Recorded April 8, 2024. This transcript has been edited for clarity.
Ileana L. Piña, MD, MPH: Hello, and welcome to my blog. Today, I'm at the American College of Cardiology in Atlanta. I want to introduce and welcome Dr Kosiborod: from the Mid America Heart Institute, who has presented a very impactful paper, STEP HFpEF DM, that is in The New England Journal of Medicine right now. This is about semaglutide. A lot of patients ask me to give them that pill that makes them lose weight. I see primarily patients with heart failure (HF). So, Mikhail, congratulations on your presentation. Give us a little synopsis of what the trial is about.
The STEP HFpEF Program
Mikhail N. Kosiborod, MD: First of all, it is always a pleasure to be with you. Maybe a quick word about the STEP HFpEF program that included two trials: The first is STEP HFpEF, which was a trial of patients with obesity-related HF with preserved ejection fraction (HFpEF) who did not have diabetes, which we presented and published at European Society of Cardiology in August last year.
The second installment of the program is the STEP HFpEF diabetes trial, which is essentially the same population of patients except they also have type 2 diabetes. I guess your question would be why we did two trials instead of just doing one trial that included patients, both with and without diabetes. I'll come back to that shortly.
The crux of the hypothesis behind the program is that we all know the prevalence of HFpEF has increased dramatically in the past couple of decades. When I was a fellow in training, it was rare for me to see a patient with HF who had preserved EF. A majority of patients had HF with reduced EF. Now, the majority of people we see have HFpEF: Why did that happen? There are a lot of different reasons for the dramatic change in epidemiology. But certainly, one of them, at least in our opinion, is that the obesity epidemic has a lot to do with it. In fact, if you look at the population of patients with HFpEF in the United States, 80% of them are living with overweight or obesity. The hypothesis behind the program was that obesity is not just a comorbidity. It doesn't just happen to coexist by accident in this patient population, it may in fact be causing their HF. It may be a critical factor in the development and progression of HFpEF.
In order to test our hypotheses, patients were randomly assigned to semaglutide, with the target dose of 2.4 mg once a week or matching placebo and treated for 52 weeks, or 1 year. The reason we did two separate trials is because part of that hypothesis was that if obesity is in fact the cause of HF, then certainly, weight loss would be probably not the only factor but "an important factor in the potential benefits of semaglutide in this patient population, provided that semaglutide is beneficial which of course we ultimately demonstrated.
But what we knew from weight-loss trials — not HF trials but weight-loss trials of medications like semaglutide and also other anti-obesity medications like tirzepatide and others — is that people with diabetes tend to lose a lot less weight. With these medications, there's about a 40% less weight loss in people with type 2 diabetes. Lots of theoretical reasons why that could be the case. Nobody really knows for sure.
We knew from the beginning that the weight loss likely was going to be different. Then, of course, there are other things that happen in people with diabetes: They have more severe HFpEF phenotype, and people with more severe disease sometimes don't respond to treatment the same way as those with less severe disease. Finally, we knew when we started the trial, which was back around 2019, 2020, that people with diabetes would be more likely to be treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. At the time, we didn't have the data for SLT2 inhibitors in HFpEF, but we knew that were going to be tested. There was, of course, an expectation that they may well be beneficial. For all of these reasons, we said, "You know what, the treatment effects may well be different between the patient population, but let's study them separately."
Piña: It makes everything much more clean when you can separate them like that.
Kosiborod: Precisely. In the first trial back in August of last year, semaglutide significantly improved the Kansas City Cardiomyopathy Questionnaire, Clinical Summary Score (KCCQ CCS). That's the domain of KCCQ, which is the gold standard for assessing symptoms and typical limitations in people with HF. We showed a nearly 8-point improvement on average, which is a very large improvement. We also showed that of course people lost more weight, and they had an improvement in 6-minute walking distance reduction and inflammation reduction in N-terminal pro B-type natriuretic peptide (NT-proBNP), which is interesting. HF hospitalization and urgent visits were also numerically fewer.
