Clues to How SGLT2 Inhibitors Work: CAMEO-DAPA

Recorded 3/31/2023 This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hi, everyone. I'm Ileana Piña from Thomas Jefferson University, and this is my blog.

I have with me today Barry Borlaug, who is from Mayo Clinic in Rochester. He is well known for his description of the exercise hemodynamics of patients with heart failure with preserved ejection fraction (HFpEF). It's a diagnosis that some of my colleagues wrestle with because the patient may show up with hypertension; they may show up with diabetes; or they may show up simply because they can't breathe, they're obese, and they're not walking very well. These are primarily women, usually older women, who have many comorbidities.

Now, we have the sodium-glucose cotransporter 2 (SGLT2) inhibitors in the guidelines for this group of patients with HFpEF, which, by our new definition today, is an ejection fraction above or equal to 50%. I think this fits with what Dr Eugene Braunwald has been saying for a long time: That's the real HFpEF.

Probably one of the best diagnostic things that we can do for these patients is to figure out what their left atrial pressures are with activity. That may distinguish them from other things.

How do these SGLT2 inhibitors work? We have all these slides with all these mechanisms, but nobody knows. Barry and his team really took this on and studied it. They did a trial called CAMEO-DAPA.

Barry, welcome. Our audience should be very interested in this. Tell us what you did.

True HFpEF

Barry A. Borlaug, MD: Sure. Thanks for having me, Ileana.

As you know, HFpEF is a hemodynamic disorder fundamentally, characterized by high filling pressures at rest and then especially with activity. We know that SGLT2 inhibitors work but we don't know why. We were hypothesizing that there may be hemodynamic benefits that we would see on both rest and exercise hemodynamics.

In this study, we took patients with HFpEF (ejection fraction of 50%-plus) and did a baseline invasive hemodynamic exercise test at maximal effort, and we also did direct measures of blood, plasma, and red blood cell volumes; body weight; and other standard measures.

Then, we randomized them to treatment with dapagliflozin (dapa) 10 mg once daily or placebo once daily, double blind, for 6 months. Then they came back and did another invasive hemodynamic exercise test and another blood volume test.

Piña: How did you measure the blood volume?

Borlaug: There's a radiolabeled indicator dilution technique. The manufacturer is called Daxor. It's a nuclear medicine test that we use. It's nice because it's not an estimate of plasma volume, which is what we usually kind of have to look at.

Piña: That's what we live with, the estimates.

Borlaug: Exactly. As you know, these drugs cause osmotic diuresis and natriuresis. There's thinking that the reduction in plasma volume might be key, so we wanted to look at that.

We enrolled 37 patients. One withdrew and 36 completed. We found that compared with placebo, treatment with dapa had reduced resting and exercise wedge pressure. The effect size at rest was a reduction of 3.5 mm Hg, which doesn't sound like much, but that's about 20%-25%. That's a pretty good effect size. With exercise, there was a reduction in wedge pressure > 6 mm Hg, which was very impressive, I think.

We looked at other measures. We actually saw a trend for a reduction in blood volume, which was not significant. There was a reduction in plasma volume, but it was pretty modest. It was about 170 mL.

We know that the SGLT2 inhibitors also, on average, in the prior studies, usually, led to about a 1- to 2-kg weight reduction. In our study, where the patients were a bit heavier than some others, we saw a 3.5-kg reduction with dapa vs placebo.

The amount of weight reduction was correlated with the reduction in wedge pressure, both at rest and exercise, which I thought was kind of interesting too. This sheds some new light on how these drugs work to help people with HFpEF feel better.

Diuretic Effect?

Piña: What about diuretics? Were they on any diuretics at all? It sounds like if I gave a diuretic, maybe I'd do the same thing.

Borlaug: Yes. About the usual proportion that you would see in more of an ambulatory HFpEF group, I think about three quarters or so were on diuretics. I actually looked to see if there were any changes during the course of the study, and there really weren't. A couple people went up and a couple people went down in both groups.

Piña: In spite of diuretics.

Borlaug: Yes. With diuretics.

Piña: Were any of them on things like spironolactone, an angiotensin-receptor blocker (ARB), or any of those?

Borlaug: Yes. It a was pretty typical proportion [of patients] on background therapies with mineralocorticoid receptor antagonists (MRAs). Maybe a little lower at 20%-30%. Unfortunately, that's often what we see in trials these days, even though the drugs look pretty good. A majority were on angiotensin-converting enzyme (ACE) inhibitors or ARBs and beta-blockers.

