Experts Debate Future of Rosiglitazone in the Wake of Critical Senate Report

February 24, 2010

February 24, 2010 (Silver Spring, Maryland) — A massive document released late last week, the result of a two-year investigation into rosiglitazone (Avandia, GlaxoSmithKline) by the Committee on Finance of the US Senate, once again highlights the health risks associated with the use of the drug but provides very few surprises or new information to those familiar with the controversial thiazolidinedione (TZD) [1].

"I think the findings are consistent with what we and others have documented previously," Dr David Juurlink (University of Toronto, ON) told heartwire . "We know that this class of drugs, both rosiglitazone and pioglitazone (Actos, Takeda Pharmaceuticals), can cause heart failure, but the real question for a patient who is going to be prescribed one of these drugs is, Is there any reason to use rosiglitazone over pioglitazone? In my mind, the answer is no. There is an abundance of evidence suggesting that rosiglitazone is less safe than pioglitazone. There is not a single study that suggests the converse."

Juurlink, the lead author of a study published in 2009 in BMJ, reported by heartwire at that time, previously showed that the risk of dying or being hospitalized with heart failure was lower among older diabetic patients taking pioglitazone than among those taking rosiglitazone [2]. The data, from a retrospective analysis of outpatient data in Ontario, Canada, led him to suggest to heartwire at the time that the evidence was convincing enough to avoid using the drug altogether. Data have also continued to accrue linking rosiglitazone with an increased risk of MI.

There is an abundance of evidence suggesting that rosiglitazone is less safe than pioglitazone. There is not a single study that suggests the converse.

"Even if you were skeptical of the data, I have yet to hear anyone offer a cogent explanation for justifying the use of rosiglitazone," he said. "It's all well and good to say that these comparisons are indirect or are based on observational data, but I think the suggestion that we need a large, randomized, controlled trial to sort this out once and for all is ludicrous. What is the justification for that sort of trial?"

More Questions for Glaxosmithkline About Rosiglitazone

Released over the weekend by Committee on Financechair Sen Max Baucus (D-MT) and ranking member Sen Chuck Grassley (R-IA), the report concludes that there are "serious health risks associated with Avandia." The report also takes aim at the Food and Drug Administration, criticizing the structure of the agency, because those who make decisions about drug approvals are the same experts who must later oversee drug safety.

In addition, the report has strong words for GlaxoSmithKline, saying the company failed to disclose the cardiovascular risks to clinicians and patients. The report includes more than 250 000 pages of documents provided by the company, the FDA, and several research institutes, as well as interviews with numerous people at GlaxoSmithKline, the FDA, and "anonymous whistleblowers."

In one of the accompanying documents, Drs David Graham and Kate Gelperin, both with the FDA, conclude that rosiglitazone should be removed from the market. Others believe the drug should remain available because the existing evidence is contradictory.

The 2007 Meta-Analysis

Concerns about the cardiovascular safety profile of rosiglitazone gained widespread attention with the publication of a 2007 meta-analysis by Dr Steven Nissen and Kathy Wolski (Cleveland Clinic, OH), a study reported by heartwire [3]. In that analysis of 42 trials, the use of rosiglitazone was associated with a 43% increased risk of MI and a borderline but statistically insignificant 64% increase in risk of cardiovascular death.

Commenting on the Senate report for heartwire , Dr David Nathan (Harvard Medical School, Boston, MA) said that while the conclusions aren't too surprising, he was surprised at the extent of criticism directed toward the company and the FDA.

"I think the document is surprising in how hard it hits the FDA and GlaxoSmithKline with regard to their pursuit of this issue," said Nathan. "Many of us who have opined on this issue since 2007, though, basically swore off rosiglitazone, because even though the results were inconclusive and still remain inconclusive--there are no new data to shed enormous light on this topic--there is enough concern regarding rosiglitazone and its possible effect on myocardial infarction. Most of us said we weren't going to use it. I have to say that I wasn't using it a lot anyway."

Speaking with heartwire , Nissen was direct, saying, "It is time to pull the drug.

It is time to pull the drug.

"We have a safe drug in the class with pioglitazone," he said, "and nearly all the data suggest that rosiglitazone increases the risk of myocardial ischemic events. Given that you have two drugs in the class, one of which is harmful and one of which is helpful, why would you keep the harmful drug on the market? The drug has lost sales, but it's still a billion-dollar drug."