STEP HFpEF Diabetes
We wanted to expand on what we found in the diabetes trial. As expected, we saw about 40% less weight loss than we saw in the first STEP HFpEF trial in people without diabetes. Of course, patients treated with semaglutide still lost more weight than did those on placebo, but the difference was about 6.4%. There was more than a 10% difference between treatment groups in the first trial. Despite that, the HF benefits were very similar to what we saw in the first trial.
The improvement in the KCCQ CCS was nearly identical. We also saw an improvement in 6-minute walking distance, we saw reductions in high-sensitivity C-reactive protein (hsCRP) and reductions in NT-proBNP — quite substantial at an about 20% reduction in NT-proBNP. Just like in the first trial, there were numerically fewer HF hospitalizations and urgent visits. Out of 25 patients that had at least one of those events, seven were in the semaglutide group, and 18 were in the placebo group. The findings on the HF side were nearly identical, whereas the degree of weight loss was 40% less than in the first trial.
Piña: Why do you think this happens? Does it have something to do with the insulin that they're getting for treatment? Was there a difference between those who had insulin and those who didn't?
Kosiborod: We have not dissected these findings to this extent yet. But that's one of the hypotheses. People with diabetes get treated with medications like insulin and sulfonylureas, which actually make people gain weight. If you don't have diabetes, you are not going to be on insulin. That's one of the leading theories for why we see less weight loss. But to be perfectly honest, we don't really know.
Why Do Patients Feel Better?
Piña: I was looking at your slides in the data. What pushes the patient to feel so much better… It's captured on the KCCQ. I know for myself that when I lost weight, I felt lighter. I could do more. Maybe that's one of the things that the drop in obesity does: It makes patients feel lighter, that they can do more. It's not because they were symptomatic from HF. They're New York Heart Association (NYHA) Class II primarily.
Kosiborod: As you well know, there is a disconnect between the KCCQ and NYHA Class. If you look at NYHA Class, about one third were Class III and IV, and about two thirds were Class II. Let's come back to the discussion about insulin in a minute, because in the The Lancet paper wherein we combined the two projects, there were some very interesting findings about severity of HF and that treatment effect.
We had one third in Class III and IV and two thirds in Class II: That' very typical of an HF trial. If you look at the DELIVER trial, PARAGON, and EMPEROR-Preserved, it's very similar. But KCCQ at baseline was much lower than what was seen in those other trials, instead of having KCCQs in the low 70s.
Piña: It was in the 40s and 50s.
Kosiborod: Yeah, in the 50s. These people were really symptomatic and functionally impaired. Their 6-minute walk distance was very low. It was about 280 m.
Piña: That's below 300 m, which is considered severe.
Kosiborod: Back to your question on what exactly gets better? We examined that in the first STEP HFpEF trial, which we published in Circulation and presented at the American Heart Association in 2023, essentially nearly every domain of KCCQ improved. The symptoms got better, physical limitations got better, quality of life improved. All key KCCQ domains improved. Even the social limitation domain improved, which we almost never see with HF treatments. Social limitation is a lagging indicator, and it's very difficult to actually see an improvement in social function. That indicates that this is a substantially effective treatment because not only is there a large quantitative effect but it actually makes symptoms and physical limitations improvements translate into improvements in social function.
The largest improvement was in the symptom burden and symptom frequency. It was more than a 10-point average. Now, to your point about whether people just feel lighter. Is it what we sometimes call mechanical unloading through weight loss and not really a pathobiology benefit on the disease modification for HF. As I mentioned, we just presented a combined paper published in The Lancet that offers some very interesting insight.
There was 40% less weight loss in the people with diabetes, but the HF benefits were very similar. If this were all about weight loss, you would have expected that if there is a lot less weight loss, then there would be also less HF benefit. But it's not what we see at all. We see that the HF benefits are very similar, which indicates that it's not just weight loss.
