Among patients aged 65 years and older, rosiglitazone (Avandia, GlaxoSmithKline) is associated with an increased risk of stroke, heart failure and all-cause mortality when compared with pioglitazone (Actos, Takeda Pharmaceuticals), based on a study published online July 28 in the Journal of the American Medical Association, in advance of an upcoming FDA meeting that will review the safety of rosiglitazone.

“Rosiglitazone and pioglitazone are the only thiazolidinediones…currently marketed in the U.S.,” the authors wrote. “Studies have suggested that the use of rosiglitazone may be associated with an increased risk of serious cardiovascular events compared with other treatments for type 2 diabetes.”

David J. Graham, MD, from the FDA's Center for Drug Evaluation and Research in Silver Springs, Md., and colleagues evaluated data from 227,571 Medicare beneficiaries (average age, 74.4 years) who started treatment with rosiglitazone or pioglitazone through a Medicare Part D prescription drug plan from July 2006 through June 2009.

The researchers followed the patients for up to three years after the initiation of the medications.

During follow-up, there were 1,746 incidents of acute MI (21.7 percent fatal), 1,052 strokes (7.3 percent fatal), 3,307 hospitalizations for heart failure (2.6 percent fatal), and 2,562 deaths for all causes among cohort members, the authors reported.

An analysis showed no differences in the risk for MI between rosiglitazone and pioglitazone, but the study found that rosiglitazone was associated with a 1.25-fold increase in risk of heart failure compared with pioglitazone.

These data suggest that “rosiglitazone was associated with a 1.27-fold increased risk of stroke and a 1.14-fold increased risk of death compared with pioglitazone,” according to Graham and colleagues.

In a population of more than 227,000 patients 65 years or older who initiated treatment with a thiazolidinedione, the researchers found that “compared with pioglitazone, rosiglitazone was associated with an increased risk of stroke, heart failure and death and the composite of acute MI, stroke, heart failure or death.”

In an accompanying editorial, David Juurlink, MD, PhD, from the departments of medicine and pediatrics, as well as health policy, management and evaluation at the University of Toronto and the Sunnybrook Research Institute in Toronto, highlighted the importance of the findings of the report by Graham and colleagues in terms of understanding the risks of rosiglitazone.

“The epilogue of the rosiglitazone story has yet to be written, but a few observations can now be made with confidence,” Juurlink said.

His observations were:

• There is no direct evidence that rosiglitazone prevents vascular events in patients with diabetes.
• Converging lines of evidence suggest that rosiglitazone is less safe than pioglitazone, whereas no data suggest that the converse might be true.
• Because the evidence to date is not conclusive, differing views have emerged on how to proceed in the face of uncertainty.

 
“Whether rosiglitazone and pioglitazone really do have different cardiovascular safety profiles is an intriguing question but one with a misplaced focus,” Juurlink wrote. “Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative.”