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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 (see Table 1).1 Presentations by FDA staff members suggested that a subgroup of patients with type 2 diabetes who are at higher risk for these events includes those with long-term nitrate use and those receiving concomitant insulin therapy. Still, there were several caveats inherent in the meta-analyses, including the facts that most of the clinical trials lasted only 6 months (although the two largest trials, which contributed most of the end points, were longer), that there were relatively few myocardial events overall, and that differences existed in adjudication of ischemic events. Ultimately, the committee voted to recommend not that rosiglitazone be removed from the market but rather that label warnings and extensive educational efforts be instituted immediately. The committee also requested further studies, but disconcertingly, none of the several proposed analyses of the ongoing clinical trials is likely to define an absolute risk for myocardial ischemic events in patients with diabetes who are taking this drug.
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It has been 80 years since insulin was discovered and 50 years since sulfonylureas were introduced. Since those developments occurred, tremendous strides have been made in understanding the origins and sequelae of diabetes mellitus. For example, because it accelerates atherosclerosis, type 2 diabetes quadruples the risk of macrovascular disease. And ischemic heart disease continues to be a major cause of death among patients with diabetes. Yet the results of our current therapies fall short of our high expectations for chronic disease management.
For example, we know that in type 1 diabetes, metabolic control can reduce the risk of microvascular complications. On the other hand, the two largest randomized, placebo-controlled trials in patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study and the University Group Diabetes Program, failed to find a significant reduction in cardiovascular events even with excellent glucose control.2 Moreover, we are facing a troubling paradox: preliminary data that were presented at the meeting and published by Gerrits et al.3 suggest that among the thiazolidinediones — a class of drugs that has been shown to improve metabolic control — rosiglitazone may increase cardiovascular risk whereas pioglitazone 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.
Not surprisingly, glycemic control has been the centerpiece of therapeutic interventions in type 2 diabetes for many years. Within the past decade, several new drugs that result in "glycemic durability" — a reduction in the glycated hemoglobin level — have been approved by the FDA. However, change in the glycated hemoglobin level is a relatively poor surrogate for cardiovascular outcomes in type 2 diabetes, accounting for only 5 to 15% of the variation in ischemic risk.2 This finding represents a major dilemma for practitioners, regulatory agencies, and patients who seek the newest and best treatments for this disease.
The controversy surrounding biochemical surrogates versus clinical outcomes was also highlighted at the FDA meeting when the advisory committee reviewed one of the largest randomized trials of rosiglitazone, A Diabetes Outcome Prevention Trial, or ADOPT. In that study, the percentage decrease in glycated hemoglobin was greater with rosiglitazone than with metformin or sulfonylureas, yet the risks of congestive heart failure and cardiovascular ischemia were higher.4 These data 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 end points. This is not a radical proposal: 20 years ago, the FDA shifted its primary efficacy end point for osteoporosis drugs from bone mineral density (a reasonable surrogate for the risk of fracture) to fractures themselves. Without a regulatory sea change with regard to diabetes drugs, we are certain to be in the same position 5 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 chronic disease but that may do more harm than good.
Drugs are approved or removed from the market on the basis of evidence from randomized, controlled trials. In the FDA hearing on rosiglitazone, several meta-analyses (see Table 1) revealed a significant increase in the risk of myocardial ischemic events among patients taking rosiglitazone. However, an interim analysis of the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial, which was designed specifically to assess cardiovascular risk among patients receiving rosiglitazone, failed to demonstrate a similar risk.5 In addition, two large observational studies, one conducted by Tricare for the Department of Defense and one conducted by WellPoint (the largest health insurer in the United States), noted no appreciable signal of increased cardiovascular risk with either of the available thiazolidinediones (see Table 2). The contrasts among the levels of evidence and the results regarding the safety of rosiglitazone raised new questions about relative and absolute risks but also highlighted the weaknesses of observational studies examining events that are common and whose rates are likely to be increased only slightly by a given drug, even in a large cohort (such as that used by WellPoint, which comprised 160,000 patient records).
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The rosiglitazone story thus carries lessons for scientists, practitioners, and regulators alike. One can only hope that the energy generated by the advisory committee meeting will be channeled into improving the open hearing process to better serve all interested parties.
Dr. Rosen chaired the FDA advisory committee meeting on rosiglitazone on July 30, 2007; the views expressed in this article are those of the author and do not necessarily reflect those of the advisory committee or the FDA.
Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly, Merck, and Novartis. No other potential conflict of interest relevant to this article was reported.
Source Information
Dr. Rosen is an endocrinologist and a senior staff scientist at the Maine Center for Osteoporosis, St. Joseph Hospital, Bangor, and the Jackson Laboratory, Bar Harbor — both in Maine.
This article (10.1056/NEJMp078167) was published at www.nejm.org on August 8, 2007.
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