Cleveland, OH - The publication earlier this week in the New England Journal of Medicine (NEJM) of a meta-analysis suggesting an increased risk of MI and cardiovascular death with the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]) [1] led to a media furor, with headlines telling of deaths and articles describing irresponsible behavior of regulatory agencies. This has inevitably led to widespread patient panic. Was this justified given that the authors of the meta-analysis themselves admit that their study had severe limitations? Many experts think not.

Rosiglitazone is taken by about seven million people worldwide and brings in sales of more than $3 billion for GlaxoSmithKline. Analysts have warned that these new safety concerns could cut sales by 50%, and shares in GlaxoSmithKline have plummeted

Was the NEJM right to publish?
Several opinion leaders contacted by heartwire expressed concern that the meta-analysis, which was led by Dr Steve Nissen (Cleveland Clinic), was published in such a high-profile journal, with an editorial that fueled the flames [2], when the data were so far from perfect.

Dr Steven Haffner (University of Texas Health Science Center, San Antonio), who was involved in the ADOPT study of rosiglitazone, said the paper needed to be published, but it should have undergone a more extensive review, and there should have been a different editorial with more emphasis on the flaws of the study. "The NEJM was irresponsible to go to [Drs Bruce] Psaty and [Curt] Furberg for the editorial—they were always going to emphasize concerns about drug safety; that's what they do," he commented. "But I'm not surprised this paper was published like this. The three major medical journals are becoming more like British tabloid newspapers—all they lack is a bare-chested woman on page 3," he jibed.

Dr Brian Strom (University of Pennsylvania, Philadelphia) agrees. "Drugs are given because they have benefits. Where there's a scare, people stop taking them. So you can do more harm than good if the scare is not based on correct information. I do believe this meta-analysis should have been published, but a less sensational editorial would have been better," he told heartwire.

Other doctors highlighted the stress caused to patients by all the media coverage of the study. Dr Darren McGuire (University of Texas Southwestern, Dallas) commented to heartwire: "All the sensationalism surrounding this observation has created unnecessary chaos and confusion at the patient level." Dr Jim Meade, a family doctor from Watertown, WI, was more outspoken on this issue: "To say that rosiglitazone might be causing heart attacks and CV deaths is above what this study is powered to do. Now that media attention is drawn to this, though, I have to go through the statistical problems with this study just to reassure all the patients who have called me. This type of hype is making life for doctors harder. It confuses patients, erodes trust, and in the end erodes trust even in the research we rely on."

No need for Molotov cocktails

Haffner said the results of Nissen's analysis were not a surprise, as the two large studies conducted recently with rosiglitazone (ADOPT and DREAM) suggested some increased cardiovascular risk. "The FDA was well aware of the cardiovascular data with rosiglitazone. The cardiorenal advisory board has a calm and sedate head, unlike Steve Nissen. They would have come to the right decision to put a black-box warning on the label, which is what they will still do, in my view. They are not going to pull it from the market. So, the data would have come out anyway, but without so many fireworks. I don't think throwing Molotov cocktails is the way to go about these things."

Don't panic

An editorial published online May 23, 2007 in the Lancet weighs in on the debate, urging calm [3]. It points out that the two most reliable studies to inform decision-making are ADOPT and DREAM. The DREAM study showed MI rates of 0.6% for rosiglitazone group vs 0.3% for controls, and the MI/stroke/cardiovascular composite occurred in 1.2% of rosiglitazone vs 0.9% of control patients, with neither result reaching statistical significance. The only significantly relevant finding in the ADOPT trial was an excess of congestive heart failure episodes for rosiglitazone-treated patients compared with glyburide (22 vs 9 events), the editorial adds.

"Taken together, these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone's safety. But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes. Until the results of RECORD are in, it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses. To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody," the Lancet editorial concludes.

Inaccurate estimate of risk

On the limitations of Nissen's analysis, Haffner explained that one of the main concerns he has is the fact that it used a statistical technique that weighted the studies by the number of subjects included. "This would be acceptable if the studies were of a similar length, but the analysis included two large-scale studies with long-term follow-up and 40 smaller studies with much shorter follow-up. Under these circumstances, the smaller studies have been overweighted," he said.