Piña: They had good background medical therapy.

Borlaug: Yes.

Piña: What was your mean ejection fraction?

Borlaug: About 61%. They were all real HFpEF, above 50%.

Piña: This was the real McCoy. Mostly women, right?

Borlaug: Yes. Two thirds women, 70% obese, and the mean body mass index was 35, which is pretty typical of HFpEF in the US. It's a little lower in Asia and Europe, but for us, that's pretty typical.

NT-ProBNP Levels

Piña: What about their N-terminal pro b-type natriuretic peptides (NT-proBNPs)?

Borlaug: They were modestly elevated, but not markedly elevated. We know that's often the case in HFpEF, related to the obesity, in large part. Their filling pressures were only modestly elevated at rest. On average, it was about 16 mm Hg at rest but > 30 mm Hg with exercise. These are volume-overloaded patients. These are more of the typical ambulatory patients with exertional breathlessness.

Piña: What do you think the drug is actually doing if they had been on diuretics and that didn't change much? That's still an impressive drop in fill pressure, right?

Borlaug: Yes. I think part of it is related to a diuretic-type effect. I think there might also be changes in the distribution of blood volume — the venous capacitance, the stressed blood volume vs unstressed volume.

There also may be myocardial effects. We weren't really positioned to see that, but there's evidence that these can also help by enhancing myocardial function and favorably modifying loading conditions, I think that the total sum of all of this leads to a hemodynamic improvement.

Piña: You did have a drop in weight too.

Borlaug: Yes.

Piña: Even though it was modest. If given a loop diuretic at home, they may lose a couple of pounds. I think you had a more dramatic drop.

Borlaug: We actually did DXA scans. We haven't reported any of this yet. The initial manuscript's getting ready to go out. We saw reductions in fat mass, too, so it's not just fluid.

Piña: There's something metabolic going on. For something happens so quickly, when the curves split apart so early, there's something metabolic going on.

Borlaug: Yes.

Piña: What it is? We're not sure. What's next? What are you going to do next?

Borlaug: We're not planning a follow-up with dapa. I think we're going to do more analyses from these data, which we haven't had the opportunity to do yet. We're going to look very carefully at metabolism.

The study CAMEO is cardiac and metabolic effects, and so far, we've looked mostly at the cardiac effects. We also, working with my colleague, Mike Jensen at Mayo, taking a very close look at glucose and fat oxidation. We actually measured both labeled and unlabeled free fatty acids, glucose, ketones, and other metabolites in arterial blood, and also in this study, we cannulated the coronary sinus.

Piña: Oh my goodness.

Borlaug: We have coronary sinus effluent blood, so we can look at transcardiac uptake.

Piña: You hardly ever see that. You should be able to do some metabolomics. Wow. The coronary sinus, the downplay of all the blood in the coronary tree. That's great.

Borlaug: Yes. Exactly.

Piña: Well, I'll be very, very interested. I hope you come back and tell us about that.

Borlaug: I'd be happy to.

Piña: In summary, we all think, Are we really going to start an SGLT2 inhibitor for HFpEF? Really? Yet, you see both the EMPEROR-Preserved and the DELIVER trial having curves that just split apart within the first 3 months, and you think, What the heck is going on here?

It's a group of patients who are hard to identify, and boy, are they hard to treat. They often get lumped in, even in the hospital, without the right diagnosis, which I think that's where the phenotyping that you and I have talked about before needs to start. Phenotype may be something you can add. Metabolomic phenotyping may be quite different.

Borlaug: I agree.

Piña: Great work, Barry, as usual. I always quote you to the fellows here, saying, "You really want the diagnosis of HFpEF? Let's do it right. Get that catheter in that left atrium and mimic the Borlaug Lab."

Thank you for joining me, and good luck. I'll be looking forward to seeing your manuscript.

To my audience, I hope you find this helpful. I remind you that it is in the guidelines, and that we do it as a class effect. Barry's work today was on dapa, but the guidelines have taken this as a class effect.

We also have empagliflozin approved for HFpEF and there are a couple of others coming down the pike. We know that canagliflozin and sotagliflozin are each a little bit different, but still within that class effect.

I hope that you use it on your patients. Apply the guidelines. That's why all this work gets done.

I want to thank you for joining me today. I'm Ileana Piña, signing off.

Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA's Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.

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