The recent debate over the cardiovascular safety of GlaxoSmithKline’s Avandia (rosiglitazone) suggests an urgent need to make clinical outcomes, rather than surrogate markers such as glycaemic control, the primary endpoints in the regulatory assessment of drugs for type 2 diabetes.

That is the personal view of Dr Clifford Rosen, chairman of the US Food and Drug Administration advisory panel that evaluated Avandia and other thiazolidinedione antidiabetics on July 30. He also draws a wider conclusion from the findings of two independent observational studies of the thiazolidinediones whose results were presented at the meeting last month.

While more support for Phase IV post-marketing studies has been posited as a means of determining the safety of newly approved drugs, Dr Rosen notes, the “indeterminacy” of the observational study outcomes, due to “the inevitable effects of the many confounding variables inherent in such studies,” illustrates “why this approach alone will neither solve the overriding problems of drug safety nor ultimately help a chronically underfunded federal agency,” he writes in the New England Journal of Medicine.

The joint meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee ended with a 22 to 1 vote in favour of keeping Avandia on the US market. However, the committees also concluded that the use of Avandia in type 2 diabetes was associated with a greater risk of myocardial ischaemic events than placebo, metformin or sulfonylurea antidiabetics. The panel recommended that label warnings (including a black-box warning) and extensive educational efforts to this effect should be put in place immediately.

While the panel also requested further studies on the risks of Avandia, “disconcertingly, none of the several proposed analyses of the ongoing clinical trials is likely to define an absolute risk for myocardial ischaemic events in patients with diabetes who are taking this drug,” Dr Rosen comments.

Macrovascular conundrum

Because it accelerates atherosclerosis, type 2 diabetes quadruples the risk of macrovascular disease, he writes. Moreover, ischaemic heart disease remains a major cause of death among patients with diabetes. Yet “the results of our current therapies fall well short of our high expectations for chronic disease management.”

It is known that metabolic control in type 1 diabetes can reduce the risk of macrovascular complications. However, the two largest randomised placebo-controlled trials in patients with type 2 diabetes (the UK Prospective Diabetes Study and the University Group Diabetes Program) “failed to find a significant reduction in cardiovascular events even with excellent glucose control,” Dr Rosen points out.

Moreover, preliminary data presented at the FDA advisory committee meeting suggested that among the thiazolidinediones – a class of drugs that has been shown to improve metabolic control in diabetes – rosiglitazone (Avandia) may increase cardiovascular risk while pioglitazone (Takeda/Eli Lilly’s Actos) may reduce it.

“Until we have a better grasp of the pathogenesis of atherosclerosis in type 2 diabetes, it will be difficult to design therapies to prevent this complication or even to determine how the currently available agents that act at multiple sites may affect clinical outcomes in very different ways,” Dr Rosen says.

More harm than good

Glycaemic control has been the focus of therapeutic interventions in type 2 diabetes for many years and the FDA has approved several new drugs promising ‘glycaemic durability’ or a reduction in the glycated haemoglobin level, he notes. Nonetheless, this is “a relatively poor surrogate for cardiovascular outcomes in type 2 diabetes, accounting for only 5%-15% of the variation in ischaemic risk.”

The results of the ADOPT (A Diabetes Outcome Prevention Trial) study, which showed that the percentage reduction in glycated haemoglobin with Avandia was greater than with metformin or sulfonylureas while the risks of congestive heart failure and cardiovascular ischaemia were higher, “suggest that we urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary endpoints,” Dr Rosen argues.

This is not a radical proposal, he adds. Twenty years ago the FDA shifted its primary efficacy endpoint for osteoporosis drugs from bone mineral density to actual fractures. “Without a regulatory sea change with regard to diabetes drugs,” Dr Rosen writes, “we are certain to be in the same position five years from now that we are in now: we will again find ourselves in possession of a new wonder drug that is designed to treat a devastating disease but that may do more harm than good.”

There is no doubt that undertaking “true safety and efficacy studies” of new drugs using clinical outcomes as primary endpoints will be costly, he acknowledges. In the long run, though, “these efforts will save time, energy, and money.”