Benefits of Semaglutide in Obesity-Related HFpEF Are “Transformational” at Highest BMI Levels, Additional Data Show

A new study showing that semaglutide offers quality-of-life and other benefits for patients with obesity and heart failure with preserved ejection fraction (HFpEF) also found that the higher a patient’s initial body mass index (BMI), the greater the changes after a year of treatment.

In fact, more than 50% of patients in the STEP-HFpEF trial saw improvements of 15 points or more on the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) after taking a 2.4 mg weekly dose of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist.

Kosiborod

“Just for a matter of perspective, [if] people who have a KCCQ-CSS improvement of 15 points or greater, it’s a truly transformational change in their symptoms and physical limitations,” said Mikhail Kosiborod, MD, PhD, the trial’s principal investigator and vice president for Research at Saint Luke's Health System in Kansas City.

Kosiborod drew worldwide headlines after presenting the initial results for STEP-HFpEF on August 25, the opening day of the European Society of Cardiology 2023 Congress in Amsterdam, the Netherlands. The trial found 10% greater weight loss for those with semaglutide compared with placebo, along with a net gain of nearly 8 points on the KCCQ-CSS.¹ Two days later, he presented the prespecified analysis, published in Nature Medicine,² which examined the relationship between patients’ initial BMI and final KCCQ-CSS and other metrics.

Semaglutide, marketed in subcutaneous formulations as Ozempic to treat type 2 diabetes and as Wegovy to treat obesity, is made by Novo Nordisk.

Kosiborod's August 27 presentation was part of a symposium, “Weight loss as a new therapeutic target in HFpEF: dawn of a new era?” which examined the mechanics of what obesity does to the body in patients with HFpEF, as well as clinical trial data on ways to address obesity through multiple strategies: exercise, calorie restriction, bariatric surgery, and pharmacological intervention.

Obesity affects most patients who have HFpEF. “This is not an accident,” Kosiborod said, repeating his earlier statement that these patients’ obesity was a “root cause” of their heart disease. Again, he noted there are no specific treatments for this type of heart failure approved by FDA.

As he stated on August 25, the STEP-HFpEF data support the use of semaglutide to help patients lose weight, as part of a treatment strategy to treat obesity phenotype HFpEF. His fellow panelists addressed why obesity phenotype HFpEF is such a challenging disease and why a single strategy is often insufficient.

Key findings from the Nature Medicine article, which Kosiborod highlighted in the symposium, are:

• The analysis examined the relationship between initial BMI and the change in dual primary and key secondary end points; BMI was stratified across obesity Classes I (30.0 kg/m2 to 34.9 kg/m2), Class II (35.0 to 39.9 kg/m2), and Class III (40 kg/m2 and above). Semaglutide consistently improved outcomes across all obesity categories.
• In semaglutide-treated patients, improvement in KCCQ-CS was greater with larger body weight reduction; authors reported a 6.4-point improvement for each 10% reduction in body weight (95% CI, 4.1 to 8.8).
• For treatment group patients, there was a 14.4-meter improvement in the 6-minute walk test for every 10% body weight reduction (95% CI, 5.5 to 23.3).
• In those with obesity phenotype of HFpEF, authors reported that “semaglutide improved symptoms, physical limitations and exercise function and reduced inflammation and body weight across obesity categories,” with a direct relationship to weight loss.

“In semaglutide-treated patients, extent of weight loss during the trial was associated with greater improvements in heart-failure related symptoms and physical limitations, and larger reduction in inflammation,” Kosiborod said.

Mechanics of oxygen output. Mark Kaykovsky, PhD, research chair on aging and quality of life, Faculty of Nursing, University of Alberta, Edmonton, Canada, presented extensive data on how patients with Class III can experience extreme shortness of breath and fatigue when performing exercise or even routine daily activities, known as “exercise intolerance.”