In response to the Senate report, GlaxoSmithKline issued a press release rejecting the conclusions. In the release, the company writes that conclusions about the drug's safety "are based on analyses that are not consistent with the rigorous scientific evidence supporting the safety of the drug" and "cherry-picks" information, mischaracterizing GlaxoSmithKline’s efforts to research the drug.

Intrigue in the Corporate Offices of GlaxoSmithKline

Like a story pulled straight from the pages of an undercover-detective novel, the New York Times yesterday reported on the details of a private meeting that took place between Nissen and GlaxoSmithKline executives [4].

Meeting in 2007, just a week before his meta-analysis was to be published in the New England Journal of Medicine (NEJM), Nissen secretly recorded the meeting out of fears he would face pressure from the company. In the taped conversation, Nissen, who shared the recording with the Times, said GlaxoSmithKline wanted him not to publish his study and wait for the results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial instead.

According to the Times article, Dr Ronald Krall, the company's chief medical officer, almost predicts the final results of that study, even though the results should not have been known at the time. At one point, he asks Nissen what he would do if, hypothetically, RECORD showed a hazard ratio of 1.12, which was very close to the 1.11 hazard ratio for hospitalizations or death from cardiovascular causes that RECORD did show.

Krall denies knowing the results of RECORD, saying he did not learn of them until later.

Equally strange, the meeting played out with GlaxoSmithKline having inappropriately seen the full results of Nissen's yet-unpublished meta-analysis, although neither party discussed the results. As reported previously, Dr Steven Haffner (University of Texas Health Science Center at San Antonio), a peer reviewer for the NEJM meta-analysis,leaked the paper to the company weeks ahead of publication.

The NYT article also notes that in the Senate report, GlaxoSmithKline is taken to task by Congress for threatening researchers critical of the drug's safety profile. For example, the company complained to the supervisors of Dr John Buse (University of North Carolina, Chapel Hill), a researcher who also gave presentations warning of rosiglitazone's risks.

The Other Side of the RECORD

Also weighing in, and providing a different take on the Senate report, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) said he did not find Gelperin and Graham's arguments for pulling rosiglitazone off the market compelling. Like others, Kaul was critical of the Nissen meta-analysis when it was published and actually failed to find an increased risk when he performed his own analysis of the data [5]. He said the evidence is contradictory, and as a result it is impossible to determine the safety and efficacy of rosiglitazone with certainty. 

Kaul is also a member of the American Heart Association/American College of Cardiology writing committee that issued an advisory February 23, 2010 on diabetes drugs and cardiac risk [6]. In that joint advisory, the authors reiterate the inconclusiveness regarding the data about the cardiovascular risks associated with rosiglitazone and pioglitazone. They say that the drugs should continue to be used by patients with "close monitoring" from their physician.

To heartwire , Kaul said rosiglitazone should be a teaching opportunity for the FDA on drug approvals.

"The Avandia story underscores the current shortcomings inherent in drug evaluation and approval," he said. "It also makes a compelling argument for lifecycle evaluations. Nearly 11 years have passed since Avandia was first approved, and we still have no idea regarding its benefit or harms on cardiovascular outcomes."

Dr Michael Farkouh (Mount Sinai School of Medicine, New York), who wrote an editorial with Dr Valentin Fuster (Mount Sinai School of Medicine) calling the Nissen meta-analysis a "rushed and incomplete examination" [7], said the best level of evidence to date is derived from the RECORD trial [8], published last year in the Lancet and reported by heartwire at that time.

The Avandia story underscores the current shortcomings inherent in drug evaluation and approval.

"It's a very difficult subject because there isn't clear evidence that there is excess risk," said Farkouh in an interview with heartwire . "The trials pretty much rule out a benefit, but excess risk was not borne out in the large outcomes trial. When we look at levels of evidence, of course, randomized trials have the highest levels of evidence. Large outcomes trials really provide us with the best evidence, and in that trial there was not an excess risk of myocardial infarction."

When presented in 2009 at the American Diabetes Association meeting in New Orleans, RECORD investigators showed there were no significant differences between treatment groups in risk of the individual end points of cardiovascular death, MI, or stroke, although the hazard ratio for MI was elevated by a nonsignificant 14%. At the time, lead RECORD investigator Dr Philip Home (Newcastle University, Newcastle upon Tyne, UK) was cautious in his interpretation of the results but ultimately concluded there were no reasons to distinguish rosiglitazone from other oral antiglycemic agents.

