Friday, September 28, 2007

Ensuring drug safety: lessons from the thiazolidinediones

Ensuring drug safety: lessons from the thiazolidinediones


The Lancet, Current Issue, Volume 370, Number 9593, 29 September 2007

In today's Lancet, Rodrigo Lago and colleagues add to the ongoing analysis of the safety of thiazolidinediones for control of hyperglycaemia. Initial concerns about the cardiovascular risks of one of the thiazolidinediones, rosiglitazone, erupted in a firestorm of controversy when a meta-analysis by Nissen and Wolski was published online in the New England Journal of Medicine in May. Nissen and Wolski found that rosiglitazone (Avandia, GSK) was associated with a significantly increased risk of myocardial infarction, and a risk of death from cardiovascular causes that was of borderline statistical significance. The authors acknowledged that their analysis was limited by the public availability of trial results and a lack of access to patient-level data, and that the pooled studies were not designed to assess cardiovascular outcomes. But they concluded that the risks of rosiglitazone use in diabetes should be carefully considered by both doctors and their patients.

Response to these findings was swift. An editorial that accompanied the paper, while acknowledging the findings' “fragility”, called for urgent regulatory action; GSK vigorously defended its product, saying that studies show Avandia's cardiovascular profile to be comparable to other oral antidiabetes agents; and this journal counselled against a rush to judgment, advising patience until the final results of RECORD, a phase III trial designed to assess cardiovascular outcomes, were available. Media coverage was extensive. A US Congressional hearing was hastily called, as was a Food and Drug Administration (FDA) Advisory Committee meeting. The Congressional hearing was a spectacular display of partisan agendas and bipartisan ignorance. The FDA meeting resulted in a 22 to 1 vote to keep Avandia on the market, and to add a “black box” warning on the label of the risks of the drug's use in patients with congestive heart failure. If this sequence of events sounds familiar, it is because a nearly identical path was trodden when the safety of selective cyclo-oxygenase 2 (COX-2) inhibitors was called into question. Then, as now, the question was about the drugs' cardiovascular effects.

Other analyses of the thiazolidinedione have followed the NEJM paper, including two papers that appeared in JAMA on Sept 12, one on the risk of cardiovascular events with pioglitazone, the only other available agent in the thiazolidinedione class (Actos, Takeda), and one assessing long-term cardiovascular risk with rosiglitazone. Here, both drugs were associated with an increased risk of heart failure, though without an associated increase in mortality. This is the same conclusion reached by Lago and colleagues: patients taking thiazolidinediones seem to have a higher risk of congestive heart failure, but do not have a higher risk of death from cardiovascular causes.

Is there then a bottom line to all these bits of evidence? What should doctors and patients do? Is there in fact enough good evidence on which to decide anything? It seems that the jury is still out for the thiazolidinediones as a class. But there are many interim take-home messages. Some of these are highlighted by Comments in today's issue. First, it must be remembered that meta-analysis is a technique with important limitations. And the studies on which the thiazolidinedione meta-analyses are based have thus far all involved surrogate markers; the studies were not designed to assess cardiovascular outcomes, but rather improved glycaemic control. This outcome, as Victor Montori and colleagues note, is not a patient-centred one. The current clinical emphasis on glucose control (as measured by HbA1c) skirts the outcomes that matter most to patients—microvascular and macrovascular complications, quality of life, and survival.

These commentators highlight issues that must be taken into account in the ongoing debate about thiazolidinediones. Future trials ought to be designed with these issues firmly in mind. Further, it is no secret that the regulatory system is also in urgent need of repair. Manufacturers must do—in a timely fashion—postmarketing studies that assess the long-term safety of their drugs, and regulatory agencies must hold manufacturers' feet to the fire to ensure that these are performed, performed properly, thoroughly evaluated, and made available to guide decisions about prescribing. Agencies like the US FDA must have the resources and authority to close what is now a potentially dangerous gap. Unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the thiazolidinediones might simply become the latest in a series of preventable drug disasters.

The Lancet

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