• Post category:Journal Club

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the STEP-HFpEF Trial

Table of contents for the The STEP-HFpEF Trial summary:

November 28th 2023

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity1

M.N. Kosiborod, S..Z. AbildstrØm, B.A. Borlaug, J. Butler, S. Rasmussen, M. Davies, G.K Hovingh, D.W. Kiltman, M.L. Lindegaard, D.V. Moller, S.J Shah, M.B. Treppendahl, S. Verma, W. Abhayaratna, F.Z. Ahmed, V. Chopra, J. Ezekowitz, M. Fu, H. Ito, M. Lelonek, V. Melenovksy, B. Merkely, J. Nunez, E. Perna, M. Schou, M. Senni, K. Sharma, P. Van der Meer, D. von Lewinski, D. Wolf, and M.C Petrie, for the STEP-HFpEF Trial Committees and Investigators*

Relevant literature

  1. The STEP-HFpEF group has previously published the study design and baseline patient characteristics  of this RCT2
    1. Relevant RCT’s below:

Relevant Guidelines

2022 AHA/ACC/HFSA Guidelines of the Management of Heart Failure: A Report of the ACC/AHA Joint Committee on Clinical Practice Guidelines.8

2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure9

Study Rationale

The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing in the U.S., accounting for over half of all cases of heart failure.10,11 Many patients with HFpEF have the obesity phenotype.12,13 Growing evidence suggests that obesity and excess visceral adiposity are more than coexisting conditions in HFpEF, playing a significant role in the development and disease progression of HFpEF.13 HFpEF with obesity phenotype is characterized by greater symptom severity, worse functional capacity, more adverse hemodynamics, and greater risk of heart failure hospitalization than those with HFpEF without obesity.14,15 There are limited medications available to help patients with HFpEF, particularly the obesity phenotype. This study investigated whether the use of pharmacotherapies specifically targeting obesity7 can help reduce symptoms and physical limitations in this HFpEF phenotype.

Study Objectives

The study aims to assess efficacy of treatment with Semaglutide (a GLP1-receptor agonists) on symptoms, physical limitations, exercise function, and weight loss in patients with HFpEF and obese phenotype.   

  • TrialThe STEP-HFpEF Trial
    • Conducted at 96 sites in 13 countries in Asia, Europe, North America, and South America
    • Randomized 529 patients between March 2021 and March 2022.
  • Intervention
  1. Randomly assigned 1:1 to subcutaneous Semaglutide 2.4 mg once-weekly for 52 weeks or placebo
    1. Semaglutide treatment was initiated at a dose of 0.25mg once-weekly for the first 4 weeks. The dose was then escalated every 4 weeks with the aim of reaching the maintenance dose (2.4 mg) by week 16.
  2. Randomization was stratified according to baseline body mass index (BMI) <35kg/m2 vs. ≥35kg/m2

Enrollment Criteria

Primary Outcome

  • Primary Outcomes: Dual primary endpoints including change in KCCQ-CSS questionnaire score and percentage change in body weight from baseline at 52 weeks.
    • KCCQ-CSS questionnaire: 23-item instrument that quantifies heart failure-related symptoms (frequency, severity, and recent changes), physical function, quality of life, and social function. Scores are ranked from a range of 0 to 100, with higher scores reflecting better health status.

Secondary Outcome:

  • Secondary Outcomes: Changes in waist circumference, body fat, body lean mass, and metabolic risk factors including levels of plasma glucose, insulin sensitivity, serum lipids, and blood pressure

Statistical Analysis

  1. Full details previously published2 and can also be found in the STEP group statistical analysis plan at
    1. Statistical analysis approach sought strong control for type I error
    1. All endpoints addressing intervention efficacy were analyzed using intention-to-treat approach
    1. All endpoints addressing intervention safety were analyzed using per-protocol approach
    1. Efficacy endpoints analyzed using 2 estimands
      1. Treatment Policy Estimand: intention to treat analysis; these results are presented in the primary text and tables/figures
      1. Trial Product Estimand: per-protocol analysis; these results presented in supplementary table 4
    1. Sample size: Using certain assumptions and previously validated methods, it was determined that­ a sample size of 516 would provide 90% power to detect a 4.1 mean difference in change in KCCQ-CSS and 99% power to detect a 9.9% mean difference in change in body weight
      1. Alpha of 0.05 was split between the two primary endpoints, 0.04 for KCCQ-CSS and 0.01 for body weight
    1. Primary analysis model for the dual primary endpoints is a linear regression analysis of covariance
      1. Missing data points filled using an established and previously described2 imputation modelthat uses baseline characteristics, prior endpoint data, and group data to produce an unfavorable value
    1. Statistical testing hierarchy
      1. Used treatment policy estimand results
    1. Confirmatory secondary endpoints were meant to represent the overall clinical benefit/harm of the intervention. Thus, a composite endpoint analyzed via hierarchical testing was utilized
      1. For excellent overviews of the basics of composite endpoints and hierarchical testing, check out these Tweetorials by Akiva Rosenzveig

Baseline Characteristics

  • Baseline demographics and clinical characterizations were similar in both treatment groups. About 56.1% were women and 95.8% where white.
  • 14.6% of the participants qualified for participation based on elevated filling pressures, 13.4% based on hospitalization for heart failure within 12 months in combination with ongoing diuretic treatment or echocardiographic abnormalities (or both), and 72.0% based on NT-proBNP levels plus echocardiographic abnormalities
  • Median body weight and BMI of participants were 105.1 kg and 37.0kg/m2, respectively
  • At baseline, patients had substantial degree of heart failure related symptoms, physical limitations, and poor exercise tolerance


