Rosiglitazone analysis sparks safety controversy

A meta-analysis of studies of rosiglitazone, a drug used in the treatment of diabetes, suggests a significantly increased risk of myocardial infarction (heart attack) and a borderline increased risk of death from cardiovascular causes.

However, the findings, published online on May 21 by the New England Journal of Medicine, have been strongly contested by rosiglitazone’s manufacturer Glaxo SmithKline, and the US Food and Drug Administration says it wants more time to study the data before asking the manufacturer to do anything.

HIV-positive men on antiretroviral therapy are three to four times more likely to be diagnosed with diabetes compared to HIV-negative men, and untreated HIV-positive men have a higher risk of diabetes than their HIV-negative counterparts too, suggesting that antiretroviral drugs are not the sole factor contributing to the development of the condition. A French cohort study found that 10% of people who started protease inhibitor-based therapy had developed diabetes within three years (Saves 2002).

Rosiglitazone is one of the drugs that may be used to treat type 2 diabetes. Marketed in the United States and Europe as Avandia, rosiglitazone is a thiazolidinedione.

Researchers from the Cleveland Clinic in the United States carried out a meta-analysis of data from randomised studies of rosiglitazone in order to determine whether the drug has any effect on death or morbidity due to the microvascular and macrovascular complications of diabetes, since the initial individual studies were not powered to detect these outcomes.

A meta-analysis pools data from multiple studies and submits it to particular statistical analyses designed to take into account some of the differences in design between the studies, in order to arrive at a more `powerful` result.

In the case of the rosiglitazone meta-analysis, Dr Steven Nissen and Kathy Wolski found 42 randomised studies that had lasted more than 24 weeks and which had collected information on cardiovascular events. The trials included 15,560 patients assigned to rosiglitazone and 12,283 patients who received a comparator treatment.

The average age of participants was approximately 56 years, and the mean baseline glycated haemoglobin level was approximately 8.2%. There were 86 myocardial infarctions in the rosiglitazone group and 72 in the control group. There were 39 deaths from cardiovascular causes in the rosiglitazone group and 22 in the control group.

In the rosiglitazone group the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P = 0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P = 0.06) as compared with the control group.

The authors admit that the odds ratios could change if a relatively small number of cardiovascular events had been classified differently. In a press statement Glaxo SmithKline highlighted this problem, saying that large safety studies specifically designed to look for cardiovascular events had so far shown no evidence of a significantly increased risk of myocardial infarction.

Rosiglitazone might increase the risk of cardiovascular disease because it raises levels of LDL cholesterol, which is associated with an increased risk of heart disease. However the studies analysed were generally of short duration, and the short-term elevations in LDL cholesterol seen in these studies are probably not sufficient to explain “the rapidity and magnitude of the apparent hazard,” said the researchers.

They point out that one experimental drug in the same class, muraglitazar, was terminated after an increased rates of cardiovascular events were seen in phase II and III studies.

“PPAR agonists such as rosiglitazone have very complex biologic effects, resulting from the activation or suppression of dozens of genes… 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,” say the researchers.

But they note that pioglitazone, the other anti-diabetes drug in the same class, showed a significant reduction in myocardial infarction and stroke and death from cardiovascular causes, and suggest that effects of drugs on blood glucose measurements may not be the best measure of the effectiveness of anti-diabetes drugs in preventing the most serious consequences of diabetes, such as a greatly elevated risk of death from cardiovascular disease.

The US Food and Drug Administration said yesterday that it would convene an expert advisory board as soon as possible, and in meantime advised patients to discuss with their doctors the new information, “especially those who are known to have underlying heart disease or who are at high risk of heart attack”.