BOSTON – The ELIXA trial confirms that the GLP-1 receptor agonist lixisenatide neither decreases nor increases the risk of major adverse cardiac events in postacute coronary syndrome patients, and that it improves glucose control, compared with placebo, and provides modest benefits with respect to body weight, blood pressure, progression of albuminuria, and hypoglycemia rates, Dr. Silvio E. Inzucchi said at the annual scientific sessions of the American Diabetes Association.
Particularly encouraging was the lack of any signal for pancreatic injury, thyroid cancer, or heart failure. The latter finding is especially timely given recent concerns raised by DPP-4 inhibitors, said Dr. Inzucchi, who was invited by the ADA to comment on the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial findings.
As for whether the ELIXA trial represents a high-quality study with believable results and an important end point, “the answer to this is a resounding yes,” he said, congratulating the investigators, who “have done a fine job of conducting this study, which represents another example of the great collaboration between diabetologists and cardiologists.”
“We all see the same patients and we need to work more and more together to find out the best treatments for our patients,” he said, noting that finding a glucose-lowering agent that has a clearcut cardiovascular benefit represents the “holy grail.”
The neutral finding, as opposed to a positive one, in ELIXA with respect to effects on cardiovascular outcomes is not surprising, said Dr. Inzucchi, professor of medicine and director of the Yale Diabetes Center at Yale University in New Haven, Conn.
“Hypoglycemia is more tightly linked to micro- than to macrovascular outcomes, so not surprisingly it is much easier to show a benefit on these microvascular complications from controlling blood glucose. Any cardiovascular benefit accrues over many years, outside the time course of most of our randomized clinical trials, and any cardiovascular benefit is likely to be attenuated in those with pre-existing atherosclerosis,” he said.
Although Dr. Inzucchi said that he is skeptical that any of the numerous ongoing cardiovascular outcomes trials (CVOTs) will be able to show such a benefit unless a particular agent shows “some dramatic off-target effect on atherosclerosis,” which is an unlikely outcome since glucose lowering has only a modest effect that is disclosed only after a number of years, he noted. It is “just kind of fun to think that, if one of these CVOTs does turn positive … that drug may potentially be positioned as the favored treatment in addition to metformin. Obviously, it depends on the degree of risk reduction and other effects as well, but only then will we have achieved the holy grail.”