Controversy over the cardiovascular risks of Avandia for Type 2 diabetes

A controversial study reporting that rosiglitazone (Avandia) increases the risk of a myocardial infarction and death from cardiovascular disease was published last week in the journal The New England Journal of Medicine.

In this study, the authors combined the results from 42 randomized-controlled clinical trials. Each study had to last for more than six months, include a control group other than Avandia, and include outcomes data on data myocardial infactions and deaths from cardiovascular disease. The authors reported that Avandia increased the risk of a myocardial infarction by 43% and the risk of death from cardiovascular causes by 64%.

The authors noted that this study had several limitations: 1) results were pooled from trials that were not intended to explore cardiovascular outcomes, 2) definitions of a myocardial infarction were not available, 3) many of the trials were small and of short duration, and as a result there were few adverse cardiovascular events or deaths. As a result, getting to the nittry gritty statistical stuff (switch off now if you want to), the confidence intervals for the odds ratios were wide, causing uncertainty on the magnitude of the harmful effect of Avandia.

Not surprisingly, GSK shares plummeted by 8% on the day that this paper was released on-line. But, GSK’s problems didn’t stop there. The FDA released safety alert for Avandia and advised patients who take it to consult their doctors (http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html). In this report, the FDA mention that GSK provided them with a meta-analysis of 42 studies, which according to the FDA ‘suggested that patients receiving short-term treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy.’

Even worse, the medical director at GSK, has reported that 4,450 patients enrolled in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial, which aims to evaluate the long-term risk of Avandia and other rosiglitazones, have dropped out this week because of these safety concerns.(http://www.nytimes.com/2007/05/26/business/26drug.html). This could result in the trial being stopped early if the target number of patients cannot be reached. This could mean trouble for GSK as the results of this study, if they are positive, would have helped to allay any fears regarding Avandia.

Finally, I note with some amusement that the lead author on the study, Dr Nissen, discloses his affiliation with several pharmaceutical companies, some of whom have competitor products to Avandia, notably Eli-Lilly and Takeda who produce Actos (pioglitazone) also for type 2 diabetes (see the disclosure stament from Dr Nissen below). One has to wonder whether any inherent bias has creeped into this meta-analysis when Dr Nissen was performing his review of the clinical trials. Perhaps it should have been performed by an independent body?

‘Dr. Nissen reports receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. No other potential conflict of interest relevant to this article was reported.‘

Source: http://content.nejm.org/cgi/content/full/NEJMoa072761