CONFERENCE UPDATE: ACC 2024

Weight and HF outcomes in obese HFpEF and T2DM patients with semaglutide in the STEP-HFpEF DM trial

CARDIOLOGY DIABETES & ENDOCRINOLOGY
15 Jul 2024

STUDY DESIGN

Excessive adiposity is associated with the development and progression of both heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM).1 Comorbidity of T2DM in patients with HFpEF is common, resulting in a greater symptom burden and worse functional status.1 Semaglutide is a once-weekly glucagon-like peptide-1 receptor agonist (GLP-1RA) shown to significantly improve heart failure (HF)-related symptoms, physical limitations and body weight in patients with obesity-related HFpEF without T2DM.1

The STEP-HFpEF DM trial is the first randomized, double-blind, placebo-controlled phase 3 trial to investigate the efficacy of once-weekly semaglutide in patients with obesity-related HFpEF and T2DM.1 The study included adult patients with body mass index (BMI) ≥30kg/m2.1 They had T2DM and class II-IV HF by the New York Heart Association (NYHA) functional classification, a left ventricular ejection fraction (LVEF) ≥45%, <90 points on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), and a 6-minute walking distance test (6MWD) result of ≥100 meters.1 Patients were randomized 1:1 to receive the standard of care plus either subcutaneous semaglutide 2.4mg (n=310) or a matching placebo (n=310) once weekly for 52 weeks.1

The primary endpoints were the change in KCCQ-CSS and the percentage change in body weight from baseline to week 52.1 Secondary endpoints included the change in 6MWD and change in C-reactive protein (CRP) levels from baseline to week 52.1 Hierarchical composite endpoint which comprised time to all-cause mortality, number and time to HF events requiring hospitalization, and differences in KCCQ-CSS change and 6MWD from baseline to week 52 was also assessed.1

 

Primary endpoints: 
  • The dual primary endpoints were the change in KCCQ-CSS and percentage change in body weight from baseline to week 521
  • Improvements in KCCQ-CSS were greater in patients treated with semaglutide compared to those treated with placebo (estimated treatment difference [ETD]: 7.3 points; 95% CI: 4.1-10.4; p<0.001)1
  • Moreover, patients receiving semaglutide experienced a significantly greater reduction in body weight (ETD: -6.4%; 95% CI: -7.6 to -5.3; p<0.001)1

Secondary endpoints:
  • Secondary outcomes were the change in 6MWD and CRP as well as the hierarchical composite endpoint comprising time to all-cause mortality, number and time to HF events requiring hospitalization, an at least 5-, 10-, and 15- point change in KCCQ-CSS, and a ≥30 meters change in 6MWD from baseline to week 521
  • The 6MWD was 12.7 meters in the semaglutide group compared with -1.6 meters in the placebo group (ETD: 14.3 meters; 95% CI: 3.7-24.9; p=0.008)1
  • The semaglutide group had a significantly higher proportion of wins in the hierarchical composite endpoint than the placebo group (58.7% vs. 36.8%; stratified win ratio: 1.58; 95% CI: 1.29-1.94; p<0.001)1
  • Moreover, the ratio of mean CRP levels relative to baseline was further lowered with semaglutide over placebo (estimated treatment ratio [ETR]=0.67; 95% CI: 0.55-0.80; p<0.001)1
  • Subgroup analysis revealed greater improvements with semaglutide regardless of background SGLT2 inhibitor use in KCCQ-CSS (pinteraction=0.35) and body weight outcomes (pinteraction=0.04)1

Safety:

  • Compared to the placebo group, a significantly lower proportion of patients in the semaglutide group experienced serious adverse events (SAEs) (17.7% vs. 28.8%; p=0.002) and cardiac disorders (6.1% vs. 13.1%; p=0.004)1
  • A lower proportion of patients in the semaglutide group died (1.9% vs. 3.3%) compared to the placebo group1
  • A higher proportion of patients in the semaglutide group experienced AEs leading to discontinuation compared to the placebo group (10.6% vs. 8.2%) which were mainly due to gastrointestinal adverse events (AEs) (6.5% vs. 2.9%)1

 

“In patients with obesity-related HFpEF and T2DM, semaglutide 2.4mg produced larger reductions in HF-related symptoms and physical limitations, greater weight loss, and greater improvements in exercise function than placebo”

Dr. Mikhail N. Kosiborod
Department of Cardiovascular Disease,
University of Missouri-Kansas City School of Medicine,
Kansas City, United States

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