With the publication of two new papers Avandia appears to be caught again between a Nissen and a hard place. In the first paper, FDA official David Graham and colleagues analyze Medicare data and find an increased risk of heart failure, stroke, and death in elderly people taking rosiglitazone compared to those taking pioglitazone. In the second paper, Steve Nissen and Kathy Wolski update their original meta-analysis that ignited the entire Avandia controversy.
The Graham study, published online in JAMA, found that when compared to pioglitazone, rosiglitazone was associated with an increased risk of stroke, heart failure, and death from any cause among elderly people. This is the same paper whose manuscript was made public several weeks ago, as reported by CardioBrief. (Following an internal controversy at the FDA, Graham expressed concern in an email message, also made public, that he would not be allowed to submit the paper in time for publication prior to the July FDA advisory panel on Avandia.)
Along with colleagues from Acumen and CMS, Graham analyzed data from more than a quarter of a million Medicare beneficiaries taking either rosiglitazone or pioglitazone. The authors did not find any difference between the drugs in the rate of MI, but did find a 1.25-fold increased risk of heart failure, a 1.27-fold increased risk of stroke, and a 1.14-fold increased risk of death for rosiglitazone when compared with pioglitazone.
In an accompanying editorial, David 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.”
In their updated meta-analysis, published online in Archives of Internal Medicine, Nissen and Wolski analyzed 56 trials involving 35,531 patients, 19,509 of whom received rosiglitazone and 16,022 who received other medications, and found a significant 28-39% increased risk of myocardial infarction associated with the use of rosiglitazone. There was no increase in the risk of cardiovascular death, however.
Nissen and Wolski write:
“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. 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.”
Here are the JAMA and Archives press releases:
Type 2 Diabetes Medication Rosiglitazone Associated With Increased Risk of Stroke, Heart Failure and Death, Compared to Pioglitazone
CHICAGO—A new study published online today by JAMA shows that among patients age 65 years and older, rosiglitazone (a medication for treating Type 2 diabetes) is associated with an increased risk of stroke, heart failure, and all-cause mortality (death) when compared with pioglitazone (another medication for diabetes). The study was published online today 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 (a class of drugs for treating diabetes) 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, 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 patients were followed for up to three years after the initiation of the medications.
“During follow-up, there were 1,746 acute myocardial infarctions [heart attacks] (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 heart attack 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 AMI (heart attack), stroke, heart failure or death.”
(JAMA. doi:10.1001/jama.2010.920.)
Editorial: Rosiglitazone and the Case for Safety Over Certainty
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.”
(JAMA. doi:10.1001/jama.2010.954.)
New Meta-Analysis Demonstrates Heart Risks Associated With Rosiglitazone
CHICAGO—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, according to a report posted online today that will appear in the July 26 print issue of Archives of Internal Medicine, one of the JAMA/Archives journals. 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 (high blood glucose levels) 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 (heart attack) 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, or “bad” cholesterol) 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.”
(Arch Intern Med. 2010;170[12]:(doi:10.1001/archinternmed.2010.207).
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