Haffner added that if the 43% increase in risk shown in the analysis had occurred in the ongoing RECORD study with rosiglitazone, it would have been stopped a year ago. "I think if a proper meta-analysis were done with rosiglitazone, it would probably show some increased risk, but this would not be significant. The hazard ratio would not be 43%—but it may be 30%. That doesn't mean it has a clean bill of health, but it doesn't justify pulling it off the market, either. It's ludicrous to suggest taking a drug off the market based on flawed data showing p values of 0.03 and 0.06."

Strom also feels there has been an overreaction to these data. "Nissen did a good job with the data he had, but this meta-analysis is very far from being definitive. If this is all the evidence they have for harm, then people are overreacting. Yes, this meta-analysis is important—but it should be viewed as raising questions, not providing answers."

Strom makes the point that a meta-analysis cannot deal with studies in which no outcomes were seen, which is why such studies were excluded, but from a safety point of view, these studies give important information. He also highlighted the lack of individual data as a huge drawback. "They recognized this and stated it as a limitation in their paper, but you can't do the correct analysis without the individual data, and maybe they shouldn't have tried. They ended up doing the wrong analysis. These are very borderline findings—p values of 0.03 for MI and 0.06 for CV death, and doing a different analysis could easily have generated a different answer. Their findings are therefore only suggestive at most.

"I'm not panicking about this. I think these drugs are overused, but I do have some patients on rosiglitazone, and I will not take them off it just because of this study. It is an interesting hypothesis but far from conclusive," Strom added.

What is the absolute increase in risk?

McGuire believes a cardiovascular safety signal does exist within the rosiglitazone data set, but he adds that "to present the data as point estimates of risk without the clear context of the absolute signal is irresponsible and alarmist." He explains that the worst-case scenario from these data is that rosiglitazone would elevate risk for MI from 1.4% to 2%. "So, a safety signal—yes. An emergency call to remove the drug from the market and cause global chaos among patients taking the drug? No. At least three large-scale trials currently under way will have much more robust power to evaluate these effects. With this small safety signal, we can afford to wait for the additional data being accumulated."

"These are the data we have-they shouldn't be ignored"

One unlikely source of support for Nissen's paper came from GlaxoSmithKline's CEO, Jean-Pierre Garnier, who told journalists that the controversy was "an overreaction to a publication that was actually quite sensibly written."

But Dr David Nathan (Harvard Medical School, Boston, MA), who was one of the reviewers of the NEJM paper, is not so sure that people have overreacted. "Yes, this was an imperfect analysis. It can't be looked at as definitive, but at the same time the findings shouldn't be ignored," he told heartwire. "GlaxoSmithKline had the opportunity to collaborate, and they chose not to. They say they have more data, but why have they not published it? If they can produce convincing data, we can become more relaxed about this drug. But for the moment all we have is Nissen's analysis," he added.

"I'm advising patients to discuss this with their doctors—there are other choices for the treatment of diabetes. It certainly doesn't make much sense to me to use a drug that is potentially cardiotoxic in a condition that causes heart disease. Given the choice of all the drugs available I would be very cautious about using this medicine," Nathan said.

What about pioglitazone?

And what effect will all this have on the other thiazolidinedione (TZD)—pioglitazone (Actos, Takeda)? Opinions on this also seem to vary. Nathan believes pioglitazone is a better bet than rosiglitazone, as it does not have the same adverse lipid profile. "I don't use a lot of these drugs, but if I do use one it would be pioglitazone. PROACTIVE in my opinion was a terribly done study, but even with its flaws, the data appear to show that, if anything, there may be a protective effect of pioglitazone against heart disease."