Primary Outcome

Co-primary endpoints for Semaglutide vs placebo from baseline to week 52:

Change in KCCQ-CSS 16.6 points vs 8.7 points (estimated difference, 7.8 points; 95% CI 4.8 to 10.9, p<0.001)

Mean percentage change in body weight: -13.3% vs -2.6% (p<0.001)

Secondary Outcomes

Change in 6-minute walk distance from baseline to week 52: 21.5 m vs 1.2 m (95% CI 8.6 to 32.1; p<0.001)

Semaglutide favored over placebo on all components of the hierarchical composite end point (death, heart failure events, change in KCCQ-CSS, and 6MWD), with a difference of at least 15 points in the change in KCCQ-CSS contributing the most to Semaglutide’s benefit. Overall win ratio of 1.72 (95% CI, 1.37 to 2.15; p<0.001)

43.5% Reduction of CRP level with Semaglutide vs 7.3% reduction with placebo at 52 weeks

Semaglutide achieved greater percentage reduction in NT-proBNP from baseline to week 52 (-20.9%) vs.  placebo (-5.3%; 95% CI 0.71 to 0.98)

Adverse Events

  • Serious adverse events were reported in 13.3% of Semaglutide and 26.7% in the placebo group. Overall, the discontinuation rate for serious adverse events between Semaglutide and placebo was similar.
  • The trial was designed to estimate the treatment effects of once-weekly subcutaneous Semaglutide among obese patient with HFpEF.
    1. This study ultimately found that once-weekly subcutanoues Semaglutide was superior to placebo in improving body weight (~11% greater weight loss) and patient-oriented quality of life (QoL) outcomes including KCCQ-CSS and 6MWD at 52 weeks in HFpEF patients with obesity phenotype.
  • Adverse events were reported in 13.3% patients in the Semaglutide group vs 26.7% in the placebo group.

Limitations and Considerations

  1. The number of non-white participants was low, which may limit the generalizability of results.
  2. The trial was not adequately powered to evaluate clinical events such as hospitalization for heart failure or urgent visits, however a nonsignificant reduction in HF hospitalizations was noted in the Semaglutide group vs. placebo.
  3. The percentage of patients treated with SGLT2 inhibitors was low. A separate trial is investigating once-weekly Semaglutide 2.4 mg compared with placebo in obese patients with HFpEF and type 2 diabetes is ongoing. It will be important to determine the roles of GLP-1 agonisms as compared to SGLT2i in this patient population.
  4. The study was only studied over one year time frame. Semaglutide requires continued use of medication to maintain weight loss, with prior trials demonstrating discontinuation of medication associated with weight gain within 6 months to 1 year16. It will be important to continue monitoring side effect tolerability of the medication in the long term.
  5. It is unclear whether the symptomatic improvements favoring Semaglutide over placebo were driven by the weight loss alone or an additional intrinsic benefit of the medication. Future studies investigating the effect of GLP-1 agonism on more heart failure endpoints will be needed.

1. 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. N Engl J Med. 2023;389(12):1069-1084. doi:10.1056/nejmoa2306963

2. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Christensen L, Davies M, et al. Design and Baseline Characteristics of STEP-HFpEF Program Evaluating Semaglutide in Patients With Obesity HFpEF Phenotype. JACC: Hear Fail. 2023;11(8):1000-1010. doi:10.1016/j.jchf.2023.05.010

3. Sorli C, Harashima S ichi, Tsoukas GM, Unger J, Karsbøl JD, Hansen T, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251-260. doi:10.1016/s2213-8587(17)30013-x

4. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/nejmoa1411892

5. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314(7):687-699. doi:10.1001/jama.2015.9676

6. O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637-649. doi:10.1016/s0140-6736(18)31773-2

7. Wilding JPH, Batterham RL, Calanna S, Davies M, Gaal LFV, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183

8. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/cir.0000000000001063

9. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Hear J. 2023;44(37):3627-3639. doi:10.1093/eurheartj/ehad195

10. Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction. JAMA. 2023;329(10):827-838. doi:10.1001/jama.2023.2020

11. Roger VL. Epidemiology of Heart Failure. Circ Res. 2021;128(10):1421-1434. doi:10.1161/circresaha.121.318172

12. Kitzman DW, Nicklas BJ. Pivotal Role of Excess Intra-Abdominal Adipose in the Pathogenesis of Metabolic/Obese HFpEF ∗. JACC: Hear Fail. 2018;6(12):1008-1010. doi:10.1016/j.jchf.2018.08.007

13. 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. 2022;118(18):3434-3450. doi:10.1093/cvr/cvac120

14. 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(1):6-19. doi:10.1161/circulationaha.116.026807

15. Reddy YNV, Lewis GD, Shah SJ, Obokata M, Abou-Ezzedine OF, Fudim M, et al. Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study. Mayo Clin Proc. 2019;94(7):1199-1209. doi:10.1016/j.mayocp.2018.11.037 16. Wilding JPH, Batterham RL, Davies M, Gaal LFV, Kandler K, Konakli K, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes, Obes Metab. 2022;24(8):1553-1564. doi:10.1111/dom.14725

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