Expert: Semaglutide's Benefits in Obesity-Related Heart Failure, the Role of Pharmacists in Diabetes Care

In an interview with Pharmacy Times, Mikhail N Kosiborod MD Saint Luke's Mid America Heart Institute, reviewed results from the STEP-HFpEF trials, shared at the American Diabetes Association (ADA) 84th Scientific Sessions. Kosiborod noted that semaglutide significantly improved heart failure symptoms and quality of life through weight loss and direct effects on heart tissue, independent of weight loss. He also discussed how the diabetes treatment landscape is shifting to prioritize medications like SGLT2 inhibitors and GLP-1 receptor agonists that provide organ protection beyond glucose control. Additionally, Kosiborod highlighted the importance of pharmacists in implementing evidence-based guidelines through coordinated, team-based care approaches to help more patients benefit from these advances.

Pharmacy Times

Can you give a brief overview on what was assessed in the STEP-HFpEF and STEP-HFpEF-DM trials.

Mikhail N Kosiborod

The hypothesis that we tested and STEP-HFpEF programs that had two trials, STEP-HFpEF and STEP-HFpEF diabetes, or DM was to try to understand whether targeting obesity can actually improve heart failure related symptoms and physical limitations in people that live with a particular kind of heart failure — that we call heart failure with preserved ejection fraction. This is a type of heart failure where the squeezing function of the heart is actually normal, but the heart tends to be stiff, and the pressures of the heart tend to be high, which is what causes symptoms of congestion and the clinical syndrome of heart failure. This type of heart failure has been increasing dramatically in terms of its prevalence, and it's now the most common type of heart failure that we see in the US. It is increasingly becoming more and more common around the world as well. The prevalence of this type of heart failure has risen substantially over the past couple of decades. What we've been observing is that majority of patients that have this type of heart failure in the US — roughly about 80% of those patients also have overweight obesity. The hypothesis behind the program was that perhaps obesity and obesity epidemic are in fact, what's responsible for this dramatic rise in the prevalence of this type of heart failure. Perhaps, obesity is not just a comorbidity that accidentally happens to coexist in the majority of patients that have heart failure with preserved ejection fraction, but rather, maybe obesity is what's actually causing heart failure in many of these patients. Maybe it's a key driver in the development of progression of this type of heart failure.

So, to test this hypothesis, we designed the HFpEF program that had 2 trials, STEP-HFpEF in people with obesity related heart failure with preserved ejection fraction— the type of heart failure I just talked about. And STEP-HFpEF diabetes, with this type of heart failure, but also presence of type 2 diabetes. The reason we designed these 2 trials separately is because a part of the hypothesis was if we target obesity with the purpose of inducing a clinically meaningful weight loss, that weight loss would be an important factor in potential benefits that we observe in the trials provided, the trials were positive. We already knew at that time that patients with diabetes tend to lose less weight with anti-obesity medications then people without diabetes. That's why we decided to have 2 separate trials to have a clear answer in people without diabetes and clear answer in people with diabetes.

That's a great question. So how can obesity actually cause heart failure— there are a number of ways. First, there are systemic factors that actually happen when obesity develops. As people gain weight, and the body surface area goes up, there can be a commensurate expansion of plasma volume of blood volume. It's not just circulating blood volume, but also what we call stress blood volume. That's a blood volume that's sitting in the periphery but can be mobilized with physical activity. That's really, really important because many of the patients that have this type ofheart failure with preserved ejection fraction or HFpEF, they may not necessarily be symptomatic at rest — some of them are, and some of them actually have elevated filling pressures filling pressures, that's the pressures in the heart, even at rest— but many of them actually feel okay when they're sedentary but become short of breath with relatively minimal physical activity. Part of the reason is, with this increase in strength, blood volume, as one starts to do any type of physical activities that stress blood volume that sitting in the periphery can get metabolized into systemic circulation. When you couple that, with structural abnormalities, which are very common in the setting of obesity, and things like left ventricular hypertrophy, with a left ventricle as a main pumping chamber of the heart seconds, and that in part happens, because obesity also drives higher blood pressure and hypertension. That can cause thickening of the heart muscle, it can also cause the increased stiffness of the heart muscle as well and then obesity also drives inflammation, which can promote not just thickening of the heart muscle, but also fibrosis or scar development in the heart that makes a heart even stiffer. So, when you compose that increase in blood volume, especially the stress blood volume, with a stiff, non-compliant left ventricle, especially in the setting of physical activity, can create a situation with increased blood volume is going into non-compliant heart, substantially raising the pressures in the heart and ultimately driving the symptoms of heart failure.

