

Insulin sensitivity did not change in the glyburide group. Cell function increased more in the glyburide group during the first 6 months but declined thereafter in all three groups. The annual rate of decline was greatest for glyburide (6.1%), intermediate with metformin (3.1%), and least for rosiglitazone (2.0%).

Over 5 years, mean weight increased by 4.8 kg with rosiglitazone and dropped by 2.9 kg with metformin. With glyburide, the patients gained 1.6 kg in the first year and remained stable after that.

As for cardiology adverse events, an independent panel identified 51 possible cases of heart failure (HF). The panel judged 21 of these to be true heart failure involving 9 patients in the rosiglitazone group, 8 in the metformin group, and 4 with glyburide. HF rates associated with rosiglitazone were similar to those seen in other studies.

Earlier this year, the American Diabetes Association and the European Society for the Study of Diabetes issued joint guidelines calling for metformin as first-line treatment for type 2 diabetes, with thiazolidinediones (TZDs), sulfonylureas, and insulin as possible second-step medications. The two organizations plan to review the ADOPT findings along with other data that have been published since the guidelines came out.