A fortnight ahead of a full-on review by US regulators, GlaxoSmithKline’s Avandia is again at the centre of controversy with the release of data from three studies, two of which are negative while the third shows that the diabetes drug appears to be safe.
The safety of Avandia (rosiglitazone) has been called into question since a 2007 meta-analysis published in the New England Journal of Medicine concluded that the drug was associated with a significant increase in the risk of myocardial infarction and an increase in the risk of death from cardiovascular causes. Now, an updated meta-analysis, authored again by Steven Nissen (chairman of the Department of Cardiovascular Medicine at Cleveland Clinic and long-time critic of GSK’s conduct concerning Avandia), claims to “systematically review the effects of rosiglitazone therapy on MI and mortality”.
The study, published in the Archives of Internal Medicine looked at 56 clinical trials involving 35,531 patients, over 19,500 of whom were on Avandia. The findings showed that patients who took the drug had a 28%-39% increased risk of MI compared to control therapy although not for cardiovascular or all-cause mortality. Dr Nissen wrote that 12 classes of drugs are approved to lower blood sugar levels and “because no unique benefits of Avandia use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify.”
A second study, published in the Journal of the American Medical Association and carried out by a team led by US Food and Drug Administration safety official David Graham (another critic of Avandia), looked at data on 227,571 US Medicare patients comparing the GSK drug with Takeda’s Actos (pioglitazone). Those who received Avandia had a 27% higher risk of stroke, a 25% greater risk of heart failure, and a 14% higher risk of dying than patients who took the Japanese drugmaker’s treatment. However the data showed no difference in the risk for heart attack between the two drugs.
Then as night fell in the UK, new data was unveiled at the American Diabetes Association meeting in Orlando which demonstrated that Avandia poses no significant increased risk of death, stroke or heart attack,although it does increase the risk of fractures. The findings came from analysing 4.5 years of follow-up data for patients who were being treated with rosiglitazone, compared to those not taking any thiazolidinediones.
This third study found that while no protective cardiovascular benefit was shown, the rate of death, heart attack and stroke tended to be about 28% lower among patients taking Avandia. As has been seen with other studies of TZDs, the rate of congestive heart failure was significantly higher among patients taking rosiglitazone, but this difference was not statistically significant. There was, however, a 45% increase in fracture rates for those taking Avandia, compared to those not taking any TZD medications.
Lead researcher Richard Bach of the Washington University School of Medicine said “I think these data are important because they suggest there is no significant cardiovascular harm posed by taking rosiglitazone for patients with type 2 diabetes and coronary heart disease”. He noted that there is an increase in fractures, “but when one considers the dramatic morbidity and mortality associated with ischemic cardiovascular events in patients with diabetes, these data are reassuring”.
As for GSK, the company noted that “there are strengths and limitations of each type of analysis that must be considered in their evaluation”. It stressed, however, that “randomised clinical trials remain the gold standard for evaluating scientific and medical questions” and results from six such studies have been reported since the joint advisory committees of the FDA reviewed questions about the cardiovascular safety of Avandia in 2007.
Taken together, GSK says, “these trials show that rosilglitazone does not increase the overall risk of heart attack, stroke or death”. The drugs major added that “we look forward to participating in a rigorous scientific discussion of the data on the cardiovascular safety of rosiglitazone” with the FDA advisory committees on July 13-14.