Regardless, RECORD was criticized by some who consider the trial flawed, especially since the study was an open-label design and underpowered for cardiovascular events.

"The RECORD trial was designed to show that rosiglitazone had a benefit," said Nathan. "The results, with regard to myocardial infarction, still went in the wrong direction. The problem is with the study itself: it was underrecruited, and there were too few events. So the one direct study with rosiglitazone to date, with regard to cardiovascular disease, was underpowered. I think the authors came to those conclusions, too. Whether that's enough to have the FDA remove the drug or whether it means we shouldn't be using this drug because of the data, well, that's a tough call."

Whether that's enough to have the FDA remove the drug or whether it means we shouldn't be using this drug because of the data, well, that's a tough call.

Farkouh, although he feels the strongest evidence to date is from the RECORD trial, believes the data still favor pioglitazone considering rosiglitazone's lack of cardiovascular benefits and questionable risk. Most of his patients who can tolerate rosiglitazone can also tolerate pioglitazone, so they have been switched over. He expects rosiglitazone will be relegated to a "back-room" drug but that it should remain on the market because it is an alternative for specialists looking to treat select patients, such as those who can't tolerate other agents or have trouble achieving glycemic control.

"Practically speaking, as a doctor who specializes in cardiology and diabetes, the totality of the evidence has directed us away from Avandia and toward pioglitazone," said Farkouh. "Pioglitazone just has more favorable outcomes, including surrogate outcomes and in large outcome trials, such as PROactive."

When Will the TIDE Come in?

In 2007, a black-box warning was added to the US labeling for rosiglitazone, stating that it was associated with an increased risk of myocardial ischemic events, such as angina or MI, but that, "in their entirety, the available data on the risk of myocardial ischemia are inconclusive."

In the wake of the new labeling, the FDA mandated a new study to compare the cardiovascular risks of rosiglitazone and other diabetes drugs. The result was the ongoing Thiazolidinediones Intervention with Vitamin D Evaluation (TIDE) trial, which is comparing rosiglitazone with pioglitazone in type 2 diabetes patients at risk for cardiovascular disease. Concerns, however, have also been raised about this trial, with FDA officials on the record stating this study would be "unethical and exploitative" given the questionable safety of rosiglitazone.

To heartwire , Juurlink and Nissen agreed with the FDA assessment of the study, saying that patients should not be exposed to the drug. For Juurlink, the rationale that existing data on rosiglitazone are not definitive is not a good enough reason to continue with the trial. "I think that the TIDE trial is not an ethical one, and patients who are well informed by well-informed and unbiased physicians would be very reluctant to enter such a trial," said Juurlink.

Farkouh and Nathan, on the other hand, called the rosiglitazone-vs-pioglitazone comparison more a corporate decision, one that is unlikely to change the hearts and minds of cardiologists and diabetes experts, because most physicians have switched to pioglitazone based on other evidence.

Frankly, from a clinician's point of view, I don't understand why we would still study rosiglitazone.

"Frankly, from a clinician's point of view, I don't understand why we would still study rosiglitazone," said Nathan. "It's just not worth the effort as far as I'm concerned, but I don't make the drug. I'm sure the company has a very different take on it. On the one hand, I guess there would be some interest in terms of establishing its safety by comparing the two, but on the other hand, as a clinician, I don't get it. . . . I feel bad that we've thrashed the drug without definitive data, but to me, as a clinician, there are other [drug] choices that aren't painted with the same brush."

Currently, the TIDE trial is still enrolling, although one investigator, Dr Henning Beck-Nielson (Odense University Hospital, Denmark), told heartwire that his institution has not yet enrolled any patients in TIDE, and "we will now await the response from the FDA before we consider whether to start."

The Fallout

The whole saga, according to Kaul, should be an important lesson not lost on Congress, the FDA, drug sponsors, the media, or the public. He believes that only provisional approvals should be granted for drugs that clear surrogate–end-point hurdles, as rosiglitazone did in 1999 when it was approved on the basis of improving glycemic control. These conditional approvals would then hinge on the study sponsors conducting large, sufficiently powered safety and efficacy studies designed to address clinical outcomes with cardiovascular disease end points.

"Such lifecycle evaluations might provide effective remedies against the current shortcomings inherent in drug evaluation and approval," he said. "Congress has a shared responsibility along with the FDA to ensure that the sponsors do not renege on their postmarketing commitments of conducting outcome trials in large populations."

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