Cardiovascular Outcome Trials for Diabetes Medications


Robert Busch, MD, provides an overview of the clinical trials supporting improved cardiovascular disease outcomes in patients with and without diabetes.

Dhiren Patel, PharmD, CDE, BC-ADM, BCACP: OK. That’s helpful. Dr. Busch, I can’t think of a clinical trial that you probably have not been an investigator in, but maybe help us walk through some of these larger trials as they pertain to GLP-1 and SGLT-2 [sodium-glucose cotransporter-2] inhibitors. You’ve seen the progression over the years where, you know, first it was secondary prevention, now we’re seeing primary prevention, as well as some of these additional indications.

Robert Busch, MD: OK. The DPP-4 [dipeptidyl peptidase 4] is still very commonly used, no cardiac benefit, they’re safe in the heart. Some increase the risk of heart failure a little bit, but certainly at least safe. Then the SGLT-2s, EMPA-REG started the ball rolling. And then EMPA-REG in the purely cardiac patients who had any kind of ASCVD [atherosclerotic cardiovascular disease] with diabetes, lowered MI/stroke death 14% and cardiac death 38%. It also lowered heart failure, but that wasn’t an end point. It was a secondary end point and not in the label for it at that time. Canagliflozin also lowered MI/stroke death in sort of a mixed population, two-thirds cardiac, one-third not cardiac, but unfortunately that got outshadowed by the amputation fear. But then eventually it did get into their label to lower MI/stroke death.

Then dapagliflozin was very creative because they studied primary prevention as well. Knowing the results of EMPA-REG, that it lowered heart failure and death, they had 2 primary end points. One was MI/stroke death, which it was safe for that, but interestingly, dapagliflozin has the primary prevention indication to prevent heart failure hospitalization.

Then we have the GLPs [glucagon-like peptides]. Long acting exenatide is safe for the heart. Unfortunately, in that study, the placebo group had too much SGLT-2, so it benefitted the placebo group. It probably would have been beneficial if there wasn’t so much SGLT-2 in the placebo group. But, as we know, SGLT-2s benefit the heart, so the placebo was more likely to be on an SGLT-2 because their A1C wasn’t as good.

Then the LEADER trial with liraglutide lowered MI/stroke death as well as cardiac death, has that indication. And then semaglutide, the weekly GLP, lowered MI/stroke death. Interestingly, oral semaglutide, the study was not long enough. Even though it showed beneficial trends, the FDA [Food and Drug Administration] said, no, you must do a bigger study. Fortunately for us, we are in that study. That is the SOUL trial. So maybe for our cardiologists, there will be a pill of GLP-1 that has that indication. Right now, that pill is only safe. Interestingly, 2.4 semaglutide for weight loss is doing a cardiac outcome study in the nondiabetics, so nondiabetics, obese patients with heart disease. So that may get that indication. I wouldn’t be surprised if it did because it worked in 1.0 in diabetics, but we shall see. So that is the SGLT-2 and GLP studies.

The only one that was not a positive study was ertugliflozin, was safe for the heart, but it also lowered heart failure. All of them lowered heart failure. Then, of course, we have the heart failure studies as was mentioned, you had DAPA-Heart Failure with reduced ejection fraction and you have EMPEROR[-Reduced] with reduced ejection fraction, with very similar results in those two. I guess the pillars of therapy that you’ll talk about are ARNI [angiotensin receptor neprilysin inhibitor], beta blocker, aldosterone inhibitor, and now SGLT-2 as well.

Dhiren Patel, PharmD, CDE, BC-ADM, BCACP: That is excellent. I think the body of evidence has continued to grow. Recently I saw that there are a few HFrEF [heart failure with reduced ejection fraction] studies with the GLP-1s. I think it’s going to be great to continue to see what comes out of it.

Transcript edited for clarity.

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