In order to be eligible, for the STEP-HFpEF program, patients had to have heart failure with preserved ejection fraction, where again, your patients have clinical heart failure, but the squeezing function of the heart is normal or near normal preserved. Actually, patients could be eligible if they had a mildly reduced or preserved left ventricular ejection fraction. They had to have a BMI of at least 30 and above. Then there were a number of other requirements in order to be eligible for the trial. Then if they did not have type 2 diabetes, they were in the STEP-HFpEF trial and if they have type 2 diabetes, they were in the STEP-HFpEF diabetes trial. Other than presence or absence of type 2 diabetes, the trials were otherwise designed in a very similar way. Patients were randomly assigned to semaglutide, a potent once weekly GLP-1 receptor agonist at a target dose of 2.4 mg once a week, or matching placebo and treated for 52 weeks. The dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score, or KCCQ TSS. That's a gold standard of assessing heart failure related symptoms and physical limitations due to heart failure. The second primary endpoint was change in body weight. There were a number of other what we call confirmatory secondary endpoints. Those endpoints that were tested in a predefined sequence with appropriate statistical methods to ensure that the testing is statistically rigorous.

Pharmacy Times

Key Takeaways Trials demonstrated semaglutide's benefits for reducing heart failure symptoms through both weight loss and direct effects on heart tissue independent of weight loss, showing promise as a novel treatment for obesity-related heart failure. The diabetes treatment paradigm is shifting to prioritize medications like SGLT2 inhibitors and GLP-1 receptor agonists that provide cardioprotective and organ protective benefits beyond glucose control. Pharmacists play an important role in implementing evidence-based guidelines through coordinated, team-based approaches to care, which can help more patients benefit from advances in diabetes and heart failure treatment

How does overweight and obesity relate to heart failure with persevered ejection fraction?

Mikhail N Kosiborod

Now those are the systemic effects, there are also local effects that can occur in the setting of obesity as well. For example, in people, especially with severe obesity, we commonly see deposition of adipose tissue in the epicardial space. That's a space around the heart and it's a fixed volume space. When there is a lot of deposition of adipose tissue, eventually the pressure around the heart starts rising. That essentially develops the conditions where there is a constriction around the heart. That constriction around the heart can lead to symptoms of heart failure as well. It's really both the systemic factors that happened in setting of obesity as well as the local visceral adiposity around the heart, that can lead to the development and progression of heart failure.

Pharmacy Times

Can you describe improvements that were displayed in the study regarding quality of life, body weight, and A1C.

Mikhail N Kosiborod

First, in terms of the primary endpoint, what we observed in both trials was that patients that were randomized to semaglutide had a significantly larger improvements in heart failure related symptoms and physical limitations as compared to those treated with placebo. That was observed both in the STEP-HFpEF trial and also in the STEP-HFpEF diabetes trial. In fact, the improvements in heart failure related symptoms and limitations with semaglutide were relatively similar in both trials, regardless of presence or absence of type 2 diabetes. The magnitude of improvements was quite large. It's actually the largest improvement in this particular outcome. The KCC questionnaire that we've seen with any pharmacologic intervention in this type of heart failure. In terms of body weight, as some was expected with semaglutide, because we know semaglutide, of course, causes significant weight loss. We saw greater reductions in body weight with semaglutide versus placebo also in both trials. But people in the STEP-HFpEF trial without type 2 diabetes lost quite a bit more weight than those in the STEP-HFpEF diabetes trial. Again, consistent with what we've seen previously, where people with diabetes tend to lose less weight with increased in based treatments, and specifically GLP-1 receptor agonists such as semaglutide, as compared to those without type 2 diabetes. What's important here is that there was about 40% less weight loss in the diabetes trial, as compared to trial of patients without diabetes, but the heart failure benefits were very, very similar, indicating that while weight loss is probably an important factor, in the benefits that we see, it doesn't appear to be the only factor. There are probably other direct effects that may well be weight loss independent, as well, of semaglutide. Since we've published the main results of both trials, we've had a number of additional presentations and publications where we see continuous signals, very consistent signals, that in addition to weight loss, there may well be weight loss, independent, direct effects of semaglutide— beneficial effects on heart failure pathobiology, indicating that what we're observing is probably not just mechanical unloading from weight loss. Meaning it's not just people who have obesity and heart failure, and they lose weight and feel better because they've lost weight. But in fact, semaglutide appears to have disease modifying beneficial effects on heart failure pathobiology. One of the most common questions we've been asked is, 'is it the weight loss, or is it the drug?' I think the correct answer to the question based on everything we're observing so far, is that it's both. It is the weight loss and the drug, so that's the primary endpoints.

