Semaglutide's Big Step in HFpEF With Obesity: Investigator Interview

Interviewer: Tricia Ward; Interviewee: Mikhail Kosiborod, MD


August 31, 2023

Recorded August 26, 2023. This transcript has been edited for clarity.

Tricia Ward: Hi. I'm Tricia Ward from Medscape Cardiology, reporting from the 2023 European Society of Cardiology Congress in Amsterdam. I'm joined today by Dr Mikhail Kosiborod from Saint Luke's Mid America Heart Institute. Welcome.

Mikhail N. Kosiborod, MD: Thank you. Great to be with you.

Ward: You presented the STEP-HFpEF trial. Can you tell us the top-line findings of that trial?

STEP-HFpEF Key Findings

Kosiborod: Sure. It was a randomized, double-blind trial of semaglutide 2.4 mg once weekly vs placebo in patients with symptomatic heart failure with preserved ejection fraction and obesity as evidenced by body mass index of at least 30 kg/m2 or higher. These patients were treated for 52 weeks in total, and we had dual primary endpoints. These were change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, which is the gold standard for assessing heart failure–related symptoms and physical limitations, and change in body weight. There were a number of secondary endpoints and exploratory endpoints as well.

The bottom line is that in these patients who are quite symptomatic and functionally impaired at baseline, treatment with semaglutide resulted in marked improvements in symptoms, physical limitations, and patients' quality of life. And it also, not surprisingly, produced substantial weight loss as compared with placebo.

As I mentioned, we had a number of other endpoints, what we call confirmatory secondary endpoints — meaning that they were tested in a hierarchical sequence with appropriate control for type I error, and these included change in 6-minute walking distance. That improved significantly, by more than 20 m with semaglutide compared with placebo. Inflammation went down, as measured by C-reactive protein. And we also had this direct composite endpoint, which included clinical events as well as changes in symptoms and physical limitations and walking distance. That was quite favorable for semaglutide compared with placebo. All of these were highly statistically significant. The improvements in symptoms and physical limitations were the largest that we've seen with any drug ever in this patient population, so, pretty substantial benefits.

Ward: The question now is, are the GLP-1 receptor agonists a weight loss drug — and because you affected the weight loss, you have this effect — or are they going to be a heart failure with preserved ejection fraction (HFpEF) drug?

Kosiborod: The whole point of the trial was really to demonstrate that in many patients, these two conditions are intricately linked. I mean, it's a little bit of an artificial distinction. People always want to put these things into buckets and say, "Well, what kind of drug is it? What kind of drug is the SGLT2 inhibitor?" I'm playing devil's advocate here. Is it a heart failure drug? Is it a kidney drug? Is it a diabetes drug? Well, it's all of the above.

And I think GLP-1 receptor agonists are a pluripotent class of medications. Why is that? Well, let's take obesity, for example. The concept and hypothesis of the STEP-HFpEF trial was that in a large number of patients who have HFpEF, obesity is not just a coexisting condition; it's a root cause and the key reason they developed heart failure, and the key driver of worsening heart failure progression. By targeting obesity and treating it, you're treating heart failure. So I think it's a bit of an artificial separation because the whole point is, if obesity is the root cause, then you have to address it to effectively treat heart failure. I think the reason we see such dramatic improvements in patient symptoms and physical limitations due to heart failure is because we are addressing the root cause of the problem.

Is the Weight Loss With Semaglutide Fat Loss?

Ward: One of the discussants noted that sometimes weight loss isn't necessarily fat loss. In this trial, you also measured waist circumference.

Kosiborod: We did measure waist circumference; it went down significantly and was one of the secondary endpoints. So that was clearly favorable to semaglutide and not surprising, given the extent of weight loss that we saw. We didn't do body composition analysis in this particular trial, but there have been other trials with semaglutide or other GLP-1 receptor agonist–based treatments that show that the vast majority of weight loss is due to loss of fat mass. It's not 100%. I mean, it's very difficult to lose weight with any intervention and purely lose fat; that really does not happen. But most of the weight loss is due to fat loss.

Ward: Is the CRP reduction that you saw because obesity is basically an inflammatory condition?

Kosiborod: It is well documented that people with obesity, whether they have heart failure or not, have elevated C-reactive protein (CRP) and it's a proinflammatory condition. The question is whether the reduction in CRP is mediated by weight loss or whether it is weight loss–independent. And I think the data we have with these agents suggests that it's both; you have some reduction on inflammation that maybe is weight loss–mediated, but certainly not all of it. There is probably some direct anti-inflammatory effect as well.

Ward: And in terms of administration, patients take this medication themselves? They self-inject?

