Zile Michael R, Borlaug Barry A, Kramer Christopher M, Baum Seth J, Litwin Sheldon E, Menon Venu, Ou Yang, Weerakkody Govinda J, Hurt Karla C, Kanu Chisom, Murakami Masahiro, Packer Milton
RHJ Department of Veterans Affairs, Health Care System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.).
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Circulation. 2025 Mar 11;151(10):656-668. doi: 10.1161/CIRCULATIONAHA.124.072679. Epub 2024 Nov 18.
Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients.
We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance.
Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41-0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3-10.6; <0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9-26.7; <0.001), and EQ-5D-5L 0.06 (95% CI, 0.03-0.09; <0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44-2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54-3.31]; both <0.001) and required fewer heart failure medications (=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17-2.28]; =0.004).
Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04847557.
射血分数保留的心力衰竭患者合并肥胖时，会出现严重功能障碍且心力衰竭频繁加重。我们推测，葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体的长效激动剂替尔泊肽，会改善这类患者一系列综合临床终点，包括健康状况、功能能力、生活质量、运动耐量、患者幸福感及药物负担等指标。
我们将731例II至IV级心力衰竭、射血分数≥50%且体重指数≥30kg/m²的患者随机（双盲）分为替尔泊肽组（皮下注射，每周滴定至15mg；n=364）或安慰剂组（n=367），在背景治疗基础上用药，中位时间为104周（四分位间距1，66；四分位间距3，126周）。主要终点为替尔泊肽是否降低心血管死亡或心力衰竭恶化的联合风险，以及是否改善堪萨斯城心肌病问卷临床总结评分。当前的扩展分析包括主要终点的敏感性分析、6分钟步行距离、EQ-5D-5L健康状态指数、患者总体健康严重程度印象评分、纽约心脏协会分级、心力衰竭药物使用情况，以及基于全因死亡、心力衰竭恶化、堪萨斯城心肌病问卷临床总结评分和6分钟步行距离的52周变化的分层综合指标。
患者年龄为65.2±10.7岁；53.8%（n=393）为女性；体重指数为38.2±6.7kg/m²；堪萨斯城心肌病问卷临床总结评分为53.5±18.5；6分钟步行距离为302.8±81.7米；53%（n=388）在过去12个月内发生过心力衰竭恶化事件。与安慰剂相比，替尔泊肽在所有死亡和心力衰竭恶化事件的综合指标上均产生了一致的有益效果，以首次事件发生时间分析（风险比，0.41 - 0.67）。在52周时，替尔泊肽使堪萨斯城心肌病问卷临床总结评分提高了6.9分（95%CI，3.3 - 10.6；<0.001），6分钟步行距离增加了18.3米（95%CI，9.9 - 26.7；<0.001），EQ-5D-5L增加了0.06（95%CI，0.03 - 0.09；<0.001）。替尔泊肽组患者总体健康严重程度印象评分向更有利方向转变（比例优势比，1.99[95%CI，1.44 - 2.76]），纽约心脏协会分级也向更有利方向转变（比例优势比，2.26[95%CI，1.54 - 3.31]；均<0.001），且所需心力衰竭药物更少（P=0.015）。广泛的疗效体现在分层综合指标的获益上（胜率，1.63[95%CI，1.17 - 2.28]；P=0.004）。
替尔泊肽在多个互补领域对心力衰竭产生了全面、有意义的改善；增强了健康状况、生活质量、功能能力、运动耐量和幸福感；减轻了射血分数保留的心力衰竭合并肥胖患者的症状和药物负担。
