Expert committees of the United States Food and Drug Administration have recommended that the type 2 diabetes drug rosiglitazone remain on the market but that label warnings and extensive educational efforts about possible adverse cardiovascular effects be instituted immediately.
Chaired by endocrinologist Dr Clifford Rosen, a endocrinological and metabolic drugs advisory committee and a drug safety committee met on 30 July, amidst considerable media and public interest. The 24 experts at the meeting concluded that the use of rosiglitazone was associated with a greater risk of myocardial ischaemic events than placebo, metformin or sulfonylureas.
"That conclusion was based primarily on three independently conducted meta-analyses demonstrating an increase in the relative risk of myocardial infarction, angina or sudden death among patients taking rosiglitazone," Dr Rosen said. The odds ratio of serious ischaemic events was 1.4, increasing from an absolute risk of 0.8% in control patients to 1.0% in those taking rosiglitazone.
There were some caveats to the recommendation including the short duration of most clinical trials, a relatively small number of myocardial events overall, and differences in the adjudication of ischaemic events.
Dr Rosen said one of the most important issues was the lessons for the future development and approval of new medications. Three basic requirements were that the pathogenesis of disorders including type 2 diabetes must be better understood, treatment options should be clarified through evidence-based systems, and a uniform method was needed to assess societal benefits and risks.
The fact that rosiglitazone appeared to increase cardiovascular risk while pioglitazone decreased it indicated there was much more to learn about links between type 2 diabetes, atherosclerosis and thiazolidinediones.
Changes in A1C had proved to be a poor surrogate for cardiovascular outcomes during diabetes treatment, accounting for only 5-15% of the variation in risk. "We urgently need to change the regulatory pathway...to make clinical outcomes, not surrogates, the primary end points," he said. Without such a change, the current situation was certain to be repeated.
Observational postmarketing studies rarely provided definitive answers. Investment in longer and more rigorous clinical trials that assessed clinical outcomes would end up being cheaper and more efficient, by providing clear and durable answers on the risks and benefits of new medications.
Reference
Rosen, C. 2007, 'The rosiglitazone story — lessons from an FDA advisory committee meeting.' New England Journal of Medicine published online.
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