The Avandia scandal

An investigation by the BMJ published this week calls for the withdrawal of the daibetes drug, Avandia, immediately from the market because of the concerns that it may increase the risk of myocardial infarction and the paucity of good evidence to support its use.

Rosiglitazone, also known as Avandia, was GSK's second biggest selling drug, introduced in 1999 and is widely used to lower blood glucose levels in patients with type 2 diabetes. It was approved by the EMA in 2000 despite concerns over its safety.

In 2007, several studies found Avandia having harmful effects and issued serious health warnings. The researchers questioned why Avandia is still available on the market and why physicians would prescribe it to diabetic patients when there are other drugs without these side effects. They called for Avandia to be withdrawn from the market. Since then, the sales of Avandia fell sharply.

The BMJ investigators found that in July, the UK Commission on Human Medicines advised the MHRA to withdraw Avandia as the risks of Rosiglitazone outweigh its benefits. This has raised a lot of questions about the quality of the data used in the studies and the lack of trial results made available to the public. The investigators also ask why the regulators accept such poor evidence on benefit and safety, why patients in the UK and Europe are not make aware of the concerns about this drug and whether the current regulatory body is doing its job properly. They said that doctors are advising that no new patients shoud use this drug, existing diabetic patients should review their options and those at high risk of heart disease should stop taking it.

In the accompanying editorial, the authors said that clinicians had focused on the wrong endpoint and lost sight of the main reason for treating this disease, "which is not to reduce glycaemia but to prevent complications". They went on to say that clinicians need to be "absolutely certain that the long term treatment for type 2 diabetes are not causing the harm they are meant to prevent" and should insist on robust evidence of benefits and harms.

Professor Freemantle noted in the accompanying commentary that the Avandia studies were hindered by inadequate data due to high levels of loss to follow-up. He wrote "In order to learn from our mistakes, we must improve the quality of safety data from clincal trials on all new healthcare interventions, not just antidiabetic drugs" and an overhall in the standards of regulatory trials is needed.


Sources : free f/t
Rosiglitazone: what went wrong? BMJ 2010; 341:c4848 (Published 6 September 2010) Editorial - Licensing drugs for diabetes BMJ 2010; 341:c4805 (Published 6 September 2010)
Commentary: What can we learn from the continuing regulatory focus on the thiazolidinediones?BMJ 2010; 341:c4812 (Published 6 September 2010)

Diabetes drug linked to higher heart attack risk

Avandia and competitor drug, Actos, are commonly used diabetes drugs. Avandia has been found having harmful effects since 2007 while Actos seems safer apparently.

2 studies published last week reported serious health warnings. One study, published in June 28 issue of JAMA, reviewed the data of 227,000 patients takng either Avandia or Actos, found that Avandia increased the risk of heart attack, stroke or death by 17%.

The second study, published in the Archive of Internal Medicine, analysed 56 clinical trials involving 35,000 patients confirmed these findings. The reserachers questioned why Avandia is still available on the market and why physicians would prescribe it to diabetics when there are other drugs without these side effects. They called for Avandia to be withdrawn from the market.

However, some doctors said that the evidence is inconclusive.

Source:
1). David Juurlink. "Rosiglitazone and the Case for Safety Over Certainty". JAMA. 2010;304(4):(doi:10.1001/jama.2010.954). free f/t

2). Steven Nissen; Kathy Wolski. "An Updated Meta-analysis of Risk for Myocardial Infarction and Cardiovascular Mortality". Arch Intern Med. 2010;170(14), free f/t

Diabetes drugs double heart failure risk

More than 1.5 million prescriptions for rosiglitazone (Avandia) and pioglitazone (Actos) were issued in England alone last year, but experts warn these 2 commonly used diabetes drugs could double the risk of heart failure, even for those who have never suffered the condition, in a new study in the journal Diabetes Care.

The two drugs are prescribed to millions of patients to treat type 2 diabetes and approved by NICE for use on the NHS. Experts call for a re-evaluation of the benefits and risks of both drugs in view of the concerns on cardiovascular safety.

Drug agencies urge patients not to panic over research findings and should contact their doctors if concerned. Read more ...

Avandia and pharmacovigilance

An interim analysis published by NEJM added new data to the previous meta-analysis and found that Avandia (Rosigilitazone) is associated with an increased risk of myocardial infarction.

BMJ published an editorial, "Rosiglitazone and implications for pharmacovigilance: postsurveillance data should be systematically collected and publicly available." Kazi D. BMJ 2007; 334: 1233-4 (16 June) and concluded that "the ongoing use of rosiglitazone merits careful deliberation." ( You can access the full text with an Athens password).

The author said that pharmacovigilance is the weakest in the regulatory processes of drug safety on both sides of the Atlantic and called for a radical change in the culture of existing regulatory agencies.

Avandia - an interim analysis

Following the concerns raised about the drug Avandia's heart risk, NEJM has published a report online on 5 June 2007 "Rosiglitazone evaluated for cardiovascular outcomes - an interim analysis " with new data that come from the RECORD trial, sponsored by the drugmaker Glaxo, designed to assess the drug's effect on the heart.

The authors concluded that the interim findings from this study were inclusive, "Rosiglitazone was associated with an increased risk of heart failure", but "the data were insufficient to determine whether the drug was associated with an increase in the risk of myocardial infarction."

Calmer approach to Avandia : The Lancet

Since the NEJM paper ( see posting on 25 May 2007) was published on May 21, frightened diabetes patients flooded their doctors with calls, many patients have stopped taking Avandia or switched to a rival drug Actos although some experts caution there is no urgent need for diabetes patients to stop taking Avandia.

The Lancet published an editorial online on May 23, 2007 to point out that there are important weaknesses in Nisson's meta analysis and call for "a calmer and more considered approach to the safety of Rosiglitazone" in response to the alarm raised by Dr Steven Nisson in NEJM.

According to The Lancet, the 2 most reliable studies to inform decision-making are ADOPT (published by NEJM) and DREAM (published by The Lancet). Although the results of these studies "indicate the need for more reliable information about rosiglitazone's safety", patients should calm down and wait for the results of the RECORD trial, a multi-centre study designed to monitor cardiac risk.

Avandia and myocardial infarction

A leading cardiologist, Steven Nissen, found that Avandia (generic name: rosiglitazone), a diabetes drug, "was associated with significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance."

The study concluded that despite the study's limitation, " patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes."

His findings were based on an analysis of 42 RCTs and published online on May 21 by NEJM. "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes". The article will appear in the June 14 issue of the Journal.

Avandia is a top-selling diabetes drug manufacturered by GlaxoSmithKline, introduced in 1999 and is widely used to lower blood glucose levels in patients with type 2 diabetes mellitus. Nissen’s analysis on Avandia has caused the Glaxo stock down more than 6% in midday trading.

Dr. Nissen is a strong critic on drug safety, he and colleague, Eric Topol, a well-known cardiologist, raised concerns about the safety of Vioxx in JAMA in 2001 that led to the withdrawal of the drug from the market in 2004. Dr Topol lost his job after testimony against the drug manufacturer Merck in federal trial.