Some patients with obesity phenotype HFpEF must expend their peak oxygen volume output (VO₂) on simple activities, such as getting dressed. For these patients, their VO₂ falls below the “frailty threshold,” which is the level needed to carry oxygen through the capillaries to the muscles. As Kaykovsky explained, this becomes more likely once BMI reaches 32 kg/m² or above. “Your absolute cardiac output is high—you’ve got to carry around this large mass,” he said.

Patients can sometimes handle short bursts of activity, but they need frequent breaks, which makes it difficult to complete activities of daily living, such as mowing the lawn or vacuuming the house. These patients come to Kaykovsky’s clinic not only because they are fatigued, but also because “most of them have [reached] a level that's well below that functional independence threshold.”

Exercise is prescribed, but it’s not the typical walk or bicycle routine at first. “When you do whole body exercise on the bike or the treadmill, the heart and lungs are limiting but you never get to them,” he said, “because the true weak links are the peripheral muscles.”

Instead, the clinic uses modified exercises that isolate individual muscles, using a single limb at a time, which have been developed to improve peak VO₂ levels over time. This method is especially important for female patients, who come to the clinic in larger numbers, have higher BMI, and “because they don’t extract as much oxygen from muscle as men.”

Thus, measuring improvements in peak VO₂ as exercise training continues is one way to see progress. Working to lose fat without losing muscle, especially around the heart, is challenging as patients get older, because the process of myosteatosis—increased fat in the muscle—escalates with age.

Kaykovsky said exercise as an intervention for patients with Class III obesity is very difficult, because simple movements exhaust for these patients. “Whatever you do and whatever your therapy, you’ve got to keep muscle intact,” he said.

Caloric restriction. Matthew M.Y. Lee, PhD, MBChB, of the University of Glasgow, Scotland, reviewed evidence and guidelines surrounding obesity and HFpEF, noting that often, recommendations are for heart failure with reduced ejection fraction (HFrEF) or for HF generally, rather than specific to HFpEF. The American College of Cardiology 2023 expert consensus report is an exception: for HFpEF, weight loss is proposed, “to improve hemodynamics, functional status, and quality of life.” In this recommendation, semaglutide and tirzepetide are listed.

The most recent ESC guidelines date to 2021 and recommend bariatric surgery when dieting does not work. These guidelines highlighted the SECRET trial, which found that over 20 weeks, diets were more beneficial than no diets and exercise training was more beneficial than no exercise among patients with mean BMI of 39 kg/m² and HFpEF (LVEF 69%). Lee noted this was intentional weight loss, as opposed to unintentional weight loss.

“There are several critical gaps in the evidence base,” Lee said. “We need to understand how we can improve adherence with diet and exercise. We need to understand how to increase accessibility, and also to minimize costs.”

He said 3 important trials in this area are ongoing: AMEND-Preserved, which will measure symptoms and patients’ views of them; and REHAB-HFpEF and REACH-HFpEF, which will each measure a mix of hard outcomes, quality-of-life assessments, and mobility tests.

Bariatric surgery. Dror Dicker, MD, director of Internal Medicine, Rabin Medical Center in Petah Tikva, Israel, first reviewed the 3 surgical methods—adjustable gastric banding, sleeve gastrectomy, and roux-en-y gastric bypass. He then outlined the case for surgery with Lancet data involving overweight and obese patients: there is a 29% increased risk of cardiovascular disease for every 5-point increase in BMI above 25 kg/m², which is the cutoff between normal and overweight. A study from the National Swedish Registry found that among patients with an obesity diagnosis, here was higher incidence of heart failure and death among non-surgical patients compared with those who had bariatric surgery; the hazard ratio (HR) for HF-free survival was 0.37 (CI 95%, 0.29-0.46).

