Rosiglitazone and the Case for Safety Over Certainty
Authors: David N. Juurlink
Journal: JAMA (2010)

APPROXIMATELY 10 YEARS AGO, THE THIAZOLIDINEdiones rosiglitazone and pioglitazone were introduced for the treatment of type 2 diabetes. Like their forerunner troglitazone, which was removed from the market following reports of hepatotoxicity, these drugs act on the gamma subtype of peroxisome proliferator-activated receptors (PPAR) in the cell nucleus, resulting in heightened insulin sensitivity and improved glycemic control. Because insulin resistance is a common feature of type 2 diabetes, the biological effects of thiazolidinediones made these drugs appealing to patients with diabetes and to their physicians who were looking for yet another way to avoid the need for insulin. Within a few years, both drugs became multibillion-dollar products despite no direct evidence that they actually prevented the complications of diabetes. As the popularity of rosiglitazone and pioglitazone increased, reports surfaced of peripheral edema and congestive heart failure during treatment. It quickly became apparent that these medications could cause both conditions, which are now thought to result from activation of PPARin the distal nephron, leading to increased reabsorption of sodium and water. The lesson here is that pharmacological tinkering with a nuclear receptor is likely to have consequences anywhere that receptor is expressed. In May 2007, safety concerns regarding the thiazolidinediones attracted widespread attention with the publication of a meta-analysis suggesting that, compared with other treatments for diabetes, rosiglitazone was associated with a 43% higher risk of myocardial infarction (P=.03) and a 64% higher risk of cardiovascular death (P=.06). Several other metaanalyses involving rosiglitazone followed, and while their methods and conclusions varied, these reports provided a relatively consistent message that rosiglitazone might indeed increase the risk of myocardial ischemic events, albeit with an inconsistent message regarding mortality. In contrast, a meta-analysis of 19 trials involving pioglitazone suggested that even though the drug appeared to increase the risk of heart failure, it might reduce the risk of myocardial infarction, stroke, or death. Along with these meta-analyses, several large-scale pharmacoepidemiologic investigations have used health care databases to provide “real-world” data on the safety of the thiazolidinediones. While some of these studies were more rigorous than others and several did not specifically focus on the comparative safety of rosiglitazone and pioglitazone, studies in which these drugs were compared consistently showed that rosiglitazone was associated with greater risk than pioglitazone, or at best, the risks associated with these drugs were not statistically different. In this issue of JAMA, Graham and colleagues report the results of a large cohort study examining the risk of cardiovascular events in 227 571 patients 65 years or older who were treated with rosiglitazone or pioglitazone. The authors found that, compared with pioglitazone, rosiglitazone was associated with an increased risk of adverse cardiovascular events, including heart failure and death. While the overall findings are not novel, this study is large, rigorously conducted, and exceptionally timely. The report by Graham et al has limitations, as the authors note. Like all observational studies, because treatment assignment (in this instance, rosiglitazone or pioglitazone) was not randomized, the findings may reflect unrecognized biases or confounding—potential threats to validity that can be reliably mitigated only by randomization. However, a countervailing observation is that such studies can, when conducted carefully and with respect for their limitations, offer powerful insights into the real-world consequences of drug therapy. This is something conventional clinical trials cannot do.