Sex differences in treatment effects of semaglutide in obesity-related HFpEF

In a pooled analysis of the 2 STEP-HFpEF trials among patients with obesity-related HFpEF, semaglutide improved HF outcomes compared with placebo regardless of sex. However, women lost more weight with semaglutide than men.

This summary is based on the publication of Verma S, Butler J, Borlaug BA, et al. - Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials. J Am Coll Cardiol. 2024 Jun 19:S0735-1097(24)07445-X [Online ahead of print]. doi: 10.1016/j.jacc.2024.06.001

Introduction and methods

Background

Patients with HFpEF are more commonly women. They often have worse symptoms, more physical limitations, and more comorbidities than men, but also better survival rates and fewer HF hospitalizations [1-5]. In women, obesity is a more potent risk factor for HF compared with men [6].

The GLP1-RA semaglutide reduced HF-related symptoms, physical limitations, and body weight and improved exercise function compared with placebo in patients with obesity-related HFpEF, as recently shown by the STEP-HFpEF and STEP-HFpEF DM trials [7-11]. Interestingly, previous studies on semaglutide treatment indicated women with obesity tend to lose more weight than men [12,13].

Aim of the study

In a prespecified pooled analysis of individual patient-level data from the 2 STEP-HFpEF trials, the authors evaluated the influence of sex on the baseline characteristics and treatment effects of semaglutide in patients with obesity-related HFpEF.

Methods

The STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity; n=529) and STEP-HFpEF DM (Effect of Semaglutide 2.4 mg Once-weekly on Function and Symptoms in Subjects With Obesity-related Heart Failure With Preserved Ejection Fraction, and Type 2 Diabetes; n=616) trials were international, multicenter, double-blind, placebo-controlled, phase 3 RCTs. In both trials, patients with LVEF ≥45%, NYHA class II–IV HF symptoms, KCCQ – Clinical Summary Score (CSS) <90 points, and BMI ≥30 kg/m² were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks. Median follow-up duration was 401 days (IQR: 400–404). Of the 1145 patients, 570 (49.7%) were female.

Outcomes

The dual primary endpoints were the change in KCCQ-CSS and percentage change in body weight from baseline to 52 weeks. Confirmatory secondary endpoints included the change in 6-minute walk distance (6MWD); a hierarchical composite endpoint 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 CRP level.

Safety endpoints included serious adverse events; and serious adverse events leading to premature treatment discontinuation and deaths.

Main results

Baseline characteristics

• At baseline, women had a higher median BMI, LVEF, and CRP level, presented with worse HF symptoms and more physical limitations, were less likely to have AF or coronary artery disease (CAD), and were less likely to be treated with SGLT2 inhibitors or RAASis (all P≤0.004).

Efficacy of semaglutide

• Semaglutide improved the KCCQ-CSS from baseline to 52 weeks compared with placebo regardless of sex (mean difference in women: +7.6 points; 95%CI: 4.5–10.7; mean difference in men: +7.5 points; 95%CI: 4.3–10.6; P for interaction=0.944).
• Treatment with semaglutide versus placebo resulted in a greater body weight reduction at 52 weeks in women than men (mean difference in women: –9.6%; 95%CI: –10.9% to –8.4%; mean difference in men: –7.2%; 95%CI: –8.4% to –6.0%; P for interaction=0.006).
• Sex also did not influence the treatment effects of semaglutide versus placebo on the improvement of the 6MWD (P for interaction=0.207), the greater number of wins for the hierarchical composite endpoint (P for interaction=0.658), and the reduction of CRP level (P for interaction=0.232).

Safety outcomes

• The frequencies of serious adverse events, serious cardiac disorders, and serious adverse events leading to premature treatment discontinuation were lower in semaglutide-treated patients than placebo-treated patients, with no apparent different differences between the sexes.

Conclusion

In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials among patients with obesity-related HFpEF, women had a higher BMI and CRP level, worse HF-related symptoms, and more physical limitations at baseline compared with men despite having a higher LVEF and fewer comorbidities such as AF and CAD. In both sexes, semaglutide reduced the HF-related symptoms and physical limitations, improved exercise function, and decreased the rate of serious adverse events compared with placebo. However, women lost more weight with semaglutide than men.

Find this article online at J Am Coll Cardiol.

References

1. Borlaug BA, Sharma K, Shah SJ, Ho JE. Heart failure with preserved ejection fraction: JACC scientific statement. J Am Coll Cardiol. 2023;81:1810–1834. https://doi.org/10.1016/j.jacc.2023.01.049
2. Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2023;118:3434–3450. https://doi.org/10.1093/cvr/cvac120
3. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. 2017;136:6–19. https://doi.org/10.1161/CIRCULATIONAHA.116.026807
4. Sorimachi H, Omote K, Omar M, et al. Sex and central obesity in heart failure with preserved ejection fraction. Eur J Heart Fail. 2022;24:1359–1370.https://doi.org/10.1002/ejhf.2563
5. Butler J, Filippatos G, Siddiqi TJ, et al. Effects of empagliflozin in women and men with heart failure and preserved ejection fraction. Circulation. 2022;146:1046–1055. https://doi.org/10.1161/CIRCULATIONAHA.122.059755
6. Savji N, Meijers WC, Bartz TM, et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. J Am Coll Cardiol HF. 2018;6:701–709. https://doi.org/10.1016/j.jchf.2018.05.018
7. Borlaug BA, Kitzman DW, Davies MJ, et al. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. 2023;29:2358–2365. https://doi.org/10.1038/s41591-023-02526-x
8. Verma S, Borlaug BA, Butler J, et al. A big STEP for treatment of heart failure with preserved ejection fraction. Cell Metab. 2023;35:1681–1687. https://doi.org/10.1016/j.cmet.2023.08.003
9. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024;390:1394–1407. https://doi.org/10.1056/NEJMoa2313917
10. 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 STEPHFpEF DM randomised trials. Lancet. 2024;403:1635–1648. https://doi.org/10.1016/S0140-6736(24)00469-0 
11. 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. https://doi.org/10.1056/NEJMoa2306963
12. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002. https://doi.org/10.1056/NEJMoa2032183
13. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397:971–984. https://doi.org/10.1016/s0140-6736(21)00213-0