Could semaglutide help obese patients with heart failure?

HFpEF – commonly known as ‘hef-pef’ – refers to heart failure with preserved ejection fraction, a condition for which no treatment has hitherto been available. Current thinking suggests that obesity may be a causative factor in HFpEF rather than a co-morbidity. “In the U.S. about 80 percent of patients with HFpEF also have obesity”, says Ms Ruszala Therefore, STEP-HFpEF was designed to investigate whether treating obesity in such patients had an impact on their heart failure.

The trial had dual primary endpoints comprising quality of life (using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score) and weight loss.

How semaglutide impacts HFpEF

“The findings [of the STEP-HFpEF trial] were very definitive”, says Ms Ruszala. There was an eight-point difference in the KCCQ score. (A minimum four-point difference is clinically significant). “The patients who were on semaglutide felt much better, had far, far [fewer] symptoms and were able to do more in their daily life with increased exercise capacity”, she explains. In addition, there was an 11 percent greater body weight loss in the semaglutide group compared with the placebo group. Both endpoints were statistically significant. Furthermore, the hierarchical secondary endpoints were all met.

Previous trials of weight loss combined with exercise have shown benefits in quality of life but not to the same extent as those seen with semaglutide. Moreover, “the weight loss itself wasn’t significant enough in many of the previous trials, so there was something extra seen in [this trial] that wasn’t previously”, says Ms Ruszala.

Semaglutide for prevention or cure of HFpEF?

The results of the STEP-HFpEF trial point towards routine use of GLP-1 agonists in heart failure but this has to be balanced against conflicting guidelines and cost pressures in the NHS. “We know there’s benefit [from] GLP-1s in kidney disease, we know there’s benefit [from] GLP-1s in type 2 diabetes; we now know there’s benefit in heart failure as well”, says Ms Ruszala.

The new ESC guidance (European Society of Cardiology guidance) for heart failure or heart disease and diabetes that was launched in August [2023], already says anyone who has heart failure and type 2 diabetes should be given dual therapy with an SGLT-2 (sodium-glucose co-transporter-2 inhibitor) and a GLP-1 agonist. However, this is not yet in the UK heart failure guideline and this presents UK cardiologists with a dilemma.

Currently the UK approach to the use of semaglutide in heart failure is different from the approach elsewhere in Europe. “I think it goes back to the prevention versus cure [question]. At the moment our guidance is set up as cure …… [but] this kind of medicine is preventative. If you give semaglutide or another GLP-1 to somebody early in their diabetes pathway, early in their HFpEF pathway, the likelihood is that they will be much better, fitter and [generally well] for much longer” says Ms Ruszala.

However, semaglutide is not available in the UK currently and it’s not likely to be available in the UK until 2024. Much can be achieved with the existing treatment protocols and there should be a strong focus on optimising treatment with the available medicines, she suggests.

About Vicky Ruszala

As a specialist cardiology pharmacist, a large part of Vicky Ruszala’s work involves optimising medications for heart failure. She works on the specialist cardiology ward and also has two heart failure clinics each week.  She is an independent prescriber and has her own patient caseload.

Read and watch the full series on our website or on YouTube.

The STEP-HFpEF trial excluded people with type 2 diabetes but there are ongoing trials with glucagon-like peptide 1 (GLP-1) agonists in patients with obesity, type 2 diabetes and heart failure with preserved ejection fraction (HFpEF).  Nevertheless, the results of the trial add to the understanding of cardio-renal-metabolic disease. “We know there’s benefit [from] GLP-1s in kidney disease, we know there’s benefit [from] GLP-1s in type 2 diabetes; we now know there’s benefit in heart failure as well”, says Ms Ruszala.

As a result, “cardiologists are now looking to say, well actually, anybody who’s got a BMI over 30 – because that was one of the cutoffs in the trial – should be given a GLP-1 agonist.   …..In the new ESC guidance (European Society of Cardiology guidance) for heart failure or heart disease and diabetes that was launched in August [2023], it already says anyone who has heart failure and type 2 diabetes should be given dual therapy with an SGLT-2 (sodium-glucose co-transporter-2 inhibitor) and a GLP-1”, she says. However, this is not yet in the UK heart failure guideline. “So, we have a lot of cardiologists that are looking to Europe and trying to do what Europe is doing whilst living in an NHS environment”, she says.

In theory, the trial paves the way for treatment of a group of patients who would derive significant benefit from receiving a GLP-1 agonist. Ms Ruszala’s previous experience as specialist pharmacist in diabetes taught her that it was “a huge struggle” to persuade prescribers to use a GLP-1 agonist for type 2 diabetes because of costs and organisational issues.

Should GLP-1s be routine treatment in heart failure?  

There are still many questions to be answered about the role of GLP-1 agonists. Ms Ruszala explains: “The difficulty we have in the NHS is the cost and …. the supply chain issue at the moment, you know. Let’s not stand aside from the fact that semaglutide is actually not available in the UK currently – it’s not likely to be available in the UK until 2024. So, we are sitting in a place where the science says it will be great and everybody kind of wants to do it and we know that we probably should do it. We have guidelines that say we shouldn’t, because we have nothing for HFpEF. We have [semaglutide for] type 2 diabetes but only if you’ve tried four or five other things [first].”

Currently the UK approach to the use of semaglutide in heart failure is different from the approach elsewhere in Europe. “I think it goes back to the prevention versus cure [question]. At the moment our guidance is set up as cure – when this has happened treat like this. [But] this kind of medicine is preventative. If you give semaglutide or another GLP-1 to somebody early in their diabetes pathway, early in their HFpEF pathway, the likelihood is that they will be much better, fitter and [generally well] for much longer throughout their journey.  So, we’re talking about more preventative, social kind of engineering to allow people to lose weight and thereby exercise more, … have less symptoms and …. be more productive”, she explains.

