Scientists at the Center for Drug Evaluation and Research (CDER) at the US FDA have accumulated substantial evidence that the once-popular diabetes drug rosiglitazone (Avandia) can increase a patient's risk of stroke, heart failure, and death when compared to pioglitazone (Actos), which is equally as effective in regulating blood glucose.
Despite this growing evidence, an advisory committee for the Food and Drug Administration met in July to review the mounting literature and voted 20-12 to recommend that rosilglitazone remain on the market with sufficient warnings about the possible risks. A week after the meeting the FDA ordered the maker of rosiglitazone, GlaxoSmithKline, to stop enrolling patients in a study that the company started to compare its drug to pioglitazone. The company can still keep the study going and complete its analysis.
Both rosiglitazone and pioglitazone belong to the drug class known as thiazolidinediones, and they are the only drugs in that class marketed in the US. Earlier studies have reported an increased risk for acute myocardial infarction and stroke in patients taking thiazolidinediones, specifically rosiglitazone. (See “Earlier Studies Find Elevated Cardiovascular and Stroke Risk with Thiazolidinediones.”)
“The whole point of using these drugs is to prevent vascular complications of Type 2 diabetes,” said David J. Graham, MD, MPH, associate director for science and medicine in the CDER division of the FDA.
Dr. Graham led the study, which was published online in June before the print edition of the Journal of the American Medical Association (JAMA). His studies and others have identified an increase in cardiovascular events in patients taking rosiglitazone. There is growing debate about using rosiglitazone given these side effects and the availability of pioglitazone that does not cause similar side effects.
No one is exactly sure about the mechanisms of action of rosiglitazone that lead to this increased risk.
In the JAMA study, Dr. Graham and colleagues reviewed data on 228,000 patients from a national Medicare database who were taking either rosiglitazone and pioglitazone from 2006 to 2009. They looked at outcomes data for myocardial infarction (in patients that made it to the hospital) and stroke, heart failure, and all-cause mortality.
Dr. Graham and his colleagues reported there was a significantly increased risk for stroke, heart failure, and all-cause mortality but not for myocardial infarction in those patients who had been taking rosiglitazone. Patients on pioglitazone did not have an increase in these cardiovascular events.
During a mean follow-up of 105 days, 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, they reported.
Rosiglitazone was associated with a 1.25-fold increase in risk of heart failure, a 1.27-fold increased risk of stroke, and a 1.14-fold increased risk of death compared with pioglitazone.
“We think that myocardial infarction was increased in those taking rosiglitazone also but the majority of people may have died on their way to the hospital and were not counted in our sample,” said Dr. Graham.
Dr. Graham noted that in 2007, GlaxoSmithKline, which manufactures rosiglitazone, agreed to conduct a clinical trial to compare their drug against piogliatazone. The study is still ongoing and Dr. Graham thinks that the whole premise of the study — to prove that rosiglitazone increases the risk for these cardiovascular events — is unethical.
The average age of the patients in Dr. Graham's study was 74. And based on our findings, “it would be unethical to use this drug in elderly people,” he said.
“This drug [rosiglitazone] should be taken off the market,” and is doing more harm than good, said Dr. Graham, who contends that the evidence from observational studies is strong and convincing enough that clinical studies should not be carried out. “It is unethical to test this drug when we know from these observational studies that it increases the risk for cardiovascular problems,” said Dr. Graham. “There is no question about it.”
He said that the problem is that his side of the agency does not have power to remove harmful drugs from the market. “The same people who approve the drugs are the same ones making decisions after these drugs have been on the market,” said Dr. Graham. He said that it is an inherent problem in the regulatory process: the same people are policing their own decisions.
Steven E. Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, called the new study “compelling and robust.” He said that the findings “are not surprising at all,” adding: “One drug is going in the direction of hazard and the other is going in the direction of benefit.”
In a 2007 meta-analysis published in The New England Journal of Medicine, Dr. Nissen reported a 43 percent increased risk of cardiovascular events in patients taking rosigitazone compared to placebo or other diabetes medicines outside of the thiazolidinedione drug class.
“The epilogue of the rosiglitazone story has yet to be written,” David Juurlink, MD, PhD, division head of Clinical Pharmacology and Toxicology, of the Sunnybrook Research Institute at the University of Toronto, wrote in an editorial on the study in the same issue of JAMA. “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.”
The question, Dr. Juurlink added, is why a “physician would choose to prescribe it when there is an available and quite possibly safer alternative.”
The diabetes drug rosiglitazone was found to increase a patient's risk of stroke, heart failure, and death when compared to another drug in the same drug class, pioglitazone, which is equally as effective in regulating blood glucose.
BY JAMIE TALAN
David J. Graham, MD, MPH, associate director for science and medicine in the CDER division of the FDA, has been talking about the problems with rosiglitazone since 2007 when a Steven Nissen, MD, a cardiologist from the Cleveland Clinic published a meta-analysis in the New England Journal of Medicine, comparing the two diabetes drugs. Dr. Nissen reported a 43 percent increased risk of cardiovascular events in studies of patients taking rosigitazone compared to placebo or other diabetes medicines outside of the same class of drugs, thiazolidinediones.
In 2007, following FDA hearings, the class of drugs remained on the market with a black box warning that it should not be used in people with heart failure. Both GlaxoSmithKline's (GSK) rosiglitazone (Avandia) and Takeda's pioglitazone (Actos) carried the warning.
In June, Dr. Nissen's second meta-analysis was released in an online version of the Archives of Internal Medicine. This new study replicated what he found three years ago: that rosiglitazone increased a patient's risk for heart attack.
Dr. Nissen, chairman of the department of cardiovascular medicine, and Kathy Wolski, MPH, 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 other diabetic medicines. 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.
The AAN has partnered with the Health Care Notification Network (HCNN) to provide AAN members an online service that delivers timely neurology-specific FDA-mandated patient safety drug alerts electronically. For more information about the alerts, visit www.hcnn.net . This service is available free to AAN members, but requires registration through the HCCN: www.hcnn.net/registration/AAN/registration.aspx .
Graham J, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. 2010; E-pub 2010 June 28.
Nissen SE, Wolski K, Rosiglitazone revisited: An updated metaanalysis of risk for myocardial infarction and cardiovascular mortality. 2010;170(14); 2010 E-pub June 28.