Abstract: Background The multi-target effects of semaglutide make it a breakthrough therapy for managing diabetes and obesity, offering comprehensive benefits particularly for patients with cardiovascular disease. However, its clinical applications for patients with heart failure (HF) are still under active investigation. Objective To systematically review the efficacy and safety of subcutaneous semaglutide in the treatment of HF regardless of the presence of obesity or type 2 diabetes (T2DM). Methods We searched Cochrane Library, PubMed, Embase, CNKI, Wanfang Data and VIP database from inception to November 2, 2024 for randomized controlled trials about subcutaneous semaglutide in the treatment of HF, where the experimental group received subcutaneous semaglutide and the control group received placebo. Data on HF hospitalization rate, cardiovascular death rate, all cause death rate, serious adverse events, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and 6-minute walk distance (6-MWD) were collected and analyzed by two investigators who independently screened the literature,extracted the data, and evaluated the risk of bias of the included studies. Subgroup analyses were performed based on comorbidities and different dosages, and data were statistically analyzed using Review Manager 5.3 software. Results A total of 4 randomized controlled studies, with a total of 6 109 (3 070 in the experimental group and 3 039 in the control group). Meta-analysis results showed that compared with placebo, subcutaneous semaglutide reduced the risk of cardiovascular death (RR=0.75, 95%CI=0.61-0.92, P=0.005), all-cause death (RR=0.81, 95%CI=0.67-0.98, P=0.03) and serious adverse events (RR=0.53, 95%CI=0.41-0.68, P<0.000 01). Subgroup analysis found that subcutaneous semaglutide could increase KCCQ-CSS (MD=7.58, 95%CI=4.40-10.77, P<0.000 01) and 6-MWD (MD=16.91, 95%CI=8.98-24.83, P<0.000 1) and reduced the risk of HF hospitalization (RR=0.41, 95%CI=0.26-0.65, P=0.000 1) of patients in HFpEF with obesity. In patients without T2DM, semaglutide was superior to placebo in reducing the risk of HF hospitalization (RR=0.16, 95%CI=0.04-0.68, P=0.01) and cardiovascular death (RR=0.76, 95%CI=0.60-0.97, P=0.03); similarly, in patients with a weekly dose of 2.4 mg, semaglutide reduced the risk of HF hospitalization (RR=0.29, 95%CI=0.14-0.58, P=0.000 5) and cardiovascular death (RR=0.75, 95%CI=0.59-0.95, P=0.02) compared with placebo, but the efficacy of the weekly dose of 1.0 mg was not significant compared with placebo. Conclusion Current evidence shows that subcutaneous semaglutide can reduce the risk of cardiovascular death, all-cause death and serious adverse events of heart failure patients while improving quality of life and activity tolerance and reducing risk of HF hospitalization in patients with HFpEF and obesity. Due to limited quantity and populations of the included studies, more high-quality studies are needed to verify the above conclusion.

Key words: Heart failure, Semaglutide, Efficacy, Safety, Meta-analysis

摘要： 背景 司美格鲁肽的多靶点作用使其成为糖尿病和肥胖管理的突破性药物，尤其是对合并心血管疾病的患者具有综合获益，但其对于心力衰竭（HF）患者的疗效和安全性应用仍在探索中。目的 系统评价皮下注射司美格鲁治疗HF的疗效和安全性，不管是否肥胖或存在2型糖尿病（T2DM）。方法 计算机检索Cochrane Library、PubMed、Embase、中国知网（CNKI）、万方数据知识服务平台（Wanfang Data）和维普网（VIP），检索时限自建库至2024-11-02。筛选皮下注射司美格鲁肽治疗HF的随机对照试验，其中试验组为皮下注射司美格鲁肽，对照组为安慰剂。由两名研究者独立筛选、数据提取并评价纳入研究的偏倚风险，对因HF再入院、心血管死亡和全因死亡发生率、严重不良事件、堪萨斯城心肌病调查问卷评分（KCCQ-CSS）和6分钟步行距离（6-MWD）等数据收集和分析。基于合并症和不同给药剂量进行亚组分析，使用Review Manager 5.3软件进行Meta分析。结果 共纳入4项随机对照试验，总计6 109例患者，其中试验组3 070例，对照组3 039例。Meta分析结果表明：与安慰剂相比，皮下注射司美格鲁肽降低心血管死亡（RR=0.75，95%CI=0.61~0.92，P=0.005）、全因死亡（RR=0.81，95%CI=0.67~0.98，P=0.03）和严重不良事件风险（RR=0.53，95%CI=0.41~0.68，P<0.000 01）；亚组分析发现，皮下注射司美格鲁肽增加肥胖的射血分数保留的 HF（HFpEF）患者KCCQ-CSS（MD=7.58，95%CI=4.40~10.77，P<0.000 01）和6-MWD（MD=16.91，95%CI=8.98~24.83，P<0.000 1），降低因HF再入院风险（RR=0.41，95%CI=0.26~0.65，P=0.000 1）；在不合并T2DM的患者中，司美格鲁肽在降低因HF再入院（RR=0.16，95%CI=0.04~0.68，P=0.01）和心血管死亡风险（RR=0.76，95%CI=0.60~0.97，P=0.03）方面优于安慰剂；同样，在2.4 mg/周剂量组的患者中，与安慰剂相比，皮下注射司美格鲁肽降低因HF再入院（RR=0.29，95%CI=0.14~0.58，P=0.000 5）和心血管死亡风险（RR=0.75，95%CI=0.59~0.95，P=0.02），但1.0 mg/周剂量组的疗效与安慰剂相比并不显著。结论 皮下注射司美格鲁肽可安全、有效地降低HF患者的心血管死亡、全因死亡和严重不良事件发生风险，改善肥胖的HFpEF患者的生活质量和运动耐量，降低因HF再入院风险。受纳入研究数量和人群限制，上述结论尚需开展更多高质量研究予以验证。

关键词: 心力衰竭, 司美格鲁肽, 有效性, 安全性, Meta 分析