Examining CV Evidence with Antidiabetes Medications

Peter L. Salgo, MD: You were talking about the ELIXA trial. That’s a different class of drugs, right?

Rosemarie Lajara, MD, FACE: Yes.

Peter L. Salgo, MD: Tell me about ELIXA trial.

Rosemarie Lajara, MD, FACE: ELIXA, basically, is one of the GLP-1 [glucagon-like peptide-1] receptor agonist agents; specifically, lixisenatide, which falls in the shorter-acting category—obviously due to the FDA mandate to show cardiovascular safety. The results were published in 2015 in the New England Journal of Medicine. It showed no major issues with cardiovascular events—no harm.

Peter L. Salgo, MD: So, no harm compared to benefit.

Karol E. Watson, MD, PhD, FACC: No. Everyone starts out with no harm.

Peter L. Salgo, MD: Benefit versus no benefit.

Rosemarie Lajara, MD, FACE: Otherwise, they don’t make it past...

Karol E. Watson, MD, PhD, FACC: Past that preregistration.

Peter L. Salgo, MD: Right. What about the LEADER trial with a GLP-1 receptor agonist?

Rosemarie Lajara, MD, FACE: It used a different agent.

Peter L. Salgo, MD: Liraglutide.

Rosemarie Lajara, MD, FACE: Liraglutide. And, again, it showed a significant difference in terms of the composite outcome. Basically, it was reduced by 13%. Again, this was the first occurring cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. And there were fewer cardiovascular-related deaths—22%, actually.

Peter L. Salgo, MD: So, pure benefit?

Rosemarie Lajara, MD, FACE: Absolutely.

Karol E. Watson, MD, PhD, FACC: Cardiovascular deaths were not significant.

Christian T. Ruff, MD, MPH: There was trend.

Karol E. Watson, MD, PhD, FACC: Trend.

Stephen A. Brunton, MD, FAAFP: I think that is a differentiation, now, between the short-acting and the long-acting therapies. There’s another trial, the SUSTAIN trial, that looked at semaglutide. It is not yet on the market, but it also shows some very dramatic cardiovascular benefits. So, I think with all of the GLP-1s that are now in study, some are going to give us results earlier than later. Semaglutide, in every prelaunch, has shown some very dramatic results.

Karol E. Watson, MD, PhD, FACC: Semaglutide has been available in Europe. It’s dosed once weekly, and it’s a pretty exciting agent.

Rosemarie Lajara, MD, FACE: Right.

Christian T. Ruff, MD, MPH: But then, I think what’s interesting, now, is there’s emerging data that report that these drugs are working in different ways. We could say they actually all have the same primary endpoint—cardiovascular death, nonfatal MI, and nonfatal stroke. But where the SGLT2 [sodium-glucose co-transporter 2] inhibitors really seem to have this pronounced effect is not on atherosclerotic events, and not on MI and stroke, but on dying of other types of death. The GLP-1s don’t have any heart failure signal, and they do seem to be more effective in reducing MI and stroke.

Rosemarie Lajara, MD, FACE: It seems to be atherosclerosis.

Christian T. Ruff, MD, MPH: Right.

Karol E. Watson, MD, PhD, FACC: What we expected.

Christian T. Ruff, MD, MPH: You start to think, “Could these be complementary? Are we are targeting cardiovascular risk in 2 different mechanisms and reducing heart failure with 1 drug, or class of drugs, and reducing atherosclerotic events in the others?” It’s a really kind of an exciting time.

Rosemarie Lajara, MD, FACE: It is. It’s a great day.

Peter L. Salgo, MD: It isn’t just about sugar any more.

Rosemarie Lajara, MD, FACE: No.

Karol E. Watson, MD, PhD, FACC: In fact, it’s never been just about sugar.

Peter L. Salgo, MD: If I were to be a late-night sales person on cable television, I’d say, “But wait, there’s more.” Because we’ve got some other trials out there. The TZDs [thiazolidinediones], right? We’ve got an IRIS study. What’s IRIS?

Christian T. Ruff, MD, MPH: This was with the TZD, pioglitazone. The results from the IRIS study are actually quite interesting. This builds upon prior data. There was a proactive study that was, before, looking at patients with cardiovascular disease, and there actually was a signal for cardiovascular benefit. And the IRIS study was interesting in that it took patients who actually had insulin resistance, but not overt diabetes and it looked at an interesting population who had a recent TIA [transient ischemic attack], or stroke. There actually was a significant reduction in stroke and myocardial infarction, although not cardiovascular mortality.

Here, again, we have a drug that seems to be reducing, in a high-risk patient population (not even diabetic), atherosclerotic events. But unlike these other trials that we mentioned, there was a downside to TZDs that are sort of well-established. You do get weight gain and you do get heart failure. So, these drugs are not good for patients who have overt heart failure. And, actually, there were significant fractures. The side effect profile for the TZDs was, unfortunately, a little bit of a mixed bag, although I think the fact that there was a cardiovascular benefit in a prediabetic population was very interesting.

Rosemarie Lajara, MD, FACE: Yes. One thing that I think is worth mentioning is that the dose that was used in this trial was the highest dose.

Christian T. Ruff, MD, MPH: That’s a good point.

Rosemarie Lajara, MD, FACE: I wonder what they would have found if they would have done a dose analysis?

Karol E. Watson, MD, PhD, FACC: Don’t get greedy.

Rosemarie Lajara, MD, FACE: Yes, don’t get greedy.

Peter L. Salgo, MD: Well, that was actually one of the problems with the early statins.

Christian T. Ruff, MD, MPH: Absolutely.

Peter L. Salgo, MD: There was a statin that was taken off the market. But when you actually looked at the dose they were giving, it was a huge dose.

Rosemarie Lajara, MD, FACE: Right.

Stephen A. Brunton, MD, FAAFP: This flies in the face of why the cardiovascular outcomes trials went down in the first place. They’re concerned about the cardiovascular safety of the TZDs. And it turns out that, now, with rosiglitazone, obviously, we’ve thrown in the question and people think it is safe (from a cardiovascular perspective). So, other than the heart failure (you know it’s edema that one gets), it still is not a dangerous drug. It may have benefits.

Transcript edited for clarity.