Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular–kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) −5 mmHg, 95% confidence interval (CI) −7 to −3; P < 0.001), decreased estimated blood volume (ETD −0.58 l, 95% CI −0.63 to −0.52; P < 0.001) and reduced C-reactive protein levels (ETD −37.2%, 95% CI −45.7 to −27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min⁻¹ 1.73 m⁻² yr⁻¹, 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin–creatinine ratio (ETD 24 weeks, −25.0%, 95% CI −36 to −13%; P < 0.001; 52 weeks, −15%, 95% CI −28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks −10.5%, 95% CI −20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks −10.4%, 95% CI −16.7 to −3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume–pressure overload and systemic inflammation and mitigated cardiovascular–kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557.

射血分数保留 （HFpEF） 的肥胖相关心力衰竭患者表现出循环容量扩张和压力超负荷，导致心血管-肾脏终末器官损伤。在 SUMMIT 试验中，HFpEF 和肥胖患者被随机分配到长效葡萄糖依赖性促胰岛素多肽受体和胰高血糖素样肽-1 受体激动剂 tirzepatide （n = 364， 200 名女性） 或安慰剂 （n = 367， 193 名女性）。如其他报道，tirzepatide 减少了心血管死亡或心力衰竭恶化。在这里，在 SUMMIT 试验的机制二次分析中，与安慰剂相比，52 周时的 tirzepatide 治疗降低了收缩压（估计治疗差异 （ETD） -5 mmHg，95% 置信区间 （CI） -7 至 -3;P < 0.001），估计血容量降低 （ETD -0.58 l，95% CI -0.63 至 -0.52;P < 0.001）和 C 反应蛋白水平降低 （ETD -37.2%，95% CI -45.7 至 -27.3;P < 0.001）。这些变化与估计肾小球滤过率的增加相结合（ETD 2.90 ml ^min-1 1.73 ^{m-2 yr-1,95}% CI 0.94 至 4.86;P = 0.004），尿白蛋白-肌酐比值降低（ETD 24 周，-25.0%，95% CI -36 至 -13%;P < 0.001;52 周，-15%，95% CI -28 至 0.1;P = 0.051），N 末端激素原 B 型利钠肽水平降低（ETD 52 周 -10.5%，95% CI -20.7 至 1.0%;P = 0.07）和肌钙蛋白 T 水平降低（ETD 52 周 -10.4%，95% CI -16.7 至 -3.6;P = 0.003）。 在事后探索性分析中，tirzepatide 治疗后估计血容量减少与血压降低、微量白蛋白尿减少、堪萨斯城心肌病问卷临床总结评分改善和 6 分钟步行距离增加显著相关。此外，C 反应蛋白水平降低与肌钙蛋白 T 水平降低和 6 min 步行距离改善相关。总之，tirzepatide 减少了 HFpEF 和肥胖患者的循环容量压力超负荷和全身炎症，减轻了心血管-肾脏终末器官损伤，为 tirzepatide 的获益机制提供了新的见解。ClinicalTrials.gov 注册：NCT04847557。