GLP-1 Receptor Agonists and Cardiovascular Benefit

John Anderson, MD: There are several cardiovascular outcomes trials that have now come to fruition looking at the GLP-1 receptor agonist class. Let’s go back and just take a quick look at a couple of them. The first was lixisenatide, which is marketed in Europe and has been around for a long time. It’s a once-a-day GLP-1, but it’s a shorter acting postprandial GLP-1 receptor agonist. Sanofi brought this trial design so that they could get lixisenatide approved in the United States, meeting the criteria that the FDA had set out in 2008 for cardiovascular safety. So, they looked at patients who were then 60 to 90 days after an acute MI [myocardial infarction] and randomized them to lixisenatide versus usual care. And they proved its safety after a 2-year trial. This trial was never designed nor powered to try to show cardiovascular benefit, because that really wasn’t the interest of the trial the first time. It was to simply be able to get this product to the market and to prove safety—and they did. So, there has been a lot of criticism that it showed neutral results, but I don’t think you can look at it that way.

The next one that came up was in June in New Orleans over a year ago, which was the LEADER trial, and it was with liraglutide, the once-a-day product that is a longer acting GLP-1 receptor agonist. It met its primary endpoint for reduction in 3-point MACE, and that’s major adverse cardiovascular events. The composite of non-fatal MI, non-fatal stroke, and cardiovascular death all produced a benefit. The difference as you look at these data versus what we might have seen with the SGLT2 inhibitors is that they took a little longer.

You didn’t really see curves separate for about a year. You saw this reduction in stroke and heart attack, and the thought here is that maybe the GLP-1 receptor agonists have an entirely different mechanism for why they are providing cardiovascular benefit. We know they reduce weight. We know they can reduce systolic blood pressure. Perhaps this is atherosclerosis as opposed to cardiovascular death, heart failure, sudden arrhythmia, or whatever might have driven the results in the 2 SGLT2 trials. So, liraglutide just got approval from the FDA this year for cardiovascular benefit in people with diabetes and cardiovascular disease. And LEADER was powered heavily with most of these people having had cardiovascular disease and cardiovascular events. So, again, it had a different trial design.

Another 2 agents have reported out. SUSTAIN-6 was looking at semaglutide, which is not even in the United States marketplace yet, but it has been submitted for FDA approval. Most people think it will be approved by the end of the year. It showed a cardiovascular benefit as well, but it was all driven by a reduction in stroke. Now, this was a real head scratcher. People were looking at this going, “Hmm, really, how’s that?” Now, with the other things—cardiovascular death, nonfatal MI myocardial infarction—there was a small benefit. But, the big statistical driving force was this reduction in stroke. Again, the curves took about a year to separate. Is this atherosclerosis? I suspect that when they get approved in the United States marketplace, they will be seeking an identification or an approval from the FDA for cardiovascular risk reduction.

One of the trials that just finished is the EXSCEL trial, and it looked at once-a-week exenatide, again looking at that 3-point MACE. It was just presented at EASD in Europe this past month. There were very interesting results: reduction in non-fatal MI, reduction in non-fatal stroke, and reduction in cardiovascular death, but it did not meet a statistical probability, a statistical P value, of less than .05. It was .06. So, there was a lot of benefit, but it just missed statistical probability. It also had a lot of patients in it who were at high risk, but did not have cardiovascular events. Think back to the CANVAS trial, a little more like that. A lot of patients who were at lower risk might have diluted what could have been potentially a statistically significant result. For me, personally, if you get to a P value of .06, you pretty much got there. I’m believing the results in terms of cardiovascular risk reduction.

This is another example of how you look at each individual and try make sense of what you think the real benefit to your patients is going to look like. And so, those are the few trials. Dulaglutide has a once-a-week formulation and its trial, the REWIND trial, won’t be available for another year, year-and-a-half, to see the results. It’s another large cardiovascular outcomes trial with a GLP-1 receptor agonist. So, we’ve had a couple of mixed results with GLP-1 receptor agonists, whereas the 2 SGLT2 inhibitors seem to be on top of each other in terms of their results.

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