Rosiglitazone linked to MI, CV death

Meta-analysis shows higher odds ratios of MI and cardiovascular death among patients given diabetes medication.

Issue: June 2007

Rosiglitazone has been linked to a greater risk for myocardial infarction and cardiovascular death.

Steven E. Nissen, MD, chairman of the department of cardiovascular medicine, Cleveland Clinic, and Kathy Wolski, MPH, a statistician at the Cleveland Clinic, observed an increased odds ratio of 43% for MI and 64% for cardiovascular death among patients who took rosiglitazone compared with other diabetes drugs or placebo, according to the results of their meta-analysis.

The investigators conducted the meta-analysis using published literature, the FDA website and Glaxo SmithKline’s clinical trials registry for studies (n=42) that lasted longer than 24 weeks, used a randomized control group and had available outcome data for cardiovascular events and death.

GlaxoSmithKline disputed the results from the meta-analysis. The manufacturer said a meta-analysis is “not the most rigorous way to reach definite conclusions about adverse events.”

Nissen and Wolski stand by their results. “I have no hidden agenda. I just want to do what is right for patients,” Nissen told Endocrine Today.

In all, there were 86 reports of MI (OR=1.43; 95% CI, 1.03-1.98) and 39 reports of death related to cardiovascular causes (OR=1.64; 95% CI, 0.98-2.74) in patients who used rosiglitazone compared with 72 reports of MI and 22 reports of cardiovascular-related death in controls. These numbers are of borderline significance, according to Nissen.

Rosiglitazone may be capable of provoking MI or cardiovascular death in patients even after short-term exposure, the investigators wrote in The New England Journal of Medicine.

Initial studies of rosiglitazone were not powered to determine risks associated with cardiovascular events. However, Nissen and Wolski said these data are important because more than 65% of deaths in patients with diabetes are cardiovascular-related.

The possibility of associated cardiovascular benefit seems remote, according to Bruce M. Psaty, MD, PhD, and Curt D. Furberg, MD, PhD, who wrote an accompanying editorial. They said there seems to be no clear rationale for prescribing rosiglitazone at this time.

Nissen and Wolski acknowledged that their analysis was limited by a lack of access to original source data, which would have enabled time-to-event analysis.

In 2006, the FDA updated the drug label and included new information about potentially increased risk for MI and chest pain. Also included on the label are reports of possible heart failure and other cardiovascular problems when the drug is taken with insulin. Rosiglitazone has been shown to raise LDL cholesterol by roughly 18%, which can contribute to the increased risk for MI, according to the investigators.

The results do not indicate a class effect with thiazolidinedione drugs, according to Nissen. Additionally, rosiglitazone is not the first peroxisome-proliferator-activated receptor reported to increase cardiovascular events. Muraglitazar also demonstrated a higher risk for MI and was withdrawn in 2005.

According to the FDA, trials like ADOPT and DREAM showed contradictory results and a lower risk for cardiovascular events with rosiglitazone.

National attention

GlaxoSmithKline argued that it has been consistent in sharing safety data with the FDA and the public through its clinical trials register. However, GlaxoSmithKline’s disclosure of safety data on rosiglitazone from clinical trials was insufficient, according to Nissen and Wolski.

“The manufacturer has all the source data for completed clinical trials and should make these data available to an external academic coordinating center for systematic analysis,” Nissen and Wolski wrote. “Further analyses of data available to the FDA and manufacturer would enable a more robust assessment of the risks of this drug.”

Psaty and Furberg wrote that this “represents a major failure of the drug-use and drug-approval processes in the United States.”

“Patients should not stop any drug on the basis of a news report. Hopefully physicians will read the manuscript carefully, come to their own conclusions and will do what they feel is best for their patients,” Nissen said. The FDA recommends that physicians discuss treatment options with concerned patients, as well.

At this time, the FDA has not asked the manufacturer to take any specific action. More in-depth analyses will look at these data. Thus far, the FDA has not confirmed any clinical significance of the reported increased risk.

“The FDA is in a quandary. They tend to be slow in reacting to these things. I don’t think this is a time to be cautious because there are a lot of people at risk here,” Nissen said. – by Katie Kalvaitis

For more information:
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; doi: 10.1056/NEJMoa072761. Accessed May 24, 2007.
Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;doi: 10.1056/NEJMe078099. Accessed May 24, 2007.