Semaglutide Equally Effective in Women With HFpEF, Obesity

ORLANDO, Fla. — Women with heart failure with preserved ejection fraction (HFpEF) and obesity, with or without diabetes, derive the same benefit from the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide (Wegovy, Ozempic) as men did, according to a newly published analysis of data from two large international trials.

In the prespecified secondary analysis, researchers analyzed pooled data from the STEP-HFpEF and the STEP-HFpEF-DM trials, which both compared once-weekly semaglutide injections (2.4 mg) with placebo over 52 weeks in a total of 1145 participants, 570 of whom were women.

“Despite differential weight loss and key differences in baseline characteristics by sex, we found no significant treatment-by-sex interactions for any of the HF outcomes assessed,” wrote the authors of the study, which was published online in JAAC and presented simultaneously at the American Diabetes Association (ADA) 84th Scientific Sessions.

Women lost more weight than men did, 12.6% at 1 year compared with 10.2%, but otherwise had similar improvements in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS).

The study is significant in part because “there have been no prior trials that have looked at sex and obesity-related HFpEF,” lead author Subodh Verma, MD, PhD, professor and Canada Research Chair in Cardiovascular Surgery at the University of Toronto, Ontario, Canada, said at the meeting. 

“Sex modifies the entire journey of heart failure, specifically heart failure with preserved ejection fraction, from the genesis to the pathobiology to the natural history, to the response to therapy,” he said.

Women who enrolled in the STEP trials had a higher body mass index than did men (BMI; mean of 39 vs mean of 37, respectively), and significantly worse symptoms, physical limitations, and exercise capacity compared with men, even though they had higher left ventricular ejection fraction, Verma reported.

Though the women had lost more weight than men did, “the benefits cannot entirely be explained by weight loss per se,” he said.

In the female-specific analysis as well as in another analysis looking at New York Heart Association (NYHA) class function simultaneously published in JACC, “there was a 20% reduction” in N-terminal pro b-type natriuretic peptide (NT-proBNP), he noted.

“You don’t reduce NT-proBNP if you’re not modifying the pathobiology of heart failure,” Verma said.

Aside from having worse symptoms and higher BMI at baseline, the women enrolled in the STEP trials were younger than the participants in previous trials. “This may relate to the fact that patients with the obesity phenotype of HFpEF are, on average, a decade younger than those with HFpEF without obesity,” wrote the authors.

Female participants had similar rates of hypertension and diuretic use and less atrial fibrillation compared with men. 

Compared with placebo, semaglutide improved KCCQ-CSS similarly in both sexes; the adjusted mean difference was +7.5 points (95% CI, 4.3-10.6) in men and +7.6 points (95% CI, 4.5-10.7) in women (P =.944) at 1 year.

Thirty-five percent of the women had a ≥ 20-point improvement on the KCCQ-CSS compared with 39% of men. Only 21% of women and 25% of men on placebo had such an improvement.

Improvements in 6-minute walking distance, systolic blood pressure, and waist circumference for women were all similar to results found in men.

Sex-Related Findings Important for Clinical Care

The totality of the findings “emphasize important sex-related differences in HFpEF pathophysiology and provide implications for clinical care, research and training priorities, as well as healthcare service design,” wrote Anuradha Lala, MD, and John W. Ostrominski, MD, in an editorial comment in JAAC.

A surprising result was that greater weight loss among women “did not lead to

commensurate increases in improvement,” in the KCCQ-CSS, 6-minute walking distance, or C-reactive protein (CRP) levels, they added.

“The authors should be congratulated for an important analysis,” Lala and Ostrominski wrote, but they noted several key limitations, including that the STEP trials were not designed to evaluate treatment effects of semaglutide according to sex. 

The researchers did not explicitly address sex-specific variation in background medications known to impact weight and HF-related health status, and, the editorialists added, given that the enrollees were almost exclusively White, “generalizability to women of other racial and ethnic backgrounds is limited.”

Even so, the study gives insight into sex-specific effects of GLP-1 RAs and “corroborates previously reported characteristics of the obesity-related HFpEF phenotype among females,” they stated.

Functional Improvement = Patients Feel Better

In a separate prespecified analysis, STEP investigators examined the effect semaglutide had on NYHA functional class. 

They assessed and reported NYHA functional class at baseline, 20, and 52 weeks, focusing on the two prespecified categories: functional class II (785 patients) and functional classes III and IV, which were combined into a single group (360 patients).

At 1 year, 32.6% of semaglutide-treated patients had an improvement in NYHA functional class compared with 21.5% of placebo-treated patients (odds ratio [OR], 2.20; P <.001 and="" only="" semaglutide-treated="" patients="" experienced="" deterioration="" in="" nyha="" functional="" class="" compared="" with="" of="" on="" placebo="">P =.003). 

Semaglutide improved KCCQ-CCS scores across all NYHA categories but was greater for those in the class III and IV category (a 10.5-point increase compared with a 6-point increase for those in the functional class II category). Patients taking semaglutide also had improved 6-minute walking distance and reduced C-reactive protein and NT-proBNP across all NYHA functional class categories.

The NYHA results are important, especially to patients, co-author Mikhail N. Kosiborod, MD, a cardiologist with Saint Luke’s Mid America Heart Institute, Lees Summit, Missouri, told ADA attendees.

“When you actually ask patients who have HFpEF, what’s most meaningful to them, the majority will say that it’s improvement of their daily symptoms and function,” he said. “That’s more important than almost anything else, including survival.” 

In another editorial comment in JACC, Theresa McDonagh, professor and consultant cardiologist in the School of Cardiovascular Medicine & Sciences at King’s College in London, United Kingdom, and colleagues agreed with Kosiborod that “in practice, physicians place more weight on prescribing therapies that reduce mortality,” despite a stated goal of improving symptoms.

The JACC study results were impressive in improving symptoms, they wrote.

Improvement Better Than With SGLT2 Inhibitors

“Semaglutide was associated with a significant improvement in NYHA functional class, regardless of the changes in KCCQ, and an attenuation of the functional decline of over time,” McDonagh and colleagues wrote in their commentary. 

“These effects are numerically greater than those of Sodium Glucose Cotrasporter-2 inhibitors (SGLT2-i),” they wrote. 

In addition, “the effect of semaglutide is larger in more symptomatic patients,” and “seem to be unrelated to the changes in body weight, suggesting an independent beneficial effect of semaglutide in HFpEF patients,” they added. 

Those independent effects are supported by the reduction in CRP and NT-pro-BNP across the NYHA classes, they pointed out. “Notably, the reduction in NT-proBNP was proportionally greater in those with higher starting natriuretic peptide concentrations, a finding that parallels and lends credence to the larger KCCQ improvements in those worse NYHA symptom severity.”

The studies were funded by Novo Nordisk. Kosiborod has multiple disclosures, including that he is a paid consultant for Novo Nordisk. Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada; holds the Tier 1 Canada Research Chair in Cardiovascular Surgery; and has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, 

Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Lala reported that she is on the Speakers Bureau for Abiomed and Zoll, participates in contracted research for Merck, Bayer, and Astra Zeneca, and serves on advisory boards for Novo Nordisk and Boehringer Ingelheim. McDonagh reported no conflicts. 

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X @aliciaault.