Effects of semaglutide on cardiac structure and function in obesity-related HFpEF

In an echocardiographic substudy of the STEP-HFpEF Program among patients with obesity-related HFpEF, semaglutide for 52 weeks appeared to attenuate the progression of adverse cardiac remodeling compared with placebo.

This summary is based on the publication of Solomon SD, Ostrominski JW, Wang X, et al. - Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure. J Am Coll Cardiol. 2024 Oct 22;84(17):1587-1602. doi: 10.1016/j.jacc.2024.08.021

Introduction and methods

Background

Obesity is thought to be a major driver of both adverse cardiac remodeling and the development and progression of HFpEF [1-6]. In the STEP-HFpEF Program, treatment with semaglutide reduced HF-related symptoms, physical limitations, and body weight and improved exercise function in patients with obesity-related HFpEF [ 7]. However, the effects of semaglutide on cardiac structure and function in this population still need to be elucidated.

Aim of the study

In an echocardiographic substudy of the STEP-HFpEF Program, the authors characterized the cardiac structural and functional profiles of patients with obesity-related HFpEF and evaluated the effects of semaglutide on cardiac remodeling.

Methods

The STEP-HFpEF Program was a pooled analysis of 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 (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes; n=616) trials. In these international, multicenter, double-blind, placebo-controlled, phase 3 RCTs, patients with LVEF ≥45%, NYHA class II–IV HF symptoms, KCCQ – Clinical Summary Score <90 points, and BMI ≥30 kg/m² were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks. In the STEP-HFpEF trial, patients with HbA1c ≥6.5% were excluded, whereas inclusion criteria for the STEP-HFpEF DM trial were a T2D diagnosis ≥90 days before screening and HbA1c ≤10%. Median follow-up duration was 401 days (IQR: 400–404).

Resting transthoracic echocardiography was performed at randomization and 52 weeks in 491 of the 1145 study participants (43%), of whom 253 were assigned to semaglutide and 238 to placebo.

Outcomes

The prespecified primary endpoint of this echocardiographic substudy was the change in left atrial (LA) volume from baseline to 52 weeks. Prespecified secondary endpoints were changes in other echocardiographic parameters, such as the E-wave velocity and ratio of early mitral inflow velocity to early diastolic mitral annular velocity (E/e′).

Main results

Cardiac structure and function at baseline

• At baseline, mean ± SD LV mass was increased (207.8 ± 69.2 g), whereas the mean LV global longitudinal strain (GLS) was reduced (−14.4% ± 3.7%).
• Of the 491 participants, 140 (28.5%) had evidence of LV hypertrophy.
• The mean LV end-systolic volume was 31.4 ± 15.9 mL, the mean LV end-diastolic volume was 74.3 ± 28.4 mL, and the mean LVEF was 58.9% ± 7.7%.
• The mean LA volume was also elevated (69.7 ± 26.5 mL), as was the mean E/e′ ratio (lateral E/e′ ratio: 10.9 ± 5.2; septal E/e′ ratio: 13.8 ± 6.1).

Treatment effects of semaglutide on echocardiographic parameters

• The change in LA volume from baseline to 52 weeks was smaller in patients treated with semaglutide than those receiving placebo (6.89 vs. 13.02 mL; estimated mean difference (EMD): –6.13 mL; 95%CI: –9.85 to –2.41; P=0.0013).
• Subgroup analysis showed generally consistent results for the primary endpoint across subgroups stratified by baseline variables, such as age, sex, BMI, and the presence of T2D or AF (all P for interaction>0.05).
• Treatment with semaglutide versus placebo reduced the changes in early/late mitral inflow velocity ratio (EMD: –0.14; 95%CI: –0.24 to –0.04; P=0.0075), E-wave velocity (EMD: –5.63 cm/s; 95%CI: –9.42 to –1.84; P=0.0037), and E/e’ ratio (EMD: –0.79; 95%CI: –1.60 to 0.01; P=0.05).
• In addition, semaglutide decreased the changes in RV end-systolic area (EMD: –1.41 cm²; 95%CI: –2.42 to –0.40; P=0.0064) and RV end-diastolic area (EMD: –1.99 cm²; 95%CI: –3.60 to –0.38; P=0.016) compared with placebo.
• However, semaglutide did not change LV mass, LV GLS, LV volumes, LVEF, or LA strain between baseline and 52 weeks compared with placebo.

Associations between changes in body weight and echocardiographic parameters

• Greater weight loss with semaglutide versus placebo was associated with greater LA volume reduction (P for interaction=0.033) but not with changes in peak E-wave velocity, E/e’ ratio, or RV end-diastolic area (all P for interaction>0.05).

Conclusion

In this echocardiographic substudy of the STEP-HFpEF Program among patients with obesity-related HFpEF, the prevalences of abnormal cardiac structure and function, including LA dilatation, LV hypertrophy, impaired LV mechanics and diastolic function, and RV dysfunction, were high. Treatment with semaglutide 2.4 mg for 52 weeks appeared to attenuate the progression of adverse cardiac remodeling compared with placebo. The authors note their findings were exploratory, as the 2 STEP-HFpEF trials were not specifically designed to evaluate the treatment effects of semaglutide versus placebo on cardiac structure and function.

Find this article online at J Am Coll Cardiol.

References

1. Savji N, Meijers WC, Bartz TM, et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail. 2018;6(8):701–709.
2. Lai Y-H, Liu M-E, Su C-H, et al. Obesity-related changes in cardiac structure and function among Asian Men and Women. J Am Coll Cardiol. 2017;69(23):2876–2878.
3. Litwin SE, Adams TD, Davidson LE, et al. Longitudinal changes in cardiac structure and function in severe obesity: 11-year follow-up in the Utah Obesity Study. J Am Heart Assoc. 2020;9(12):e014542.
4. Borlaug BA, Jensen MD, Kitzman DW, et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2023;118(18):3434–3450.
5. Bello NA, Cheng S, Claggett B, et al. Association of weight and body composition on cardiac structure and function in the ARIC Study (Atherosclerosis Risk in Communities). Circ Heart Fail. 2016;9(8):e002978.
6. Wong CY, O’Moore-Sullivan T, Leano R, et al. Association of subclinical right ventricular dysfunction with obesity. J Am Coll Cardiol. 2006;47(3):611–616.
7. Butler J, Shah SJ, Petrie MC, et al, STEP-HFpEF Trial Committees and Investigators. 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. Lancet. 2024;403(10437):1635–1648.