Current CV Evidence Across SGLT2 Inhibitors

Peter L. Salgo, MD: The CVD-REAL retrospective study, what’s that?

Christian T. Ruff, MD, MPH: One of the things in this now exploding field is, it’s amazing that these drugs work. Do we have any other data that these drugs work? They’re all approved for a long period of time. The CVD-REAL study was a very large retrospective study looking at over 300,000 patients in over 6 countries. And this study, I think, has 3 important take home points.

One is it’s a much lower-risk population. The EMPA-REG study was patients who had cardiovascular disease. Over 80% of these patients were relatively low risk—no established disease. And it appears that these signals of reduction and heart failure and mortality are still robust. So, it extends the data (although it’s observational data), into the lowest population.

Secondly, I think it’s important that when you look at the geographical use of these drugs, there are some drugs that are used more in the United States and others that are used more in Europe. The results seem robust, irrespective of the agent. So, we were waiting for CANVAS, with canagliflozin, and then there’s a trial with dapagliflozin—that’s the third agent. So, it looks like, at least in this observational study, there didn’t seem to be heterogeneity in how these drugs worked, at least in the real-world experience. But I think the biggest thing is extending it to lower-risk populations to ask, “Could these drugs have a role in patients who don’t have established cardiovascular disease but are at risk for it because they’re diabetic?”

Rosemarie Lajara, MD, FACE: Right.

Peter L. Salgo, MD: This goes to what you were saying, which is, this disease has been brewing for years before we see it show up with an elevated blood glucose.

Rosemarie Lajara, MD, FACE: Right. Unlike diabetes in which we have A1C or the sugar determination, for cardiovascular disease, it’s usually an event.

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

Peter L. Salgo, MD: I love these numbers. The numbers in the first study were impressive enough—14%, 38%. These numbers are even better. You’ve got a 51% reduced rate of death from any cause?

Christian T. Ruff, MD, MPH: Yes, and remember, I want to caution, too, it’s obviously not a randomized trial. There can be some confounding evidence in the real-world data. But I do think what you mentioned is, the magnitude, whether it’s 30% or 50%, is high and robust. What I like to say about real-world data is, if you have a clinical trial that shows an incredible benefit, you worry. “Is that just 1 trial?” But if you get confirmatory evidence in the real-world data that supports the clinical trial, that’s a really nice story. It shows that that’s a generalizable result, and with CANVAS (now the second trial report), we’re seeing multiple randomized trials, real-world data, that are all telling us the same thing: these cardiovascular benefits are real.

Karol E. Watson, MD, PhD, FACC: There’s something real there.

Peter L. Salgo, MD: These results are ginormous. They scream credibility and they’re well done. And this is, again, a retrospective study. It’s looking at the SGLT2 [sodium-glucose co-transporter 2] inhibitors versus all other antidiabetic medications. All of them.

Karol E. Watson, MD, PhD, FACC: If that was all we had, it wouldn’t be as impactful. But we have, now, 2 clinical trials. And the real-world data are pretty impressive.

Stephen A. Brunton, MD, FAAFP: We also see some benefits there with GLP-1s [glucagon-like peptide-1s], as well. The LEADER trial showed the benefit of a GLP-1 agonist, as well. So, it’s like there’s more going on. It’s the issue about getting to that process. Treating diabetes has a benefit that we haven’t seen before.

Karol E. Watson, MD, PhD, FACC: But it also is true that it has to be agent-specific.

Rosemarie Lajara, MD, FACE: I was going to say that. And unlike what we’ve seen so far with the data that has been produced for the SGLT2s, GLP-1 seems to be agent-specific.

Christian T. Ruff, MD, MPH: I’m excited about GLP-1, but a very interesting fact about these trials is, when we’re talking about treating diabetes in a hyperglycemic patient, which is how these trials were designed, we’re actually not seeing one of the arms having better glucose control than the other, really.

Karol E. Watson, MD, PhD, FACC: They’re matched.

Christian T. Ruff, MD, MPH: They’re matched. So, actually, these benefits are independent of the hypoglycemia, which is fascinating. It’s not all about, “This is just a really effective drug at lowering glucose, and we know glucose is bad for the heart.” It’s independent of the hemoglobin A1C and glucose. There’s something about these agents we don’t understand.

Rosemarie Lajara, MD, FACE: We don’t know why, right?

Karol E. Watson, MD, PhD, FACC: But we have to remember, there’s a little weight loss, there’s a little blood lowering, and there’s a little A1C lowering, so it’s probably all of the above.

Stephen A. Brunton, MD, FAAFP: With regards to heart failure, which is what they all showed dramatic results in with the SGLT2s, they kind of make sense. You have a glucuronic, so you’re really having a diuretic function, as well. In fact, there are probably, as you say, other activities that are occurring.

Christian T. Ruff, MD, MPH: It is. But on the cardiovascular side, this benefit in heart failure (in a patient population, that’s not necessarily original heart failure), is much higher than the benefit we are studying in heart failure phase 3 trials. So, the magnitude is what’s enormous—much more than we’d expect by a couple of pounds of diuresis. Clearly, volume is important, especially with the SGLT2s.

Rosemarie Lajara, MD, FACE: Let’s not forget that, at least for empagliflozin, data suggest that it has an effect in our fear of stiffness.

Peter L. Salgo, MD: So, compliance is improved?

Rosemarie Lajara, MD, FACE: Yes, the preload and the afterload both...

Karol E. Watson, MD, PhD, FACC: Which means if you lose weight…

Peter L. Salgo, MD: Statins do that too, though. Statins, alone, aren’t getting this kind of result.

Christian T. Ruff, MD, MPH: And I’m curious, but I heard a hypothesis that they actually make the heart work more efficiently.

Rosemarie Lajara, MD, FACE: There’s a theory that the ketones are making the heart more efficient, using it as a fuel.

Peter L. Salgo, MD: We know that diabetes starts before you know it. We know that these drugs help prevent death. So, I have measured my glucose, and I have measured my glycoside and hemoglobin. It’s normal. Maybe I should just start taking these drugs, now? Could you write me a script?

Karol E. Watson, MD, PhD, FACC: There is 0 data for that. But I will say that I’ve heard the murmurings of planning of trials in a nondiabetes population with heart failure, etc, looking for other ancillary benefits.

Peter L. Salgo, MD: This is outstanding.

Christian T. Ruff, MD, MPH: That’s how statins started, right? Treat patients who had it, and now you start moving it back, saying that if you actually start treating earlier, you’ll prevent them from ever having overt death.

Peter L. Salgo, MD: This is crazy exciting.

Transcript edited for clarity.