Novo Nordisk A/S, Søborg, Denmark.
Novo Nordisk A/S, Søborg, Denmark.
Lancet Diabetes Endocrinol. 2019 Mar;7(3):179-188. doi: 10.1016/S2213-8587(18)30372-3. Epub 2019 Jan 21.
Oral insulin 338 (I338) is a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate. We investigated the efficacy and safety of I338 versus subcutaneous insulin glargine (IGlar) in patients with type 2 diabetes.
This was a phase 2, 8-week, randomised, double-blind, double-dummy, active-controlled, parallel trial completed at two research institutes in Germany. Insulin-naive adult patients with type 2 diabetes, inadequately controlled on metformin monotherapy or combined with other oral antidiabetic drugs (HbA 7·0-10·0%; BMI 25·0-40·0 kg/m), were randomly assigned (1:1) to receive once-daily I338 plus subcutaneous placebo (I338 group) or once-daily IGlar plus oral placebo (IGlar group). Randomisation occurred by interactive web response system stratified by baseline treatment with oral antidiabetic drugs. Patients and investigators were masked to treatment assignment. Weekly insulin dose titration aimed to achieve a self-measured fasting plasma glucose (FPG) concentration of 4·4-7·0 mmol/L. The recommended daily starting doses were 2700 nmol I338 or 10 U IGlar, and maximum allowed doses throughout the trial were 16 200 nmol I338 or 60 U IGlar. The primary endpoint was treatment difference in FPG concentration at 8 weeks for all randomly assigned patients receiving at least one dose of trial product (ie, the full analysis set). The trial has been completed and is registered at ClinicalTrials.gov, number NCT02470039.
Between June 1, 2015, and Oct 19, 2015, 82 patients were screened for eligibility and 50 patients were randomly assigned to the I338 group (n=25) or the IGlar group (n=25). Mean FPG concentration at baseline was 9·7 (SD 2·8) in the I338 group and 9·1 (1·7) in the IGlar group. Least square mean FPG concentration at 8 weeks was 7·1 mmol/L (95% CI 6·4-7·8) in the I338 group and 6·8 mmol/L (6·5-7·1) in the IGlar group, with no significant treatment difference (0·3 mmol/L [-0·5 to 1·1]; p=0·46). I338 and IGlar were well tolerated by patients. Adverse events were reported in 15 (60%) patients in the I338 group and 17 (68%) patients in the IGlar group. The most common adverse events were diarrhoea (three [12%] patients in each group) and nasopharyngitis (five [20%] in the I338 group and two [8%] in the IGlar group). Most adverse events were graded mild (47 of 68 events), and no severe adverse events were reported. One patient in the IGlar group had a treatment-emergent serious adverse event (urogenital haemorrhage of moderate intensity, assessed by the investigator as unlikely to be related to treatment; the patient recovered). Incidence of hypoglycaemia was low in both groups (n=7 events in the I338 group; n=11 in the IGlar group), with no severe episodes.
I338 can safely improve glycaemic control in insulin-naive patients with type 2 diabetes with no evidence of a difference compared with insulin glargine, a widely used subcutaneously administered basal insulin. Further development of this particular oral insulin project was discontinued because I338 doses were high and, therefore, production of the required quantities of I338 for wide public use was deemed not commercially viable. Improvement of technologies involved in the product's development is the focus of ongoing research.
Novo Nordisk.
口服胰岛素 338（I338）是一种长效、基础胰岛素类似物，与吸收增强剂癸酸钠制成片剂。我们研究了 I338 与皮下注射甘精胰岛素（IGlar）在 2 型糖尿病患者中的疗效和安全性。
这是一项在德国的两个研究机构进行的为期 8 周的、随机、双盲、双模拟、阳性对照、平行试验。胰岛素初治的 2 型糖尿病成年患者，在接受二甲双胍单药治疗或联合其他口服降糖药物治疗的情况下血糖控制不佳（HbA1c 7.0-10.0%；BMI 25.0-40.0 kg/m2），随机（1:1）接受每日一次 I338 加皮下安慰剂（I338 组）或每日一次 IGlar 加口服安慰剂（IGlar 组）治疗。按基线接受口服降糖药物治疗分层进行交互网络反应系统随机分组。患者和研究者对治疗分组均不知情。每周调整胰岛素剂量，以达到自我监测的空腹血糖（FPG）浓度 4.4-7.0 mmol/L。推荐的起始日剂量为 2700 nmol I338 或 10 U IGlar，整个试验期间允许的最大剂量为 16200 nmol I338 或 60 U IGlar。主要终点是所有接受至少一剂试验产品（即全分析集）的随机分配患者的 FPG 浓度在 8 周时的治疗差异。该试验已完成并在 ClinicalTrials.gov 上注册，编号为 NCT02470039。
在 2015 年 6 月 1 日至 2015 年 10 月 19 日期间，有 82 名患者被筛选符合纳入标准，50 名患者被随机分配到 I338 组（n=25）或 IGlar 组（n=25）。I338 组的基线平均 FPG 浓度为 9.7（SD 2.8）mmol/L，IGlar 组为 9.1（1.7）mmol/L。I338 组和 IGlar 组在 8 周时的最小二乘均数 FPG 浓度分别为 7.1 mmol/L（95%CI 6.4-7.8）和 6.8 mmol/L（6.5-7.1），无显著治疗差异（0.3 mmol/L[-0.5 至 1.1]；p=0.46）。I338 和 IGlar 均被患者耐受良好。15 名（60%）I338 组患者和 17 名（68%）IGlar 组患者发生不良事件。最常见的不良事件是腹泻（两组各 3 例，12%）和鼻咽炎（I338 组 5 例，20%；IGlar 组 2 例，8%）。大多数不良事件为轻度（68 项事件中的 47 项），没有严重不良事件报告。IGlar 组有 1 例患者发生治疗后严重不良事件（中度强度的泌尿生殖系统出血，研究者评估不太可能与治疗有关；患者康复）。两组低血糖发生率均较低（I338 组 7 例，IGlar 组 11 例），无严重发作。
I338 可安全改善胰岛素初治的 2 型糖尿病患者的血糖控制，与广泛使用的皮下基础胰岛素甘精胰岛素相比，无证据表明存在差异。由于 I338 剂量较高，因此开发这种特殊的口服胰岛素项目已被停止，因此认为生产广泛使用所需数量的 I338 没有商业可行性。目前正在进行涉及产品开发的相关技术改进的研究。
诺和诺德。
