April 1, 2025

Managing Obesity-related Heart Failure and Diabetes with Semaglutide

With the rising prevalence of obesity, heart failure with preserved ejection fraction (HFpEF) has emerged as a common type of heart failure.1 Approximately 45% of HFpEF patients also have type 2 diabetes mellitus (T2DM).2 Patients with both conditions experience greater symptom burden, worse functional capacity and a 70% higher risk of hospitalisation and death than those without T2DM.3,4

As there are currently no specific therapeutic options for managing obesity-related HFpEF and T2DM, this has led to interest in exploring potential treatments that may address both conditions. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist has shown to effectively improve glycaemic control in patients with T2DM and improve weight loss among overweight or obese adults. On top of that, its favourable effects on cardiometabolic risk factors have led to semaglutide being explored as a therapeutic option in the HFpEF landscape.5,6

The Semaglutide Treatment Effect in People with Obesity and Heart Failure with Preserved Ejection Fraction and Diabetes Mellitus (STEP-HFpEF DM) trial aims to assess its potential benefits in this patient population.3 The STEP-HFpEF DM trial included 616 participants with obesity-related HFpEF and type 2 diabetes, of which 310 received semaglutide, while 306 received placebo. Participants who received a weekly dose of semaglutide (2.4 mg) over 52 weeks showed substantial improvement compared to those on placebo therapy.3

The dual primary end points reported were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), with higher scores indicating fewer symptoms and physical limitations, and the percentage change in body weight from baseline to week 52.3

  • Based on the KCCQ-CSS, participants in the semaglutide group reported a mean change of 13.7 points from the baseline, compared to 6.4 points in the placebo group (estimated difference, 7.3 points; p < 0.001).3
  • The mean percentage change in body weight at week 52 was -9.8% in the semaglutide group and -3.4% in the placebo group (estimated difference, -6.4%; p < 0.001).3

The confirmatory secondary endpoints reported include the change in 6-minute walk distance, a hierarchal composite end point which included death, heart failure events, and differences in the change in KCCQ-CSS and 6 minute-walk distance, as well as change in the C-reactive protein (CRP) level from baseline to week 52.3

  • The mean change in the 6-minute walk distance in the semaglutide group was 12.7 m, while the placebo group reported -1.6 m (estimated difference, 14.3 m; p = 0.008).3
  • Analysis of the hierarchical composite end point (a direct comparison of each participant in semaglutide group with participant in placebo group) resulted in more wins for the semaglutide group, with a win ratio of 1.58 (p < 0.001).3
  • Participants in the semaglutide group reported a 42% reduction in CRP levels, compared with a 12.8% reduction with placebo at 52 weeks (estimated treatment ratio, 0.67; p < 0.001).3

In the STEP-HFpEF DM trial, once-weekly semaglutide (2.4mg) led to fewer heart failure–related symptoms, reduced physical limitations and greater weight loss than placebo at 1 year. These findings indicate that semaglutide may have potential benefits for individuals with both obesity-related HFpEF and T2DM, a population with heavy symptom burden and few therapeutic options. While the study results are promising, further research is required to assess the long-term clinical outcomes and its application in routine practice.

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References:

1.           Roger VL. Epidemiology of Heart Failure: A Contemporary Perspective. Circ Res. 2021;128(10):1421-34.

2.           Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, et al. Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: Findings from Get With The Guidelines–Heart Failure registry. American Heart Journal. 2016;182:9-20.

3.           Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, et al. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024;390(15):1394-407.

4.           Lindman BR, Dávila-Román VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014;64(6):541-9.

5.           Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. New England Journal of Medicine. 2023;389(12):1069-84.

6.           Kommu S, Berg RL. Efficacy and safety of once-weekly subcutaneous semaglutide on weight loss in patients with overweight or obesity without diabetes mellitus-A systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2024;25(9):e13792.

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