Beyond Weight Loss
Piña: There's something else going on in here.
Kosiborod: There is something else going on. The changes in NT-proBNP are interesting. We know that when people with diabetes lose weight with lifestyle modification — from the LOOK AHEAD trial— the NT-proBNP went up. There are theoretical reasons for why that would be the case that have to do with visceral adiposity and the effect it has on natriuretic peptide levels. Here, we saw a 20% reduction in NT-proBNP despite weight loss.
Piña: Do you think this is anti-inflammatory?
Kosiborod: For sure. We know that from the STEP HFpEF trials, right? We had a 33% reduction in hsCRP for a treatment ratio of 0.67. The NT-proBNP goes down, and there is a decongestion effect. hsCRP goes down, so there is an anti-inflammatory effect. Some of it's probably due to weight loss, but some of it may be a direct effect.
The other thing I will mention, which indicates to me at least that this is not just weight loss, is our combined subgroups. Essentially almost all of the subgroup analysis was done on a combined, STEP HFpEF and STEP HFpEF diabetes basis because then, we had twice as many patients, and we prespecified that we were going to do it that way. What we saw was the higher the NT-proBNP at baseline, the higher NYHA class at baseline, on loop diuretics vs not at baseline, with atrial fibrillation vs not at baseline — all the markers of HF severity — the larger the benefit was with semaglutide vs placebo than for those with less severe HF.
Don't get me wrong. Those with less severe HF still got a very large benefit. This is not an interaction in terms of severity of HFpEF. Everybody benefits, and everybody has a large benefit. But it was that the benefits were even more pronounced in people with more severe HF, so the interaction was in the magnitude of improvement.
These people with more severe HF got larger benefit as seen on KCCQ despite the amount of weight loss experienced being identical to those that had less severe HF. All of these findings taken together suggest quite strongly that we can't explain everything by weight loss. There is something else going on. There are likely decongestive effects and anti-inflammatory effects of semaglutide that probably explain what we're seeing here. It's not just weight loss.
Piña: To me, the NT-proBNP going down is proof that there's something physiologic. Did you collect any echoes?
SGLT2 Inhibitors, Less Weight Loss
Kosiborod: We did collect echoes, and that's forthcoming. We are analyzing that data right now, and we're hoping to present and publish that soon. The other thing I will mention, which I think is relevant, is that in the STEP HFpEF DM publication, we did a subgroup analysis looking at people who were or were not on SGLT2 inhibitors at baseline.
About one third of the patients in the diabetes trial were on SGLT2 inhibitors at baseline. There were consistent benefits in terms of KCCQ improvement and whether patients were or were not on SGLT2 inhibitors. When it came to weight loss, there was a bit more weight loss in those that were not receiving SGLT2 inhibitors at baseline.
Piña: Interesting.
Kosiborod: But of course, both groups lost a lot more weight with semaglutide vs placebo. But again, the magnitude was a bit more in those who weren't on SGLT2 inhibitors at baseline.
Piña: I think this is very consistent with other drug trials, etc., that we've seen: that the sicker the patients, the greater the benefit. Everybody may be afraid of putting the patients on the drug because they are older or too sick, but on the contrary, those are the people that usually get the highest benefit. I urge our audience to read the papers in The New England Journal and The Lancet.
When you have that patient in front of you, think about what you can do to decrease their obesity, which patients get very troubled with and have a very hard time getting rid of the weight. They really want to do it. Every day in clinic, I hear, "I am going to get on it. I'm going to start exercising. I'm going to eat less." But it's so hard to do. And obesity is a huge problem in the United States. It's going to be costing us many tax dollars as a society to deal with this. Congratulations again. You have spent many years working on this. Since I've known you, you've been working on the diabetes part of HF. You're my go-to person for diabetes and HF. Thank you for joining us. Have a great day.
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.
