June 29, 2007 (Chicago, IL) – Not unlike a prizefighter battered and bruised, rosiglitazone (Avandia, GlaxoSmithKline) continued to take it on the chin this week, with a new analysis from A Diabetes Outcome Progression Trial (ADOPT) expanding upon the risks of the thiazolidinedione (TZD) and showing an increase in the risk of fracture in women taking the controversial medication [1].

"In ADOPT, the increased risk of bone fractures in women with type 2 diabetes was accentuated with rosiglitazone," said lead investigator Dr Steven Kahn (University of Washington, Seattle) during a late-breaking clinical-trials session here at the American Diabetes Association 2007 Scientific Sessions this week. "It appears to increase fractures principally in the upper and lower limbs, and there was no observed increase in spinal fractures with rosiglitazone."

Kahn, however, pointed out that this adverse effect of rosiglitazone is also observed with pioglitazone (Actos, Takeda Pharmaceuticals). Based on these data, the ADOPT investigators say that "special attention should be paid to bone health in women with type 2 diabetes who are receiving thiazolidinediones."

A bad month altogether for rosiglitazone

Previously reported by heartwire , ADOPT was a multicenter, randomized, double-blind clinical trial involving 4360 patients who had not received pharmacologic treatment for recently diagnosed type 2 diabetes. Patients were treated with rosiglitazone, metformin, or glyburide, and investigators showed that initial treatment with rosiglitazone slowed the progression to monotherapy failure more effectively than either metformin or glyburide. Investigators concluded that there was a clinically meaningful difference between rosiglitazone and glyburide, but the difference between rosiglitazone and metformin, based on glucose control, was less significant.

As noted during the trial, however, the side-effect profile differed significantly among the agents, with the risk of congestive heart failure associated with rosiglitazone similar to metformin, a risk that was higher in both drugs compared with glyburide. In addition, investigators also observed an increased risk of fracture in female rosiglitazone-treated patients, and the purpose of this analysis, compiled from adverse- and serious-adverse-events data during follow-up, was to further analyze and quantify that risk.

In terms of the overall fracture risk in men, there was no significant difference when investigators compared those treated with rosiglitazone with those treated with metformin, nor was there a difference in fracture risk in a comparison between rosiglitazone and glyburide. In women, however, there was 81% increase in the incidence of fracture among those treated with rosiglitazone compared with those treated with metformin. The risk of fracture was even higher in a comparison between the rosiglitazone- and glyburide-treated female patients. This increased risk of fracture appears to start after about one year of treatment with the TZD, said Kahn.

In looking to determine when women at increased risk could be identified, Kahn said there were more postmenopausal women included in the study, and those taking metformin and glyburide had less fracture risk than those taking rosiglitazone. Regarding premenopausal women, there was significantly less fracture in the glyburide-treated patients, but only a trend toward less fracture in the metformin-treated patients. Overall, more fractures were observed in the lower and upper limbs, including the hand, humerus, and foot, but no difference in fracture rates in the spine and hip. The baseline characteristics, including medication use, were similar in the three study arms, and there was no observed difference in fracture risk among ADOPT women taking estrogen or calcium supplements. Therewas a greater risk of fracture among women taking a bisphosphonate, investigators found.

Not to leave pioglitazone out of the mix, Kahn also analyzed existing pioglitazone data involving more than 8000 patients treated with the TZD and compared the risk of fracture with approximately 7400 patients taking a comparator drug. Treated, on average, for 3.5 years, there was no increased fracture risk in men, but a similar risk to rosiglitazone was observed in women treated with pioglitazone.

"It would appear that this is a class effect," said Kahn. At this time, however, no clear recommendations can be made, he said, except for clinicians to continue to monitor their patients. He noted that type 2 diabetes alone increases the risk of fracture, and this risk increases with the duration of disease.

  1. Kahn S, on behalf of the ADOPT investigators. Increased incidence of fractures in women who received rosiglitazone in ADOPT. American Diabetes Association 2007 Scientific Sessions; June 26, 2007; Chicago, IL.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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