Rosiglitazone ( Avandia ) is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined.
Steven E. Nissen and Kathy Wolski, of Cleveland Clinic, have conducted a meta-analysis on 42 trials met the inclusion criteria.

Data have shown that, as compared with placebo or with other antidiabetic regimens, treatment with Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that was of borderline significance.

However, these findings are based on limited access to trial results from publicly available sources, not on patient-level source data. Furthermore, results are based on a relatively small number of events, resulting in odds ratios that could be affected by small changes in the classification of events.

The mechanism for the apparent increase in myocardial infarction and death from cardiovascular causes associated with Rosiglitazone remains uncertain. One potential contributing factor may be the adverse effect of the drug on serum lipids. The FDA-approved Rosiglitazone product label reports a mean increase in low-density lipoprotein ( LDL ) cholesterol of 18.6% among patients treated for 26 weeks with an 8-mg daily dose, as compared with placebo.
In observational studies and lipid-lowering trials, elevated levels of LDL cholesterol were associated with an increase in adverse cardiovascular outcomes. Thus, an increase in LDL cholesterol of the magnitude observed in the rosiglitazone group may have contributed to adverse cardiovascular outcomes, although the rapidity and magnitude of the apparent hazard was not consistent with an effect produced by lipid changes alone.

Several other properties of Rosiglitazone may contribute to adverse cardiovascular outcomes. Rosiglitazone and other thiazolidinediones are known to precipitate congestive heart failure in susceptible patients.
Congestive heart failure is a physiological state that is associated with an increased intravascular volume. Volume overload increases stress on the left ventricular wall, a factor that determines myocardial oxygen demand. In susceptible patients, an increase in myocardial oxygen demand could theoretically provoke ischemic events.

The administration of thiazolidinediones, including Rosiglitazone, also produces a modest reduction in the hemoglobin level. In susceptible patients, a reduced hemoglobin level may result in increased physiological stress, thereby provoking myocardial ischemia. A study of Rosiglitazone that was conducted in rats reported an increase in the rate of death after experimentally induced myocardial infarction.

Rosiglitazone is not the first PPAR agonist that has been reported to increase adverse cardiovascular events. Muraglitazar, an investigational dual PPAR-alpha and PPAR-gamma agonist, increased adverse cardiovascular events, including myocardial infarction, during phase 2 and 3 testing.
After publication of an analysis of cardiovascular outcomes, muraglitazar was not approved by the FDA, and further development was subsequently halted by the manufacturer.
Development programs for many other PPAR agonists have been terminated after evidence of toxicity emerged during preclinical studies or initial trials in humans.

PPAR agonists such as Rosiglitazone have very complex biologic effects, resulting from the activation or suppression of dozens of genes. The patterns of gene activation or suppression differ substantially among various PPAR agonists, even within closely related compounds. The biologic effects of the protein targets for most of the genes influenced by PPAR agonists remain largely unknown. Accordingly, many different and seemingly unrelated toxic effects have emerged during development of other PPAR agents. Some drugs have provoked multispecies, multi–organ system cancers; others have resulted in rhabdomyolysis or nephrotoxicity. Troglitazone ( Rezulin ) was withdrawn from the market for rare, but sometimes fatal, liver toxicity.

Source: The New England Journal of Medicine, 2007

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