美国礼来公司Manige Konig团队研究了口服Orforglipron治疗2型糖尿病患者的疗效和安全性。这一研究成果于2023年6月23日发表在《柳叶刀》杂志上。

Orforglipron是一种口服非肽胰高血糖素样肽-1（GLP-1）受体激动剂，正开发用于治疗2型糖尿病和肥胖症。研究组评估了Orforglipron与安慰剂或杜拉鲁肽在2型糖尿病患者中的疗效和安全性。

在这项为期26周的临床2期双盲、随机、多中心研究中，研究组从美国、匈牙利、波兰和斯洛伐克的45个中心（私人诊所、医院和研究中心）招募参与者。18岁及以上患有2型糖尿病的成年参与者接受饮食和运动治疗，服用或不服用二甲双胍，糖化血红蛋白（HbA_1c）为7.0–10.5%，稳定BMI为23 kg/m²或以上，通过互动网络反应系统随机分配（5:5:5:5:5:3:3:3:3）安慰剂、杜拉鲁肽1.5 mg每周一次，或Orforglipron 3 mg、12 mg、24 mg、36 mg（第1组），36 mg（第2组）、45 mg（第1组）或45 mg（2组），每天一次，无食物或水限制。对36 mg和45 mg队列中的每一组分别评估了两种不同的剂量递增方案。

参与者对研究药物杜拉鲁肽和安慰剂双盲。主要疗效结局是在第26周时，Orforglipron与安慰剂相比，HbA_1c从基线的平均变化。对所有随机分配的参与者进行疗效分析，这些参与者至少接受了一剂研究药物，并排除了永久停止研究药物或开始抢救药物后的数据。对所有至少接受一剂研究治疗的参与者的安全性进行了分析。

在2021年9月15日至2022年9月30日期间，569名参与者接受了筛查，383人被登记并随机分配到一组。352人（92%）完成了研究，303人（79%）完成了26周的治疗。基线时，平均年龄为58.9岁，HbA_1c为8.1%，BMI为35.2 kg/m²，226名（59%）为男性，157名（41%）为女性。在第26周，Orforglipron组HbA_1c的平均变化高达-2.10%（安慰剂校正后为-1.67%），而安慰剂组为-0.43%，杜拉鲁肽组为-1.10%。与安慰剂相比，Orforglipron的HbA_1c降低在统计学上更为显著。

在第26周时，Orforglipron的平均体重变化高达-10.1 kg（安慰剂校正后为-7.9 kg），而安慰剂为-2.2 kg，杜拉鲁肽为-3.9 kg。Orforglipron治疗组的治疗突发不良事件发生率为61.8%至88.9%，而安慰剂组为61.8%，杜拉鲁肽组为56.0%。大多数是轻度至中度的胃肠道事件（Orforglipron组为44.1%至70.4%，安慰剂组为18.2%，杜拉鲁肽组为34.0%）。三名接受Orforglipron治疗的参与者和一名接受杜拉鲁肽治疗的参与者患有临床显著的低血糖症（<54 mg/dL[<3 mmol/L]），没有参与者患有严重低血糖症。安慰剂组发生1例死亡，与研究治疗无关。

研究结果表明，在这项2期临床试验中，与安慰剂或杜拉鲁肽相比，剂量为12 mg或更大的新型口服非肽GLP-1受体激动剂Orforglipron显示出HbA_1c和体重的显著降低。不良事件概况与处于类似发展阶段的其他GLP-1受体激动剂相似。Orforglipron可能为注射型GLP-1受体激动剂和口服索马鲁肽提供一种替代品，有望减轻2型糖尿病患者的用药负担，实现治疗目标。

附：英文原文

Title: Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

Author: Juan P Frias, Stanley Hsia, Sarah Eyde, Rong Liu, Xiaosu Ma, Manige Konig, Christof Kazda, Kieren J Mather, Axel Haupt, Edward Pratt, Deborah Robins

Issue&Volume: 2023-06-23

Abstract:

Background

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes.

Methods

In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0–10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed.

Findings

Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to –2·10% (–1·67% placebo adjusted), versus –0·43% with placebo and –1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference –0·8% to –1·7%). Change in mean bodyweight at week 26 was up to –10·1 kg (95% CI –11·5 to –8·7; 7·9 kg placebo adjusted [–9·9 to –5·9]) with orforglipron versus –2·2 kg (–3·6 to –0·7) for placebo and –3·9 kg (–5·3 to –2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment.

Interpretation

In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes.

DOI: 10.1016/S0140-6736(23)01302-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01302-8/fulltext