Semaglutide reduces body weight to a greater extent in women with obesity-related heart failure with preserved ejection fraction (HFpEF) than in men, and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) to the same extent in both women and men, according to results from a prespecified secondary analysis of pooled data from the STEP-HFpEF program presented at the American Diabetes Association’s 2024 Scientific Sessions and simultaneously published in JACC.

The double-blind, placebo-controlled STEP-HFpEF program consisted of two trials: STEP-HFpEF of patients with obesity-related HFpEF without type 2 diabetes (T2D) and STEP-HFpEF DM of patients with obesity-related HFpEF plus T2D. The trials were conducted at 129 sites across 18 countries in Asia, Europe, North America and South America. Overall, 1,145 patients (49.7% women, 89.6% White, LVEF ≥45%, KCCQ-CSS <90 points) were randomized to either weekly semaglutide 2.4 mg subcutaneous injections or placebo for 52 weeks (added to background glucose-lowering medications for patients with T2D). Randomization was stratified by BMI (<35 kg/m² vs. ≥35 kg/m²).

The present analysis conducted by Subodh Verma, MD, PhD, Mikhail N. Kosiborod, MD, et al., to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF program, had dual primary endpoints: percentage change in body weight and change in KCCQ-CSS score from baseline to 52 weeks. Baseline BMI was 38.8 kg/m² in women and 37.1 kg/m² in men. Baseline KCCQ-CSS score was 54.7 in women and 63.0 in men.

Results showed that in the semaglutide group, percentage change in body weight was greater in women than men (mean difference in women −9.6% vs. −7.2% in men; P_interaction=0.006). For change in KCCQ-CSS score, there was a similar improvement with semaglutide in both sexes (mean difference in women +7.6 points vs. +7.5 points in men; P_interaction=0.94).

Semaglutide was also associated with an improved six-minute walking distance (6MWD) and a hierarchical composite endpoint comprising all-cause death, HF events, KCCQ-CSS change, 6MWD and C-reactive protein (CRP), as well as fewer adverse events in both sexes with no difference between women and men.

The authors note that at baseline women had higher BMI, LVEF, CRP and worse HF symptoms and that compared with men they were less likely to have atrial fibrillation or coronary artery disease. “Greater adiposity, symptom severity, and exercise limitation in females suggests pathophysiologic sex differences, reinforcing the importance of aggressive treatment in females with obesity-related HFpEF,” they write.

“The authors should be congratulated for an important analysis of two landmark clinical trials that laudably prioritized feel-and-function endpoints and achieved equal sex representation,” write John W. Ostrominski, MD, and Anuradha Lala, MD, FACC, in an accompanying editorial comment. “The central role of obesity in the onset and progression of HFpEF in females amplifies the need for integrative, patient-centered approaches prioritizing weight management.”

In a related prespecified analysis from the STEP-HFpEF program, also published in JACC, that assessed the change in NYHA functional class from baseline to 52 weeks, researchers found that more patients in the semaglutide-treated group had improvement compared with the placebo-treated group (32.6% vs. 21.5%, respectively; odds ratio [OR], 2.20; p<0.001). Fewer semaglutide-treated patients experienced deterioration in NYHA functional class as well (2.09% vs. 5.24% with placebo, respectively; OR, 0.36; p=0.003).

Furthermore, Morten Schou, MD, Mikhail N. Kosiborod, MD, et al., report that semaglutide compared with placebo improved KCCQ-CSS scores across NYHA functional classes, particularly in NYHA class III/IV (10.5 points vs. 6.0 points in NYHA class II; P_interaction=0.06). However, reduction of body weight was similar with semaglutide vs. placebo, regardless of baseline NYHA class (8.4% for NYHA functional class II and 8.3% for NYHA functional classes III/IV; P_interaction=0.96).

“Semaglutide, compared with placebo, consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories,” they write.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure

Keywords: Coronary Artery Disease, Atrial Fibrillation, Body Mass Index, Heart Failure, Diabetes Mellitus, Type 2