The GLP1RA semaglutide reduces N-terminal pro-brain natriuretic peptide (NTproBNP) in patients with obesity-related HF with preserved ejection fraction (HFpEF), and it may hold greater benefits for patients who start treatment with a higher baseline NTproBNP, according to a prespecified secondary analysis of pooled data from two double-blind trials, STEP-HFpEF and STEP-HFpEF DM, presented at ESC Heart Failure 2024 and simultaneously published in JACC.

The placebo-controlled trials, conducted at 129 sites across 18 countries in Asia, Europe, and North and South America, randomly assigned 1,145 patients with obesity-related HFpEF (with a left ventricular EF [LVEF] of ≥45% and a body mass index [BMI] ≥30kg/m²) to either a 2.4 mg weekly dose of semaglutide or placebo and standard care for 52 weeks. Tertiles of NTproBNP at baseline were <300 pg/mL, 300-810 pg/mL and >810 pg/mL.

Results from the secondary analysis, conducted by Mark C. Petrie, MD, et al., showed that semaglutide, compared with placebo, reduced NTproBNP by week 20 (–27.6% for semaglutide, –11.1% for placebo), with a persistent effect at 52 weeks (–22.19% for semaglutide, –4.87% for placebo; estimated treatment ratio: 0.82; 95% CI, 0.74-0.91; p=0.0002). There were also fewer serious adverse events (SAEs) and cardiac SAEs in patients in the semaglutide group compared with placebo.

Patients starting with a higher baseline NTproBNP (who tended to be older with lower BMI and LVEF, shorter 6-minute walking distance (6MWD) and more likely to be on loop diuretics and beta-blockers) experienced similar weight loss as those with a lower level at baseline (interaction p=0.21). However, patients with the higher baseline level experienced a larger reduction in the other dual primary endpoint of HF-related symptoms and limitations as measured by the KCCQ-CSS (estimated difference: tertile 1, 4.5 points; tertile 2, 6.2 points; tertile 3, 11.9 points; interaction p=0.02; baseline NTproBNP as a continuous variable: interaction p=0.004.)

"The very large improvement (approximately 11 points) in those in the highest tertile is especially notable," Petrie et al., write, "as it exceeds benefits seen with other established HFpEF therapies." The write this improvement gained in health status despite a similar degree of weight loss as those with less severe HF, suggesting a possible weight loss-independent HF effect, or that a similar degree of weight loss may be of more benefit among patients with more severe obesity-related HFpEF.

In an accompanying editorial comment, Roland R. J. van Kimmenade MD, PhD, and Carlijne Hassing, MD, PhD, heralded the study for moving away from a "one-size-fits-all approach" to cardiovascular care. "The authors took the initiative to go beyond the classical strategy of testing HFrEF [HF with reduced ejection fraction] strategies in HFpEF and now report a successful therapy in the HFpEF subpopulation," they write, which, "Allows us to better adapt our therapy to fit the patient, rather than stretch the patient to fit the therapy."

This was just one of the studies simultaneously published in JACC and presented at ESC Heart Failure 2024. Read here for more.