Semaglutide improves NYHA functional class in obesity-related HFpEF
In a prespecified analysis of the STEP-HFpEF program among patients with obesity-related HFpEF, semaglutide improved functional status, as assessed with NYHA functional class, compared with placebo.
This summary is based on the publication of Schou M, Petrie MC, Borlaug, BA, et al. - Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program. J Am Coll Cardiol. 2024 Jul 16;84(3):247-257. doi: 10.1016/j.jacc.2024.04.038.
Introduction and methods
Background
In the STEP-HFpEF program, semaglutide reduced HF symptoms, physical limitations, and body weight and improved exercise function compared with placebo in patients with obesity-related HFpEF with and without T2D [1-3]. It remains unclear whether treatment with semaglutide improves functional status, as assessed with NYHA functional classification, over time.
Aim of the study
The goal of this prespecified analysis of the STEP-HFpEF program was to evaluate the effect of semaglutide on changes in NYHA functional class over time. Moreover, this analysis aimed to evaluate the treatment effects of semaglutide across baseline NYHA functional class categories.
Methods
The STEP-HFpEF program consists of 2 different RCT’s, namely STEP-HFpEF and STEP-HFpEF DM, which investigated the effects of semaglutide versus placebo on a broad range of clinical outcomes in patients with obesity-related HFpEF (LVEF ≥45%, BMI ≥30 kg/m², NYHA functional class II/IV) with no diabetes (STEP-HFpEF; n=529) and with T2D (STEP-HFpEF DM; n=616) (combined total of 1145 patients). Patients were randomized to once-weekly semaglutide 2.4 mg subcutaneously or matching placebo on top of standard of care for 52 weeks.
NYHA functional class was assessed at baseline, week 20 and week 52. At baseline, 785 patients (69%) were classified in NYHA functional class II and 360 patients (31%) in NYHA functional class III/IV (358 patients were in functional class III and 2 patients in functional class IV).
Outcomes
The main outcome of this analysis was the change in NYHA functional class from baseline to 52 weeks.
The dual primary outcomes of the STEP-HFpEF program were the change in KCCQ - Clinical Summary Score (CSS) and percentage change in body weight from baseline to 52 weeks. Confirmatory secondary outcomes included the change in 6-minute walk distance (6MWD); a hierarchical composite outcome comprising all-cause mortality, HF events (adjudicated hospitalization or urgent hospital visit requiring intravenous therapy), differences in KCCQ-CSS change of ≥15, ≥10, or ≥5 points, and difference in 6MWD change of ≥30 m; and change in hsCRP level.
Safety outcomes of the current analysis included serious adverse events (SAEs), cardiac SAEs, gastrointestinal SAEs and SAEs leading to premature treatment discontinuation.
Main results
Changes in NYHA functional class over time
- At 52 weeks, more patients in the semaglutide group than in the placebo group had an improvement in NYHA functional class (34.6% vs. 23.3%; OR: 2.20; 95%CI: 1.62-2.99; P<0.0010).
- Improvements in NYHA functional class with semaglutide versus placebo were already evident at 20 weeks (23.6% vs. 18.1%; OR: 1.79; 95%CI: 1.27-2.52; P<0.001).
- Fewer semaglutide-treated than placebo-treated patients experienced a deterioration in NYHA functional class at 52 weeks (2.09% vs. 5.24%; OR: 0.36; 95%CI: 0.19-0.70; P=0.003).
- At 20 weeks, there was no difference between treatment groups in deterioration in NYHA functional class (OR: 1.26; 95%CI: 0.64-2.50; P=0.500).
Treatment effects of semaglutide
- Semaglutide improved KCCQ-CSS compared with placebo across baseline NYHA functional class subgroups, but the effects were more pronounced among patients in NYHA functional class III/IV (mean difference: 6.0 points; 95%CI: 3.4-8.6 for NYHA class II; and 10.5 points; 95%CI: 6.6-14.4 for NYHA class III/IV; P for interaction=0.061).
- Semaglutide consistently reduced bodyweight, hsCRP and NT-proBNP, and improved 6MWD and the win ratio for the hierarchical composite endpoint across baseline NYHA functional class subgroups (all P for interactions>0.05).
Safety outcomes
- The frequency of SAEs and cardiac SAEs were lower in semaglutide-treated patients than in placebo-treated patients, regardless of NYHA functional class.
- The frequency of gastrointestinal SAEs and SAEs leading to premature treatment discontinuation were similar between semaglutide-treated patients and placebo-treated patients, regardless of NYHA functional class.
Conclusion
In this prespecified analysis of the STEP-HFpEF program among patients with obesity-related HFpEF, more semaglutide-treated than placebo-treated patients experienced an improvement, and fewer a deterioration, in NYHA functional class at week 52. Semaglutide improved HF-related symptoms, body weight, physical limitations, exercise function, hsCRP and NT-proBNP compared with placebo, regardless of NYHA functional class. The beneficial effect of semaglutide on KCCQ-CCS were more pronounced among patients in NYHA functional class III/IV compared with patients in NYHA functional class II.
References
- Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389:1069–1084.
- Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. STEP-HFpEF DM Trial Committees and Investigators. N Engl J Med. 2024;390:1394–1407.
- Butler J, Shah SJ, Petrie MC, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. STEP-HFpEF Trial Committees and Investigators. Lancet. 2024;403: 1635–1648.