Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. OBJECTIVES: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. METHODS: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. RESULTS: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. CONCLUSIONS: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Multi-Ethnic Study of Atherosclerosis Early Heart Failure Study: Rationale, Design, and Baseline Characteristics.

BACKGROUND: Current prevalence estimates of heart failure (HF) are primarily based on self-report or HF hospitalizations. There is an unmet need to define the prevalence and pathogenesis of early symptomatic HF, which may be undiagnosed and precedes HF hospitalization. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) Early HF study was conducted during MESA exam 6 to determine the prevalence of early HF and investigate the transition from risk factors to early HF in a diverse population-based cohort of older adults. Between 2016 and 2018, 3285 MESA participants from 6 field centers underwent comprehensive speckle-tracking echocardiography with passive leg raise maneuver, Kansas City Cardiomyopathy Questionnaire, 6-minute walk test, arterial stiffness assessment, and proteomics (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). RESULTS: Median age was 73 (25th-75th percentile 67-81) years, 53.2% were female, 25.6% were Black, 12.8% were Chinese, and 40.0% were White. The prevalence of HF risk factors was high: hypertension, 61.9%; former or current smoking, 53.7%; obesity 34.8%; diabetes; 24.7%; and chronic kidney disease; 22%. Overt cardiovascular disease, which ranged from 2.1% (HF) to 13.6% (atrial fibrillation), was less common. Of the 3285 participants, 96% underwent proteomics, 94% Kansas City Cardiomyopathy Questionnaire, 93% speckle-tracking echocardiography with passive leg raise, 82% arterial stiffness exam, and 77% 6-minute walk test. Feasibility of resting speckle-tracking echocardiography (87%-99% across cardiac chambers) and passive leg raise Doppler/speckle-tracking echocardiography (>84%) measurements was high. A total of 120 unique echocardiographic indices were measured. CONCLUSIONS: The MESA Early HF study is a key resource for cardiovascular researchers who are interested in improving the epidemiological and phenotypic characterization of early HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005487.

Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of worsening heart failure (HF) and cardiovascular death in patients with HF irrespective of left ventricular ejection fraction. It is important to determine whether therapies for HF improve symptoms and functional capacity. METHODS: The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) double-blind, placebo-controlled, multicenter trials assessed the efficacy of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) in 313 patients with HF with reduced ejection fraction (DETERMINE-Reduced) and in 504 patients with HF with preserved ejection fraction (DETERMINE-Preserved) with New York Heart Association class II or III symptoms and elevated natriuretic peptide levels. The primary outcomes were changes in the KCCQ-TSS, KCCQ-PLS, and 6MWD after 16 weeks of treatment. RESULTS: Among the 313 randomized patients with HF with reduced ejection fraction, the median placebo-corrected difference in KCCQ-TSS from baseline at 16 weeks was 4.2 (95% CI, 1.0, 8.2; P=0.022) in favor of dapagliflozin. The median placebo-corrected difference in KCCQ-PLS was 4.2 (95% CI, 0.0, 8.3; P=0.058). The median placebo-corrected difference in 6MWD from baseline at 16 weeks was 3.2 meters (95% CI, -6.5, 13.0; P=0.69). In the 504 patients with HF with preserved ejection fraction, the median placebo-corrected 16-week difference in KCCQ-TSS and KCCQ-PLS was 3.2 (95% CI, 0.4, 6.0; P=0.079) and 3.1 (-0.1, 5.4; P=0.23), respectively. The median 16-week difference in 6MWD was 1.6 meters (95% CI, -5.9, 9.0; P=0.67). In an exploratory post hoc analysis of both trials combined (DETERMINE-Pooled), the median placebo-corrected difference from baseline at 16 weeks was 3.7 (1.5, 5.9; P=0.005) for KCCQ-TSS, 4.0 (0.3, 4.9; P=0.036) for KCCQ-PLS, and 2.5 meters (-3.5, 8.4; P=0.50) for 6MWD. CONCLUSIONS: Dapagliflozin improved the KCCQ-TSS in patients with HF with reduced ejection fraction but did not improve KCCQ-PLS or 6MWD. Dapagliflozin did not improve these outcomes in patients with HF with preserved ejection fraction. In a post hoc analysis including all patients across the full spectrum of ejection fraction, there was a beneficial effect of dapagliflozin on KCCQ-TSS and KCCQ-PLS but not 6MWD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.

