Transcript
Use with ChatGPT / Claude Auto-scroll A
The hosts introduce HFpEF and review how treatment has historically focused on diuretics and comorbidity management. Dr. Borlaug explains the early evidence for spironolactone and sacubitril valsartan and how these led to modest guideline recommendations.
Speaker A
You.
Welcome back to Mayo Clinic Cardiovascular Podcast series Interviews with the Experts.I'm your host, Sharon Hayes.I'm a non invasive cardiologist, vice chair of faculty development and academic advancement for the Department of Cardiovascular Medicine here in Rochester, Minnesota.Today I'm joined by my colleague Dr. Barry Borlaug.He's a professor of medicine, chair of research for circulatory failure and invasive heart failure, cardiologist Also here in Rochester, Minnesota today our topic is managing heart failure with preserved ejection fraction.
So Barry, we know that half of patients with heart failure have HFpEF, their EF is normal, but there haven't been many treatment options and we've covered diagnosis in another podcast with you which has been very helpful.But now that we can diagnose it better, we now can get excited perhaps and perhaps educate ourselves about new treatments.This is exciting.So tell us how this traditional approach is evolving.
Speaker B
Thanks, Sharon.
So you know, it is, it's even more than half of all heart failure.And we've been saying this for years, but for years we've had nothing to offer.We started out very logically, I think, trying to treat HFPEF like heart failure with reduced EF or so called systolic heart failure.But trials of drugs like angiotensin receptor blockers and ACE inhibitors, limited data and beta blockers, walkers, even digoxin, there really wasn't any significant, you know, evidence of significant efficacy.So for years the, the mantra was, you know, give diuretics for congestion, level of evidence C and think about using things like ACE inhibitors to control blood pressure and treat comorbidities.Like that's gonna, you know, treat their heart failure.And of course you're always going to treat comorbidities, you're always going to treat, but you know, high blood pressure and things like that.But in the last couple of years we've started to see more.
It started with mineralocorticoid antagonist spironolactone in the TOPCAT trial.Overall, that trial was neutral, was not significant.
Spironolactone as compared to placebo did not reduce the risk of heart failure, hospitalization, cardiovascular death.
But about half of the patients were enrolled in the Americas, half were in Eastern Europe and Russia.And when they looked at the two sides of the world, they saw some important differences.The event rates were very low in Eastern Europe and Russia.And when they just looked, suggesting that they didn't really have HFPEF in the first place, and when they looked only in the Americas post hoc, they saw that spironolactone did work, so that was given a 2B recommendation in the guidelines, something we can consider, but not strongly evidence based.Then came sacubitril valsartan, which was tested in the Paragon trial.
And this was a very large trial.As compared to placebo, sacubitril valsartan almost reduced the risk of total number of heart failure events or cardiovascular death.P value 0.06.It was a modest effect size and it was borderline significant.So the guidelines also gave that a 2B that we can consider it, we can think about it.
So we had some signal of evidence that we could think about these.
This section covers the breakthrough trials showing SGLT2 inhibitors reduce heart failure events in HFpEF and why they became a class I treatment. Dr. Borlaug also explains proposed mechanisms, hemodynamic benefits, and key safety considerations.
Speaker B
But things really changed with the introduction of the SGLT2 inhibitors.As you know, the FDA required diabetes drugs to be tested on cardiovascular outcomes years ago.And we serendipitously noted that patients with diabetes treated with these drugs had lower rates of heart failure hospitalization.So that was first tested in heart failure with reduced EF and then more recently in two large cardiovascular outcome trials in HFpEF, the Emperor preserved trial, and then more recently in the Deliver trial.They were both published in the New England Journal.And they both showed that as compared to placebo treatment with SGLT2 inhibitors, empagliflozin and dapagliflozin, 10 milligrams once daily reduced the risk of heart failure, hospitalization or cardiovascular death by about 20%.So now we have strong two trial level of evidence.A class one will be class one in the updated guidelines treatment for HFpEF.So this has been a real, real game changer.
In addition to all the other things that we've been thinking about with diuretics and maybe considering spironolactone and sacubitril valsartan.
Speaker A
How do we think that these work?
Speaker B
Yeah, that's a really good question.The SGLT2 inhibitors have widespread protein effects, as you know.So they, they, they cause loss of glucose in the urine.
This leads to a little bit of an energy deficit, a little bit of weight loss.It's usually not that remarkable.There can be a natural effect.Of course, there is a little bit of a reduction in plasma volume, which can help, but after that we don't know for sure.At the cellular level, there's evidence that they enhance clearance of toxic accumulation byproducts in the cells, they reduce oxidative stress, they reduce signaling pathways that are indicative of a nutrient excess, which we think are bad for a number of reasons.