There were a number of other things we evaluated as well, and I'll just mentioned them briefly. We saw significant improvements in exercise function with semaglutide versus placebo. We measure that by a six-minute walking distance, which is a very commonly used endpoint in heart failure trials where we measure patient's ability to walk within the six minutes and we actually measure the distance they walk. That went up significantly, with semaglutide versus placebo as well. We also saw substantial reductions in biomarker of inflammation called high sensitivity CRP or C- reactive proteins, that went down by nearly 40%. There was also a significant reduction in the biomarker of congestion, called N-terminal or NT-proBNP, a marker, we frequently measure in patients with heart failure. That was somewhat unexpected because as the trials of weightless interventions, specifically lifestyle mediated weight loss interventions, and a look ahead trial, for example, where patients with diabetes were randomized to a lifestyle intervention for weight loss versus usual care. As patients lost weight, natriuretic peptide actually went up the NT-proBNP went up. There are lots of different reasons why that may be the case. But here despite substantial weight loss, we actually saw substantial reductions in that natriuretic peptide, again, suggesting that semaglutide probably has direct effects on heart failure pathobiology — disease modifying effects above and beyond just weight loss.

Finally, the last thing I will mention is that while STEP-HFpEF trials were not outcome trials, we did collect clinical events of heart failure hospitalizations, and urgent visits. There were fewer of them in the semaglutide group as compared with the placebo group. The number of those events was small, but they were very favorably distributed for semaglutide, as compared with placebo, suggesting that they may be a potential benefit on clinical events, as well. But that's, of course, something that will need to be definitively tested on future trials, within frequent based treatments. Finally, the safety of semaglutide also looked quite favorable as well. There were fewer serious adverse events, with semaglutide than with placebo in both trials — mostly driven by fewer cardiac disorders. More people on semaglutide had nausea, which it's not surprising. We of course, know that these medications can produce nausea. But ultimately, the number of people who stopped the investigational product, whether it was semaglutide, or placebo was quite similar. So, more people stopped semaglutide due to nausea, but more people stopped placebo for other reasons. At the end of the trials, the number of people who stopped the medication prematurely was quite similar between the treatment groups.I guess the best way I can summarize it is that both trials were quite positive as they met all of their primary and secondary endpoints. Collectively the data strongly suggest that semaglutide may represent an efficacious and novel treatment for people with this type of heart failure, which is, of course, clinically quite important because these patients right now have very few treatment options. They suffer from very high burden of heart failure related symptoms and physical limitations and poor quality of life.

Now, you did ask me about hemoglobin A1C, and that was one of the secondary endpoints in the diabetes trial. We saw a significant reduction in hemoglobin A1C about 0.8%, even though hemoglobin and once he was quite well controlled at baseline, was about 6.8, to baseline. Despite that, it went down significantly with semaglutide versus placebo. What we are presenting at ADA, in addition to that, there are a number of other metabolic effects of semaglutide. Just to hit the highlights, first of all, we saw that the heart failure benefits of semaglutide were consistent, regardless of baseline levels of hemoglobin A1C, on all of the key heart failure trial endpoints. We also observed that patients in the semaglutide group were a lot more likely to discontinue as a glucose lowering medications during the trial. There were a lot less likely to start new glucose lowering medications, as compared with those in the placebo group. This whole point about polypharmacy, we know of course that patients with diabetes tend to be on lots of medications. In addition to all of the heart failure affects that I just described, there was a benefit also on being able to stop additional glucose lowering medicines, and there was a less need of starting new glucose lowering medications as well. Finally, there were actually fewer hypoglycemic events in the semaglutide group as compared with a placebo group as well.

Pharmacy Times

How is the diabetes landscape changing?

