A new study published online on June 28 by JAMA shows that among patients age 65 years and older, rosiglitazone is associated with an increased risk of stroke, heart failure, and all-cause mortality when compared with pioglitazone. The study was published online in advance of an upcoming Food and Drug Administration meeting that will review the safety of rosiglitazone. The paper will appear in the July 28 print issue of JAMA.

"Rosiglitazone and pioglitazone are the only thiazolidinediones currently marketed in the United States," the authors provide as background information. "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, M.D., M.P.H., from the Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, M.D. 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 patients were followed for up to three years after the initiation of the medications.

"During follow-up, there were 1,746 acute myocardial infarctions (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 report. Analysis showed no differences in the risk for myocardial infarction (MI) between rosiglitazone and pioglitazone, but "…our study found that rosiglitazone was associated with a 1.25-fold increase in risk of heart failure compared with pioglitazone," and "…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 the authors.

In conclusion, the authors write: "…in a population of more than 227,000 patients 65 years or older who initiated treatment with a thiazolidinedione, we 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."

This study was funded by the Office of the Assistant Secretary for Planning and Evaluation (ASPE), the Centers for Medicare & Medicaid Services (CMS), and the U.S. Food and Drug Administration (FDA).

In an accompanying editorial, David Juurlink, M.D., Ph.D., of the Sunnybrook Research Institute; the Departments of Medicine, Pediatrics and Health Policy, Management, and Evaluation at the University of Toronto; and the Institute for Clinical Evaluative Sciences, Toronto, highlights the importance of the findings of the report by Graham and colleagues in terms of understanding the risks of rosiglitazone.

Dr. Juurlink writes, "The epilogue of the rosiglitazone story has yet to be written, but a few observations can now be made with confidence. First, there is no direct evidence that rosiglitazone prevents vascular events in patients with diabetes. Second, converging lines of evidence suggest that rosiglitazone is less safe than pioglitazone, whereas no data suggest that the converse might be true. Third, 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. 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."

Results from another study that will appear in the July 26 print issue of Archives of Internal Medicine show that eleven years after the introduction of the diabetes drug rosiglitazone, data from available clinical trials demonstrate an increased risk for heart attack associated with its use and suggest an unfavorable benefit-to-risk ratio. The study was published online in advance of an upcoming Food and Drug Administration meeting that will review the safety of rosiglitazone.

Rosiglitazone was approved in 1999 to treat hyperglycemia among patients with type 2 diabetes, according to background information in the article. Concerns about the cardiovascular safety of rosiglitazone first arose in 2007, when a meta-analysis demonstrated a significantly increased risk for myocardial infarction and a borderline significant increase for cardiovascular death. The debate over the medication's safety has continued during the past three years, and the U.S. Senate Committee on Finance recently released a report providing additional details about internal analyses conducted by the U.S. Food and Drug Administration and by GlaxoSmithKline (GSK), the drug's manufacturer.

No large, definitive cardiovascular outcomes trials have been conducted with rosiglitazone. However, as a consequence of a 2004 court settlement in New York, GSK was required to post clinical trial results on a public web site. Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., of The Cleveland Clinic Foundation, searched this GSK data and MEDLINE through February 2010 and identified 56 trials involving 35,531 patients, 19,509 of whom received rosiglitazone and 16,022 who received control medications.

In the combined studies, rosiglitazone therapy was associated with a significantly increased risk of myocardial infarction by an estimated 28 percent to 39 percent, although the risk of cardiovascular death was not increased. "An alternative analysis that included trials with no cardiovascular events found a similar hazard," the authors write. "Subgroups classified by study duration and comparator drug also showed elevated odds ratio estimates."

"These findings are consistent with prior meta-analyses conducted by GSK, the FDA and most independent investigators demonstrating an increased risk of myocardial infarction in patients treated with rosiglitazone," they continue. "The FDA has announced that it will conduct an advisory committee meeting in July 2010 to consider whether to remove rosiglitazone from the market."

The mechanisms by which rosiglitazone may cause cardiovascular harm are not clear, the authors note, but could involve increases in low-density lipoprotein (LDL) levels or genetic effects associated with the production of an enzyme linked to plaque rupture.

"The public health implications of these results are considerable. There are more than 23 million persons with diabetes in the United States alone and nearly 300 million worldwide. Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, representing approximately 68 percent of all causes of mortality," the authors conclude. "Although hyperglycemia has been associated with an increased risk of microvascular adverse events, there are now 12 classes of drugs that are approved to lower blood glucose levels, including insulin. Because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify."

Dr. Nissen has received research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Resverlogix, Takeda, Daiichi-Sankyo and Sanofi-Aventis through The Cleveland Clinic Center for Clinical Research in within the last five years. He has consulted for a number of pharmaceutical companies without financial compensation. All honoraria, consulting fees or any other payments from any for-profit entity are paid directly to charity, so he receives neither income nor tax deduction.