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. 2023 Nov 28;82(22):2087-2096.
doi: 10.1016/j.jacc.2023.09.811. Epub 2023 Oct 8.

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction

Javed Butler  1 , Steen Z Abildstrøm  2 , Barry A Borlaug  3 , Melanie J Davies  4 , Dalane W Kitzman  5 , Mark C Petrie  6 , Sanjiv J Shah  7 , Subodh Verma  8 , Walter P Abhayaratna  9 , Vijay Chopra  10 , Justin A Ezekowitz  11 , Michael Fu  12 , Hiroshi Ito  13 , Małgorzata Lelonek  14 , Julio Núñez  15 , Eduardo Perna  16 , Morten Schou  17 , Michele Senni  18 , Peter van der Meer  19 , Dirk von Lewinski  20 , Dennis Wolf  21 , Rebecca L Altschul  2 , Søren Rasmussen  2 , Mikhail N Kosiborod  22
Affiliations

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction

Javed Butler et al. J Am Coll Cardiol. .

Abstract

Background: Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF).

Objectives: In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial.

Methods: STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n = 85), 50% to 59% (n = 215), and ≥60% (n = 229).

Results: At 52 weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95% CI: -2.7 to 12.8 points], EF 50%-59%: 9.8 points [95% CI: 5.0 to 14.6 points], and EF ≥60%: 7.4 points [95% CI: 2.8 to 12.0 points]; P interaction = 0.56) and body weight (EF: 45%-49%: -7.6 [95% CI: -10.7 to -4.4], EF 50%-59%: -10.6 [95% CI: -12.6 to -8.6] and EF ≥60%: -11.9 [95% CI: -13.8 to -9.9]; P interaction = 0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction = 0.19), hierarchal composite endpoint (P interaction = 0.43), and high-sensitivity C-reactive protein (P interaction = 0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (P interaction = 0.96). Semaglutide was well-tolerated across LVEF categories.

Conclusions: In patients with HFpEF and obesity, semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511).

Keywords: GLP-1 receptor agonists; HFpEF; functional status; obesity; semaglutide; symptoms.

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Conflict of interest statement

Funding Support and Author Disclosures The STEP-HFpEF trial was funded by Novo Nordisk A/S. Dr Butler is a consultant to 3live, Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Borlaug has received research support from the National Institutes of Health and the U.S. Department of Defense; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is a named inventor (U.S. Patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has received consultancy and committee payments for AbbVie, Akero, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiorentis, Horizon Therapeutics, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, Takeda, Teikoku, and Vifor. Dr Shah has received consulting fees from Abbott, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, Metabolic Flux, MyoKardia, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Verma has received research grants or consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Napp Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; has served on committees for AbbVie, Akero, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, New Amsterdam, Novo Nordisk, Resverlogix, and Teikoku; and is Director of Global Clinical Trial Partners (GCTP). Dr Abhayaratna has received honoraria and/or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Chopra has received speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy’s, Lupin, Mankind, Novartis, Novo Nordisk, Pfizer, Sanofi, Sun Pharma, and Torrent. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and serves as an advisor to US2.ai. Dr Ito has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Lelonek has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. Dr Núñez has received honoraria and/or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Novartis, Novo Nordisk, Pfizer, Rovi, and Vifor. Dr Perna has received honoraria from Novo Nordisk. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Senni has received honoraria and/or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, and Vifor. Dr van der Meer has received institutional payments for consultancy fees and/or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. Dr von Lewinski has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. Dr Wolf is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (German Research Foundation); and has received consultancy fees from Novo Nordisk and Novartis. Drs Abildstrøm, Altschul, and Rasmussen are employees of and hold shares in Novo Nordisk. Dr Kosiborod has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

CENTRAL ILLUSTRATION
CENTRAL ILLUSTRATION. Treatment Effects (Semaglutide vs Placebo) on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score Change Across Left Ventricular Ejection Fraction
P values are for the test for interaction between treatment and LVEF subgroups except for *the treatment difference for semaglutide vs placebo. KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LVEF = left ventricular ejection fraction.
FIGURE 1
FIGURE 1. Treatment Effects (Semaglutide vs Placebo) on Selected Outcomes Across LVEF
P values are for the test for interaction between treatment and left ventricular ejection fraction (LVEF) subgroups except for *the treatment difference between semaglutide vs placebo. 6MWD = 6-minute walk distance; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro-brain natriuretic peptide.
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