COMMENTARY
Semaglutide Benefits in HFpEF Take a Step Beyond Weight Loss
Ileana L. Piña, MD; Mikhail N. Kosiborod, MD
DISCLOSURES
| April 12, 2024Recorded April 8, 2024. This transcript has been edited for clarity.
Ileana L. Piña, MD, MPH: Hello, and welcome to my blog. Today, I'm at the American College of Cardiology in Atlanta. I want to introduce and welcome Dr Kosiborod: from the Mid America Heart Institute, who has presented a very impactful paper, STEP HFpEF DM, that is in The New England Journal of Medicine right now. This is about semaglutide. A lot of patients ask me to give them that pill that makes them lose weight. I see primarily patients with heart failure (HF). So, Mikhail, congratulations on your presentation. Give us a little synopsis of what the trial is about.
The STEP HFpEF Program
Mikhail N. Kosiborod, MD: First of all, it is always a pleasure to be with you. Maybe a quick word about the STEP HFpEF program that included two trials: The first is STEP HFpEF, which was a trial of patients with obesity-related HF with preserved ejection fraction (HFpEF) who did not have diabetes, which we presented and published at European Society of Cardiology in August last year.
The second installment of the program is the STEP HFpEF diabetes trial, which is essentially the same population of patients except they also have type 2 diabetes. I guess your question would be why we did two trials instead of just doing one trial that included patients, both with and without diabetes. I'll come back to that shortly.
The crux of the hypothesis behind the program is that we all know the prevalence of HFpEF has increased dramatically in the past couple of decades. When I was a fellow in training, it was rare for me to see a patient with HF who had preserved EF. A majority of patients had HF with reduced EF. Now, the majority of people we see have HFpEF: Why did that happen? There are a lot of different reasons for the dramatic change in epidemiology. But certainly, one of them, at least in our opinion, is that the obesity epidemic has a lot to do with it. In fact, if you look at the population of patients with HFpEF in the United States, 80% of them are living with overweight or obesity. The hypothesis behind the program was that obesity is not just a comorbidity. It doesn't just happen to coexist by accident in this patient population, it may in fact be causing their HF. It may be a critical factor in the development and progression of HFpEF.
In order to test our hypotheses, patients were randomly assigned to semaglutide, with the target dose of 2.4 mg once a week or matching placebo and treated for 52 weeks, or 1 year. The reason we did two separate trials is because part of that hypothesis was that if obesity is in fact the cause of HF, then certainly, weight loss would be probably not the only factor but "an important factor in the potential benefits of semaglutide in this patient population, provided that semaglutide is beneficial which of course we ultimately demonstrated.
But what we knew from weight-loss trials — not HF trials but weight-loss trials of medications like semaglutide and also other anti-obesity medications like tirzepatide and others — is that people with diabetes tend to lose a lot less weight. With these medications, there's about a 40% less weight loss in people with type 2 diabetes. Lots of theoretical reasons why that could be the case. Nobody really knows for sure.
We knew from the beginning that the weight loss likely was going to be different. Then, of course, there are other things that happen in people with diabetes: They have more severe HFpEF phenotype, and people with more severe disease sometimes don't respond to treatment the same way as those with less severe disease. Finally, we knew when we started the trial, which was back around 2019, 2020, that people with diabetes would be more likely to be treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors. At the time, we didn't have the data for SLT2 inhibitors in HFpEF, but we knew that were going to be tested. There was, of course, an expectation that they may well be beneficial. For all of these reasons, we said, "You know what, the treatment effects may well be different between the patient population, but let's study them separately."
Piña: It makes everything much more clean when you can separate them like that.
Kosiborod: Precisely. In the first trial back in August of last year, semaglutide significantly improved the Kansas City Cardiomyopathy Questionnaire, Clinical Summary Score (KCCQ CCS). That's the domain of KCCQ, which is the gold standard for assessing symptoms and typical limitations in people with HF. We showed a nearly 8-point improvement on average, which is a very large improvement. We also showed that of course people lost more weight, and they had an improvement in 6-minute walking distance reduction and inflammation reduction in N-terminal pro B-type natriuretic peptide (NT-proBNP), which is interesting. HF hospitalization and urgent visits were also numerically fewer.