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.

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.

Frailty Status Modifies the Efficacy of ICD Therapy for Primary Prevention Among Patients With HF.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy is recommended to reduce mortality risk in patients with heart failure with reduced ejection fraction (HFrEF). Frailty is common among patients with HFrEF and is associated with increased mortality risk. Whether the therapeutic efficacy of ICD is consistent among frail and nonfrail patients with HFrEF remains unclear. OBJECTIVES: The aim of this study was to evaluate the effect modification of baseline frailty burden on ICD efficacy for primary prevention among participants of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). METHODS: Participants in SCD-HeFT with HFrEF randomized to ICD vs placebo were included. Baseline frailty was estimated using the Rockwood Frailty Index (FI), and participants were stratified into high (FI > median) vs low (FI ≤ median) frailty burden groups. Multivariable Cox models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether baseline frailty status modified the treatment effect of ICD for all-cause mortality. RESULTS: The study included 1,676 participants (mean age: 59 ± 12 years, 23% women) with a median FI of 0.30 (IQR: 0.23-0.37) in the low frailty group and 0.54 (IQR: 0.47-0.60) in the high frailty group. In adjusted Cox models, baseline frailty status significantly modified the treatment effect of ICD therapy (Pinteraction = 0.047). In separate stratified analysis by frailty status, ICD therapy was associated with a lower risk of all-cause mortality among participants with low frailty burden (HR: 0.56; 95% CI: 0.40-0.78) but not among those with high frailty burden (HR: 0.86; 95% CI: 0.68-1.09). CONCLUSIONS: Baseline frailty modified the efficacy of ICD therapy with a significant mortality benefit observed among participants with HFrEF and a low frailty burden but not among those with a high frailty burden.

Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial.

AIMS: Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. METHODS AND RESULTS: The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. CONCLUSIONS: Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.

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

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).

Effect of Dapagliflozin on 6-Minute Walk Distance in Heart Failure With Preserved Ejection Fraction: PRESERVED-HF.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00-2.75]; P=0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33-0.94]; P=0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03030235.

Relationship of Race With Functional and Clinical Outcomes With the REHAB-HF Multidomain Physical Rehabilitation Intervention for Older Patients With Acute Heart Failure.

Background The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) randomized trial demonstrated that a 3-month transitional, tailored, progressive, multidomain physical rehabilitation intervention improves physical function, frailty, depression, and health-related quality of life among older adults with acute decompensated heart failure. Whether there is differential intervention efficacy by race is unknown. Methods and Results In this prespecified analysis, differential intervention effects by race were explored at 3 months for physical function (Short Physical Performance Battery [primary outcome], 6-Minute Walk Distance), cognition, depression, frailty, health-related quality of life (Kansas City Cardiomyopathy Questionnaire, EuroQoL 5-Dimension-5-Level Questionnaire) and at 6 months for hospitalizations and death. Significance level for interactions was P≤0.1. Participants (N=337, 97% of trial population) self-identified in near equal proportions as either Black (48%) or White (52%). The Short Physical Performance Battery intervention effect size was large, with values of 1.3 (95% CI, 0.4-2.1; P=0.003]) and 1.6 (95% CI, 0.8-2.4; P<0.001) in Black and White participants, respectively, and without significant interaction by race (P=0.56). Beneficial effects were also demonstrated in 6-Minute Walk Distance, gait speed, and health-related quality of life scores without significant interactions by race. There was an association between intervention and reduced all-cause rehospitalizations in White participants (rate ratio, 0.73 [95% CI, 0.55-0.98]; P=0.034) that appears attenuated in Black participants (rate ratio, 1.06 [95% CI, 0.81-1.41]; P=0.66; interaction P=0.067). Conclusions The intervention produced similarly large improvements in physical function and health-related quality of life in both older Black and White patients with acute decompensated heart failure. A future study powered to determine how the intervention impacts clinical events is required. REGISTRATION URL: https://www.clinicaltrials.gov. Identifier: NCT02196038.

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.

BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).