GLP-1 Agonists: CV Outcomes Data in Type 2 Diabetes

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Let’s go on to the cardiovascular outcomes trial with the GLP-1 [glucagon-like peptide-1] inhibitors. It’s really agonists; it’s not inhibitors. So explain to us again—and you don’t have to go really deep into the pathophysiology—what these drugs are, and then talk about the outcomes trials.

Christopher P. Cannon, MD: Well, I’m probably least capable of doing it. But this is related to GLP for pathway but has seen really wonderful effects—bearing some similarities, I’d say, to SGLT-2s [sodium-glucose cotransporter 2] in terms of the clinical effects. A surprise trial, the LEADER trial, led the pack, but there are now 6 trials with this class of drugs that have shown clinical benefits, many significant. Some are just strong trends. But it does look like a good class effect of the GLP-1 receptor agonist class.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: What was the LEADER trial?

Christopher P. Cannon, MD: LEADER used the agent liraglutide, and that also found a reduction in MACE [major adverse cardiovascular events], the safety end point that the FDA mandated—so cardiovascular death, MI [myocardial infarction], or stroke—and a significant reduction in cardiovascular death. But a balanced one that also is seeing reductions in MI and stroke, not necessarily significant on each individual end point. And then also seeing the renal benefit that has been seen—so protection over time of renal function, less of a difference in heart failure with this class of drugs. But the MACE and the renal protection has been seen.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Not bad for heart failure, but not as powerful an effect as you see with the SGLT-2 inhibitor?

Christopher P. Cannon, MD: Exactly. So trending a little bit less, but there’s probably not a reduction in heart failure with the GLP-1 receptor agonists.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: I’m going to ask Melissa about how to use these drugs on a daily practice, and there’s another trial you didn’t mention called REWIND. I want a few comments on that. How do you use these? They’re not oral. They’re injectables. Is that making it difficult for the patients?

Melissa L. Magwire, RN, MSN, CDE: I think that’s a provider perceived, the injection barrier. I think once you explain to the patient why the medication is in injectable form, that it’s a protein, currently it can’t be made into an oral tablet as such. And then the needles that are used with these injectable medications are extremely small, very fine. And once you’ve shown the patient the technique, which is really easy, depending on which pen you’re using, the acceptance of it is pretty broad, especially if you say you’re going to get additional benefits—not just the glucose lowering, but you’re likely going to lose some weight. And now we can say with these, as well, we’re going to protect your heart. So it’s all in the education of the patient to get that adherence and get that buy-in. But I’ve really not had a pushback. The most pushback I get, unfortunately, is among peers, and it’s that provider perceived. But patients, in general, if you explain the benefits of the drugs, really have no issue. And especially since a lot of them now are once weekly.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Both of the classes of the newer drugs, the SGLT-2 inhibitors and the GLP-1 agonists, appear therefore to assist with weight loss?

Melissa L. Magwire, RN, MSN, CDE: Yes.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: One of them has an approval for weight loss. Which drug is that?

Melissa L. Magwire, RN, MSN, CDE: Actually, that is a different one, that’s Saxenda. It’s the same molecule, but it’s actually a different formulation of liraglutide specifically. So the ones that are out for the management of diabetes say they’re not indicated for weight loss. But you see anywhere from 5 to 7 pounds, and with semaglutide even more in some of the studies. So you do see significant weight loss with the GLP-1 receptor agonist class.

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: I would add to this. If we look at the SGLT-2s and the GLP-1s, there’s just a little different efficacy profile. The reduction in glycated hemoglobin A1C among the 2 is about the same. The weight loss with the GLP-1 is a little bit more than the SGLT-2. The blood pressure reduction with a GLP-1 is a little less than what we see with the SGLT-2. When we get to clinical outcomes, the GLP-1 agonists seem to map toward atherosclerotic events, reductions in stroke, and MI, and cardiovascular death, and that pathway and less with respect to heart failure. And then finally the renal effect seems to be almost all mediated through microalbuminuria and proteinuria and really not GFR [glomerular filtration rate], so related as the GLP-1s. So these drugs are different in terms of their efficacy.

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: So you’re painting the picture for using both of them, really. Is what you’re doing, right?

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: I have a few patients in my practice where they’re both used, and I think we really are going to need data to find our way forward here before there’s too much enthusiasm and people start to.

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: Too much excitement, no?

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: A lot of these trials have excluded some of the other drugs in the class. The vast majority of patients are on metformin, a sulfonylurea, and potentially insulin, and then they go on to 1 of these 2 drugs.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: We talked earlier about racial and ethnic disparities, and unfortunately, when you look at some of these diabetic studies, it’s only 3%, 4%, 5% in most blacks. I just completed a published study in Circulation of 150 patients. Not outcomes but blood pressure, which is a powerful risk; and using empagliflozin, 10 mg to 25 mg compared with placebo; 24-hour ambulatory blood pressure, which is the gold standard; 10.33 mm Hg systolic blood pressure reduction at 24 weeks, so very powerful. And if you placebo subtract, 8.5 mg, still really statistically powerful. So these appear to have a real blood pressure effect. It’s probably why you’re wise to drop back a little bit on the diuretics because you’re going to get that blood pressure effect with the SGLT-2 inhibitors. We’re going to close GLP-1 with 1 study you may not have much to say about because I don’t think it’s finalized, but REWIND.

Christopher P. Cannon, MD: Well, REWIND, and in between, that’s actually the fifth of 6 trials. And so we always look for consistency. So LEADER was the first, and SUSTAIN 6 was a moderate-size trial, showed benefit of semaglutide. Then EXSCEL with extended-release exenatide, had a strong trend and a lower mortality. Harmony Outcomes is an agent that was approved and then withdrawn with albiglutide, had a significant reduction in MACE. And then either REWIND trial with dulaglutide, which is a widely used agent. We’ve had just the preliminary announcement about the reduction in cardiovascular events there as well and PIONEER 6 with oral semaglutide also. That’s always reassuring to see that this is not a fluke, but this mechanism is 1 that can be helpful and mechanistically should be additive to SGLT-2, but we do need some more data. I should point out that DPP-4s [dipeptidyl-peptidase-4s] and GLP-1s shouldn’t be used together because that’s a complete overlap.

Transcript edited for clarity.