Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; Duke Molecular Physiology Institute, Durham, North Carolina, USA.
Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA.
JACC Heart Fail. 2024 Jun;12(6):999-1011. doi: 10.1016/j.jchf.2024.02.018. Epub 2024 Apr 17.
Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF.
The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF.
Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed.
The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction.
Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).
尽管钠-葡萄糖协同转运蛋白 2 抑制剂（SGLT2is）可改善射血分数保留的心力衰竭（HFpEF）相关症状和结局，但潜在机制仍不清楚。在射血分数降低的心力衰竭中，达格列净改变了酮体和脂肪酸代谢物与安慰剂相比的情况；然而，SGLT2is 在 HFpEF 中的代谢特征尚未得到很好的阐明。
本研究的目的是评估 SGLT2i 治疗是否改变了 HFpEF 中的全身代谢途径及其与结局的关系。
对来自 PRESERVED-HF（达格列净在射血分数保留的心力衰竭中的应用）的 293 名参与者进行了 64 种代谢物的靶向分析，这是一项为期 12 周的安慰剂对照的达格列净试验。线性回归评估了主要成分分析（PCA）定义的代谢物因子在达格列净与安慰剂之间的变化。还评估了代谢物因子变化与研究终点变化之间的关系。
平均年龄为 70±11 岁，58%为女性，29%为黑人。治疗组之间的 12 个 PCA 衍生的代谢物因子没有显著差异，包括反映酮体、脂肪酸或支链氨基酸（BCAA）途径的代谢物。将治疗组合并，BCAA 和支链酮酸的变化与 N 末端 pro-B 型利钠肽的变化呈负相关；中/长链酰基肉碱的变化与 N 末端 pro-B 型利钠肽的变化呈正相关，与 6 分钟步行试验距离的变化呈负相关；酮体的变化与体重的变化呈负相关，与治疗无交互作用。
利用 HFpEF 的 SGLT2i 安慰剂对照试验中的靶向代谢组学，与报告的射血分数降低的心力衰竭的作用相反，达格列净并未改变反映循环代谢物的全身代谢。反映支链氨基酸、酮体和脂肪酸代谢的代谢物生物标志物与疾病严重程度的标志物相关，表明可能有新的潜在治疗靶点。（达格列净在射血分数保留的心力衰竭中的应用 [PRESERVED-HF]；NCT03030235）。
