GlaxoSmithKline’s type-2 diabetes treatment Avandia is the subject of another unfavourable meta-analysis but a similar study of Takeda’s Actos presents a rosy picture of the latter’s safety profile.

Two new meta-analyses have been published in the September 12 issue of the Journal of the American Medical Association and the one dealing with Avandia (rosiglitazone) makes fairly unpleasant reading for GSK. The Avandia meta-analysis, which included findings from just four randomised trials involved 6421 diabetics who received the GSK drug and 7,870 on control therapy, with a follow-up of one to four years.

The data demonstrated that rosiglitazone significantly increased the risk, by 42%, of myocardial infarction and more than doubled the possibility of heart failure, compared with control therapy. The findings largely mirrored the controversial meta-analysis published in May in the New England Journal of Medicine and authored by Steven Nissen, which claimed that Avandia increased cardiovascular risks, but the results of the latest report also showed that the drug did not significantly increase the risk of cardiovascular mortality.

Nevertheless, Sonal Singh, co-author of the latest meta-analysis, said that “the public heath impact of potential harm with Avandia is substantial" adding that a conservative extrapolation from the number needed to harm seen in the study "would result in an estimated more than 4,000 excess myocardial infarctions and 9,000 excess heart failure events", the authors (Dr Singh, Curt Furberg and Yoon Loke) said.

They added that "health plans and physicians should not wait for regulatory actions" and should avoid using the drug in patients at risk of cardiovascular events, "especially since safer alternatives exist". However GSK was non-plussed and issued a statement saying that “these analyses do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments for their patients”.

The firm added that “this limited meta-analysis, in the context of all the other evidence, we believe it is inappropriate for the author to advise doctors to disregard the US Food and Drug Administration's advice which is to keep patients who are effectively controlling their diabetes on Avandia."

The other meta-analysis published in JAMA, conducted by Dr Nissen and Michael Lincoff, noted that Takeda's Actos (pioglitazone) actually reduced the rate of death, myocardial infarction or stroke by 18%. This involved 19 trials in more than 16,390 patients, the biggest such study of Actos.

The results demonstrated that death, myocardial infarction or stroke occurred in 4.4% of patients who received Actos, compared with 5.7% of patients who received control therapy. However, serious heart failure was reported in 2.3% of those administered the Takeda drug, compared with 1.8% in the control group.

Protective effect of Actos

Dr Lincoff noted that "what we can say about pioglitazone is not only does it not have the detrimental effect that has been seen with rosiglitazone, but it actually has a protective effect." Takeda noted that “this meta-analysis adds important information to the body of evidence regarding Actos and macrovascular ischaemic events, and supports the consistency of data from both observational and prospective studies”.

Dr Nissen suggested that the results from both studies put "pressure on regulatory agencies around the world to take some sort of action of rosiglitazone", but GSK responded by saying that they do not confirm a difference in the safety profile of Avandia and Actos. “These analyses reflect limitations that are common to all meta-analyses, by the authors’ own admission,” the company added, saying that “these analyses do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments”. Comparisons between different meta-analyses with different endpoints and patient populations “are even more unreliable”, GSK concluded.