We published a study earlier this year in the journal Circulation where we looked at the invasive hemodynamic effects of dapagliflozin for six months.And we saw about a 20% reduction in both resting and exercise left atrial pressure measured by wedge pressure.So there's definitely a hemodynamic benefit and that sort of fits with what we've seen with improvement in quality of life, improvement in exercise capacity measured by six minute walk distance.This was both looked at in a trial called preserved HF and then the reduction in heart failure events.But we still, there's, you know, there's a lot of other possibilities.
There may be direct myocardial effects, there may be anti sympathetic effects.A lot of research is still focusing on this because, you know, even though we've done better with treatment, the residual risk of people who are on guideline directed treatment is still high.So we've still got a long ways to go.
Speaker A
So can you share a little bit about safety and cautions related to the patient population we may be considering these medications for?
Speaker B
Yeah, I think that's, that's always in addition to efficacy, safety is crucial and the SGLT2 inhibitors are quite safe.
People, you know, worried about hypoglycemia, obviously they're diabetes drugs, but unless you're being treated with insulin, providing therapies, either insulin or sulfonylureas, for example, there wasn't an excess risk of hypoglycemia.So that's one important feature.There wasn't a significant excess risk of like ketoacidosis.What there is is an increase in the risk of urogenital infections, which can happen.Obviously you're, you're increasing the content of glucose in the urine, you're making that a better environment for microbes.So that is one thing that we do run into a little bit and something that we need to caution our patients about.
The discussion shifts to obesity-related HFpEF and the STEP HFpEF trial of semaglutide. Dr. Borlaug describes the phenotype, the trial results, and how weight-loss therapy may complement SGLT2 inhibitors in practice.
Speaker B
But really the uptake has been very quick.As we were mentioning earlier, you know, primary care physicians are more comfortable prescribing these medicines now certainly cardiologists are more comfortable prescribing these and they work, they work a little bit better.The absolute risk reduction is even greater in people with obesity.And that takes us to an even more recent trial called STEP HFpEF.
And you know, for years we thought about HFPEF as this disorder of, you know, older aged women, hypertensive, hypertrophy, small hearts.But in the last 10 years we've really noted that a lot of people with HFPEF have obesity and that's risen to become the dominant sort of phenotype.Is this people with obesity related HFpEF and they have many of the same features that we see in non obese patients with HFpEF, but there are some important differences.They have more visceral fat, they have more epicardial fat, they have more volume overload, they have more systemic inflammation, their CRP levels are higher.You know, obviously they have more diabetes and glucose intolerance.
And the step trial, step HFpEF trial followed on the heels of the other step trials of semaglutide, a GLP1 receptor agonist that leads to pretty significant weight loss.And step HFpEF was a trial that randomized patients with obesity and HFPEF to treatment with semaglutide or placebo for one year and was just recently published.And the primary endpoint, dual primary endpoints were body weight reduction and quality of life and both of those were highly significantly improved.Secondary endpoints included exercise capacity, 6 minute walk distance, a composite endpoint, and CRP levels as a measure of inflammation.And all of those very consistently were very highly, significantly improved.
So now, in addition to the SGLT2 inhibitors, for people that are living with obesity and HFP, we have semaglutide.Of course the issues are availability and cost, but we have something else to offer as well.
Speaker A
So getting to just a really practical.I'm a cardiologist, I'm not a heart failure doc, I'm a family medicine or general internist.I've got a patient who I either have made a diagnosis with the help of a cardiologist or pretty confident because of the likelihood.
When and how do I start these treatments?I mean, right away, do I need to do much else before I initiate one of these drugs?
Speaker B
I think so, if they look like they're so SGLT2 inhibitors clearly have the strongest data and they can treat volume overload.And between patient variability and how much they reduce, volume can be variable.So I would say the first thing, once you've securely made the diagnosis would be to start them on an SGLT2 inhibitor.
Unless there's a contraindication for some reason, I would follow them up in not to if they're volume overloaded, if they have jugular distension, edema and things like that, I'd probably see them back within a couple weeks because if they're still volume overloaded after starting the SGLT2 inhibitor, then you'd probably want to get them on a diuretic as well.But for some people who are congested, just starting the SGLT2 inhibitor will take care of that.So that would be first and Foremost, I think that if you see them back, if they weren't congested, you start the SGLT2 inhibitor, you'll see them back in a couple months.If they still have significant symptoms, that's when you're going to think about some of these other possibilities, as I mentioned earlier, like spironolactone or sacubitril Valsartan.And there are certain patient populations where you might lean on these earlier.
