Davies Melanie, Pieber Thomas R, Hartoft-Nielsen Marie-Louise, Hansen Oluf K H, Jabbour Serge, Rosenstock Julio
Diabetes Research Centre, University of Leicester, Leicester, United Kingdom.
Medical University of Graz, Graz, Austria.
JAMA. 2017 Oct 17;318(15):1460-1470. doi: 10.1001/jama.2017.14752.
Glucagon-like peptide-1 (GLP-1) receptor agonists are effective therapies for the treatment of type 2 diabetes and are all currently available as an injection.
To compare the effects of oral semaglutide with placebo (primary) and open-label subcutaneous semaglutide (secondary) on glycemic control in patients with type 2 diabetes.
DESIGN, SETTING, AND PATIENTS: Phase 2, randomized, parallel-group, dosage-finding, 26-week trial with 5-week follow-up at 100 sites (hospital clinics, general practices, and clinical research centers) in 14 countries conducted between December 2013 and December 2014. Of 1106 participants assessed, 632 with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized. Randomization was stratified by metformin use.
Once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.
The primary end point was change in hemoglobin A1c (HbA1c) from baseline to week 26. Secondary end points included change from baseline in body weight and adverse events.
Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, -0.7% to -1.9%) and subcutaneous semaglutide (-1.9%) and placebo (-0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, -0.4% to -1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, -2.1 kg to -6.9 kg) and subcutaneous semaglutide (-6.4 kg) vs placebo (-1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, -0.9 to -5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.
Among patients with type 2 diabetes, oral semaglutide resulted in better glycemic control than placebo over 26 weeks. These findings support phase 3 studies to assess longer-term and clinical outcomes, as well as safety.
clinicaltrials.gov Identifier: NCT01923181.
胰高血糖素样肽-1（GLP-1）受体激动剂是治疗2型糖尿病的有效疗法，目前均为注射剂。
比较口服司美格鲁肽与安慰剂（主要）以及开放标签皮下注射司美格鲁肽（次要）对2型糖尿病患者血糖控制的影响。
设计、地点和患者：2013年12月至2014年12月在14个国家的100个地点（医院诊所、全科医疗和临床研究中心）进行的2期随机、平行组、剂量探索性、为期26周的试验，并有5周的随访。在1106名评估参与者中，632名仅通过饮食和运动或稳定剂量二甲双胍血糖控制不佳的2型糖尿病患者被随机分组。随机分组按二甲双胍使用情况进行分层。
每日一次口服2.5毫克（n = 70）、5毫克（n = 70）、10毫克（n = 70）、20毫克（n = 70）的司美格鲁肽，40毫克4周剂量递增（标准递增；n = 7）、40毫克8周剂量递增（缓慢递增；n = 70）、40毫克2周剂量递增（快速递增；n = 70），口服安慰剂（n = 71；双盲）或每周一次皮下注射1.0毫克司美格鲁肽（n = 70），共26周。
主要终点是从基线到第26周糖化血红蛋白（HbA1c）的变化。次要终点包括体重相对于基线的变化和不良事件。
各治疗组的基线特征具有可比性。在632名随机分组的患者中（平均年龄57.1岁[标准差10.6]；男性395名[62.7%]；糖尿病病程6.3年[标准差5.2]；体重92.3千克[标准差16.8]；体重指数31.7[标准差4.3]），583名（92%）完成了试验。从基线到第26周，口服司美格鲁肽（剂量依赖性范围为-0.7%至-1.9%）、皮下注射司美格鲁肽（-1.9%）和安慰剂（-0.3%）组的HbA1c水平平均变化均降低；口服司美格鲁肽组与安慰剂组相比降低显著（口服司美格鲁肽与安慰剂的剂量依赖性估计治疗差异[ETD]范围为-0.4%至-1.6%；2.5毫克时P = 0.01，其他所有剂量时P < 0.001）。与安慰剂组（-1.2千克）相比，口服司美格鲁肽（剂量依赖性范围为-2.1千克至-6.9千克）和皮下注射司美格鲁肽（-6.4千克）组体重减轻更多，口服司美格鲁肽10毫克及以上剂量与安慰剂相比体重减轻显著（剂量依赖性ETD范围为-0.9至-5.7千克；P < 0.001）。口服司美格鲁肽组63%至86%（490名患者中的371名）、皮下注射司美格鲁肽组81%（69名患者中的56名）和安慰剂组68%（71名患者中的48名）报告了不良事件；轻度至中度胃肠道事件最为常见。
在2型糖尿病患者中，口服司美格鲁肽在26周内血糖控制优于安慰剂。这些发现支持进行3期研究以评估长期疗效、临床结局以及安全性。
clinicaltrials.gov标识符：NCT01923181
