A phase III study – Semaglutide improves symptoms for heart failure patients with preserved ejection and obesity

Background: Heart failure with preserved ejection fraction (HFpEF) is one of the leading causes of death, with increasing prevalence due to the pandemic of metabolic disorders. About 80% of HFpEF patients are obese, along with other metabolic diseases, and there is no effective treatment available. Previous studies have demonstrated that weight reduction can improve HFpEF symptoms. Thus, we determined the effect of semaglutide, a GLP1 receptor agonist, on the HFpEF condition in obese patients without diabetes.

Method: An international multicenter, double-blinded study recruited 529 participants and randomized them in a 1:1 ratio stratified by BMI, for semaglutide 2.4 mg and a placebo group. The drug was given as a subcutaneous weekly injection. Both groups underwent a 16-week dose escalation period, where doses were increased every 4 weeks - 0.25 mg, 0.5 mg, 1 mg, and 1.7mg - to finally 2.4 mg, which was administered till end of 52 weeks, followed by endpoint measurements. The primary endpoint was the change in the KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire- clinical summary score) and percent body weight from baseline to 52 weeks. The secondary endpoints include change in 6-minute walking distance, inflammation as measured by C-reactive protein, and overall clinical benefit as measured by multiple parameters.

Result: The mean change in KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo, with a difference of 7.8 points, 95% confidence interval (CI): 4.8 to 10.9, P<0.001. The mean change in body weight was -13.3% with semaglutide and -2.6% with placebo, a difference of -10.7%, 95% CI: -11.9 to -9.4, P<0.001. The secondary endpoints were also significantly improved, the difference in – 6 minute walk distance was 20.3 m, 95% CI: 8.6 to 32.1, P<0.001; CRP levels was 0.61, 95% CI: 0.51 to 0.72, P<0.0001; and overall health parameter win ratio was 1.72, 95% CI: 1.37 to 2.15, P<0.001 in semaglutide group compared to placebo. The frequency and percentage of patients affected by adverse events were lower in the semaglutide group as compared to placebo.

Conclusion: Semaglutide improved HFpEF symptoms in obese patients by reducing physical limitation, weight, and improving exercise ability compared to placebo.

Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT047885511.