Talking to patients

Many patients will have seen headlines about the use of semaglutide in patients with heart failure and may be wondering if it is a suitable treatment for them. Ms Ruszala suggests there are some key points that could be included in conversations about this:

• This is the first trial of its kind and others will follow e.g. the SUMMIT trial which is to assess the efficacy and safety of tirzepatide in participants with HFpEF and obesity
• At present semaglutide is unavailable in the UK
• There should be a focus on optimising treatment with the available medicines. “Make sure people are on SGLT2 Inhibitors because they aid weight loss – they also treat diabetes like the GLP-1s”, says Ms Ruszala. “What pharmacists should be doing is encouraging patients to take control of themselves from a …. lifestyle perspective and supporting that change. Also ….. thinking about – ‘what can I use that I’ve currently got?’ – making sure people are on maximum dose ACE-inhibitors, making sure people are on beta-blockers if they’ve got a fast heart rate, getting an SGLT2 inhibitor in. All of those drugs that we currently have access to will still be of huge benefit”, she emphasises.

“Let’s use this as a good time to start doing all the other things and getting everything else better”, she says.

About Vicky Ruszala

As a specialist cardiology pharmacist, a large part of Vicky Ruszala’s work involves optimising medications for heart failure. She works on the specialist cardiology ward and also has two heart failure clinics each week.  She is an independent prescriber and has her own patient caseload.

Read and watch the full series on our website or on YouTube.

“The findings [of the STEP-HFpEF trial] were very definitive”, says Ms Ruszala. There was an eight-point difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. (A minimum four-point difference is clinically significant). “The patients who were on semaglutide felt much better, had far, far less symptoms and were able to do more in their daily life with increased exercise capacity”, she explains. In addition, there was an 11 percent greater body weight loss in the semaglutide group compared with the placebo group. Both endpoints were statistically significant. Furthermore, the hierarchical secondary endpoints were all met.

The key points to note are:

• There was a significant difference in the 6-minute walk distance (6MWD)
• There were 13 heart failure events (e.g. death or hospitalisation) in total, 12 of which occurred in the placebo group
• Greater reductions were seen in C-reactive protein (CRP) levels and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in the treatment group

The results suggest that obesity may have a causative role in heart failure and that this is related to inflammatory processes. If semaglutide reduces inflammatory activity, “potentially, you are going to end up with cardiac remodelling and Improvement overall in how the heart functions by using this drug versus not doing anything at all. It’s not just the weight loss that’s causing the benefits”, explains Ms Ruszala.

Previous trials of weight loss combined with exercise have shown benefits in quality of life but not to the same extent as those seen with semaglutide. Weight loss is known to be beneficial in HFpEF but previous obesity trials have not looked at other markers (e.g. inflammatory markers), she explains. Moreover, “the weight loss itself wasn’t significant enough in many of the previous trials, so there was something extra seen in [this trial] that wasn’t previously. So, we know weight loss is of benefit and there’s no ….  taking away from lifestyle management – but it still didn’t achieve as much as it did in [this trial]”, concludes Ms Ruszala.

About Vicky Ruszala

As a specialist cardiology pharmacist, a large part of Vicky Ruszala’s work involves optimising medications for heart failure. She works on the specialist cardiology ward and also has two heart failure clinics each week.  She is an independent prescriber and has her own patient caseload.

Read and watch the full series on our website or on YouTube.

HFpEF – commonly known as ‘hef-pef’ – refers to heart failure with preserved ejection fraction, in contrast to HFrEF (‘hef-ref’), which is heart failure with reduced ejection fraction. Ms Ruszala explains, “the gold standard for diagnosing heart failure is with an echocardiogram and that will measure lots of different things in the heart …….. and one of the measurements that we are given is the ejection fraction, which is how much blood is pumped out of your left ventricle into the body and that’s called your ejection fraction”. An ejection fraction of less than 40 percent is associated with the classical symptoms of heart failure. This was formerly known as congestive heart failure but is now described as heart failure with reduced ejection fraction (HFrEF). It is also possible to have symptoms of heart failure with an ejection fraction of 49 percent or more and such patients “may have may have structural abnormalities within their heart, so, for example, valvular abnormalities or they may have dilated ventricles”, explains Ms Ruszala.   The HFpEFs are “not new – we’ve known about them for years but we’ve never had anything we can really do to treat – it’s always been a disease of ….. comorbidities”, emphasises Ms Ruszala.

Current thinking suggests that obesity may be a causative factor in HFpEF rather than a co-morbidity. “In the U.S. about 80 percent of patients with HFpEF also have obesity and it was kind of, you know …… chicken and egg – which one came first”, she says.  Therefore, STEP-HFpEF was designed to investigate whether treating obesity in such patients had an impact on their heart failure. “This was looking at – if we treat obesity do we treat the heart failure alongside. Semaglutide is well-known in the type 2 diabetes and obesity world for causing huge weight loss and therefore improving lots of different outcomes”, she says.

The trial had a dual primary endpoints comprising quality of life (using the Kansas City Cardiomyopathy Questionnaire (KCCQ) score) and weight loss. “The KCCQ was designed for heart failure patients and looks at improvements in quality of life, signs and symptoms and exercise capacity”, explains Ms Ruszala.

About Vicky Ruszala

As a specialist cardiology pharmacist, a large part of Vicky Ruszala’s work involves optimising medications for heart failure. She works on the specialist cardiology ward and also has two heart failure clinics each week.  She is an independent prescriber and has her own patient caseload.

Read and watch the full series on our website or on YouTube.