Global Insight Perspective | |
Significance | Separate studies published by the JAMA have concluded that GSK's diabetes drug Avandia increases the risk of heart attack by 42% and increases the risk of heart failure by 109%, while Takeda's (Japan) Actos (pioglitazone) lowers the risk of heart attack, stroke, and death by 18%. |
Implications | Both studies are meta-analyses, which are inherently limited. This means that GSK has been able to defend the safety profile of Avandia, although, predictably, Takeda has flagged up the significance of the Actos study. |
Outlook | Although the studies have led to renewed calls for Avandia to be withdrawn from the market, there is no indication that the U.S. FDA will be distracted from its ongoing review of Avandia's possible increased risk of heart attacks. The adverse publicity may, however, lead to a further downturn in the brand's sales. |
The study on Avandia, which was conducted by researchers at Wake Forest University, concluded that Avandia increased the risk of heart attack by 42% and increased the risk of heart failure by 109% in patients who had been taking the drug for at least a year. However, there was no significant added risk of cardiovascular mortality. Data for the study were compiled from MEDLINE, the GlaxoSmithKline (GSK) clinical trials register, the U.S. FDA website, and product information sheets for randomised controlled trials, systematic reviews, and meta-analyses published in English through May 2007.
The study on Actos, which was conducted by researchers at the Cleveland Clinic in Ohio, concluded that that Actos lowered the risk of heart attack, stroke, and overall death by 18%; these events occurred in 4.4% of 8,554 patients taking Actos, but in 5.7% of 7,836 patients receiving control therapy. However, serious heart failure was found in 2.3% of the Actos-treated patients compared with only 1.8% of the control patients. The study's data, which originated from Takeda, were derived from 16,390 patients enrolled in 19 clinical trials.
GSK and Takeda React to the Findings
Following publication of the two studies, GSK issued a press release stating that it believes that the conclusions "do not confirm a difference in the safety profile of Avandia and Actos". In support of its case, GSK drew attention to the fact that both studies were meta-analyses, and so were limited by nature. The company commented: "These analyses do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments for their patients. Comparisons between different meta-analyses with different endpoints and patient populations are even more unreliable."
Not surprisingly, Takeda endorsed the findings of the study on Actos, commenting: "This new meta-analysis is consistent with the depth and breadth of Actos cardiovascular data: Actos studies, conducted over the past 10 years, including short- and long-term trials, as well as prospective and observational studies, have shown no evidence that Actos is associated with an increased risk of heart attack, stroke, or death."
Outlook and Implications
Following on from the new findings, Dr Sonal Singh, who headed the Avandia study, called for an urgent review to determine whether Avandia should stay on the market. At the same time, he drew attention to the fact that cardiovascular mortality has not been adequately studied. However, despite these latest calls, it is unlikely that the latest studies will distract the FDA from its ongoing review of Avandia's possible increased risk of heart attacks (see Japan: 15 August 2007: FDA Imposes New Black Box Warning on Actos/Avandia Drugs Class), which will ultimately determine the drug's fate.
That said, the continued adverse publicity surrounding Avandia could further damage the drug's sales. By mid-July, Actos's share of the U.S. thiazolidinedione (TZD) market had risen to 67%, from around 50% in May. As the only other TZD available, Avandia's sales had fallen to 33%, although the company reports that its sales have started picking up over the past fortnight.