Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

IF 98.4 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
The Lancet Pub Date : 2024-09-07 Epub Date: 2024-08-30 DOI:10.1016/S0140-6736(24)01643-X
Mikhail N Kosiborod, John Deanfield, Richard Pratley, Barry A Borlaug, Javed Butler, Melanie J Davies, Scott S Emerson, Steven E Kahn, Dalane W Kitzman, Ildiko Lingvay, Kenneth W Mahaffey, Mark C Petrie, Jorge Plutzky, Søren Rasmussen, Cecilia Rönnbäck, Sanjiv J Shah, Subodh Verma, Peter E Weeke, A Michael Lincoff
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引用次数: 0

Abstract

Background: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established.

Methods: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete.

Findings: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]).

Interpretation: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available.

Funding: Novo Nordisk.

塞马鲁肽与安慰剂在射血分数轻度降低或保留的心衰患者中的应用:SELECT、FLOW、STEP-HFpEF 和 STEP-HFpEF DM 随机试验的汇总分析。
背景:射血分数轻度降低或保留的心力衰竭(以下简称HFpEF)是最常见的心力衰竭类型,与住院和死亡的高风险相关,尤其是在超重、肥胖或2型糖尿病患者中。在STEP-HFpEF和STEP-HFpEF DM试验中,semaglutide改善了HFpEF参与者的心衰相关症状和身体限制。塞马鲁肽是否也能减少这一群体的临床心衰事件仍有待确定:我们对四项随机安慰剂对照试验(SELECT、FLOW、STEP-HFpEF和STEP-HFpEF DM)进行了一项事后汇总的参与者水平分析,以研究每周一次皮下注射塞马鲁肽(SELECT、STEP-HFpEF和STEP-HFpEF DM中为2-4毫克;FLOW中为1-0毫克)对心衰事件的影响。STEP-HFpEF 和 STEP-HFpF DM 试验招募了肥胖相关的 HFpEF 患者,SELECT 试验招募了患有动脉粥样硬化性心血管疾病和超重或肥胖的患者,FLOW 试验招募了患有 2 型糖尿病和慢性肾病的患者。因此,在本分析中,我们纳入了 STEP-HFpEF 试验的所有参与者,以及 SELECT 和 FLOW 试验中研究者报告有 HFpEF 病史的参与者。本分析的主要结果是心血管死亡或首次心衰恶化事件(定义为因心衰住院或紧急就诊)发生时间、首次心衰恶化事件发生时间和心血管死亡时间的复合终点。疗效和安全性终点分析采用全分析集(即根据意向治疗原则随机分配接受治疗的所有参与者)。SELECT、FLOW、STEP-HFpEF和STEP-HFpEF DM试验分别在ClinicalTrials.gov上注册,注册号分别为NCT03574597、NCT03819153、NCT04788511和NCT04916470,所有试验均已完成:在这四项试验中,22282名参与者中有3743人(16%-8%)曾患有高房颤动性心力衰竭(1914人被分配接受舍马鲁肽治疗,1829人被分配接受安慰剂治疗)。在这组 HFpEF 参与者中,塞马鲁肽降低了心血管死亡或心衰事件这一综合终点的风险(塞马鲁肽组 1914 人中有 103 人 [5-4%] 发生心衰事件,安慰剂组 1829 人中有 138 人 [7-5%] 发生心衰事件;危险比 [HR] 0-69 [95% CI 0-53-0-89];P=0-0045)。塞马鲁肽还降低了心衰事件恶化的风险(54 [2-8%] vs 86 [4-7%];HR 0-59 [0-41-0-82]; p=0-0019)。仅对心血管死亡无明显影响(59 [3-1%] vs 67 [3-7%];HR 0-82 [0-57-1-16];P=0-25)。与安慰剂相比,接受塞马鲁肽治疗的患者发生严重不良事件的比例较低(572 [29-9%] vs 708 [38-7%]):在高频心衰患者中,semaglutide可降低心血管死亡或心衰恶化事件以及单纯心衰恶化事件的合并终点风险,而其对单纯心血管死亡的影响并不显著。这些数据支持使用semaglutide作为一种有效的疗法来降低HFpEF患者发生临床心力衰竭事件的风险,目前可供选择的治疗方案很少:诺和诺德公司。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
The Lancet
The Lancet 医学-医学:内科
CiteScore
148.10
自引率
0.70%
发文量
2220
审稿时长
3 months
期刊介绍: The Lancet is a world-leading source of clinical, public health, and global health knowledge. It was founded in 1823 by Thomas Wakley and has been an independent, international weekly general medical journal since then. The journal has an Impact Factor of 168.9, ranking first among 167 general and internal medicine journals globally. It also has a Scopus CiteScore of 133·2, ranking it second among 830 general medicine journals. The Lancet's mission is to make science widely available to serve and transform society, positively impacting people's lives. Throughout its history, The Lancet has been dedicated to addressing urgent topics, initiating debate, providing context for scientific research, and influencing decision makers worldwide.
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