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. 2024 Jan 16;149(3):204-216.
doi: 10.1161/CIRCULATIONAHA.123.067505. Epub 2023 Nov 12.

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial

Mikhail N Kosiborod  1 , Subodh Verma  2 , Barry A Borlaug  3 , Javed Butler  4   5 , Melanie J Davies  6 , Thomas Jon Jensen  7 , Søren Rasmussen  7 , Peter Erlang Marstrand  7 , Mark C Petrie  8 , Sanjiv J Shah  9 , Hiroshi Ito  10 , Morten Schou  11 , Vojtěch Melenovský  12 , Walter Abhayaratna  13 , Dalane W Kitzman  14 ; STEP-HFpEF Trial Committees and Investigators
Affiliations

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial

Mikhail N Kosiborod et al. Circulation. .

Abstract

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains.

Methods: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated.

Results: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all).

Conclusions: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Keywords: health status; heart failure, diastolic; obesity; quality of life; semaglutide; weight loss.

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Conflict of interest statement

Disclosures Dr Kosiborod 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; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He has also received other research support from AstraZeneca. 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 Borlaug receives 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 (US patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. 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, Impulse Dynamics, Imbria, Innolife, Inventiva, Janssen, Lexicon, Lilly, LivaNova, Medtronics, Merck, Novartis, Novo Nordisk, Occlutech, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Davies has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; an advisory board member and speaker for AstraZeneca; an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; and a speaker for Amgen, Novartis, and Sanofi. She has received grants in support of investigator and investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr Petrie has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and consultancy and committees 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 reports receiving 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. Drs Jensen, Rasmussen, and Marstrand are employees of and hold shares in Novo Nordisk. Dr Ito reports honoraria and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Schou reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Melenovský reports consulting fees from Bayer, MSD, and Novo Nordisk; research grants from Regeneron; and research support from the National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104), funded by the European Union – Next Generation EU. Dr Abhayaratna reports honoraria and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Kitzman reports receiving honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences.

Figures

Figure 1.
Figure 1.
Effects of semaglutide compared with placebo across KCCQ tertiles on heart failure symptoms and physical limitations (KCCQ-CSS; A); body weight (B); exercise function (6MWD; C); hierarchical composite end point (D); systemic inflammation (CRP; E); and NT-proBNP (F). Data are from the in-trial period for the full analysis set. Week 52 responses were analyzed using an ANCOVA model with randomized treatment, subgroup, and treatment by subgroup interaction as factors and baseline KCCQ-CSS as covariate. Missing observations for reasons other than cardiovascular death or previous heart failure events (if nonretrieved) were multiple (×1000) imputed from retrieved participants of the same randomized treatment arm. Missing observations due to cardiovascular death or previous heart failure events were imputed using a composite strategy with the least favorable value determined during the trial. P values for linear trend across the KCCQ tertiles were: 0.113 (KCCQ-CSS); 0.617 (body weight); 0.330 (6MWD); 0.478 (CRP), and 0.965 (NT-proBNP). 6MWD indicates 6-minute walk distance; CRP, C-reactive protein; CSS, Clinical Summary Score; ETD, estimated treatment difference; KCCQ, Kansas City Cardiomyopathy Questionnaire; and NT-proBNP, N-terminal pro-brain natriuretic peptide.
Figure 2.
Figure 2.
Change from baseline over time in KCCQ-CSS (A); KCCQ-OSS (B); and KCCQ-TSS (C). Observed data from the in-trial period. Error bars are ±SEM. *Estimated means are from the ANCOVA analysis. Numbers shown in the lower panel are subjects contributing to the mean. CSS indicates Clinical Summary Score; ETD, estimated treatment difference; KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; Sema, semaglutide; and TSS, Total Symptom Score.
Figure 3.
Figure 3.
Change from baseline over time in KCCQ-SBS (A); KCCQ-SFS (B); KCCQ-PLS (C); KCCQ-QoLS (D); and KCCQ-SLS (E). Observed data from the in-trial period. Error bars are ±SEM. *Estimated means are from the ANCOVA analysis. Numbers shown in the lower panel are subjects contributing to the mean. ETD indicates estimated treatment difference; KCCQ, Kansas City Cardiomyopathy Questionnaire; PLS, Physical Limitations Score; QoLS, Quality of Life Score; SBS, Symptom Burden Score; Sema, semaglutide; SFS, Symptom Frequency Score; and SLS, Social Limitations Score.
Figure 4.
Figure 4.
Responder analysis for KCCQ-CSS (A); KCCQ-OSS (B); and KCCQ-TSS (C). Analysis of data from the in-trial period. responses were analyzed using a binary logistic regression model with randomized treatment and BMI group as factors and baseline KCCQ-CSS as covariate. Missing observations for reasons other than cardiovascular death or previous heart failure events (if nonretrieved) were multiple (×1000) imputed from retrieved participants of the same randomized treatment arm. Missing observations due to cardiovascular death or previous heart failure events were imputed using a composite strategy with the least favorable value determined during the trial. BMI indicates body mass index; CSS, Clinical Summary Score; KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; and TSS, Total Symptom Score.
Figure 5.
Figure 5.
KCCQ-CSS change from baseline to week 52 (cumulative response curves). Observed data from the in-trial period for the full analysis set. The graph shows cumulative frequency distributions of change from baseline in KCCQ-CSS. To interpret this graph, select a change in KCCQ-CSS on the x axis and find the corresponding proportion of semaglutide 2.4 mg and placebo participants who achieved that degree of improvement or worsening on the y axis. For example, note that the vertical line arising from 20-point improvement intersects with semaglutide and placebo curves at 62.1% and 73.4%, respectively. Therefore, 37.9% and 26.6% in the semaglutide and placebo groups achieved a ≥20-point improvement, respectively. KCCQ-CSS indicates Kansas City Cardiomyopathy Questionnaire Clinical Summary Score.
Figure 6.
Figure 6.
Association of change from baseline to week 52 in KCCQ domains OSS (A); TSS (B); PLS (C); QoLS (D); SLS (E) and change in body weight. Analysis of data from the in-trial period. Participants with change from baseline in body weight at week 52 in the respective end point are included. The change from baseline to week 52 of each end point was analyzed using a linear regression model with treatment, subgroup, and treatment by subgroup interaction as factors and the baseline body weight and baseline value of the respective end point as covariates. P values are linear contrast test within treatment group. Results are shown for the semaglutide group only. KCCQ indicates Kansas City Cardiomyopathy Questionnaire; OSS, Overall Summary Score; PLS, Physical Limitations Score; QoLS, Quality of Life Score; SLS, Social Limitations Score; and TSS, Total Symptom Score.
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