ESC Heart Failure 2024 – In a pooled analysis of STEP-HFpEF and STEP-HFpEF DM, semaglutide reduced NT-proBNP levels in patients with obesity-related HFpEF compared with placebo.

This summary is based on the presentation of Mark Petrie, MD (Glasgow, UK) at Heart Failure 2024 - Semaglutide 2.4 mg and NTproBNP in obesity-related HFpEF: insights from the STEP-HFpEF programme.

Introduction and methods

In STEP-HFpEF programme, treatment with semaglutide for 52 weeks improved KCCQ - Clincal Summary Score (CSS), reduced body weight, increased 6-minute walk distance (6MWD), reduced CRP, and was associated with fewer HF events in patients with obesity-related HFpEF compared with placebo. It remains unclear whether the effects of semaglutide on obesity-related HFpEF are due to weight loss alone, or due to HF-modifying effects which are independent from weight loss.

There is an inverse relationship between NT-proBNP and weight (i.e. people with higher body weight have lower NT-proBNP, and vice versa). When people lose weight via diet or changes in lifestyle, there usually is an increase in NT-proBNP. There are concerns that NT-proBNP levels may increase after patients lose weight after treatment with semaglutide. On the other hand, a reduction in NT-proBNP after treatment with semaglutide would indicate a disease-modifying effect on HF pathobiology.

The STEP-HFpEF programme consists of two different clinical trials, 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) with no diabetes (STEP-HFpEF; n=529) and with T2D (STEP-HFpEF DM; n=616) (combined total of 1145 patients).

The goal of this pooled analysis of data from STEP-HFpEF and STEP-HFpEF DM was to investigate the effect of semaglutide on NT-proBNP in patients with obesity-related HFpEF. Moreover, the effect of semaglutide on primary and secondary endpoints were investigated according to baseline NT-proBNP.

Main results

• In the pooled study population, treatment with semaglutide reduced NT-proBNP levels from baseline to 52 weeks compared with placebo (estimated treatment ratio (ETR): 0.82; 95%CI: 0.74-0.91; P=0.0002).
• The effect of semaglutide on NT-proBNP were consistent in both trials of the STEP-HFpEF programme (ETR: 0.84; 95%CI: 0.71-0.98; P=0.0255 in STEP-HFpEF; ETR: 0.80; 95%CI: 0.70-0.93; P=0.0029 in STEP-HFpEF DM).
• The treatment effect of semaglutide versus placebo on KCCQ-CSS was greater in patients with higher NT-proBNP levels at baseline (difference of 4.5 points; 95%CI: 0.8-8.2 in patients with NT-proBNP <300 pg/mL; 6.2 points; 95%CI: 2.4-10.0 in patients with NT-proBNP 300-810 pg/mL; and 11.9 points; 95%CI: 8.1-15.7 in patients with NT-proBNP >810 pg/mL; P=0.02). Consistent results were obtained when analyzing NT-proBNP as a continuous variable (P for interaction=0.0044).
• Semaglutide versus placebo reduced body weight, improved 6MWD and reduced hsCRP to a similar extent across all baseline NT-proBNP tertiles.

Conclusion

In this pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide reduced NT-proBNP in patients with obesity-related HFpEF compared with placebo. Semaglutide improved HF-related symptoms and physical limitations across all baseline NT-proBNP tertiles compared with placebo, but the greatest improvements were seen in patients with higher NT-proBNP at baseline.

According to Mark Petrie, “semaglutide’s effect on NT-proBNP suggests disease-modifying mechanisms beyond weight loss. We are pretty confident that this is a proper, true heart failure effect beyond weight loss.”

- Our reporting is based on the information provided at ESC Heart Failure 2024 -