Background and Aims In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. Methods In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. Results At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. Conclusions In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. ClinicalTrials.gov registration NCT04788511 and NCT04916470

中文翻译：

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索马鲁肽和利尿剂在射血分数保留的肥胖相关性心力衰竭中的应用：STEP-HFpEF 和 STEP-HFpEF-DM 试验的汇总分析

背景和目的 在 STEP-HFpEF 试验计划中，索马鲁肽治疗对射血分数保留的肥胖相关心力衰竭 (HFpEF) 患者产生了多种有益效果。疗效可能会根据基线利尿剂的使用而有所不同，索马鲁肽治疗可以调整利尿剂的剂量。方法 在这项对 STEP-HFpEF 和 STEP-HFpEF-DM 试验 (n=1145) 汇总数据的预先指定分析中，将 HFpEF 且体重指数≥30 kg/m2 的参与者随机分配至每周一次的索马鲁肽 2.4 mg 或安慰剂组在 52 周的时间里，我们检查了疗效和安全性终点是否因基线利尿剂的使用而有所不同，以及 52 周治疗期间索马鲁肽对袢利尿剂使用和剂量变化的影响。结果 基线时，不使用利尿剂 (n=220)、仅使用非袢利尿剂 (n=223) 和袢利尿剂 (<40 [n=219]、40 [n=309] 和 > 40 [n =174] mg/天呋塞米当量）组中，高血压和心房颤动的患病率逐渐升高；以及肥胖和心力衰竭的严重程度。经过 52 周的治疗，索马鲁肽对不同利尿剂使用类别的体重变化具有一致的有益作用（与安慰剂相比，调整后的平均差异范围为 -8.8% [95% CI -10.3, -6.3] 至 -6.9% [95% CI -9.1，-4.7]从无利尿剂到最高袢利尿剂剂量类别；相互作用 P=0.39）。与未使用袢利尿剂的患者相比，堪萨斯城心肌病问卷临床总结评分改善更大（调整后的平均差与安慰剂相比：+9.3 [6.5; 12.1] vs. +4.7 分 [1.3, 8.2]；P= 0.042）。索马鲁肽对利尿剂亚组的所有次要疗效终点（包括 6 分钟步行距离）具有一致的有益作用（交互作用 P=0.24-0.92）。在利尿剂亚组中，与安慰剂相比，索马鲁肽的安全性也更佳。从基线到 52 周，索马鲁肽组袢利尿剂剂量减少了 17%，而安慰剂组则增加了 2.4%（P＜0.0001）。索马鲁肽（与安慰剂相比）更有可能导致袢利尿剂剂量减少（比值比 [OR] 2.67 [95% CI 1.70, 4.18]），并且不太可能导致剂量增加（OR 0.35 [95% CI 0.23, 0.53]；P< ；从基线到 52 周均为 0.001。结论 在肥胖相关 HFpEF 患者中，索马鲁肽改善了利尿剂使用亚组的心力衰竭相关症状和身体限制，在基线时接受袢利尿剂的患者中获益更明显。与安慰剂相比，索马鲁肽的体重减轻和运动功能改善在所有利尿剂使用类别中都是一致的。索马鲁肽还导致基线至 52 周之间袢利尿剂的使用和剂量减少。 ClinicalTrials.gov 注册 NCT04788511 和 NCT04916470