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.

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. 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. 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. 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. Novo Nordisk.

Butler J ，Shah SJ ，Petrie MC ，Borlaug BA ，Abildstrøm SZ ，Davies MJ ，Hovingh GK ，Kitzman DW ，Møller DV ，Verma S ，Einfeldt MN ，Lindegaard ML ，Rasmussen S ，Abhayaratna W ，Ahmed FZ ，Ben-Gal T ，Chopra V ，Ezekowitz JA ，Fu M ，Ito H ，Lelonek M ，Melenovský V ，Merkely B ，Núñez J ，Perna E ，Schou M ，Senni M ，Sharma K ，van der Meer P ，Von Lewinski D ，Wolf D ，Kosiborod MN ，STEP-HFpEF Trial Committees and Investigators ... -  《-》

Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA(1c) levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial.

About half of patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) have type 2 diabetes. In the STEP-HFpEF DM trial of adults with obesity-related HFpEF and type 2 diabetes, subcutaneous once weekly semaglutide 2·4 mg conferred improvements in heart failure-related symptoms and physical limitations, bodyweight, and other heart failure outcomes. We aimed to determine whether these effects of semaglutide differ according to baseline HbA1c. STEP-HFpEF DM, a double-blind, randomised, placebo-controlled trial conducted at 108 clinical research sites across 16 countries in Asia, Europe, and North and South America, included individuals aged 18 years or older with documented HFpEF (left ventricular ejection fraction ≥45%), type 2 diabetes, and obesity (BMI ≥30 kg/m2). Participants were randomly assigned (1:1), with a block size of four within each stratum using an interactive web response system, stratified by baseline BMI (<35 kg/m2vs ≥35 kg/m2), to receive either semaglutide 2·4 mg or placebo subcutaneously. The effects of semaglutide versus placebo on the efficacy endpoints were evaluated by HbA1c categories at baseline: low (<6·5%; <48 mmol/mol), medium (6·5% to <7·5%; 48 mmol/mol to <58 mmol/mol), and high (≥7·5%; ≥58 mmol/mol). The dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and bodyweight percentage from baseline to 52 weeks and were assessed in all randomly assigned participants by intention to treat. Hypoglycaemia events were also analysed to assess safety in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04916470. Between June 27, 2021 and Sept 2, 2022, 616 participants were enrolled and randomly assigned (mean age 68·4 years [SD 8·9]; 273 [44%] were female, 343 [56%] were male, and 519 [84%] were White). The low baseline HbA1c group included 227 participants (112 assigned to semaglutide and 115 to placebo), the medium baseline HbA1c group included 226 participants (124 assigned to semaglutide and 102 to placebo), and the high baseline HbA1c group included 163 participants (74 assigned to semaglutide and 89 to placebo). The median duration of follow-up in the overall trial was 401 days (IQR 400-405). The change in KCCQ-CSS from baseline to 52 weeks was 12·4 points (95% CI 8·8 to 16·0) with semaglutide versus 5·7 points (2·1 to 9·2) with placebo (mean difference 6·7 points [1·6 to 11·8]) in the low baseline HbA1c group, 14·5 points (11·0 to 17·9) versus 8·5 points (4·8 to 12·2; 6·0 points [0·9 to 11·1]) in the medium baseline HbA1c group, and 14·5 points (10·0 to 19·0) versus 4·8 points (0·7 to 8·9; 9·6 points [3·5 to 15·7]) in the high baseline HbA1c group (pinteraction=0·64; ptrend=0·46). The change in bodyweight percentage from baseline to 52 weeks was -10·8 (95% CI -12·1 to -9·5) with semaglutide versus -3·3% (-4·6 to -2·0) with placebo (mean difference -7·5% [-9·4 to -5·6]) in the low baseline HbA1c group, -9·6% (-10·8 to -8·3) versus -3·3% (-4·7 to -1·9; -6·3 [-8·2 to -4·4]) in the medium baseline HbA1c group, and -8·6% (-10·2 to -7·0) versus -3·6% (-5·2 to -2·1; -5·0 [-7·2 to -2·7]) in the high baseline HbA1c group (pinteraction=0·22; ptrend=0·083). Hypoglycaemia events occurred in 30 (10%) of 310 participants (70 events; 22·9 events per 100 person-years) in the semaglutide group compared with 21 (7%) of 306 participants in the placebo group (90 events; 29·5 events per 100 person-years). Semaglutide 2·4 mg improved heart failure-related symptoms and physical limitations, and reduced bodyweight in patients with obesity-related HFpEF and type 2 diabetes, all independently of baseline HbA1c, and resulted in lower rates of hypoglycaemia than placebo, despite a well controlled baseline HbA1c and broad use of concomitant glucose-lowering medications. Novo Nordisk.

Davies MJ ，van der Meer P ，Verma S ，Patel S ，Chinnakondepalli KM ，Borlaug BA ，Butler J ，Kitzman DW ，Shah SJ ，Harring S ，Salsali A ，Rasmussen S ，von Lewinski D ，Abhayaratna W ，Petrie MC ，Kosiborod MN ，STEP-HFpEF Trials Committees and Investigators ... -  《-》

Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.

More women than men have heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program. In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes. Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo. In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).

Verma S ，Butler J ，Borlaug BA ，Davies M ，Kitzman DW ，Shah SJ ，Petrie MC ，Barros E ，Rönnbäck C ，Vestergaard LS ，Schou M ，Ezekowitz JA ，Sharma K ，Patel S ，Chinnakondepalli KM ，Kosiborod MN ，STEP-HFpEF Trial Committees and Investigators ... -  《-》

Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.

There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes. STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete. Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m2 (6·9), waist circumference 120·1 cm (14·7), HbA1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported. Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia. Novo Nordisk. For the Spanish translation of the abstract see Supplementary Materials section.

McGowan BM ，Bruun JM ，Capehorn M ，Pedersen SD ，Pietiläinen KH ，Muniraju HAK ，Quiroga M ，Varbo A ，Lau DCW ，STEP 10 Study Group ... -  《-》

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. ClinicalTrials.gov NCT04109547. Novo Nordisk A/S.

Wang W ，Bain SC ，Bian F ，Chen R ，Gabery S ，Huang S ，Jensen TB ，Luo B ，Yuan G ，Ning G ，PIONEER 11 investigators ... -  《-》