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

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; P_interaction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (P_interaction>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.

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.

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.

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.

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.

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.

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.