Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan.
Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
Lancet Diabetes Endocrinol. 2020 May;8(5):377-391. doi: 10.1016/S2213-8587(20)30075-9.
Given the unique phenotype of type 2 diabetes in Japanese patients, novel therapies such as oral semaglutide require evaluation in this population. PIONEER 9 aimed to assess the dose-response of oral semaglutide and to compare the efficacy and safety of oral semaglutide with placebo and a subcutaneous GLP-1 receptor agonist in a Japanese population.
PIONEER 9 was a 52-week, phase 2/3a, randomised, controlled trial done at 16 sites (clinics and university hospitals) in Japan. Japanese patients aged 20 years or older with uncontrolled type 2 diabetes managed by diet or exercise or with oral glucose-lowering drug monotherapy (washed out) were randomly assigned (1:1:1:1:1) to receive double-blind once-daily oral semaglutide (3 mg, 7 mg, or 14 mg) or placebo, or open-label subcutaneous once-daily liraglutide 0·9 mg. The primary endpoint was change in HbA from baseline to week 26 with the trial product (primary) estimand (which assumes all patients remained on trial product without rescue medication use) in all randomly assigned patients. This trial is registered with ClinicalTrials.gov, NCT03018028.
Between Jan 10, and July 11, 2017, 243 patients were randomly assigned to oral semaglutide 3 mg (n=49), 7 mg (n=49), or 14 mg (n=48), or placebo (n=49), or to liraglutide 0·9 mg (n=48). Changes in HbA from baseline (mean 8·2%) to week 26 were dose-dependent with oral semaglutide (mean change -1·1% [SE 0·1] for oral semaglutide 3 mg, -1·5% [0·1] for 7 mg, and -1·7% [0·1] for 14 mg), -0·1% (0·1) with placebo, and -1·4% (0·1) with liraglutide 0·9 mg. Estimated treatment differences for change in HbA compared with placebo were -1·1 percentage points (95% CI -1·4 to -0·8; p<0·0001) for oral semaglutide 3 mg, -1·5 percentage points (-1·7 to -1·2; p<0·0001) for oral semaglutide 7 mg, and -1·7 percentage points (-2·0 to -1·4; p<0·0001) for oral semaglutide 14 mg. Estimated treatment differences for change in HbA compared with liraglutide 0·9 mg were 0·3 percentage points (95% CI -0·0 to 0·6; p=0·0799) for oral semaglutide 3 mg, -0·1 percentage points (-0·4 to 0·2; p=0·3942) for oral semaglutide 7 mg, and -0·3 percentage points (-0·6 to -0·0; p=0·0272) for oral semaglutide 14 mg. Gastrointestinal events, predominantly of mild or moderate severity, were the most frequently reported class of adverse event with oral semaglutide: constipation was most common, occurring in five to six (10-13%) patients with oral semaglutide, three (6%) with placebo, and nine (19%) with liraglutide 0·9 mg.
This study showed that oral semaglutide provides significant reductions in HbA compared with placebo in a dose-dependent manner in Japanese patients with type 2 diabetes, and has a safety profile consistent with that of GLP-1 receptor agonists.
Novo Nordisk.
鉴于 2 型糖尿病在日本患者中的独特表型，新型疗法如口服司美格鲁肽需要在该人群中进行评估。PIONEER 9 旨在评估口服司美格鲁肽的剂量反应，并比较口服司美格鲁肽与安慰剂和皮下 GLP-1 受体激动剂在日本人群中的疗效和安全性。
PIONEER 9 是一项 52 周、2/3a 期、随机、对照试验，在日本的 16 个地点（诊所和大学医院）进行。年龄在 20 岁或以上、通过饮食或运动控制或口服降糖药物单药治疗（洗脱）的未控制 2 型糖尿病患者，随机分配（1:1:1:1:1）接受每日一次口服司美格鲁肽（3mg、7mg 或 14mg）或安慰剂，或每日一次皮下注射利拉鲁肽 0·9mg。主要终点是所有随机分配患者的试验产品（主要）估计值（假设所有患者继续使用试验产品，不使用救援药物）从基线到第 26 周时的 HbA 变化。该试验在 ClinicalTrials.gov 上注册，NCT03018028。
2017 年 1 月 10 日至 7 月 11 日期间，243 名患者被随机分配至口服司美格鲁肽 3mg（n=49）、7mg（n=49）或 14mg（n=48）或安慰剂（n=49），或利拉鲁肽 0·9mg（n=48）。口服司美格鲁肽的 HbA 从基线（平均 8·2%）到第 26 周的变化与剂量有关（口服司美格鲁肽 3mg 组为-1·1%[0·1]，7mg 组为-1·5%[0·1]，14mg 组为-1·7%[0·1]），安慰剂组为-0·1%（0·1），利拉鲁肽 0·9mg 组为-1·4%（0·1）。与安慰剂相比，HbA 变化的估计治疗差异分别为口服司美格鲁肽 3mg 组-1·1 个百分点（95%CI -1·4 至-0·8；p<0·0001），口服司美格鲁肽 7mg 组-1·5 个百分点（-1·7 至-1·2；p<0·0001），口服司美格鲁肽 14mg 组-1·7 个百分点（-2·0 至-1·4；p<0·0001）。与利拉鲁肽 0·9mg 相比，HbA 变化的估计治疗差异分别为口服司美格鲁肽 3mg 组 0·3 个百分点（95%CI 0·0 至 0·6；p=0·0799），口服司美格鲁肽 7mg 组 0·1 个百分点（95%CI -0·4 至 0·2；p=0·3942），口服司美格鲁肽 14mg 组 0·3 个百分点（95%CI -0·6 至 -0·0；p=0·0272）。最常报告的胃肠道事件是口服司美格鲁肽最常见的不良事件类别，主要为轻度或中度严重程度：便秘最常见，口服司美格鲁肽组有五到六名（10-13%）患者发生，安慰剂组有三名（6%）患者发生，利拉鲁肽 0·9mg 组有九名（19%）患者发生。
这项研究表明，在日本 2 型糖尿病患者中，与安慰剂相比，口服司美格鲁肽以剂量依赖性方式显著降低 HbA，且安全性与 GLP-1 受体激动剂一致。
诺和诺德。
