Rosiglitazone Heart Risk Concerns Renewed

09/12/07 Diabetes Medications, Prediabetes and Impaired Glucose Tolerance, Type II Diabetes, Research, General

When Avandia (generic name rosiglitazone) entered the market patients and physicians were thrilled. The new thiazolidinedione lowered hemoglobin A1C measures by more than 1 percent. However, a New England Journal of Medicine article published in June argued that rosiglitazone increases the risk of heart attacks and heart disease. Today, an article in JAMA reinforced concerns that patients with type 2 diabetes or impaired glucose tolerance who take the medication rosiglitazone appear to be at increased risk for a heart attack or heart failure.

Sonal Singh, M.D., of the Wake Forest University School of Medicine, Winston-Salem, North Carolina, and colleagues reviewed research to examine the risk of heart attack, heart failure, and cardiovascular death with long-term rosiglitazone use. There have been recent reports of serious adverse events with rosiglitazone use, but information available to clinicians on the magnitude and public health impact of these events has been limited. The researchers compiled data from four trials that included 14,291 patients. 

The pooled data from the trials indicated that rosiglitazone significantly increased the risk of heart attack by 42 percent (94 of 6,421 patients who received rosiglitazone versus 83 of 7,870 patients who received control therapy) and doubled the risk of heart failure (102 of 6,421 patients verses 62 of 7,870 patients). Use of rosiglitazone was not associated with a significant increase in risk of cardiovascular death.

“Our findings have potential regulatory and clinical implications," the authors conclude. "These data suggest a reversal of the benefit-to-harm balance for rosiglitazone present at the time of approval. Thus, currently there appear to be much safer treatment alternatives. Regulatory agencies ought to reevaluate whether rosiglitazone should be allowed to remain on the market. Health plans and physicians should not wait for regulatory actions. They should avoid using rosiglitazone in patients with diabetes who are at risk of cardiovascular events, especially since safer treatment alternatives are available.”

In an accompanying editorial, "Cardiovascular Risk and the Thiazolidinediones–Déjà Vu All Over Again?", Daniel H. Solomon, M.D., M.P.H., and Wolfgang C. Winkelmayer, M.D., Sc.D., of Brigham and Women’s Hospital, Harvard Medical School, comment on the findings in this week’s JAMA regarding glycemic control medications and drug safety.

“The previous episode with the selective COX-2 inhibitors and the current one with the thiazolidinediones are instructive for designing a better drug safety system. First, early safety concerns must prompt strong and clear regulatory action. … Second, postmarketing adverse events not frequently observed in premarketing studies should be expected when there is incomplete understanding of the mechanism of action of a drug.”

“Third, after several drugs are available for a given indication, new drug approval should be based on improvement in clinical outcomes, not surrogate measures. … Fourth, the decisions for initial approval of a drug and subsequent continued marketing should by symmetric. … Finally, and perhaps most difficult, safety and efficacy must be explicitly balanced when drugs are being considered for approval or for continued marketing.”

If you have used Avandia, fhis issue is a stark reality for you, not just a print story on a page. Once a drug is approved, the forces regulating its safety are much less active and engaged. It was doctors and researchers that uncovered the apparent problems with Avandia by using large studies generated after it was approved. The FDA has been using this information to try and make determinations about whether or not to keep the medication on the market.