The much-anticipated results of the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial seem destined to become yet another element in the agent’s controversial history.

Although rosiglitazone did not increase overall cardiovascular hospitalizations or deaths compared with metformin and sulfonylurea, the risk of heart failure doubled among patients taking rosiglitazone, and there were increased heart failure deaths, reports Philip D. Home, DM, chairman of the RECORD steering committee and Professor of Diabetes Medicine, Newcastle University, UK (pictured above).

The study also confirmed previous results indicating that the insulin sensitizer doubles distal fracture risk, particularly in older women. "It’s possible there is a smaller effect on fracture risk in men as well," says Dr. Home.

However, patients treated with rosiglitazone achieved better glucose control, and rosiglitazone was associated with a nonsignificant reduction in fatal and nonfatal stroke. "We suspect that the reduction in stroke death counterbalances the increased heart failure death," Dr. Home adds.

"In overall cardiovascular terms, rosiglitazone is safe. The hazard ratio is virtually 1.0. Would it meet current FDA safety requirements? Yes," says Dr. Home. "The hazard ratio confidence interval was within 20%, and the FDA allows 30%."

Results of RECORD were published online yesterday by the Lancet.

There were too few incidences of myocardial infarction and MI death among RECORD patients to detect a significant association with rosiglitazone. "I agree with the authors," says Steven Nissen, MD, chairman, Department of Cardiovascular Medicine, Cleveland Clinic. "The results of RECORD are inconclusive with respect to the effects of the drug on the risk of heart attack."

Dr. Nissen points out, however, that in the subgroup of RECORD patients with preexisting heart disease, there was a 26% increase (p=0.055) in MI.

In 2007, Dr. Nissen published a controversial meta-analysis in the New England Journal of Medicine showing a significantly increased risk of MI in patients taking rosiglitazone.

Practice implications

"With our most recent treatment recommendations early this year, we took rosiglitazone off the list of agents to use for type 2 diabetes and left pioglitazone as a second-tier agent," says David M. Nathan, MD, chairman of the ADA Consensus Algorithm Committee. "We will look at these results and reconsider."

The Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) study is underway and will directly compare the effects of rosiglitazone and pioglitazone on cardiovascular events. Meanwhile, Dr. Home says that whether to prescribe the agent must be based on the individual patient. "Rosiglitazone should not be used by patients with heart failure, those taking a heart failure medication, or by those at increased risk of fracture."

The agent can be considered in other patients with type 2 diabetes where metformin or a sulfonylurea may also be used. "In my own practice, I determine medications by cost, and the older drugs are cheaper," Dr. Home says.

He adds that rosiglitazone may be more useful in obese patients. "These drugs actually don’t work well in thin people. They work well in heavy people, especially those with a large amount abdominal adiposity," he concludes.