Improving Drug Safety Surveillance

Abstract

The thiazolidinediones (TZDs) were introduced to the US market in 1997 as therapies to control hyperglycemia in patients with diabetes mellitus. This class of drugs (agonists of peroxisome proliferator-activated receptor γ) has a wide range of biochemical effects, including lowering blood sugar by increasing insulin sensitivity. The TZDs were adopted relatively rapidly and achieved sales of nearly $3 billion in the United States in 2009. Article see p 538 Rapid increases in TZD use occurred despite accumulating safety concerns about the drugs. The first in the class troglitazone was withdrawn from the US market in 2000 because of evidence that it could cause hepatotoxicity that was in some cases lethal. Subsequently, reports emerged that the 2 remaining TZDs available in the United States (pioglitazone and rosiglitazone, both approved in 1999) were associated with substantially higher risks of fluid retention and heart failure, complications of particularly serious consequence in patients with diabetes.1 However, TZD use remained robust, including among patients with important contraindications.2 Further, the 2 currently available TZDs have varied metabolic effects beyond lowering blood glucose, raising questions about their effects on important cardiovascular outcomes. Both agents modestly lower blood pressure but also cause weight gain and raise low-density lipoprotein cholesterol levels. Further, rosiglitazone significantly raises triglyceride and low-density lipoprotein cholesterol more than pioglitazone.3 Hypotheses about the impact of these metabolic effects on health outcomes were merely speculation until larger clinical studies became available. The cardiovascular effects of pioglitazone were studied in the Prospective Pioglitazone Clinical Trial in Macrovascular Events, a placebo-controlled clinical trial. Although the study had negative findings with respect to the primary composite cardiovascular outcome, a principal secondary end point of death and selected cardiovascular outcomes was significantly improved in patients receiving pioglitazone.4 Although this study was considered by many as inadequate evidence …