STEP HFpEF Diabetes
We wanted to expand on what we found in the diabetes trial. As expected, we saw about 40% less weight loss than we saw in the first STEP HFpEF trial in people without diabetes. Of course, patients treated with semaglutide still lost more weight than did those on placebo, but the difference was about 6.4%. There was more than a 10% difference between treatment groups in the first trial. Despite that, the HF benefits were very similar to what we saw in the first trial.
The improvement in the KCCQ CCS was nearly identical. We also saw an improvement in 6-minute walking distance, we saw reductions in high-sensitivity C-reactive protein (hsCRP) and reductions in NT-proBNP — quite substantial at an about 20% reduction in NT-proBNP. Just like in the first trial, there were numerically fewer HF hospitalizations and urgent visits. Out of 25 patients that had at least one of those events, seven were in the semaglutide group, and 18 were in the placebo group. The findings on the HF side were nearly identical, whereas the degree of weight loss was 40% less than in the first trial.
Piña: Why do you think this happens? Does it have something to do with the insulin that they're getting for treatment? Was there a difference between those who had insulin and those who didn't?
Kosiborod: We have not dissected these findings to this extent yet. But that's one of the hypotheses. People with diabetes get treated with medications like insulin and sulfonylureas, which actually make people gain weight. If you don't have diabetes, you are not going to be on insulin. That's one of the leading theories for why we see less weight loss. But to be perfectly honest, we don't really know.
Why Do Patients Feel Better?
Piña: I was looking at your slides in the data. What pushes the patient to feel so much better… It's captured on the KCCQ. I know for myself that when I lost weight, I felt lighter. I could do more. Maybe that's one of the things that the drop in obesity does: It makes patients feel lighter, that they can do more. It's not because they were symptomatic from HF. They're New York Heart Association (NYHA) Class II primarily.
Kosiborod: As you well know, there is a disconnect between the KCCQ and NYHA Class. If you look at NYHA Class, about one third were Class III and IV, and about two thirds were Class II. Let's come back to the discussion about insulin in a minute, because in the The Lancet paper wherein we combined the two projects, there were some very interesting findings about severity of HF and that treatment effect.
We had one third in Class III and IV and two thirds in Class II: That' very typical of an HF trial. If you look at the DELIVER trial, PARAGON, and EMPEROR-Preserved, it's very similar. But KCCQ at baseline was much lower than what was seen in those other trials, instead of having KCCQs in the low 70s.
Piña: It was in the 40s and 50s.
Kosiborod: Yeah, in the 50s. These people were really symptomatic and functionally impaired. Their 6-minute walk distance was very low. It was about 280 m.
Piña: That's below 300 m, which is considered severe.
Kosiborod: Back to your question on what exactly gets better? We examined that in the first STEP HFpEF trial, which we published in Circulation and presented at the American Heart Association in 2023, essentially nearly every domain of KCCQ improved. The symptoms got better, physical limitations got better, quality of life improved. All key KCCQ domains improved. Even the social limitation domain improved, which we almost never see with HF treatments. Social limitation is a lagging indicator, and it's very difficult to actually see an improvement in social function. That indicates that this is a substantially effective treatment because not only is there a large quantitative effect but it actually makes symptoms and physical limitations improvements translate into improvements in social function.
The largest improvement was in the symptom burden and symptom frequency. It was more than a 10-point average. Now, to your point about whether people just feel lighter. Is it what we sometimes call mechanical unloading through weight loss and not really a pathobiology benefit on the disease modification for HF. As I mentioned, we just presented a combined paper published in The Lancet that offers some very interesting insight.
There was 40% less weight loss in the people with diabetes, but the HF benefits were very similar. If this were all about weight loss, you would have expected that if there is a lot less weight loss, then there would be also less HF benefit. But it's not what we see at all. We see that the HF benefits are very similar, which indicates that it's not just weight loss.