Kosiborod: Yes, they do. It's self-injection in the same way they would take it for diabetes. Currently, in the US at least, that's one of the indications. The second one is chronic weight management. Our hope is that with this trial and others in the pipeline, there will be additional indications, including for heart failure, but that remains to be seen. At the dose and mode of administration that we studied in this trial, this was a subcutaneous injectable administration once a week, by the patients.

SGLT2 Inhibitors and Diabetes

Ward: You mentioned SGLT2 inhibitors. There wasn't that much use of them in the trial population.

Kosiborod: Only a small proportion of patients were on SGLT2 inhibitors, for a couple of reasons. One is that we started to trial in 2020 before EMPEROR-Preserved and the DELIVER trial data were available, and so there was very little use because there were no data yet for SGLT2 inhibitors in the absence of diabetes. And again in this particular trial, patients with diabetes were excluded. So that was another reason why the use of SGLT2 inhibitors was very low.

But we have a sister trial in a very similar patient population specific to type 2 diabetes, called STEP-HFpEF Diabetes. That trial is currently ongoing and we expect to complete it later this year. We already know and we published that at baseline, about 32% of patients are on SGLT2 inhibitors. So we will be able to see whether there is any heterogeneity in the treatment effect in patients with SGLT2 inhibitor treatment and baseline or not.

Ward: What about critics who might say that you don't have hard clinical outcomes in terms of cardiovascular outcomes?

Kosiborod: There are two answers to the question. We actually did collect adjudicated heart failure, hospitalizations, and urgent visits. There were very few of those events and the trial was not powered for those events. It was only an exploratory endpoint. With that acknowledged, out of 13 events that we had, only one was in the semaglutide group and 12 were in the placebo group. So, probably not an accident.

But if we want to understand the effect of semaglutide on hard clinical endpoints, we'd have to do a much larger trial. I think it would be great, actually, to do a trial like that because all of these outcomes are important. But on the flip side, I understand the emphasis on hard events such as hospitalizations, urgent visits, and cardiovascular death, but it's also important to keep in mind that reducing symptoms and physical limitations is a key goal of treatment in this patient population.

And if you actually ask the patients about what they value most, many of them will value improvements in daily symptoms, physical limitations, and quality of life as much — if not more than — survival. These are outcomes that are really important in their own right. But I think having a full package, if you will, with those outcomes, plus an appropriately powered trial for events such as hospitalizations and cardiovascular death, would be complementary and welcome.

Practice Implications

Ward: In terms of the practice implications, are you ready to go out tomorrow and start prescribing this, assuming you have no issues with access or prior authorization?

Kosiborod: Semaglutide 2.4 mg is already indicated, at least in the US for chronic weight management. So you can use it for chronic weight management in people who have HFpEF now. But I think it's really important to have additional indications.

The whole point of doing the trial is to demonstrate that by targeting obesity, we're treating heart failure. And the other piece of this, of course, is that right now, if you use it for chronic weight management, access to the treatment in terms of insurance coverage is very difficult. These data, along with data from SELECT, which is the large cardiovascular outcomes trial in people with obesity and atherosclerotic cardiovascular disease, we already know from the top-line data showed a 20% reduction in the primary endpoint of a traditional three-point MACE.

I really hope those data and the data from STEP-HFpEF will move the needle to say that this is not just managing weight. This is managing the complications of obesity, which is really a key driver of all of these complications. And at least in patients who have these complications, we really need to have better access so we can reduce their risk for bad outcomes and also improve their quality of life.

Ward: Of course, one of the issues with this drug is that it could be a drug that you have to take for a lifetime. The adverse events were ultimately low in this trial, but it was just 1 year.

Kosiborod: It was 52 weeks of treatment, 1 year, and the safety looked really favorable. In fact, there were half as many serious adverse events in patients treated with semaglutide compared with those treated with placebo. But yes, it's a chronic disease just like hypertension, just like elevated cholesterol, just like atherosclerotic cardiovascular disease. Because the drugs are for chronic disease management, these are long-term medications intended for chronic use.

Ward: Do you think there might be patients who dose-escalate, and when they lose the weight or if they get to a weight where they want to just maintain, could they lower their dose?

Kosiborod: There are some studies that were done in patients with obesity, but not heart failure, that looked at withdrawal of medication vs continuation of dose escalation. We know that when the medication was stopped, patients eventually regained the weight over time. If they continue the medication or actually dose-escalate, they lose more weight.

As far as dose reduction is concerned, typically we use dose reduction as a clinical tool when patients have trouble tolerating higher doses, but we don't automatically reduce a drug dose because we think they've achieved a certain target of treatment. Usually, it's maintenance of the dose that they are on at that point.

Ward: Thank you very much for your time.

Kosiborod: My pleasure. Good to be with you.

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