Background

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes.

Methods

This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20–74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete.

Findings

Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m^–2 L min^–2 kg^–1 (SE 0·03) at baseline by 1·9 pmol m^–2 L min^–2 kg^–1 (0·16) to total 2·3 pmol m^–2 L min^–2 kg^–1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m^–2 L min^–2 kg^–1 [SE 0·04]; change from baseline 0·0 pmol m^–2 L min^–2 kg^–1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59–2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m^–2 L min^–2 kg^–1 [95% CI 0·46–1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min^–1 m^–2 [51·84–152·33]) and insulin sensitivity (ETD 1·52 mg min^–1 kg^–1 [0·53–2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths.

Interpretation

The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies.

Funding

Eli Lilly.

中文翻译：

---

皮下注射替西帕肽与安慰剂或索马鲁肽对成人 2 型糖尿病患者胰岛功能和胰岛素敏感性的影响：一项多中心、随机、双盲、平行臂、1 期临床试验

背景

Tirzepatide 是一种双重葡萄糖依赖性促胰岛素多肽 (GIP)/GLP-1 受体激动剂，显示出显着的降低血糖能力，使许多长期患有 2 型糖尿病的患者达到血糖正常。我们旨在了解 tirzepatide 在 2 型糖尿病中作用的生理机制。

方法

这项多中心、随机、双盲、平行臂、1 期研究在德国的两个中心进行。符合条件的患者年龄在 20-74 岁，患有至少 6 个月的 2 型糖尿病，并且在进入研究前 3 个月接受生活方式建议和稳定剂量的二甲双胍治疗，加或不加另一种稳定剂量的另一种口服降糖药. 通过随机化表，患者被随机分配 (3:3:2) 每周一次皮下接受 tirzepatide 15 mg、semaglutide 1 mg 或安慰剂。在基线和治疗的最后一周（第 28 周）进行终点测量。主要终点是替西帕肽与安慰剂相比对从基线到治疗第 28 周的钳夹处置指数（结合胰岛素分泌和敏感性的测量）变化的影响，并在药效学分析集中进行了分析，该分析集中包括所有随机分配的参与者，他们接受至少一剂研究药物并具有可评估的药效学数据。在安全人群中分析了安全性，该人群包括接受至少一剂研究药物的所有随机分配的参与者。次要终点包括 tirzepatide 与 semaglutide 对钳夹处置指数从基线到治疗第 28 周的变化、血糖控制、总胰岛素分泌率、M 值（胰岛素敏感性）以及空腹和餐后胰高血糖素浓度的影响。探索性终点包括空腹和餐后胰岛素浓度的变化。该研究已在 ClinicalTrials.gov 注册，NCT03951753，并且已完成。

发现

在 2019 年 6 月 28 日至 2021 年 4 月 8 日期间，我们筛选了 184 名个体，招募了 117 名参与者，所有参与者均被纳入安全人群（tirzepatide 15 mg 组 45 人，semaglutide 1 mg 组 44 人，semaglutide 1 mg 组 28 人）安慰剂组）。由于因缺失或无法评估的数据而中断和排除，每个治疗组中的 39 名患者和安慰剂组中的 24 名患者构成了药效学分析组。使用 tirzepatide，钳夹处置指数从基线的最小二乘均值 0·3 pmol m ^–2 L min ^–2 kg ^–1 (SE 0·03) 增加 1·9 pmol m ^–2 L min ^–2 kg ^{– 1} (0·16) 至总计 2·3 pmol m ^–2 L min ^–2kg ^–1 (SE 0·16) 在第 28 周时，使用安慰剂时，钳夹处置指数与基线相比没有太大变化（基线时最小二乘均值 0·4 pmol m ^–2 L min ^–2 kg ^–1 [SE 0 ·04]；相对于基线的变化 0·0 pmol m ^–2 L min ^–2 kg ^–1 [0·03]；第 28 周最小二乘均值 0·3 [SE 0·03]；估计治疗差异 [ETD] 替西帕肽与安慰剂相比 1·92 [95% CI 1·59–2·24]；p<0·0001)。tirzepatide 对钳夹处置指数的改善显着大于 semaglutide (ETD 0·84 pmol m ^–2 L min ^–2 kg ^–1[95% CI 0·46–1·21]）。这一结果反映了总胰岛素分泌率 (ETD 102·09 pmol min ^–1 m ^–2 [51·84–152·33]) 和胰岛素敏感性 (ETD 1·52 mg min ^–1 kg ^{–1 ) 的显着改善}[0·53–2·52]) 用于替西帕肽与索马鲁肽。在膳食耐受性测试中，与安慰剂相比，tirzepatide 显着降低了葡萄糖波动（降低胰岛素和胰高血糖素浓度），对这些变量的影响大于使用 semaglutide。替西帕肽和索马鲁肽的安全性相似，胃肠道不良事件最常见（11 [24%]、13 [30%] 和 7 [25%] 有恶心；9 [20%]、13 [30%] ]，6 例 [21%] 腹泻；以及 3 例 [7%]、5 例 [11%] 和 1 例 [4%] 呕吐，分别用于替西帕肽、索马鲁肽和安慰剂）。没有死亡。

解释

GIP/GLP-1 受体激动剂 tirzepatide 在 2 型糖尿病中的升糖功效是由于糖尿病病理生理学的关键成分（即 β 细胞功能、胰岛素敏感性和胰高血糖素分泌）的同时改善。这些影响很大，有助于解释在 3 期研究中观察到的 tirzepatide 显着的降糖能力。

资金

礼来。