Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada.
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom.
J Am Coll Cardiol. 2024 Oct 22;84(17):1646-1662. doi: 10.1016/j.jacc.2024.08.028. Epub 2024 Aug 30.
Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined.
This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program.
This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L).
In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91).
Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).
炎症被认为是肥胖相关性射血分数保留型心力衰竭（HFpEF）发展和进展的重要机制。在 STEP-HFpEF 计划中，每周一次 2.4mg 司美格鲁肽改善了心力衰竭相关症状、身体受限和运动功能，降低了 C 反应蛋白（CRP）水平，炎症标志物，以及肥胖相关性 HFpEF 患者的体重。然而，肥胖相关性 HFpEF 患者炎症程度不同的患者的患病率和临床特征尚未得到很好的描述。此外，司美格鲁肽对 STEP-HFpEF 计划中各种 HF 疗效终点的有益影响是否受 CRP 基线水平的影响尚未完全确定。最后，体重减轻和 CRP 变化之间的关系在 STEP-HFpEF 计划中尚未完全确定。
本研究旨在：1）评估 STEP-HFpEF 计划中炎症程度不同的肥胖相关性 HFpEF 患者的基线特征和临床特征；2）确定每周 2.4mg 司美格鲁肽与安慰剂在所有关键结局上的效果是否受 CRP 水平评估的基线炎症水平的影响；3）确定 STEP-HFpEF 计划中 CRP 变化与体重减轻之间的关系。
这是对 2 项国际、双盲、安慰剂对照、随机试验（STEP-HFpEF 和 STEP-HFpEF DM）的汇总数据进行的二次分析。主要结局是根据基线 CRP 水平，从基线到 52 周时双重主要终点（健康状况[通过堪萨斯城心肌病问卷临床总结评分（KCCQ-CSS）测量]和体重）的变化。其他疗效终点包括 6 分钟步行距离（6MWD）的变化，6MWD 的变化是一个分层复合终点，包括死亡、心力衰竭事件以及 KCCQ-CSS 和 6MWD 变化的差异，以及司美格鲁肽与安慰剂治疗患者的 CRP 水平。根据基线 CRP 水平（<2、≥2 至<10 和≥10mg/L）将患者分为 3 组。
共有 1145 名患者被随机分组，其中 71%的患者有炎症证据（CRP≥2mg/L）。基线时，炎症水平较高的患者年龄较小，更可能为女性，体重指数更高，健康状况（KCCQ-CSS）更差，6MWD 更短。与安慰剂相比，司美格鲁肽可降低 HF 相关症状和身体受限，减轻体重，并改善 6MWD 和分层复合终点，这些改善在 CRP 基线类别中是一致的（所有 P 交互均无统计学意义）。无论基线 CRP 水平如何，司美格鲁肽降低 CRP 的程度均大于安慰剂（P 交互=0.32）。从基线到 52 周，CRP 的变化与体重减轻的幅度无关（P 交互=0.91）。
炎症在肥胖相关性 HFpEF 中非常普遍。司美格鲁肽在 CRP 基线类别中一致改善了 HF 相关症状、身体受限和运动功能，并降低了体重。司美格鲁肽还降低了炎症，无论基线 CRP 或试验期间体重减轻的幅度如何。（研究调查司美格鲁肽在肥胖伴心力衰竭患者中的疗效的研究 [STEP-HFpEF；NCT04788511]；研究调查司美格鲁肽在肥胖伴心力衰竭、2 型糖尿病患者中的疗效的研究 [STEP HFpEF DM；NCT04916470]）。
