Packer Milton, Zile Michael R, Kramer Christopher M, Baum Seth J, Litwin Sheldon E, Menon Venu, Ge Junbo, Weerakkody Govinda J, Ou Yang, Bunck Mathijs C, Hurt Karla C, Murakami Masahiro, Borlaug Barry A
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
N Engl J Med. 2025 Jan 30;392(5):427-437. doi: 10.1056/NEJMoa2410027. Epub 2024 Nov 16.
Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.
In this international, double-blind, randomized, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, 731 patients with heart failure, an ejection fraction of at least 50%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 30 to receive tirzepatide (up to 15 mg subcutaneously once per week) or placebo for at least 52 weeks. The two primary end points were a composite of adjudicated death from cardiovascular causes or a worsening heart-failure event (assessed in a time-to-first-event analysis) and the change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).
A total of 364 patients were assigned to the tirzepatide group and 367 to the placebo group; the median duration of follow-up was 104 weeks. Adjudicated death from cardiovascular causes or a worsening heart-failure event occurred in 36 patients (9.9%) in the tirzepatide group and in 56 patients (15.3%) in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.41 to 0.95; P = 0.026). Worsening heart-failure events occurred in 29 patients (8.0%) in the tirzepatide group and in 52 patients (14.2%) in the placebo group (hazard ratio, 0.54; 95% CI, 0.34 to 0.85), and adjudicated death from cardiovascular causes occurred in 8 patients (2.2%) and 5 patients (1.4%), respectively (hazard ratio, 1.58; 95% CI, 0.52 to 4.83). At 52 weeks, the mean (±SD) change in the KCCQ-CSS was 19.5±1.2 in the tirzepatide group as compared with 12.7±1.3 in the placebo group (between-group difference, 6.9; 95% CI, 3.3 to 10.6; P<0.001). Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 23 patients (6.3%) in the tirzepatide group and in 5 patients (1.4%) in the placebo group.
Treatment with tirzepatide led to a lower risk of a composite of death from cardiovascular causes or worsening heart failure than placebo and improved health status in patients with heart failure with preserved ejection fraction and obesity. (Funded by Eli Lilly; SUMMIT ClinicalTrials.gov number, NCT04847557.).
肥胖会增加射血分数保留的心力衰竭风险。替尔泊肽是一种葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体的长效激动剂，可导致显著体重减轻，但关于其对心血管结局影响的数据尚缺乏。
在这项国际、双盲、随机、安慰剂对照试验中，我们以1:1的比例将731例心力衰竭患者（射血分数至少为50%，体重指数[体重千克数除以身高米数的平方]至少为30）随机分配接受替尔泊肽（皮下注射，每周一次，剂量最高达15 mg）或安慰剂治疗至少52周。两个主要终点是经判定的心血管原因死亡或心力衰竭事件恶化的复合终点（在首次事件时间分析中评估），以及堪萨斯城心肌病问卷临床总结评分（KCCQ-CSS；评分范围为0至100，分数越高表明生活质量越好）从基线到52周的变化。
共364例患者被分配到替尔泊肽组，367例被分配到安慰剂组；中位随访时间为104周。替尔泊肽组有36例患者（9.9%）发生经判定的心血管原因死亡或心力衰竭事件恶化，安慰剂组有56例患者（15.3%）发生（风险比，0.62；95%置信区间[CI]，0.41至0.95；P = 0.026）。替尔泊肽组有29例患者（8.0%）发生心力衰竭事件恶化，安慰剂组有52例患者（14.2%）发生（风险比，0.54；95% CI，0.34至0.85），经判定的心血管原因死亡分别发生在8例患者（2.2%）和5例患者（1.4%）中（风险比，1.58；95% CI，0.52至4.83）。在52周时，替尔泊肽组KCCQ-CSS的平均（±标准差）变化为19.5±1.2，而安慰剂组为12.7±1.3（组间差异，6.9；95% CI，3.3至10.6；P<0.001）。导致试验药物停用的不良事件（主要为胃肠道事件）在替尔泊肽组23例患者（6.3%）中发生，在安慰剂组5例患者（1.4%）中发生。
与安慰剂相比，替尔泊肽治疗可降低射血分数保留且肥胖的心力衰竭患者发生心血管原因死亡或心力衰竭恶化复合终点的风险，并改善其健康状况。（由礼来公司资助；SUMMIT临床试验注册号，NCT04847557。）
