In a recent study published in Nature Medicine, researchers evaluated the efficacy of semaglutide in patients with the obesity phenotype of heart failure and preserved ejection fraction (HFpEF).
HFpEF prevalence has increased worldwide, with few treatments available. Around 60% of HFpEF patients show the obesity phenotype, a distinct pathophysiological type of HFpEF that is characterized by increased symptom severity, adverse hemodynamics, higher hospitalization risk, and poorer exercise capacity than HFpEF patients without obesity.
The semaglutide treatment effect in people with obesity (STEP)-HFpEF trial revealed that weekly treatment with semaglutide, a glucagon-like peptide 1 (GLP1) receptor agonist, resulted in significant improvements in weight loss, exercise function, symptoms, and physical limitations and decreased inflammation.
Nevertheless, whether its effects differ by obesity class remains unclear. Studies report worsening symptom severity, hemodynamic abnormalities, and exercise limitations with increasing body mass index (BMI), suggesting the possibility that semaglutide’s effects may be limited to HFpEF subjects with high BMI.
About the study
In the present study, researchers investigated the effects of semaglutide in HFpEF patients across obesity classes. STEP-HFpEF was an international, double-blind, randomized controlled trial assessing the safety and efficacy of 2.4 mg semaglutide administered weekly in non-diabetic patients with HFpEF obesity phenotype relative to placebo.
Patients were eligible if they had a BMI ≥ 30.0 kg/m2, left ventricular ejection fraction ≥ 45%, New York Heart Association (NYHA) functional class II–IV, and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) < 90, and at least one of the following: increased natriuretic peptide levels, elevated left ventricular filling pressures, or hospitalization for heart failure in the past year.
Eligible subjects were randomized to semaglutide or placebo arms; they were instructed to perform frequent moderate-intensity physical activity and limit the intake of red meat, salt, sweets, sugar-sweetened beverages, trans or saturated fats, and alcohol. Patients were stratified according to BMI as class I (BMI 30.0 to 34.9 kg/m2), class II (BMI 35.0 to 39.9 kg/m2), or class III (BMI ≥ 40.0 kg/m2).
The primary endpoints were changes in body weight and KCCQ-CSS from baseline after 52 weeks. Secondary endpoints included changes from baseline in six-minute walk distance (6MWD) and C-reactive protein (CRP) levels and a hierarchical composite endpoint (heart failure events, death, and changes in 6MWD and KCCQ-CSS).
The study comprised 529 participants, including 263 in the semaglutide group, with a median baseline BMI of 37.0 kg/m2. There were 34.0%, 32.3%, and 33.7% of participants with class I, II, and III obesity, respectively. Patients with more severe obesity were more likely to be younger and female and showed severe impairments in symptoms, exercise function, and physical limitations.
The researchers did not observe differences in heart failure treatment and systolic blood pressure by obesity class. However, patients with a higher obesity class were more likely to be treated with higher doses of loop diuretics, and those with a lower obesity class were more likely to receive sodium-glucose co-transporter 2 (SGLT2) inhibitors.
The prevalence of sleep apnea, hypertension, and atrial fibrillation did not differ by obesity class.
Regression analysis revealed the association of increased BMI with higher CRP and lower 6MWD and KCCQ-CSS at baseline. Semaglutide treatment led to body weight loss and improvements in KCCQ-CSS, 6MWD, overall clinical benefit (composite endpoint), and systemic inflammation relative to placebo across all obesity classes.
In the semaglutide group, weight loss was ≥ 20% in 58 patients, 15% to < 20% in 50 subjects, 10% to < 15% in 54 individuals, 5% to < 10% in 51 participants, and < 5% in 33 patients. The degree of weight loss was associated with the magnitude of CRP reduction and improvements in 6MWD and KCCQ-CSS.
Each 10% decline in body weight was associated with a 28% lower CRP, a 14.4-meter increase in 6MWD, and a 6.4-point higher KCCQ-CSS.
Together, semaglutide improved heart failure-related symptoms, exercise function, and physical limitations and reduced body weight and systemic inflammation, compared to placebo, across obesity categories.
Moreover, in the semaglutide group, the magnitude of clinical benefit was associated with the degree of weight reduction and the treatment-induced weight loss applied to all obesity classes. Overall, the findings corroborate semaglutide-induced weight decline as an essential therapeutic strategy for those with HFpEF obesity phenotype
Borlaug BA, Kitzman DW, Davies MJ, et al. (2023). Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. doi: 10.1038/s41591-023-02526-x. https://www.nature.com/articles/s41591-023-02526-x#Sec1