Beyond Weight Loss
Piña: There's something else going on in here.
Kosiborod: There is something else going on. The changes in NT-proBNP are interesting. We know that when people with diabetes lose weight with lifestyle modification — from the LOOK AHEAD trial— the NT-proBNP went up. There are theoretical reasons for why that would be the case that have to do with visceral adiposity and the effect it has on natriuretic peptide levels. Here, we saw a 20% reduction in NT-proBNP despite weight loss.
Piña: Do you think this is anti-inflammatory?
Kosiborod: For sure. We know that from the STEP HFpEF trials, right? We had a 33% reduction in hsCRP for a treatment ratio of 0.67. The NT-proBNP goes down, and there is a decongestion effect. hsCRP goes down, so there is an anti-inflammatory effect. Some of it's probably due to weight loss, but some of it may be a direct effect.
The other thing I will mention, which indicates to me at least that this is not just weight loss, is our combined subgroups. Essentially almost all of the subgroup analysis was done on a combined, STEP HFpEF and STEP HFpEF diabetes basis because then, we had twice as many patients, and we prespecified that we were going to do it that way. What we saw was the higher the NT-proBNP at baseline, the higher NYHA class at baseline, on loop diuretics vs not at baseline, with atrial fibrillation vs not at baseline — all the markers of HF severity — the larger the benefit was with semaglutide vs placebo than for those with less severe HF.
Don't get me wrong. Those with less severe HF still got a very large benefit. This is not an interaction in terms of severity of HFpEF. Everybody benefits, and everybody has a large benefit. But it was that the benefits were even more pronounced in people with more severe HF, so the interaction was in the magnitude of improvement.
These people with more severe HF got larger benefit as seen on KCCQ despite the amount of weight loss experienced being identical to those that had less severe HF. All of these findings taken together suggest quite strongly that we can't explain everything by weight loss. There is something else going on. There are likely decongestive effects and anti-inflammatory effects of semaglutide that probably explain what we're seeing here. It's not just weight loss.
Piña: To me, the NT-proBNP going down is proof that there's something physiologic. Did you collect any echoes?
SGLT2 Inhibitors, Less Weight Loss
Kosiborod: We did collect echoes, and that's forthcoming. We are analyzing that data right now, and we're hoping to present and publish that soon. The other thing I will mention, which I think is relevant, is that in the STEP HFpEF DM publication, we did a subgroup analysis looking at people who were or were not on SGLT2 inhibitors at baseline.
About one third of the patients in the diabetes trial were on SGLT2 inhibitors at baseline. There were consistent benefits in terms of KCCQ improvement and whether patients were or were not on SGLT2 inhibitors. When it came to weight loss, there was a bit more weight loss in those that were not receiving SGLT2 inhibitors at baseline.
Piña: Interesting.
Kosiborod: But of course, both groups lost a lot more weight with semaglutide vs placebo. But again, the magnitude was a bit more in those who weren't on SGLT2 inhibitors at baseline.
Piña: I think this is very consistent with other drug trials, etc., that we've seen: that the sicker the patients, the greater the benefit. Everybody may be afraid of putting the patients on the drug because they are older or too sick, but on the contrary, those are the people that usually get the highest benefit. I urge our audience to read the papers in The New England Journal and The Lancet.
When you have that patient in front of you, think about what you can do to decrease their obesity, which patients get very troubled with and have a very hard time getting rid of the weight. They really want to do it. Every day in clinic, I hear, "I am going to get on it. I'm going to start exercising. I'm going to eat less." But it's so hard to do. And obesity is a huge problem in the United States. It's going to be costing us many tax dollars as a society to deal with this. Congratulations again. You have spent many years working on this. Since I've known you, you've been working on the diabetes part of HF. You're my go-to person for diabetes and HF. Thank you for joining us. Have a great day.
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.
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
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