Eli Lilly and Company, Indianapolis, IN, USA.
Eli Lilly and Company, Vienna, Austria.
J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. doi: 10.1210/clinem/dgaa863.
Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.
Explore mechanisms of glucose control by tirzepatide.
Post hoc analyses of fasting biomarkers and multiple linear regression analysis.
Forty-seven sites in 4 countries.
Three hundred and sixteen subjects with type 2 diabetes.
Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.
Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.
Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.
Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
新型双重葡萄糖依赖性胰岛素促分泌多肽（GIP）和胰高血糖素样肽-1（GLP-1）受体激动剂（RA）替西帕肽与选择性 GLP-1RA 度拉糖肽相比，可显著改善血糖控制和体重减轻（WL）。
探讨替西帕肽改善血糖控制的机制。
空腹生物标志物的事后分析和多元线性回归分析。
4 个国家的 47 个地点。
316 例 2 型糖尿病患者。
替西帕肽（1、5、10、15mg）、度拉糖肽（1.5mg）、安慰剂。
分析胰岛β细胞功能和胰岛素抵抗（IR）的生物标志物，并评估 26 周时 WL 对 IR 改善的贡献。
与安慰剂相比，度拉糖肽和替西帕肽 5、10 和 15mg 可显著增加稳态模型评估（HOMA）2-B（P≤.02）。与安慰剂和度拉糖肽相比，替西帕肽 10 和 15mg 可显著降低空腹胰岛素原/胰岛素和胰岛素原/C 肽比值（P≤.007）。与安慰剂和度拉糖肽相比，替西帕肽 10 和 15mg 可显著降低空腹胰岛素（P≤.033），且替西帕肽 10mg 可显著降低 HOMA2-IR（P=.004）。1 或更多剂量的替西帕肽可显著增加胰岛素敏感性（IS）标志物脂联素、IGFBP-1 和 IGFBP-2（P<.05）。为了确定 IR 的改善是否直接归因于 WL，我们进行了多元线性回归分析，考虑了年龄、性别、二甲双胍、甘油三酯和糖化血红蛋白 A1c 等潜在混杂变量。与替西帕肽 10 和 15mg 相关的 IR 改善，WL 分别仅可解释 13%和 21%（P≤.028）。
与度拉糖肽相比，替西帕肽可更大程度地改善 IS 和胰岛β细胞功能的标志物。替西帕肽的 IS 作用部分归因于 WL，这表明双重受体激动剂赋予了血糖控制的独特机制。
