Understanding Cardiovascular Benefit With the LEADER Trial

John B. Buse, MD, PhD: The LEADER trial was a trial involving liraglutide, a human analog of GLP-1, and that is a once-a-day GLP-1 receptor agonist that has 24-hour coverage. In the LEADER trial, patients with prior clinical cardiovascular disease—as an example, prior MI, stroke, or cardiac revascularization—or patients at very high risk for cardiovascular events, who hadn’t had prior clinical cardiovascular disease, were randomized. They were treated for approximately 3-and-a-half years. And in the trial, there was demonstration of cardiovascular benefit. So, there was a 13% reduction in the first occurrence of heart attack, stroke, or cardiovascular death. When you look at the individual components of the composite endpoint—first MI, first stroke, or cardiovascular death—there were very similar benefits across the spectrum.

When you look at cardiovascular death, in particular, it was a 22% reduction, and a 15% reduction in total mortality. So, in many ways, it was a spectacular result, particularly in a field like diabetes where we’d gone for many, many years without one. Having the EMPA-REG study of the year before to now, at that point in time, having 2 studies that showed cardiovascular benefit was quite stunning.

On the safety side, the big concern about GLP-1 receptor agonists had been pancreatitis. In the LEADER trial, numerically, there were more cases of pancreatitis among patients treated with placebo. So, that has downregulated some of the concerns there. With liraglutide, there’s a black box warning about medullary thyroid cancer based on studies in rodents, and the only case of medullary thyroid cancer that occurred actually occurred in a patient treated with placebo. From a safety point of view, the profile looked quite good. And other than the well-known side effect of nausea and vomiting resulting from some patients just not being able to tolerate the drug, there were no new safety concerns raised. And then finally, there seems to be a benefit on kidney outcomes as well with a reduction in new and persistent albuminuria.

There are interesting questions about the mechanisms by which GLP-1 receptor agonists could reduce cardiovascular events. From the LEADER trial and a trial of a similar agent called semaglutide—a trial called SUSTAIN-6—both of which have shown cardiovascular benefits, we have a fair amount of certainty, because we have 2 studies that this effect is real and not a fluke. The question is, how does it occur?

We know the GLP-1 receptor agonists are expressed in the endothelium of blood vessels. We know they’re important in vascular remodeling, in animal studies, of brain injury. But exactly how this occurs is unclear. If I had to guess, my guess is that there’s a benefit in the underlying process of the biology of atherosclerosis. Perhaps through reduction of inflammatory pathways. Perhaps through changes in the way that fuels are metabolized, particularly postprandial fat metabolism. And I think it’s very interesting that the animal studies have shown improvement in plaque stability. But once again, we don’t really know the mechanisms. We feel like it’s really important to try and understand it because, again, we may have a more direct way of targeting those pathways than using GLP-1 receptor agonists.