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. 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 , , , , and , respectively, and all are complete. 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 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%] 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%] 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%] 708 [38·7%]). 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. Novo Nordisk.

中文翻译：

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索马鲁肽与安慰剂治疗射血分数轻度降低或保留的心力衰竭患者：SELECT、FLOW、STEP-HFpEF 和 STEP-HFpEF DM 随机试验的汇总分析


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，特别是对于超重、肥胖或 2 型糖尿病患者。在 STEP-HFpEF 和 STEP-HFpEF DM 试验中，索马鲁肽改善了 HFpEF 参与者的心力衰竭相关症状和身体限制。索马鲁肽是否也能减少该组患者的临床心力衰竭事件仍有待确定。我们对四项随机、安慰剂对照试验（SELECT、FLOW、STEP-HFpEF 和 STEP-HFpEF DM）进行了事后汇总、参与者水平分析，以检查每周一次皮下注射索马鲁肽（2·4 mg）的效果。 SELECT、STEP-HFpEF 和 STEP-HFpEF DM 中；FLOW 中 1·0 mg）对心力衰竭事件。 STEP-HFpEF 和 STEP-HFpF DM 试验招募了患有肥胖相关 HFpEF 的受试者，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受试者，FLOW 试验招募了患有 2 型糖尿病和慢性肾病的受试者。因此，在本次分析中，我们纳入了 STEP-HFpEF 试验的所有参与者以及具有研究者报告的 SELECT 和 FLOW HFpEF 病史的参与者。该分析的主要结果是心血管死亡或首次恶化心力衰竭事件（定义为因心力衰竭住院或紧急就诊）的时间、首次恶化心力衰竭事件的时间和心血管死亡时间的复合终点。使用完整的分析集（即根据意向治疗原则，将所有参与者随机分配到治疗组）来分析疗效和安全性终点。 SELECT、FLOW、STEP-HFpEF 和 STEP-HFpEF DM 试验分别在 、 、 、 和 处注册，并且全部已完成。在这四项试验中，22 282 名参与者中有 3743 名 (16·8%) 有 HFpEF 病史（1914 名被分配到索马鲁肽组，1829 名被分配到安慰剂组）。在这组患有 HFpEF 的参与者中，索马鲁肽降低了心血管死亡或心力衰竭事件联合终点的风险（索马鲁肽组中 1914 人中的 103 人 [5·4%] 发生了 1829 人中的 138 人 [7·5%] 事件。安慰剂组；风险比 [HR] 0·69 [95% CI 0·53–0·89]；p=0·0045）。索马鲁肽还降低了心力衰竭事件恶化的风险（54 [2·8%] 86 [4·7%]；HR 0·59 [0·41–0·82]；p=0·0019）。仅对心血管死亡没有显着影响（59 [3·1%] 67 [3·7%]；HR 0·82 [0·57–1·16]；p=0·25）。与接受安慰剂治疗的患者相比，接受索马鲁肽治疗的患者出现严重不良事件的比例较低（572 [29·9%] 708 [38·7%]）。在 HFpEF 患者中，索马鲁肽降低了心血管死亡或心力衰竭事件恶化以及单独心力衰竭事件恶化的综合终点风险，但其对单独心血管死亡的影响并不显着。这些数据支持使用索马鲁肽作为一种有效的疗法来降低 HFpEF 患者临床心力衰竭事件的风险，目前对于这些患者来说可用的治疗选择很少。诺和诺德。