John B. Buse, MD, PhD: The GLP-1 receptor agonists are relatively recent drugs for the treatment of type 2 diabetes. They have very broad effects. There was a lot of interest in the possibility that they might reduce cardiovascular risk because they are associated with weight loss, modest reductions in blood pressure, and really outstanding glucose lowering.
Furthermore, in animal models and detailed in vitro studies, there are a variety of mechanisms in aerobiology that are impacted by these drugs, and as an example, it has been shown to have effects on plaque stability. And so, there was a lot of interest in the possibility that they may be associated with cardiovascular benefit. With the prior track record of drugs that had great evidence for the possibility of cardiovascular benefit not panning out, we were very interested in cardiovascular outcome studies.
The first cardiovascular outcome study conducted with a GLP-1 receptor agonist came out in 2016 and involved a GLP-1 receptor agonist called lixisenatide. Lixisenatide is an analog of exenatide, which was the first GLP-1 receptor agonist. Lixisenatide is administered once a day, but it doesn’t have a 24-hour duration of action. The study that was conducted, the ELIXA trial, involved patients who had recently survived a hospitalization for acute coronary syndrome, and they used a 4-point MACE endpoint: heart attack, stroke, cardiovascular death, or hospitalization for unstable angina. It’s a little bit different than the other cardiovascular outcome trials we’ve been talking about.
They showed no evidence of harm from lixisenatide with regards to cardiovascular outcomes, but also no evidence of benefit. And so, the community was a little bit disappointed, with the background of that hope, that there wasn’t greater benefit from lixisenatide.