Department of Medicine, Division of Endocrinology, Diabetes & Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Endocrinology and Diabetes, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
Lancet. 2023 Aug 26;402(10403):693-704. doi: 10.1016/S0140-6736(23)01127-3. Epub 2023 Jun 26.
Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes.
This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete.
Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related.
Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified.
Novo Nordisk.
每日口服一次的司美格鲁肽是一种有效的 2 型糖尿病治疗药物。我们旨在研究一种新的口服司美格鲁肽制剂，在 14 毫克的批准剂量基础上，以更高的研究剂量用于血糖控制不佳的 2 型糖尿病成人患者。
这项全球性、多中心、随机、双盲、3b 期临床试验在 14 个国家的 177 个地点进行，纳入了糖化血红蛋白（HbA）8.0-10.5%（64-91mmol/mol）、BMI 为 25.0kg/m2 或以上、正在使用一种或多种口服降糖药物稳定治疗的 2 型糖尿病成人患者。参与者通过交互式网络应答系统以 1:1:1 的比例随机分配，接受每日一次的口服司美格鲁肽 14mg、25mg 或 50mg 治疗，持续 68 周。研究者、现场工作人员、试验参与者和试验赞助商工作人员在整个试验过程中对剂量分配均不知情。主要终点是在治疗意向人群中，从基线到第 52 周时的 HbA 变化，采用治疗意向估计值进行评估。在至少接受一次试验药物治疗的所有参与者中评估安全性。这项试验在 ClinicalTrials.gov 上注册，注册号为 NCT04707469，在欧洲临床试验注册中心的注册号为 EudraCT 2020-000299-39，现已完成。
在 2021 年 1 月 15 日至 9 月 29 日期间，共筛选了 2294 人，其中 1606 人（n=936[58.3%]男性；n=670[41.7%]女性；平均[标准差]年龄 58.2[10.8]岁）接受了 14mg（n=536）、25mg（n=535）或 50mg（n=535）的口服司美格鲁肽治疗。基线时，平均（标准差）HbA 为 9.0%（0.8；74.4mmol/L[8.3]），平均体重为 96.4kg（21.6）。第 52 周时，HbA 的平均（标准差）变化分别为口服司美格鲁肽 14mg 组 -1.5 个百分点（0.05）、25mg 组 -1.8 个百分点（0.06）（估计治疗差异[ETD] -0.27，95%CI -0.42 至 -0.12；p=0.0006）和 50mg 组 -2.0 个百分点（0.06）（ETD -0.53，-0.68 至 -0.38；p<0.0001）。在口服司美格鲁肽 14mg 组、25mg 组和 50mg 组中，分别有 404（76%）、422（79%）和 428（80%）名参与者报告了不良事件。大多数为轻至中度的胃肠道疾病，在口服司美格鲁肽 25mg 和 50mg 组比 14mg 组更常见。试验期间发生了 10 例死亡；均未判定与治疗相关。
在血糖控制不佳的 2 型糖尿病成人患者中，与 14mg 相比，口服司美格鲁肽 25mg 和 50mg 可更有效地降低 HbA 和体重。未发现新的安全性问题。
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