FDA panel recommends expanding on diabetes drug testing to include CVD risk

Issue: August 2008

An FDA advisory committee has recommended that drug companies be required to conduct more testing to ensure there is no increased cardiovascular disease risk in patients taking drugs prescribed for diabetes.

The question was posed to the expert panel that for antidiabetic therapy or biologics without a safety signal, should there be a requirement to conduct a long-term cardiovascular trial or to provide other equivalent evidence to rule out any unacceptable cardiovascular risk. Fourteen panel members voted yes and two voted no.

“The current preapproval process is not sufficient to rule out cardiovascular risk in a disease (diabetes) where cardiovascular morbidity and mortality is so prevalent,” Eric S. Holmboe, MD, senior vice president of quality research and academic affairs at the American Board of Internal Medicine in Philadelphia, said after his yes vote during the meeting. “This decision makes good clinical sense, because if [a drug] causes unexpected harm, that could definitely change the risk/benefit ratio from a patient’s perspective.”

Eric Felner, MD, assistant professor of endocrinology at Emory Children’s Center, Emory University, voted no to the proposal.

“[Diabetes] is a progressive disease, and in two or three to five years, it will not be determined if there are cardiovascular effects from the drug; that said, I would like to believe that the committee involved in approving the drugs is good at what they do,” Felner said.

Felner added that if too much time is spent waiting, opportunities will be lost for new drugs that may be more beneficial.

“Although cardiovascular disease is the cause of death in 75% of diabetics, there exist no well-designed, adequately-powered comparative effectiveness trials evaluating macrovascular outcomes for diabetes drugs,” said Steven Nissen, MD, medical director of the Cleveland Clinic, Cardiovascular Coordinating Center, Department of Cardiovascular Medicine. “Diabetes drugs, even within the same class, may yield dramatically different cardiovascular outcomes; clinical outcomes trials comparing alternative diabetes therapies are essential to determine the optimal approach to prevent cardiovascular morbidity and mortality.”

Cardiovascular events a factor

Recent results of the ACCORD trial demonstrated that a drug regimen designed to lower blood glucose was capable of increasing mortality in diabetic patients, according to data presented by Nissen.

“Multiple rosiglitazone meta-analyses of cardiovascular outcomes showed improved glycemic control, but an increase of myocardial ischemic events,” he said. “Many agents to treat diabetes have failed during development, some due to cardiotoxicity, and no robust cardiovascular outcomes data exist for any current diabetes therapies.”

A regimen in which there was more use of repaglinide, rosiglitazone, insulin and/or an alpha glucosidase inhibitor showed increased mortality risk in the ACCORD trial, according to Nissen.

For repaglinide, 50.2% of patients were assigned to intensive therapy and 17.7% were assigned to standard therapy; 91.7% of patients were assigned to intensive therapy and 58.3% were assigned to standard therapy for rosiglitazone. For insulin, 77.3% were assigned to intensive therapy and 55.4% were assigned to standard therapy; 23.2% of patients were assigned to intensive therapy and 5.3% were assigned to standard therapy for alpha glucosidase inhibitor.

“Somehow this regimen resulted in an increase in mortality, and I do not think that we will ever be able to know what it was about this strategy that led to the increased mortality, no matter how far we delve into the data,” Nissen said.

Many panel members felt that pre-approval trials and long-term post-approval trials would be appropriate. Approval for type 2 diabetes drugs would require longer trials to ensure cardiovascular safety if the FDA adopts the expert panel’s recommendation. – by Christen Haigh