Patients with the lower EFS, like closer to 50 or, you know, 49 or 52, they might respond better to both of those.People with more severe hypertension may do better with the sacubutril Valsartan because of the blood pressure lowering effects.People with recent hospitalizations might do a little bit better with those.And then in subgroup analysis, there was a little more evidence of benefit in women than men for sacubitril valsartan.So those are all things that might push me.If they're still significantly symptomatic on the SGLT2 inhibitor, plus minus the diuretic to add those other drugs.And now with semaglutide, I think that if they're obese and they're on an SGLT2 inhibitor, I would have a variable threshold to treat with that.If, again, if you can get it.It's currently not covered for this indication, but the trial evidence is very compelling.
Dr. Borlaug gives practical advice on when to start therapy, how to follow patients, and when to add diuretics or other agents. He also emphasizes managing common comorbidities such as atrial fibrillation, coronary disease, hypertension, and sleep apnea.
Speaker A
This is just sort of more your experience.
How many of the patients that you care for really have enough improvement with a single starter drug that you don't really have to resort to some of these others?I mean, is it, is it good enough that we, maybe even half of our patients, that might be enough to render them substantially less symptomatic, or is there still a fair amount of residual symptoms?
Speaker B
I think there's still a fair amount of residual symptoms.And when you really push people, a lot of them will say, well, I feel a lot better, but.And people like to minimize their symptoms.You know, heart failure symptoms come on gradually.And what people do, what do you do when you're short of breath with activity?Well, you reduce your activity level and then you perceive less shortness of breath.But that's because you're not being very active.And we know that that's very bad for many reasons.
So I think that when you push people on this, you see that most people are not cured by addition of these drugs and they do need more, you know, some other things I didn't go into, but you do want to think about the other comorbidities.And some of them are very common afib.You know, 2/3 of people with HFPEF will have atrial fibrillation at some point in their life.We don't have a prospective RCT specifically looking at treat, you know, rate versus rhythm or catheter ablation versus drug therapy.But we do have a lot of, a lot of smoke that suggests that there may be benefit there.The Cabana trial randomized people with AFIB in general to catheter ablation versus drug therapy.There were improvements in quality of life, there was a trend to improvement.In the primary endpoint, when they looked at people with heart failure, the signal was even stronger.
It's post hoc analysis, so we can't treat it as sort of level of evidence A but many of us, I think, really have a very low threshold to try to get people into sinus rhythm and keep them in sinus rhythm.If you suspect coronary disease.
There is observational data that revascularization can help.If they have other things like high blood pressure, obviously you're going to treat their high blood pressure.If they have sleep apnea, you're going to treat their sleep apnea.So you, you want to be a good overall doctor and treat all these other problems as well, not just focusing on the heart failure.
The conversation closes with the importance of close follow-up and the need for more treatment options. Dr. Borlaug highlights upcoming trials and the continued progress in HFpEF care before the episode wraps up.
Speaker A
I think you've made the case for really close follow up of these folks after initiation of whatever treatment you start with because there may be more that you can do for them that will continue to improve their outcomes and just their quality of life.
Speaker B
Absolutely.
Speaker A
Anything else you want to share about?Maybe.What's next?What are you looking forward to?
Speaker B
Well, I'm looking forward to more evidence, you know, so there are a number of trials.There's a trial of a different mineralocorticoid antagonist, phenerinone in HFpEF.There's a trial of another weight loss drug called tirzepatide, which is a GLP1 receptor agonist, GIP agonist called SUMMIT.There's another trial.So the STEP HFpEF trial was only in patients with obesity and HFpEF, but no diabetes.
There's a sister trial called STEP HFpEF DM, which we'll report soon, in the not too distant future to tell us more about how it does in diabetes patients.And also many of these patients will also be on SGLT2 inhibitors.So how does the effect interact with that?
And then there's a whole host of other therapies coming down the pike as well.We've made great strides, but these people, as I mentioned earlier, still have a lot of symptoms and a lot of risk of hospitalization and death.So I think that there's plenty of room more.And HFrEF, we've got seven or eight treatments and they still have risk.And it's the same thing in HFpEF.We've got a couple now in our toolbox, but there's a lot of room for more.So it's a very exciting time and I think we're going to have much more to offer in the years to come.
Speaker A
Well, thank you so much, Barry, because I know you've been involved in this space when it was unappreciated and people thought it was a dead end.And so I am thrilled that you and others are able to sort of reap this satisfaction of being able to help the people you've been studying so long.Thank you, Barry.
Speaker B
You bet.Well, that's what it's all about.Thank you, Sharon.
Speaker A
This wraps up this week's episode of Interview with the Experts, and I'd like to thank Dr. Borlaug for joining me today and discussing this really important topic.We look forward to you joining us again next week for another interview with the Expert.
Be well.