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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-min-ute 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 parti

Background: Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure–related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. Objectives: This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. Methods: This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure

Background: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. Objectives: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. Methods: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. Results: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, −6.13 mL; 95% CI: −9.85 to −2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm2; 95% CI: −3.60 to −0.38 cm2; P = 0.016; EMD in RV end-systolic area: −1.41 cm2; 95% CI: −2.42 to −0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: −5.63 cm/s; 95% CI: −9.42 to −1.84 cm/s; P = 0.0037), E/A (early/late mit

BACKGROUND: Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations. METHODS: In a voluntary substudy of the DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure), patients wore a waist-worn triaxial accelerometer for as long as possible (ideally for 24 h/d for 7 days) at 3 points during the trial, between the screening visit and randomization (baseline data), and during weeks 8 and 14 to 16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity, time spent in moderate-to-vigorous physical activity, movement intensity during walking, number of vector magnitude units‚ and total activity counts. RESULTS: Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as ≥10 hours of wear time for ≥3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference, 778 [95% CI, 240–1315]), time spent in moderate-to-vigorous physical activity (0.16 [95% CI, 0.03–0.29] hours), and in the mean vector magnitude units (25 [95% CI, 0.1–49] counts per minute). There were no between-group differences in the other accelerometer outcomes of interest. CONCLUSIONS: In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with heart failure across the entire left ventricular ejection fraction spectrum, yet did not improve 6-minute walk distance, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6-minute walk distan

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 treatme

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

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 ad

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. (Re

Lepidopterans affect crop production worldwide. The use of transgenes encoding insecticidal proteins from Bacillus thuringiensis (Bt) in crop plants is a well-established technology that enhances protection against lepidopteran larvae. Concern about widespread field-evolved resistance to Bt proteins has highlighted an urgent need for new insecticidal proteins with different modes or sites of action. We discovered a new family of insecticidal proteins from ferns. The prototype protein from Pteris species (Order Polypodiales) and variants from two other orders of ferns, Schizaeales and Ophioglossales, were effective against important lepidopteran pests of maize and soybean in diet-based assays. Transgenic maize and soybean plants producing these proteins were more resistant to insect damage than controls. We report here the crystal structure of a variant of the prototype protein to 1.98 Å resolution. Remarkably, despite being derived from plants, the structure resembles the 3-domain Cry proteins from Bt but has only two out of three of their characteristic domains, lacking the C-terminal domain which is typically required for their activities. Two of the fern proteins were effective against strains of fall armyworm that were resistant to Bt 3-domain Cry proteins Cry1Fa or Cry2A.127. This therefore represents a novel family of insecticidal proteins that have the potential to provide future tools for pest control.