A class of oral drugs used to treat type 2 diabetes may worsen the risk of heart failure and cardiovascular disease, according to an editorial published online in Heart Aug. 27 by two researchers from Wake Forest University School of Medicine in Winston-Salem, N.C.
"We strongly recommend restrictions in the use of thiazolidinediones [the class of drugs] and question the rationale for leaving rosiglitazone on the market," wrote Sonal Singh, MD, assistant professor of internal medicine, and Curt D. Furberg, MD, PhD, professor of public health sciences. “At this time, justification for use of thiazolidinediones is very weak to non-existent.”
Rosiglitazone (Avandia from the London-based GlaxoSmithKline) and pioglitazone (Actos from Osaka, Japan-based Takeda) are the two major thiazolidinediones in question which were approved for use based for use based on their FDA-approved indication to reduce blood sugar.
About 22 percent of diabetics have heart disease. Diabetics experience elevated rates of high blood pressure and high levels of cholesterol and triglyceride, which "further compound their already increased risk of developing ischemic heart disease," according to Singh and Furberg.
They added that heart disease and high blood pressure "are major precursors of congestive heart failure." Among elderly patients with diabetes, more than half will develop congestive heart failure over a 10-year period, the editorial noted.
In the June 2007 issue of Diabetes Care, the authors reported that “thiazolidinediones doubled the risk of congestive heart failure in patients with type 2 diabetes. The increased heart failure appears to be a class effect.”
In the Journal of the American Medical Association in 2007, Singh and Furberg found that after an analysis of four long-term trials, the use of rosiglitazone was associated both with increased heart attacks and a doubling of heart failure.
They said that the results from three large randomized clinical trials published in June of this year all failed to demonstrate that intensive control of blood sugar reduces mortality or events from cardiovascular disease in patients with type 2 diabetes.
The three trials were ACCORD, ADVANCE and Veterans Affairs (VA) Diabetes:
- In ACCORD, the patients who received intensive treatment to control blood sugar actually had more cardiovascular disease mortality than patients receiving standard treatment.
- In ADVANCE, intensive control of blood sugar produced no benefit; there was no effect on cardiovascular events or deaths from cardiovascular causes compared to standard oral diabetes agents.
- In the VA Diabetes trial, when intensive blood sugar control produced levels of blood sugar that were too low and led to loss of consciousness, that was a strong predictor of future cardiovascular events.
"The unfavorable findings from the three trials have not been fully realized by the medical community," Singh and Furberg wrote.
At a recent FDA advisory committee meeting, the authors said that there was overwhelming support for requiring heart disease and heart failure reductions before approving new oral hypoglycemic agents.
“Safer, cheaper and more effective treatment alternatives are available that do not carry these negative cardiovascular risks in patients with diabetes. The rationale for the use of the thiazolidinediones is unclear,” the authors concluded.