More Damning Data on Rosiglitazone

March 21, 2011

March 21, 2011 (Norwich, United Kingdom) — A new meta-analysis of observational studies has provided more evidence that the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) is associated with a higher risk of heart failure, MI, and death than a similar agent, pioglitazone (Actos, Takeda) [1].

But despite having been taken off the market in Europe, the risk evaluation and mitigation strategy (REMS) for rosiglitazone recommended by the FDA last September has still not been put into place in the US. Dr Steven Nissen (Cleveland Clinic, OH), who conducted the original meta-analysis suggesting cardiovascular harm with rosiglitazone, is particularly angry about this.

He commented to heartwire : "This latest study confirms what we have now known for years, that rosiglitazone increases cardiovascular risk compared with pioglitazone. Unfortunately, six months after the FDA promised to restrict access to rosiglitazone, it has failed to complete this action. I am concerned that the FDA announcement was designed to appease critics of the drug, but without any real change in regulatory policy. As a result, Americans continue to be exposed to a drug that has been forcibly removed from the market in Europe. When . . . new drugs are approved, companies move like lightning. This lack of action by FDA is shameful."

According to a GlaxoSmithKline spokesperson, the FDA has previously announced that it expects to approve the REMS program by spring 2011; there are approximately 90 000 patients in the US who are currently taking rosiglitazone, according to company numbers.

One of the authors of an editorial accompanying the new meta-analysis [2], Dr Victor Montori (Mayo Clinic, Rochester, MN), told heartwire that the rosiglitazone saga represents "everything that is wrong with the US healthcare system." He added: "New drugs have an uncertain risk profile and should be used very cautiously, but the opposite often occurs. New drugs are heavily promoted, and many doctors prescribe them too enthusiastically, giving them out almost like water. The limited patent life of a new drug works against a cautious approach, with the companies desperate to make their profits early on. But whose interests are we putting first here? Certainly not those of the patients. Patients will start to lose trust in their doctors if we continue on this path. Healthcare has become just another industry. This is far from the utopia of human progress we want. We need a revolution."

The Latest Data

The latest research, published online March 17, 2011 in BMJ, was conducted by a group led by Dr Yoon Kong Loke (University of East Anglia, Norwich, UK).

They note that meta-analyses of randomized controlled trials have suggested an increased risk of ischemic cardiovascular events with rosiglitazone, but similar analyses of trials of pioglitazone suggest the possibility of an ischemic benefit. As no long-term trials with cardiovascular outcomes have directly compared these two drugs, Loke et al decided to look at observational studies that directly compared the risk of cardiovascular outcomes for rosiglitazone and pioglitazone among patients with type 2 diabetes mellitus.

The meta-analysis included 16 observational studies involving 810 000 patients taking either rosiglitazone or pioglitazone. Results showed that compared with pioglitazone, use of rosiglitazone was associated with a statistically significant increase in the odds of MI, heart failure, and death.

Risk of MI, CHF and Death With Rosiglitazone vs Pioglitazone

Event Odds ratio (95% CI) p
MI 1.16 (1.07–1.24) <0.001
CHF 1.22 (1.14–1.31) <0.001
Death 1.14 (1.09–1.20) <0.001

Numbers needed to harm, depending on the population at risk, suggest 170 excess MIs, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone.

The authors note that this synthesis of data from observational studies extends the findings of a cardiovascular hazard with rosiglitazone from meta-analyses of clinical trials to real-world settings and suggests the possibility of a cardiovascular difference between the two drugs.

Both Glitazones Have Too Many Side Effects

In their editorial, Montori and Dr Nilay Shah (Mayo Clinic, Rochester, MN) point out that both glitazones can improve glycemic control, "but weight gain, MI (for rosiglitazone), heart failure, bone fractures, possibly bladder cancer (for pioglitazone), and higher out-of-pocket costs should restrain the thoughtful prescriber."

They add that in the occasional patient with uncontrolled diabetes and symptomatic hyperglycemia who is unable or unwilling to take insulin, pioglitazone may offer an acceptable compromise, but this group is "too small . . . to justify the position of pioglitazone as the eighth leading prescription drug in the US, with total sales of $3.4 billion in 2009."

To heartwire , Montori commented: "We have never used either agent much at the Mayo Clinic. But in other states, their use has been quite high, and I suspect it may still be. There is a whole range of alternatives that have the exact same effect on blood sugar without so many side effects. When we explain all this to patients, they tend to choose other agents."

Noting that more caution is needed when selecting antihyperglycemic agents, the editorialists point out that this has not been taken to heart, as the newest diabetes agents--dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagonlike peptide 1 (GLP-1) agonists--were approved relatively quickly, and DPP-4 inhibitors accounted for more than 14% of the diabetes drug market in 2010, "even though not one study supports the long-term efficacy (in reducing diabetes complications) or safety of these agents."

They end by asking: "Has the corruption of healthcare advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?"

GlaxoSmithKline Responds

In a statement on the BMJ paper, GlaxoSmithKline noted that many of the 16 observational studies included in this meta-analysis were also considered by the FDA, which concluded that, because they were largely dissimilar, "they should not be pooled into a single meta-analytic estimate." The company adds that definitive conclusions about differences in cardiovascular data of the two drugs are hard to make in the absence of long-term trials directly comparing both medicines. 

It points out that last month revisions were made to the US label for all rosiglitazone-containing medicines to include additional warnings and restrictions, and it is working closely with the FDA to finalize the REMS program. To heartwire , a GlaxoSmithKline spokesperson added: "A draft of the proposed REMS program was submitted in late 2010, within the timeframe requested by the FDA."

GlaxoSmithKline added that it "stands behind the safety and efficacy of Avandia when used appropriately. Since 2007, results from six randomized clinical trials with data related to the cardiovascular safety of Avandia have been reported. Taken together, these trials showed that Avandia does not increase the overall risk of heart attack, stroke, or death."

The authors of the meta-analysis and editorial report no disclosures. Nissen has previously disclosed receiving research support through his institution from Pfizer, AstraZeneca, Novartis, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly and reports that he consults for many pharmaceutical companies and requires them to donate all compensation directly to charity.

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