Mikhail Kosiborod, I'm a cardiologist at St Luke's Mid America Heart Institute in Kansas City, USA.

What is the importance of this study?

Well, so STEP HFpEF is a programme that has two trials in it. The first of these was the STEP HFpEF trial, which we presented at European Congress last year and published in the New England Journal of Medicine.
And then here at ACC, we just presented the second instalment, that's STEP HFpEF Diabetes trial. The idea behind the entire programme is it's not an accident that 80% of patients that have HFpEF, heart failure with preserved ejection fraction, are living with overweight and obesity.
The idea is that obesity may be, in fact causing heart failure in these patients, maybe the root cause. So, we need to target obesity as a therapeutic strategy for heart failure with preserved ejection fraction in these patients. And so that was the hypothesis that we were testing in the STEP HFpEF programme, and we already showed in the first STEP HFpEF trial last year, that treatment with semaglutide produces very large improvements in heart failure related symptoms and physical limitations, as well as exercise function, in addition to reduction in body weight.

So you can ask, why did we have to do a second trial in people with obesity related heart failure and diabetes? There are actually a number of different reasons. So people with diabetes, we already know, don't lose as much weight with incretin-based treatments like semaglutide or other, actually any other antiobesity drugs.
The same story, they don't lose as much weight as people without diabetes. And of course, we think that weight loss is a component, a factor in the benefits that we see.
So that's one reason why we needed to study them separately.
Second is patients with diabetes who have HFpEF represent a more severe phenotype that have more severe disease, which may not respond the same way to treatment. And the third is that they're much more likely to be treated with SGLT2 inhibitors, which, of course could potentially have an impact in terms of treatment response as well.

So for all these reasons, we did actually two separate trials. We designed the programme from the beginning to have two separate trials.
One an obesity related heart failure without diabetes, and one an obesity related HFpEF with type two diabetes.

What was the study design and patient population?

So both trials were designed in the same way. So for STEP HFpEF Diabetes trial, patients that had documented HFpEF with additional kind of enhancing features and a BMI of 30 and above were randomly assigned to either semaglutide with a target dose of 2.4 milligrammes once a week or matching placebo and treated for 52 weeks and the two dual primary endpoints were a change in the Kansas City Cardiomyopathy questionnaire, which is the gold standard of evaluating heart failure related symptoms and physical limitations, and the second was change in body weight and we also had a number of confirmatory secondary endpoints including looking at exercise function with six minute walking distance hierarchical composite, which also integrated clinical events, like death and heart failure, hospitalizations and urgent visits, in addition to KCCQ on six minute walking distance and also changes in CRP, which is a marker of inflammation.

What are your key findings?

The bottom line is that semaglutide significantly improved heart related symptoms and physical limitations as measured by KCCQ clinical summary score.
The between group difference was about 7.3 points in KCCQ, which is a very large improvement, and it was very similar to actually what we saw in patients without diabetes in the first STEP HFpEF trial.
There was also a greater degree of weight loss, with semaglutide versus placebo about 6.4% difference. Semaglutide also improved six-minute walking distance. There was a significant benefit on this hierarchical composite endpoint and significant reduction in inflammation.
In addition, semaglutide also reduced NT-proBNP which is a marker of congestion, significantly, by about 20%. And there were fewer heart failure events of hospitalizations and urgent visits in the semaglutide group than a placebo group.
The number of those events was small, it was not a hard outcome trial, but they were distributed quite favourably to semaglutide versus placebo.
Out of 25 patients with those events, 7 were in the semaglutide group and 18 in the placebo group. And finally, semaglutide was very well tolerated, with significantly fewer serious adverse events than in a placebo group.

What are the implications of these findings on clinical practice?

Well, I think collectively, when you combine the results of both trials in a programme, what it clearly indicates is that semaglutide is a completely novel and a very effective treatment option for patients with this type of heart failure.
I think that should have an impact on guidelines, should have an impact on clinical practise, because we truly lack effective therapies for these patient populations that sorely needs them.
And I think it opens up a whole new avenue of clinical research as well, because there is a lot going on in the antiobesity space with drug development and I think the future is very bright in terms of testing those agents, not just for weight loss but also for really significant benefits in patients with heart failure.

What are your take-home messages?


Think take home message is if you have patient with obesity related heart failure with preserved ejection fraction semaglutide is a highly effective and well tolerated treatment option. And obesity is not just a comorbidity in this patient population, but it's likely a root cause. It’s likely a root cause of the development and progression of heart failure in many of these patients should be the target for intervention.

What questions remain around semaglutide?

I think we've answered a lot of questions, but one of the questions is, are the benefits sustained long term? We only treated patients for 52 weeks, so while there was no evidence of any attenuation of benefit, in fact, it continued to amplify over time.
Studying it over a longer period of time would be a value. Obviously, the big question is, you know, do we need to do larger, longer term hard outcome trials with antiobesity medications in this space? And I think the answer is yes, we absolutely need to do that.