Haffner takes a slightly different view on this: "While the PROACTIVE trial with pioglitazone did not suggest harm, it did not show benefit either. All the talk of cardiovascular benefit in this trial has been manufactured. I don't think there is much to choose from between the two drugs. The studies overall have eliminated any idea that TZDs would protect against cardiovascular disease. It's plain now that they don't. I would say that it is not clear if they actually increase risk, as the rosiglitazone data are very thin, but we can definitely now say that they do not protect," he commented to heartwire.

"It's my guess that the TZDs will now start a long decline. These drugs are overused, but we don't have many options, and they do have a place in the treatment of diabetes. Not as first or second line—more like third line. In my view the fracture data will be more damaging to these drugs than the cardiovascular risks. They double the risk of fractures and this is a big fear factor, particularly for older women," Haffner added.

Implications for regulatory process

All the controversy generated on rosiglitazone this week has again focused attention on the process regulating drug approvals and postmarketing surveillance.

On this, Califf says: "Dr Nissen has done us a favor by pressing the issue that we have an inadequate postmarketing system that is falling further behind." And Dr Salim Yusuf (McMaster University, Hamilton, ON) also praises Nissen for demanding new standards in approving drugs. "We need data on both-long term efficacy and safety before these drugs are used widely," he commented.

McGuire points out that while the cardiovascular effects of rosiglitazone remain uncertain, so do those of every drug ever approved for the treatment of diabetes, due to the complete reliance on HbA1c as a registration end point. "We must demand more rigorous appraisal of existing and emerging therapies for diabetes with regard to CV efficacy and safety," he said.

But Strom highlights the difficulties of requiring outcome studies before approval. "The problem is that these studies take a long time to conduct, and we have to ask whether we should deny patients access to the drug while these studies are under way. My view is that these studies should be done, and the drugs should be available while they are being done, but only selectively to patients that really need them. The situation we have now is that new drugs are grossly overused too early."

Congress now involved

The Wall Street Journal (WSJ) reports that the rosiglitazone affair is now moving to Capitol Hill [4]. It says that Sen Charles Grassley (R-IA) has written to the FDA expressing concern that "tens of thousands of excess heart attacks may have occurred" since the FDA began reviewing data from Glaxo's meta-analysis, and he has also sent a letter to Glaxo mentioning "reports that GSK employees silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia." The company has called the suggestion "absolutely false." Democratic Rep Henry Waxman of California said he will hold a hearing on the matter in early June and summon the FDA commissioner, GSK's Garnier, and Nissen.

Meanwhile Europe's main medical regulator, EMEA, said it has already assessed the majority of the studies included in the NEJM paper, and the European Union product information was updated in September 2006 with information about the risk of cardiac events.

Nissen: A public safety net?

Other media coverage surrounding the rosiglitazone saga has focused on Nissen himself. The WSJ chronicled the background to the current study, noting that Nissen first became interested in rosiglitazone after finding that cardiovascular side effects were an issue with a related drug, muraglitazar. After publishing these findings, he received an email from a diabetes expert suggesting that rosiglitazone may have similar issues. Then last year, after seeing signs of cardiovascular problems in the DREAM and ADOPT studies, he started searching for more data, which he found on the FDA and GlaxoSmithKline websites. Cleveland Clinic statistician Kathy Wolski, who helped Nissen with the analysis, describes him in the WSJ article as "a dog with a bone" in his determination to investigate this issue.

As Nissen was also involved in the downfall of Vioxx (rofecoxib, Merck), he is gaining somewhat of a reputation as a drug watchdog. An Associated Press report describes Nissen as a "public safety net," adding: "As criticism of the FDA mounts, Nissen, aided by powerful medical journals and government officials, has become a de facto drug regulator."

Sources
1) Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; DOI:10.1056/NEJMoa072761. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.nejm.org%2F.
2) Psaty B and Furberg C. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; DOI:10.1056/NEJMe078099. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.nejm.org%2F.
3) Rosiglitazone: seeking a balanced perspective [editorial]. Lancet 2007; DOI:10.1016/S0140-6736(07)60787-9 1. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fwww.thelancet.com.
4) Mathews AW. Avandia concerns reopen a wider debate. Wall Street Journal, May 23, 2007, A3.