FDA panel recommends expanded diabetes drug testing

An FDA advisory committee of experts recommended drug companies be required to conduct more drug 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 anti-diabetic 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 disease 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 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 in Atlanta, 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.

He 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-mortality.”

Cardiovascular events a crucial 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 alpha glucosidase inhibitor showed increased mortality risk in the ACCORD trial, according to Nissen.

For repaginide, 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 or another 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

Type 2 diabetes is a chronic and debilitating disease with increased microvascular and macrovascular complications over time. Although pharmacologic treatment targeting adequate control of blood sugar with target HbA1c levels of 7 to 7.9 is associated with a significant reduction in microvascular complications (retinopathy, nephropathy, amputations and neuropathy), the patients with diabetes are still two- to four-times more likely than those without diabetes to die from cardiovascular diseases. There are no adequately-powered studies to show that all cause mortality or cardiovascular mortality decreases with currently available hypoglycemic agents. On the contrary, one part of the large NIH trial (ACCORD) was prematurely terminated due to increased total and cardiovascular mortality with intensive treatment aimed to reduce HbA1c level to a target of 6 compared to standard therapy aimed at a target HbA1c level of 7 to 7.9. The harm seen was independent of any type of combination of hypoglycemic agents used. This report and recent reports of increased cardiovascular morbidity associated with newer potent agents for hyperglycemic control resulted in an FDA advisory committee meeting. The committee members voted 14 to 2 that pharmaceutical companies be required to conduct appropriate trials to ensure that there is no associated increase in cardiovascular risk in patients taking prescribed drugs for diabetes. A minority of committee members expressed concern that such an approach will deny the patients potentially important new drugs which over time may have beneficial effects. The FDA advisory committee recommendations are timely. Given the high and increased prevalence of diabetes, it would be easy to carry out a large well-designed comparative trial, say in 100,000 or more patients, over a period of one to three years to ascertain any adverse effects of the medication on cardiovascular outcomes. Alternatively, an adequately designed and powered, long-term outcome trial will be needed. I would recommend a very large trial rather than a small trial for initial drug approval followed by post marketing approval trials which are often open to criticism. Such an approach will ensure patient safety and meet the first principle of good medicine, i.e., do no harm if you cannot do any good.

– Udho Thadani, MD

Professor Emeritus of Medicine, Cardiovascular Section, The University of Oklahoma Health SciencesCenter,
Staff Cardiologist ,OU Medical Center and VA Medical Center, Oklahoma City