Obesity is one of the major risk factors for heart failure with preserved ejection fraction (HFpEF). Although many patients with HFpEF are comorbid with obesity, obese patients are underrepresented in heart failure clinical trials. For the first time, the STEP-HFpEF trial investigated the efficacy of GLP-1 receptor agonists in patients with HFpEF who were obese: patients in the semaglutide group had a reduction in body weight and significant improvements in heart failure symptoms, physical limitations, and motor function compared with placebo. In the STEP-HFpEF DM trial, patients in the semaglutide group also had significant improvement in HF symptoms compared with placebo, and these findings were consistent with the results of the STEP-HFpEF trial. Given the modest size of the two trials, a pre-specified pooled analysis may help to more definitively assess the effects of semaglutide in patients with HFpEF with comorbidity (with or without diabetes) and to assess whether these effects are consistent across key patient subgroups.
Pooled analysis showed that semaglutide demonstrated significant superiority over placebo in improving heart failure-related symptoms, physical limitations, and weight loss in patients with obesity-related HFpEF, with or without type 2 diabetes.
Research Methods:
The purpose of this study was to perform a pre-specified, pooled analysis of individual patient data from two randomized, double-blind, placebo-controlled trials of STEP-HFpEF and STEP-HFpEF DM, conducted at 129 clinical sites in 18 countries. The patient was ≥ 18 years old, with a left ventricular ejection fraction (LVEF) of ≥45%, a body mass index (BMI) of ≥30 kg/m², New York Heart Association (NYHA) grade II-IV, and a clinical summary score of < 90 on the Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS).
In the STEP-HFpEF trial, 6.5% of patients with diabetes ≥ HbA1c were excluded, and in the STEP-HFpEF DM trial, patients must have been diagnosed with type 2 diabetes and 10% of HbA1c ≤ at least 90 days prior to screening. In both trials, patients were randomly assigned to receive semaglutide 2.4 mg once weekly or matching placebo for 52 weeks.
The co-primary endpoint of the study was change in KCCQ-CSS and body weight from baseline to week 52 in all randomized patients. Confirmatory secondary endpoints included change in 6MWD from baseline to week 52, stratified composite endpoints (including differences in all-cause death, heart failure events, improvement in KCCQ-CSS score, and change in 6MWD), and C-reactive protein (CRP) concentration.
In addition to this, the investigators also evaluated the heterogeneity of the efficacy of semaglutide in the subgroup of interest, as well as its safety in all patients who received at least one dose of the therapeutic drug.
Findings:
Between March 19, 2021 and March 9, 2022, 529 patients were randomized in the STEP-HFpEF trial and 616 patients in the STEP-HFpEF DM trial between June 27, 2021 and September 2, 2022. A total of 1145 patients were included in this pooled analysis, including 573 in the semaglutide group and 572 in the placebo group.
The median age of participants was 69 years, and 50% were female, 90% white, 7% Asian, and 3% black or African-American. Sixty-five percent had a BMI ≥ 35 kg/m², and 69 percent had NYHA class II symptoms. Comorbidities were common, and KCCQ-CSS score and 6MWD suggested poor health and motor function in both groups. At least 75% of patients in each group were taking β receptor blockers, diuretics, and renin-angiotensin inhibitors (Table 1).
Table 1 Baseline characteristics of patients
At a median follow-up of 401 days, patients in the semaglutide group had significantly greater improvement in KCCQ-CSS from baseline to week 52 than in the placebo group (15.0 versus 7.5; estimated difference 7.5 points [95% CI: 5.3 to -9.8] ;p<0.0001), and the percentage of weight loss was significantly greater (-8.4% [-9.2 to -7.5];p>0.0001).
Compared with placebo, patients in the semaglutide group had a significant improvement in 6MWD (difference between groups 17.1 m [95% CI : 9.2-25.0];p<0.0001), a win rate of 1.65 (95% CI: 1.42-1.91; p<0.0001) for stratified composite endpoints, an estimated treatment rate of 0.64 (95% CI: 0.56-0.72; p<0.0001) for changes in CRP levels, and a significant reduction in NT-proBNP levels.
For the dual primary endpoints, efficacy in the semaglutide arm was broadly consistent across multiple subgroups, including age, ethnicity, sex, BMI, systolic blood pressure, baseline CRP, and LVEF.
In terms of safety endpoints, serious adverse events were reported in 161 (28.7/100 person-years) and 301 (52.7/100 person-years) in the semaglutide and placebo groups, respectively. During follow-up, the semaglutide group had a reduced risk of serious cardiac disease and infectious events compared with the placebo group.
Conclusions of the study
In this pre-specified pooled analysis, semaglutide demonstrated significant superiority over placebo in improving heart failure-related symptoms, physical limitations, and weight loss in patients with obesity-related HFpEF, with or without type 2 diabetes, including across clinical subgroups.
In addition, semaglutide has a favorable safety profile and reduces the risk of hospitalization and emergency medical attention for HF compared with placebo (although there are fewer events overall), providing a reasonable basis for further evaluation of specialized outcome trials of incretin-based therapy in patients with HFpEF.
参考文献：Javed Butler,et al. 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. THE LANCET. April 07, 2024.
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