The maker of rosiglitazone is notifying health care professionals about an increased rate of fractures found in women participating in two large, long-term controlled trials of the drug, and the company is advising providers to consider these findings when prescribing rosiglitazone.
In a letter to health care professionals posted on the Food and Drug Administration's MedWatch site, GlaxoSmithKline notes that in ADOPT (A Diabetes Outcome and Progression Trial), significantly more women who received rosiglitazone monotherapy had fractures, compared with women who received metformin or glyburide.
ADOPT, a randomized, double-blind parallel group study of 4,360 recently diagnosed type 2 diabetic patients, compared glycemic control with rosiglitazone to metformin and glyburide monotherapies over 4–6 years, and was published last year (N. Engl. J. Med. 2006;355:2427–43). The trial showed that rosiglitazone monotherapy was associated with a lower treatment failure rate at 5 years than was either metformin or glyburide.
In addition, a preliminary review of interim fracture data in another large, ongoing, long-term controlled rosiglitazone study was “reported to [GlaxoSmithKline] as being consistent with the observations from ADOPT,” the letter said. The review was conducted by an independent safety committee at GlaxoSmithKline's request. The committee has recommended that the study, which is looking at cardiovascular end points in patients with type 2 diabetes, continue with no modifications; final results are expected to be available in 2009.
In ADOPT, about 9% of the women on rosiglitazone experienced a fracture during the course of the study, for a rate of 2.74 fractures per 100 patient-years. This was significantly higher than the 5% of women on metformin and 3.5% of women on glyburide who experienced a fracture, for 1.5 fractures and 1.3 fractures per 100 patient-years, respectively.
Most of the fractures among the women on rosiglitazone were in the humerus, hand, or foot, which are different from the fracture sites associated with postmenopausal osteoporosis. The number of women with a hip or spine fracture—the kind typically associated with postmenopausal osteoporosis—“was low and similar among the three treatment groups,” according to the letter, which was signed by Dr. Alexander R. Cobitz, senior director, metabolism, in clinical development and medical affairs at GlaxoSmithKline.
The incidence of fractures among the men in the study was similar in all three treatment groups.
“Presently, our understanding of the clinical significance of the findings from these two long-term trials is incomplete,” the letter said. For now, the company “believes the risk of fracture should be considered in the care of patients, especially female patients, with type 2 diabetes mellitus who are currently being treated with rosiglitazone, or when initiation of rosiglitazone treatment is being considered.”
Rosiglitazone, approved by the FDA in 1999, is marketed as Avandia and is also available in combination with metformin (Avandamet) and with glimepiride (Avandaryl) for treating type 2 diabetes.
Read the letter at www.fda.gov/medwatch/safety/2007/Avandia_GSK_Ltr.pdfwww.fda.gov/medwatch