Mikhail N Kosiborod

Well, I think the diabetes treatment landscape is changing quite dramatically. What we've seen over the past decade is a complete paradigm shift from a more of a glucose centric view of diabetes management, where it was mostly about hemoglobin A1C and glucose control, to prioritizing medications that while helping with appropriate level of glucose control, also have glucose independent cardioprotective and organ protective properties. The two class of medicines that are front and center, in that dramatic paradigm shift in how we manage people with diabetes and what's the guidelines international guidelines now state, we should prioritize our SGLT2 inhibitors and GLP-1 receptor agonist because of all the organ protective benefits we've seen in people with type 2 diabetes in many, many different trials, Now also that we're starting to see even on people without diabetes. Of course, we have trials of children two inhibitors in people both with or without diabetes and heart failure and chronic kidney disease. We now have trials of GLP-1 receptor agonist such as semaglutide in people those with or without type 2 diabetes, including the Select trial in people with overweight and obesity and atherosclerotic cardiovascular disease in STEP-HFpEF programs that we just talked about, both in people with and without type 2 diabetes that have heart failure with preserved ejection fraction in the setting of obesity.

I think the next evolution, if you will, is also recognizing that conditions such as obesity, visceral deposit insulin resistance, are, in fact, key drivers of multiple epidemics that we actually are seeing in terms of non-communicable diseases. They appear to be key drivers of type 2 diabetes, but also of cardiovascular disease. Including atherosclerotic cardiovascular disease and heart failure at least this type of heart failure — HFpEF. They appear to be drivers of development, progression of kidney disease and liver disease, sleep apnea, and many, many other related complications. In order to manage these complications, appropriately, a part of that needs to be addressing the root causes and the key drivers which again, are obesity, visceral appositives, as I mentioned before.

This past decade has really been a dramatic evolution, both in the treatment landscape based on the results of outcome trials, as well as our understanding of the root causes and downstream effects.

Pharmacy Times

What is the pharmacist role and value in the diabetes treatment landscape?

Mikhail N Kosiborod

Well, I think the pharmacists have a critical role to play here. It's always teamwork in order for us to make sure that patients are treated in a way that gives them the best chance to prevent complications. What we've seen in this space is that we, of course, do clinical trials to generate evidence on which clinical practice can be based. That's why we call it evidence-based medicine. Then once the evidence is generated, if the evidence is compelling and gets implemented, it gets built into the practice guidelines, but those practice guidelines need to be implemented. I think we've had for a while now a critical implementation gap where we have really powerful tools in our toolbox. The treatment strategies that are based on the evidence produced by clinical trials, it can really improve patient outcomes and prevent complications. But it's sometimes it takes way too long to implement as those evidence-based treatments that are guideline recommended into clinical practices, that majority of the patients that had the highest risk can actually benefit from just treatments. I'm firmly convinced that in order for us to implement these interventions more effectively, we need to have a team-based approach to implementation of guideline recommended treatments. Pharmacists are a critical part of the team-based approach and can really help make sure that protocol driven interventions in a coordinated team-based environment can help a lot of patients. We've now seen, confirmation that when these coordinated team-based approaches to care are implemented, they can dramatically improve guideline adoption within a relatively short period of time. I think seeing and incorporating pharmacy professionals into the team base coordinated approach to guideline implementation is absolutely critical. And of course, pharmacists are great advocates for their patients as well. I think both pharmacists themselves as a point of care can play a big role in making sure the right patient gets the right treatment at the right time. Also, as a part of the larger clinical team, making sure that the guidelines get implemented more effectively can play a critical role as well.

Pharmacy Times

Is there anything you'd like to add?

Mikhail N Kosiborod

The only thing I would add is these trials that we just talked about is the beginning of the story, it is not the end of the story. I think it opens up a really exciting avenue. It's very exciting on the clinical side because it highlights a novel efficacious treatment option for patients that until now had very few treatment options, those with obesity related HFpEF, but it also opens a new avenue for clinical research as well. I think there is a lot of work going on in studying anti-obesity treatment strategies. There will be lots and lots of work in this space in the next few years. I think targeting obesity to prevent cardiovascular complications is going to be absolutely central, in this very exciting journey that we're on and it will continue to evolve.

The only thing I would add is these trials that we just talked about as the beginning of the story, it sounds out there was a story. I think it opens up a really exciting Avenue. Yeah, it's very exciting on the clinical side because it highlights novel efficacious treatment options for patients that until now had very few treatment options, those with obesity related tap Bev, but it also opens a new avenue for clinical research as well. So, I think there is a lot of work going on in studying anti-obesity treatment strategies. There will be lots and lots of work in this space in the next few years. And I think targeting obesity to prevent cardiovascular complications is going to be absolutely central, in in this very exciting journey that we're on and it will continue to evolve.