Analysis from Datamonitor: after Rezulin — glitazone class still has promising future
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Rapid uptake of glitazones is likely to continue
Rezulin withdrawn from three major markets
The new class of diabetes drugs, glitazones, have been launched amid great physician anticipation and interest. However, the emergence of these drugs has been far from smooth, their most recent setback being the withdrawal of Rezulin (troglitazone), from both U.S. and Japanese Markets, following reports of liver toxicity.
Even so, a new report by Datamonitor, Treatment Algorithms 2000: Segmenting the Diabetes Patient Population, reveals that physicians are likely to continue to use the glitazones, believing them to fulfil much of the unmet need that exists in the treatment of type 2 diabetes.
Rapid uptake of glitazones is likely to continue
Even though Rezulin has now been withdrawn from all major healthcare markets, it is worth noting that this withdrawal has been accompanied by confirmations of the benefits of the glitazone class as a whole. Furthermore, it appears that the U.S. Food and Drug Administration's decision to ask for the withdrawal of Rezulin was based on evidence that the other glitazones, Actos and Avandia, are as efficacious as Rezulin without the same risks of liver toxicity.
FDA has been careful to state that withdrawal of Rezulin is more a reflection of the benefits of Actos (pioglitazone) and Avandia (rosiglitazone) than of the side effects of Rezulin per se. In the press release explaining the withdrawal of Rezulin, the FDA commented, "…we are now confident that patients have safer alternatives in this important class."
Since the withdrawal of Rezulin, the American Association of Clinical Endocrinologists (AACE) has been actively encouraging physicians and patients to consider alternative treatments, such as Actos and Avandia, for treatment of type 2 diabetes. The association reiterates that Actos and Avandia have not been reported to have liver damage effects as often as Rezulin and states that "…the drugs (glitazones) are effective in helping to control the blood glucose levels of patients with diabetes. They can thereby help to prevent devastating complications of diabetes, such as blindness, kidney failure, nerve damage, and amputations."
Physicians interviewed during the course of preparing Datamonitor's report, Treatment Algorithms 2000: Segmenting the Diabetes Patient Population, commented that they believe the glitazones address many of the unmet needs that exist in the treatment of type 2 diabetes. They improve compliance due to a favorable side effects profile and once-daily dosing, and are highly effective when used in combination with other treatments. Furthermore, they uniquely lower insulin resistance. None of the physicians interviewed had experienced any negative effects with the glitazones, and it was commented that they would continue using the compounds until any such effects became evident.
The report reveals that a number of the physicians interviewed believe that the dangers of Rezulin and the potential dangers of the glitazones class as a whole have been largely exaggerated by patient groups and the media. One of the physicians interviewed commented, "Worry about hepatic damage caused by glitazones was driven by media hysteria. We are using glitazones, and use will grow unless significant problems arise."
It therefore seems that while glitazones may be used with more caution than before, at least until the mechanism of Rezulin's adverse reactions are determined, that their use will not be substantially limited by the concerns surrounding the withdrawal of Rezulin. The benefits of the class as a whole still remain, and physicians and associations seem to consider the benefits of the glitazones to outweigh the risks. Indeed it is not at all clear that Rezulin would have been withdrawn from the U.S. market had other safer glitazones not been available.
Rezulin withdrawn from three major markets
As the first glitazone to market, Rezulin had a significant first to market advantage. The compound was able to capture a large pool of patients who were poorly controlled by, or could not tolerate the side effects of, other treatments. However, by October 1997, nine months after the launch of Rezulin in the U.S., 35 post marketing reports of liver injury of various degrees had been received by the FDA. At this time, it was not known whether Rezulin was solely responsible for all the reports of liver failure. Even so, the FDA and Warner-Lambert altered labeling to reflect the possibility of liver toxicity and recommended regular liver function tests for patients taking Rezulin.
Reported incidents of liver toxicity and related complications resulted in the withdrawal of the drug from the UK market in 1998. Since the UK was the first member state for approval of troglitazone in the EU, the compound never became available in the other European markets.
On March 7, 2000, the US consumer group Public Citizen petitioned the FDA to change the labeling on all of the glitazones to include warnings of association with heart failure in addition to liver damage. Public Citizen claimed that Rezulin was notorious for destroying some patients' livers and may also have been linked to 56 cases of heart failure. The organization called a number of times for the FDA to ban Rezulin. In a press release, Sidney Wofle, head of Public Citizen's Health Research Group said, "Do not use Rezulin at all. It is too dangerous. The other two [glitazones] we believe should stay on the market, but…they should not be first-choice drugs." He also commented that "Rezulin is one of the most dangerous drugs on the market."
On March 21 2000, the FDA asked Warner-Lambert to withdraw Rezulin from the US market following at least 61 reports of death and 7 reports of patients requiring liver transplants due to liver toxicity associated with the use of Rezulin. Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, announced that, "…when considered as a whole, the pre-marketing clinical data and post marketing safety data from Rezulin as compared to similar, alternative diabetes drugs indicate that the continued use of Rezulin now poses an unacceptable risk to patients."
For more information: Elisabeth Overend-Freeman, Datamonitor, 1 Park Ave., New York, NY. Tel: 212-686-7400, ext. 765. Fax: 212-686-2626. Email: efreeman@datamonitor.com
Edited by Angelo DePalma
Managing Editor, Drug Discovery Online and Pharmaceutical Online