Weight loss medication benefits patients with heart failure, obesity

 According to new research presented at the ESC Congress 2023, semaglutide improves heart failure-related symptoms and physical function and results in greater weight loss compared to placebo in patients with heart failure with preserved ejection fraction (HFpEF) and obesity.

Approximately half of patients with heart failure in the community have HFpEF. Most patients with HFpEF are overweight or obese, and growing evidence suggests that obesity and excess adiposity are not simply comorbidities, but may play a pivotal role in the development and progression of HFpEF.3 Patients with obesity-related HFpEF have an especially high burden of debilitating symptoms (shortness of breath, exertional intolerance, swelling/oedema) and physical limitations, which collectively result in a poor quality of life. Few treatment options are available, and there are no approved therapies specifically targeting the obesity phenotype of HFpEF.

Semaglutide is a potent glucagon-like-peptide-1 receptor agonist which has previously been shown to produce substantial weight loss in people with overweight and obesity. The STEP-HFpEF trial tested the hypothesis that treatment with semaglutide can significantly improve symptoms, physical limitations and exercise function, in addition to weight loss, in patients with HFpEF and obesity.

STEP-HFpEF was a randomised, double-blind, placebo-controlled trial conducted at 96 sites in 13 countries in Asia, Europe, North America and South America. The trial included patients with HFpEF (left ventricular ejection fraction ≥45 per cent), body mass index (BMI) ≥30 kg/m2, heart failure symptoms and functional limitations (New York Heart Association functional class II–IV and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS] <90 points).

Participants were randomly assigned in a 1:1 ratio to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 52 weeks. The trial had two primary endpoints: change from baseline to week 52 in 1) KCCQ-CSS, a gold standard measure of heart failure-related symptoms and physical limitations; and 2) body weight. Confirmatory secondary endpoints included change in 6-minute walk distance (6MWD – a validated measure of exercise function); a hierarchical composite endpoint of death, heart failure events and change in KCCQ-CSS and 6MWD; and change in C-reactive protein (CRP – a measure of inflammation).

The trial included 529 patients. The median age was 69 years and 56.1 per cent were women. The median body weight and BMI at baseline were 105.1 kg and 37.0 kg/m2, respectively. At baseline, patients had a substantial degree of heart failure-related symptoms, physical limitations and poor exercise tolerance: 66.2% were NYHA class II and 33.8 per cent were NYHA class III–IV; the median KCCQ-CSS was 58.9 points; and the median 6MWD was 320 meters.

The trial met both primary endpoints and all confirmatory secondary endpoints. The mean change in KCCQ-CSS from baseline to week 52 was 16.6 points with semaglutide versus 8.7 points with placebo (estimated treatment difference [ETD]: 7.8 points, 95 per cent confidence interval [CI] 4.8 to 10.9; p<0.001). The mean change in body weight from baseline to week 52 was -13.3 per cent with semaglutide versus -2.6% with placebo (ETD: -10.7 per cent, 95 per cent CI -11.9 per cent to -9.4 per cent; p<0.001).

Regarding secondary endpoints, the mean change in 6MWD was 21.5 meters for semaglutide versus 1.2 meters for placebo (ETD: 20.3 meters, 95 per cent CI 8.6 to 32.1; p<0.001). For the hierarchical composite endpoint, semaglutide produced more wins than placebo (win ratio 1.72, 95 per cent CI 1.37 to 2.15; p<0.001). The mean change in CRP was -43.5 per cent and -7.3 per cent with semaglutide and placebo, respectively (estimated treatment ratio 0.61, 95% CI 0.51 to 0.72; p<0.001).

In terms of exploratory endpoints, the change in NTproBNP at 52 weeks was -20.9 per cent and -5.3 per cent for semaglutide versus placebo (estimated treatment ratio 0.84, 95 per cent CI 0.71 to 0.98). One patient in the semaglutide group and 12 in the placebo group experienced an adjudicated event of heart failure hospitalisation or urgent visit (hazard ratio 0.08, 95 per cent CI 0.00 to 0.42). Serious adverse events were reported in 35 (13.3 per cent) and 71 (26.7 per cent) participants with semaglutide and placebo, respectively (p<0.001).

Principal investigator Dr. Mikhail Kosiborod of Saint Luke's Mid America Heart Institute, Kansas City, US said: “In patients with HFpEF and obesity, treatment with semaglutide 2.4 mg produced large improvements in symptoms, physical limitations and exercise function, reduced inflammation, and resulted in greater weight loss and fewer serious adverse events as compared with placebo. To our knowledge, this is the first trial of a pharmacologic agent to specifically target obesity as a treatment strategy for HFpEF, and the magnitude of the benefits we observed is the largest seen with any agent in HFpEF. This will likely have a significant impact on clinical practice, especially since there is a dearth of efficacious therapies in this vulnerable patient group. We believe that these findings should also change the nature of the conversation about the role of obesity in HFpEF, as the STEP-HFpEF results clearly indicate that obesity is not simply a comorbidity in patients with HFpEF but a root cause and a target for therapeutic intervention.” (ANI)