SGLT2 Inhibitors: CV Outcomes Data in Type 2 Diabetes

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: All right, so let me move on now to treatment options for type 2 diabetes. We have newer antidiabetic medicines. I’m not going to cover them all, but let’s first look at trials related to SGLT2 [sodium-glucose cotransporter 2] inhibitors. Chris, if you can, tell us what that class is and talk about some of the outcomes trials. You don’t have to go into all the details, but give us a broad view.

Christopher P. Cannon, MD: This has been such an exciting time, and the first of these trials was the EMPA-REG trial with empagliflozin, an SGLT2 inhibitor. It inhibits the exchanger so that glucose goes out in the urine, but changes probably pressure in the glomeruli in the kidney, you get weight loss and lots of other beneficial factors with the entire class. And so out of surprise, there was a significant reduction in cardiovascular events and indeed cardiovascular mortality. This caught everyone’s attention. It really has ushered in a new era in our thinking about how to manage cardiovascular risks in patients with diabetes. It’s been exciting to see other trials show very similar effects. The CANVAS trial followed with canagliflozin, a little bit less dramatic on mortality but same idea and probably its data falling in the confidence intervals of truth there. And then most recently with dapagliflozin.

An interesting thing emerged there that the benefits on cardiovascular death, MI [myocardial infarction], and stroke seem to segregate in people who have known atherosclerotic cardiovascular disease and a little bit less dramatic in primary prevention patients with diabetes. However, you started out pointing out the heart failure risk came on to the scene because this was a bit of a surprise to all of us, but a huge benefit, like a one-third reduction in hospitalization for heart failure. And this has been uniform in all the patients studied with SGLT2 inhibitors and so another axis of benefit.

Then a final thing that’s emerged in all of these trials was a benefit on preservation of renal function. So they weren’t focused, but they collected all the key data, and less doubling of creatinine and trends on all the other endpoints. It was announced the first of the dedicated renal trials, CREDENCE, which will be presented in mid-April, announced to be positive already. So that’s a third axis of benefit on outcomes. So we have adverse cardiac events, heart attack, stroke, cardiovascular death, heart failure, and renal benefit with this class of drugs.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: A broad range of effects.

Christopher P. Cannon, MD: Just amazing and very clinically important things in this high-risk population.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Well, Peter, let’s try to tease out some of these benefits, 3-point MACE [major adverse cardiac event], and is heart failure a component of that? Because I just heard Chris say cardiovascular events and then he switched and he said heart failure. Is 3-point MACE heart failure? Is it different or what?

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: MACE is major adverse cardiovascular events, and in 2008 the FDA guidance for the manufacturers was to study MACE, which was nonfatal MI, nonfatal stroke, and cardiovascular death, as a safety composite. And that’s what was done in these trials. The drug was set up to be noninferior to placebo on 3-point MACE. Now, fortunately, heart failure was an adjudicated other safety endpoint not included in 3-point MACE.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: So that was not part of the 3-point.

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: But it was adjudicated in these trials, and I played a role in that to make that become a reality. And, as Chris pointed out, the big effect is on heart failure and so the cardiovascular signal, the belief is really mediated through heart failure and not mediated through stroke or MI. Unlike a statin, for instance, where the cardiovascular death benefit is mediated through the nonfatal ischemic events, in this case with SGLT2s, it’s through this myocardial and renal effect.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Melissa, do you think it’s worthwhile for patients to be aware of these outcome data, or should we just stick with the numbers and let them know about their hemoglobin A1C [glycated hemoglobin], their blood pressure, the lipids? Do you ever discuss outcomes data?

Melissa L. Magwire, RN, MSN, CDE: I do, and I think the more you can arm the patient with that data, the more buy-in, the more acceptance you’re going to get. And I think doing the team approach with the patient being the center of that team and that shared decision making is very important for adherence. And explaining why we’re choosing the agents we’re choosing and the pathways we’re choosing really lends a lot to adherence and to people accepting more treatment.

Transcript edited for clarity.