Eli Lilly and Company, Indianapolis, IN, USA.
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Department of Pharmacology and Cancer Biology and Department of Medicine, Endocrinology Division, Duke University Medical Center, Durham, NC, USA.
J Clin Endocrinol Metab. 2022 Jan 18;107(2):363-378. doi: 10.1210/clinem/dgab722.
Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and insulin resistance (IR), effects only partially attributable to weight loss.
Assess plasma metabolome changes mediated by tirzepatide.
Phase 2b trial participants were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc exploratory metabolomics and lipidomics analyses were performed.
Post hoc analysis.
259 subjects with T2D.
INTERVENTION(S): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo.
MAIN OUTCOME MEASURE(S): Changes in metabolite levels in response to tirzepatide were assessed against baseline levels, dulaglutide, and placebo using multiplicity correction.
At 26 weeks, a higher dose tirzepatide modulated a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 2-hydroxybutyrate decreased compared to baseline and placebo. Changes were significantly larger with tirzepatide compared with dulaglutide and directly proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides were lowered significantly compared to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species.
Tirzepatide reduces body weight and improves glycemic control and uniquely modulates metabolites associated with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.
与胰高血糖素样肽 1 受体激动剂度拉鲁肽相比，替西帕肽可显著降低 2 型糖尿病（T2D）患者的糖化血红蛋白（HbA1c）和体重。改善血糖控制与循环甘油三酯和脂蛋白标志物降低以及β细胞功能和胰岛素抵抗（IR）标志物改善相关，这些作用部分归因于体重减轻。
评估替西帕肽介导的血浆代谢组学变化。
2b 期试验参与者被随机分配接受每周皮下注射替西帕肽、度拉鲁肽或安慰剂 26 周。进行了事后探索性代谢组学和脂质组学分析。
事后分析。
259 例 T2D 患者。
替西帕肽（1、5、10、15mg）、度拉鲁肽（1.5mg）或安慰剂。
使用多重校正，根据基线水平、度拉鲁肽和安慰剂评估替西帕肽治疗后代谢物水平的变化。
26 周时，较高剂量的替西帕肽调节了一组与 IR、肥胖和未来 T2D 风险相关的代谢物和脂质。支链氨基酸、直接代谢产物谷氨酸、3-羟基异丁酸、支链酮酸以及间接副产物如 2-羟丁酸与基线和安慰剂相比均下降。与度拉鲁肽相比，替西帕肽的变化更大，且与 HbA1c、稳态模型评估 2-IR 指数和胰岛素原水平的降低直接相关。与代谢物变化成比例，与基线、度拉鲁肽和安慰剂相比，甘油三酯和二甘油酯显著降低，且偏向于较短和高度饱和的物种。
替西帕肽可降低体重，改善血糖控制，并以改善代谢健康为方向，独特地调节与 T2D 风险和代谢失调相关的代谢物。
