Wegovy Reduces Heavy Symptom Burden of Obesity-Related Heart Failure

AMSTERDAM — Semaglutide 2.4 mg (Wegovy) led to clinically meaningful reductions in symptoms and weight among patients with obesity and heart failure with preserved ejection fraction (HFpEF), the STEP-HFpEF trial showed.

While the study was not designed to assess hard cardiovascular endpoints, it did show that semaglutide improved Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary scores to a greater extent after 1 year compared with placebo (16.6 vs 8.7 points gained over baseline, P<0.001), reported Mikhail Kosiborod, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, Missouri.

Moreover, the GLP-1 receptor agonist conferred a mean 13.3% reduction in body weight versus 2.6% with placebo (P<0.001), Kosiborod told the audience here at the European Society of Cardiology (ESC) Congress. The study was simultaneously published in the New England Journal of Medicine.

“What we know is that patients with this type of heart failure, many of them actually value improvement in symptoms and [reducing] physical limitations as much or more as survival … So I think these results are very meaningful clinically,” Kosiborod said during a press conference.

There are currently no approved treatments for the specific phenotype of combination HFpEF and obesity, the prevalence of which is large and growing with the rise of obesity, diabetes, and older age. The phenotype has a particularly high burden of physical limitations and poor quality of life.

That the KCCQ could be improved by over 15 points — a “very large change,” in Kosiborod’s words — in hard-to-treat heart failure patients is the cherry on top.

“For perspective, previous global clinical trial programs of agents such as SGLT2 inhibitors, sacubitril-valsartan [Entresto], and spironolactone for heart failure with preserved ejection fraction showed only modest changes in KCCQ scores (ranging from 0.5 to 2.3 points),” the study authors noted in their paper.

Edward Fry, MD, of Ascension St. Vincent Heart Center in Indianapolis and immediate past president of the American College of Cardiology, told MedPage Today that STEP-HFpEF is a “wake-up call” to noncardiologists and primary care physicians, by whom many of these patients are getting their care, and noted that GLP-1 receptor agonist treatment is “a good choice” for patients with obesity and HFpEF.

Yet the main issue now is access and coverage, Kosiborod said. “My hope is that will change favorably with these data and other data coming soon.”

Semaglutide was recently approved for long-term weight management in people with overweight or obesity. Since then, “the landscape’s changed a lot” and more people are asking for it for non-heart failure, non-diabetic indications and it’s a lot of pressure on the supply, said Fry, who was not involved in the study.

For STEP-HFpEF, investigators recruited heart failure patients with a left ventricular ejection fraction of at least 45%, a body mass index (BMI) of 30 or higher, and New York Heart Association functional class II, III, or IV symptoms, among other criteria.

The 529 participants had a median age of 69 years, and 56.1% were women. Baseline BMI was a median 37, and the median NT-proBNP level was 450.8 pg/mL.

Patients were randomized to once-weekly semaglutide 2.4 mg delivered subcutaneously or placebo for 52 weeks. Both groups also received advice about lifestyle.

Kosiborod reported that the trial’s secondary endpoints supported semaglutide’s benefit in HFpEF patients with obesity:

• Average change in 6-minute walk distance was +21.5 m with semaglutide and +1.2 m with placebo (P<0.001)

• A hierarchical composite endpoint (including death, heart failure events, and differences in the change in KCCQ and 6-minute walk distance) favored semaglutide over placebo (win ratio 1.72, 95% CI 1.37-2.15)

• C-reactive protein level was reduced by 43.5% with semaglutide and 7.3% with placebo (P<0.001)

Serious adverse events were reported in 13.3% of patients in the semaglutide group and 26.7% in the placebo group; 35 and 14 patients, respectively, discontinued treatment due to adverse events, predominantly related to gastrointestinal events such as nausea.

A major lingering question is how the GLP-1 receptor agonist would fare in a heart failure population using concomitant SGLT2 inhibitors, which just received endorsement in the latest ESC heart failure guidelines.

“The question is, is there an additive effect? Is there a synergistic effect? Is there less of an effect? We don’t know, but one would anticipate, since the mechanisms of action are so different, that they’d improve upon one another,” Fry said.

To help answer this question, the STEP-HFpEF authors pointed to the ongoing STEP-HFpEF DM trial that is studying the same dose of semaglutide in HFpEF patients with obesity and type 2 diabetes. The study has 32% of participants taking SGLT2 inhibitors.

Kosiborod and team acknowledged limitations to their study, including that white patients made up nearly 96% of their study population, and the fact that the durability of semaglutide’s effects are unknown beyond 1 year.

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