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Semaglutide and NYHA Class in Obesity-Related HFpEF
Quick Takes
- For patients with obesity-related HFpEF, semaglutide compared to placebo led to improvements in NYHA functional class at 52 weeks.
- Improvement in HF-related patient-reported symptoms and physical limitations, as well as reductions in bodyweight, were noted despite baseline NYHA class.
Study Questions:
For patients with obesity-related heart failure with preserved ejection fraction (HFpEF), what is the effect of semaglutide on change in New York Heart Association (NYHA) functional class over time?
Methods:
This study was a prespecified, pooled analysis of two international, randomized trials of once-weekly subcutaneous semaglutide versus placebo in patients with obesity-related HFpEF (the STEP-HFpEF trial included patients without type 2 diabetes; the STEP-HFpEF DM trial included patients with type 2 diabetes). Notable inclusion criteria for the trials were a left ventricular EF ≥45% with supporting evidence for an HF syndrome, body mass index (BMI) ≥30 kg/m2, and NYHA functional class II–IV. In the individual trials, the dual primary outcome of change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and percent change in bodyweight from baseline to 52 weeks were both met, favoring semaglutide over placebo. For this pooled analysis, the primary outcome of interest was change in NYHA class from baseline to 52 weeks.
Results:
A total of 1,145 patients were randomized across the two trials. Of these patients, 785 (69%) were NYHA class II, 358 (31%) were NYHA class III, and two were NYHA class IV at baseline. Patients in the NYHA class III/IV group compared to NYHA class II were more likely to be female, older, and White; they also had higher BMIs and C-reactive protein (CRP) levels and lower baseline KCCQ-CSS and 6-minute walk distances (6MWD). There were 77 (6.7%) patients with missing NYHA class data at 52 weeks (semaglutide group: 32; placebo group: 45).
For the primary outcome, semaglutide-treated patients compared to placebo-treated patients more frequently experienced an improvement in NYHA class (32.6% vs. 21.5%, odds ratio [OR], 2.20; 95% confidence interval [CI], 1.62-2.99; p < 0.001) and less frequently experienced a deterioration in NYHA class (2.09% vs. 5.24%, OR, 0.36; 95% CI, 0.19-0.70; p = 0.003) at 52 weeks. Similar findings were seen at 20 weeks.
When looking at the dual primary endpoints from the original trials stratified by NYHA class, semaglutide compared to placebo lead to improvements in KCCQ-CSS and reductions in percent change in bodyweight despite NYHA class. Of note, the improvement in KCCQ-CSS was greater for the NYHA class III/IV group compared to NYHA class II. The benefits of semaglutide compared to placebo were also consistently noted across NYHA classes for 6MWD, CRP, and N-terminal pro–B-type natriuretic peptide endpoints.
Conclusions:
For patients with obesity-related HFpEF, semaglutide compared to placebo led to more frequent improvement in NYHA class and less frequent deterioration in NYHA class at 52 weeks of treatment.
Perspective:
Treatments for patients with HFpEF center around improving quality of life and functional capacity. The STEP-HFpEF and STEP-HFpEF DM trials demonstrated the benefits of semaglutide for obesity-related HFpEF with respect to improvements in KCCQ-CSS and reduction in body weight. While NYHA class assessment has limitations and does not provide the same level of detail as KCCQ-CSS, it is simple to use and broadly adopted as a means to assess functional capacity. Demonstrating improvement in NYHA class in this study is clinically meaningful and easy to see for patients and clinicians. This study also highlights a potential increased benefit of semaglutide for patients with NYHA class III/IV compared to NYHA class II patients, which is encouraging news for patients with the most significant limitations at baseline. Overall, this series of trials and analyses has advanced knowledge on how to best care for patients with this obesity-related HFpEF phenotype.
Clinical Topics: Heart Failure and Cardiomyopathies, Prevention
Keywords: Heart Failure, Preserved Ejection Fraction, Obesity
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