GLP-1 Agonists in T2D: Cardiovascular Outcomes Data

John Anderson, MD: One of the things that was mandated in 2008 was that any new diabetes drug by the FDA had to prove cardiovascular safety. So we have all these cardiovascular safety trials that have come up and have been reported, and it’s changing the way we think about how we prescribe certain agents.

For example, lixisenatide, which was primarily used in Europe and is now usually used here in a coformulation, was looked at in a very short trial in patients who had just had a heart attack, and it showed neutrality, right? It was safe. Exenatide once-a-week just missed statistical significance but for cardiovascular benefit, but it also proved safe.

Semaglutide, which is the once-a-week injectable, actually showed a lowering of 3 MACE—that’s major adverse cardiovascular events—primarily driven by a real reduction in nonfatal stroke, which really drove those 3 MACE.

Liraglutide was the first agent approved by the FDA for lowering cardiovascular risk in patients with type 2 diabetes, and that was in 2016. So right now in the United States, the only agent that’s approved to lower cardiovascular risk with a GLP-1 [glucagon-like peptide-1] receptor agonist is liraglutide.

Now dulaglutide has a study called the REWIND trial that will be reported at the scientific sessions in June 2019. The early word reported is that this was a positive trial. This had a lot of primary prevention in it as well. So it will be interesting to see those results. It’ll be interesting to see how the FDA interprets those results. So as we look at the landscape of GLP-1 receptor agonists, we’re starting to think about glycemic lowering and all the things we’ve talked about. We’re also now starting to think about which agents have shown cardiovascular benefit in addition to their normal indication of lowering glucose.

Vanita Aroda, MD: In 2008 the FDA mandated cardiovascular safety studies to make sure that new therapies in type 2 diabetes are safe from a cardiovascular standpoint. In the first few studies that we saw, we saw that newer agents were safe. But what we saw with empagliflozin first and then liraglutide next was not just safety but benefit. I’ll go over a little bit more of that on liraglutide.

So the cardiovascular outcome study with liraglutide was called the LEADER trial. This randomized over 9000 patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk to liraglutide at 1.8 mg or placebo. So it’s double-blind placebo-controlled. And this is on top of standard of care. So patients were receiving whatever the current standards of care at the local sites included, including aspirin, statins, antihypertensive therapy, and glucose-lowering therapy as needed.

This study was conducted over a median follow-up of 3.8 years and found a significant reduction in its primary outcome. The primary outcome was what we call triple MACE, so the 3 major averse cardiovascular events—namely cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. And here in the LEADER study we saw a 13% reduction in that primary composite outcome. In addition, we saw a 22% significant reduction in cardiovascular death. So here we saw that choice of therapy, or which therapy you choose, could actually affect cardiovascular outcomes, and that has really ushered in a wave of excitement in the treatment of diabetes for diabetologists or endocrinologists, as well as cardiologists and the primary care provider. In the select patient population, the actual choice of therapy does influence outcomes.

The SUSTAIN 6 study was a cardiovascular-outcomes trial looking at semaglutide at 0.5 mg once a week or 1 mg once a week compared with placebo. It was also a double-blinded randomized controlled trial looking at cardiovascular effects and cardiovascular safety. It was prespecified to look at cardiovascular safety. And what was found was that, indeed, it was safe. But also, what the authors found was a 26% reduction in overall primary outcome of cardiovascular events. So that includes cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. And when the individual components of the primary outcome were evaluated, there was a significant reduction in nonfatal stroke—specifically 39%.

When the authors looked at the individual components, they also found improvements, though not significant. The very consistent findings demonstrate, again, that we have another GLP-1 showing potential cardiovascular benefit.

John B. Buse, MD, PhD: Semaglutide is a sort of tweaked version of liraglutide from the same company. The cardiovascular outcome trial that was done with semaglutide is called SUSTAIN 6. It was a smaller trial that was designed to exclude cardiovascular harm, which is a requirement for FDA approval. LEADER was a trial that was primarily designed to exclude harm but was big enough and long enough that we had a hope of showing benefit. Semaglutide was small and short, and we had no hope of showing benefit. We were just trying to prove that it wasn’t terribly harmful. And again, the community was stunned that the drug was associated with approximately a 20% reduction in the primary end point of heart attack, stroke, cardiovascular death. There, the benefit was largely driven by stroke, a bit less by heart attack, but showed no evidence for benefit with regard to cardiovascular death. And again, there was a bit of benefit around renal outcomes as well. So both of the trials have had a substantial impact on our thinking about the class of medications. In the ADA and EASD [American Diabetes Association and European Association for the Study of Diabetes] guidance we specifically call out that the level of evidence for cardiovascular benefit is greatest for liraglutide based on the LEADER trial because it was longer and bigger; and second for semaglutide because the benefit was so large, even though the trial was not designed to show benefit and was short and small; and the third level of evidence for exenatide once-weekly was in the EXSCEL trial. That trial technically did not show benefit for heart attack, stroke, and cardiovascular death—it just missed it by a hair, from a statistical point of view—but it certainly trends in the same direction. So the ADA and EASD guidance has that in third place. And soon we’ll hear the results of the cardiovascular outcome trial with dulaglutide, though that’s not fully available yet.

Vanita Aroda, MD: What we’re seeing as a whole is very consistent improvements in cardiovascular outcomes. However, the different trial designs and differences in the agents may translate to different clinical effects. For example, lixisenatide in the ELIXA study showed that it was neutral. It was safe in a very high-risk acute coronary syndrome population but did not show improvements in outcomes. It was neutral. It was safe.

The greatest evidence for cardiovascular outcomes that we’ve seen has been with liraglutide, whereby we now have an FDA label indication. Semaglutide also showed improvements but was not powered for superiority and was not prespecified as a superiority study.

Exenatide once-weekly showed consistent effects and trends toward improvement but did not reach statistical significance. And then most recently, albiglutide showed a 22% reduction in cardiovascular outcomes. So again, as a whole we’re seeing that the GLP-1 receptor agonists have improvements in cardiovascular outcomes, but there are differences between the agents. What we’re excited to see in this next year is the primary outcome reporting from the REWIND study, which is looking at dulaglutide. And in this study, unlike some of the previous studies, there were about 70% of patients who did not have established cardiovascular disease. So here we’ll see, again, differences in the patient population and perhaps differences in the findings.

Transcript edited for clarity.