Why is this so? Helping patients lose weight “changes the gut microbiota and viruses and reduces inflammation in adipose tissue,” Dicker said As he would explain in detail, excess adipose tissue does not sit idle in the body, but instead changes as people age and can promote certain harmful conditions, including atrial fibrillation, coronary artery disease, type 2 diabetes, and heart failure. Dicker called this obesity-related adipose-tissue disease (OrAD) and outlined the various mechanism through which obesity—and resulting inflammation--gives rise to HFpEF: arterial stiffness, cardiac and renal fibrosis, increased plasma, sodium, and leptin levels, along with renin/aldosterone activation. This “concentric left and right ventricular remodeling,” and wall thickness, is dramatically reversed with bariatric surgery. LV volume is reduced within 2.5 years, he said.

Dicker then explained a point with implications for US payers, including Medicare and Medicaid. “The last point I want to mention is the timing,” he said, displaying data that show the point at which range of function can still be regained with surgery “is around the age of 55.”

“Why is it? The [cardiac magnetic resonance] studies show is that around this age the fibrosis increases; meaning, once you have fibrosis, you can’t reverse the process. So, you have to operate much, much earlier.”

“Obesity paradox” is dead. In a discussion that followed the presentations, Mark Petrie, MBChB, professor of cardiology, University of Glasgow, asked Kosiborod his thoughts on the controversial “obesity paradox,” which posited that once patients have an elevated BMI, it somehow offers a protective effect against heart failure or cardiovascular death compared with losing weight.

“So, can we kiss goodbye to weight loss being a bad thing?” Petrie asked.

Kosiborod rejected the idea that intentional, medically supervised weight loss is harmful. “When you look at epidemiologic data, and you don't differentiate between intentional weight loss and unintentional weight loss, the data are uninterpretable,” he said. “Of course, when people lose weight unintentionally, in the setting of any chronic disease, there is a reason for that,” such as when a patient has cancer.

Also, “It shouldn’t be a surprise that people who lose weight unintentionally in the setting of heart failure are going to do very poorly; that has nothing to do with weight loss—it has to do with what's causing the weight loss.

“So that can't possibly be equated with intentional weight loss that can produce a number of benefits, as we've seen with lifestyle interventions, potentially with bariatric surgery, and now clearly demonstrated in well-designed randomized clinical trials, that it's remarkably beneficial in a setting of heart failure with preserved ejection fraction with semaglutide.

“So, I think we're done, I hope, with the obesity paradox now,” Kosiborod said.

Moderator John Eric Deanfield of University College London noted that the forthcoming results from the 17,000-patient SELECT trial, for which positive topline data have already been announced, should further clarify the benefits of weight loss from semaglutide, including for patients with heart failure. In response to a question, Petrie also noted the value of having a completely separate STEP-HFpEF-DM trial to clarify outcomes for patients with and without diabetes.

Kosiborod added that while investigators anticipate that the weight loss benefit in the patients with diabetes may be less dramatic, STEP-HFpEF-DM may offer other surprises.

“There is also potential amplification of other benefits of those same therapies in people with diabetes, because the underlying cardiometabolic milieu is more toxic,” he said. “We probably can predict that there will be less weight loss, because we've seen it time and time again….

“It wouldn't surprise me that it may not necessarily correlate the same ways that you may think,” Kosiborod said. “We may see something very different. I think it'll be really interesting to see what happens.”

Other questioners called for similar studies in HFrEF, and Kosiborod agreed the question should be explored.

“I think it absolutely should be tested,” he said. “I know it's been a very controversial topic, but just think about it, based on everything we just talked about. If there is extensive adiposity in visceral organs, including muscle, and you have an ejection fraction of 35%, can that possibly be good for you? I can't imagine that it would be. But we've never tested that hypothesis, I think it absolutely should be tested. That's my take on it.”

References

1. Kosiborod MN, Abildstrom SZ, Borlaug BA, et al; STEP-HFpEF trial committee and investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. Published August 25, 2023. doi:10.1056/NEJMoa2306963
2. Borlaug BA, Kitzman DW, Davies MJ, et al. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. Published online August 27, 2023. https://doi.org/10.1038/s41591-023-02526-x