Cardiovascular Benefits with SGLT2 Inhibition: EMPA-REG

Peter L. Salgo, MD: We have some studies regarding SGLT-2 (sodium-glucose co-transporter 2) inhibitors with new FDA indications. Where do we go with these?

Karol E. Watson, MD, PhD, FACC: All of the studies were initially designed as noninferiority trials. And then when they passed their noninferiority threshold, then they could start looking at superiority. So, they all had the same limitations. But the first one that received an FDA indication for reducing cardiovascular death was empagliflozin, because of the EMPA-REG study.

Peter L. Salgo, MD: Tell me about EMPA-REG. What is EMPA-REG?

Karol E. Watson, MD, PhD, FACC: This is a large cardiovascular outcomes trial which studied patients with established cardiovascular disease, and they had to have had a clinical event. So, it was established cardiovascular disease. They got all the standard medication. It was high utilization of blood pressure-lowering options, statins, etc. And then, half got empagliflozin at 2 different doses. Actually, it was a 1:1:1 randomization, so 2 different doses of empagliflozin and the other group got placebo. They were looking for noninferiority, and they passed that threshold. So, they then started looking for superiority and they found it.

They pooled the analysis with both doses of empagliflozin. Those who got the empagliflozin had a 14% reduction in their primary outcome. That was nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular events.

Peter L. Salgo, MD: Let me just stop right there. That’s a double digit. I’m used to seeing studies where they say, “Oh look, there’s an 8% reduction or a 2% reduction.” But that’s 14%. Right away, my eyebrows went up that high. That’s impressive.

Stephen A. Brunton, MD, FAAFP: The more impressive thing is that when this was released at the European Association for the Study of Diabetes meeting, they got a standing ovation because they had a 38% decrease in mortality.

Peter L. Salgo, MD: Oh, here you go—38%. I was saving that for a real surprise. But 14%, and now we’re talking 38% mortality.

Karol E. Watson, MD, PhD, FACC: Yes, you’re right—14%. If you stopped there, you’d be like, “Yay!” But we didn’t. So, if you look at that composite outcome (those nonfatal MIs, nonfatal stroke, cardiovascular death), the 2 events we’re used to seeing in statin trials (blood pressure trials are non-fatal MI reduction, non-fatal stroke reduction), they found none of that in infrared. All of the benefit was in cardiovascular mortality.

Christian T. Ruff, MD, MPH: And that’s like, what are these patients dying from? They’re dying of the heart attack.

Rosemarie Lajara, MD, FACE: And may I add, that difference was evident very acutely—very early.

Christian T. Ruff, MD, MPH: Within 3 months. If you look at statin trials, when we think of the cardiovascular trials, we know it takes a long time.

Karol E. Watson, MD, PhD, FACC: Eighteen months.

Christian T. Ruff, MD, MPH: Right. And so, to get that early benefit is amazing.

Karol E. Watson, MD, PhD, FACC: You know, Christian, when I first saw this, I was so excited, but I also said, “What the heck?” and “What are they dying of?” But there’s a lot of cardiovascular ways in which patients die.

Christian T. Ruff, MD, MPH: There are.

Karol E. Watson, MD, PhD, FACC: They’re not always MI or stroke.

Christian T. Ruff, MD, MPH: A lot of sudden death.

Karol E. Watson, MD, PhD, FACC: Heart failure deaths, there are a lot of them.

Peter L. Salgo, MD: But this is all-comers. It’s cardiovascular mortality.

Christian T. Ruff, MD, MPH: It is, and I think with these dramatic reductions in cardiovascular mortality (significantly, over a 30% reduction) and all-cause mortality, there was this incredible reduction in heart failure.

Peter L. Salgo, MD: Stop, again. You just throw these numbers out and these numbers are so crazy, crazy good. But I want people to hear them. We have 14%, 38% reduction in cardiovascular mortality, and 32% all-cause.

Christian T. Ruff, MD, MPH: Which is amazing.

Karol E. Watson, MD, PhD, FACC: The FDA did not give that indication, but some of us wondered why.

Stephen A. Brunton, MD, FAAFP: But that’s an important point. We don’t know why, and there’s all sorts of theories about that. I think the next phase is asking, “What are they dying of?” And how is it making a difference (as you mentioned) early on? Because as we talked about, in terms of atherosclerotic process, that takes years. So, something dramatic is happening and there’s no good, yet, physiological explanation.

Christian T. Ruff, MD, MPH: And I could see, talking as a cardiologist, that a lot of the reluctance is we want to know why these patients aren’t dying. If you told me, “I have a drug that reduces your LDL (low-density lipoprotein) and you’re going to have less atherosclerosis and heart attack,” it fits the store and we close the loop. And I think a lot of the excitement, now, is trying to figure out, how are we getting these dramatic reductions in mortality over a very short period of time?

Karol E. Watson, MD, PhD, FACC: The good news is that total mortality is a really hard endpoint.

Peter L. Salgo, MD: Right, and it will also reduce total hospitalizations by about 5%.

Rosemarie Lajara, MD, FACE: And the renal impact, as well. Let’s not forget about that.

Peter L. Salgo, MD: But to go back to your point, when you said, “I don’t need to measure the lipid levels, I’m going to give a statin,” I would rather have a drug (I don’t know how it works, but it gets the numbers that it does) that I know how it works, but it doesn’t do much.

Christian T. Ruff, MD, MPH: Absolutely.

Peter L. Salgo, MD: And this is that first category.

Christian T. Ruff, MD, MPH: They’re overwhelming and unexpected results.

Stephen A. Brunton, MD, FAAFP: So, this is the first trial that came out. Another trial was released—the ADA (America Diabetes Association) called this the CANVAS trial. The study looked at canagliflozin, and it had similar benefits. It’s a different patient population, somewhat, because they had the primary preventions or secondary preventions. But we’re seeing everything working in the right direction—both in terms of cardiovascular and renal protection. So, this is really an exciting time because now we’re starting to see the fruits of our labor, if you will.

Christian T. Ruff, MD, MPH: And again, the heart failure signal, too, seems to be very robust.

Transcript edited for clarity.