摘要：\u003C\u002Fh2\u003E\u003Cp\u003E1Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial (译名：口服semaglutide与皮下利拉鲁肽和安慰剂治疗2型糖尿病（PIONEER 4）：一项随机，双盲，3a期试验)\u003C\u002Fp\u003E\u003Cp\u003E发表时间：2019-07-06 \u003C\u002Fp\u003E\u003Cp\u003E原文作者：Pratley R, Amod A, Hoff ST, et al.\u003C\u002Fp\u003E\u003Cp\u003EBACKGROUND:Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E) and weight, but are currently only \u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-1\"\u003Eapp\u003C\u002Fi\u003Eroved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E背景：\u003C\u002Fstrong\u003E胰高血糖素样肽-1（GLP-1）受体激动剂是治疗2型糖尿病，降低糖化血红蛋白（HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E）和体重的有效方法，但目前仅被批准用作皮下注射。\u003C\u002Fp\u003E\u003Cp\u003EMETHODS:In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA\u003Csub\u003E1c\u003C\u002Fsub\u003Eof 7·0-9·5% (53-80·3 mmol\u002Fmol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E(oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-4\"\u003E30\u003C\u002Fi\u003E.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E方法：\u003C\u002Fstrong\u003E在这项随机，双盲，双模拟，3a期试验中，我们从12个国家的100个地点招募了2型糖尿病患者。

"\u003Cp\u003E国内外一直有“外有柳叶刀，内有新英格兰”的说法。今天小编就带领大家共同探索《柳叶刀》（ Lancet ）的神秘面纱。\u003C\u002Fp\u003E\u003Cimg src=\"http:\u002F\u002Fp3.pstatp.com\u002Flarge\u002Fpgc-image\u002FRF2VyurGHbAaML\" img_width=\"134\" img_height=\"43\" alt=\"顶级医学期刊《柳叶刀》：最新论文全文电子书限量领\" inline=\"0\"\u003E\u003Cp\u003E\u003Cstrong\u003E期刊介绍\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cp\u003E《柳叶刀》（The Lancet ）诞生于1823年，是一本综合性医学周刊。近200年来，《柳叶刀》一直致力于用最好的科学推动更好的生活。\u003C\u002Fp\u003E\u003Cp\u003E《柳叶刀》以其在全世界所拥有的高影响因子，以致有一群重要的读者阶层来支持它。期刊登载有：原创性的研究文章、评论文章（\"小组讨论\"及\"评论\"）、社论、书评、短篇研究文章、也有其它一些在刊内常登载的文章诸如：特刊消息、及案例报道等。\u003C\u002Fp\u003E\u003Cp\u003E《柳叶刀医学期刊》被视为一种\"核心的\"医学综合期刊；其它同性质的刊物有新英格兰医学期刊、美国医学协会期刊、及英国医学期刊。\u003C\u002Fp\u003E\u003Cblockquote\u003E\u003Cbr\u003E\u003Cp\u003E\u003Cstrong\u003E期刊名称：\u003C\u002Fstrong\u003ELancet\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003ESCI缩写：\u003C\u002Fstrong\u003ELANCET\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E创刊时间：\u003C\u002Fstrong\u003E1823\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E出版周期：\u003C\u002Fstrong\u003EWeekly\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E国家：\u003C\u002Fstrong\u003EEngland\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E总引用：\u003C\u002Fstrong\u003E247292\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E2018年影响因子：59.10\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cbr\u003E\u003C\u002Fblockquote\u003E\u003Cimg src=\"http:\u002F\u002Fp1.pstatp.com\u002Flarge\u002Fpgc-image\u002FRWf9sUEDJXHgd3\" img_width=\"594\" img_height=\"326\" alt=\"顶级医学期刊《柳叶刀》：最新论文全文电子书限量领\" inline=\"0\"\u003E\u003Cp\u003E今日重磅福利\u003C\u002Fp\u003E\u003Cp\u003E小编特意精选了7月份《柳叶刀》最新发布、最权威的7篇论文，为更好地交流学习，我们免费提供以上7篇论文PDF版电子书全文，欢迎\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-3\"\u003E下载\u003C\u002Fi\u003E学习。\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E领取方式很简单\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E最新论文学习\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cp\u003E\u003C\u002Fp\u003E\u003Ch2\u003E以下对柳叶刀7月6号发表的一篇论文：口服semaglutide与皮下利拉鲁肽和安慰剂治疗2型糖尿病（PIONEER 4）：一项随机，双盲，3a期试验论文进行学习。\u003C\u002Fh2\u003E\u003Cp\u003E1Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial (译名：口服semaglutide与皮下利拉鲁肽和安慰剂治疗2型糖尿病（PIONEER 4）：一项随机，双盲，3a期试验)\u003C\u002Fp\u003E\u003Cp\u003E发表时间：2019-07-06 \u003C\u002Fp\u003E\u003Cp\u003E原文作者：Pratley R, Amod A, Hoff ST, et al.\u003C\u002Fp\u003E\u003Cp\u003EBACKGROUND:Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E) and weight, but are currently only \u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-1\"\u003Eapp\u003C\u002Fi\u003Eroved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E背景：\u003C\u002Fstrong\u003E胰高血糖素样肽-1（GLP-1）受体激动剂是治疗2型糖尿病，降低糖化血红蛋白（HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E）和体重的有效方法，但目前仅被批准用作皮下注射。\u003C\u002Fp\u003E\u003Cp\u003E将口服利马鲁肽（一种新型GLP-1激动剂）与皮下利拉鲁肽和安慰剂进行比较，用于2型糖尿病患者。\u003C\u002Fp\u003E\u003Cp\u003EMETHODS:In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA\u003Csub\u003E1c\u003C\u002Fsub\u003Eof 7·0-9·5% (53-80·3 mmol\u002Fmol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E(oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-4\"\u003E30\u003C\u002Fi\u003E.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E方法：\u003C\u002Fstrong\u003E在这项随机，双盲，双模拟，3a期试验中，我们从12个国家的100个地点招募了2型糖尿病患者。\u003C\u002Fp\u003E\u003Cp\u003E符合条件的患者年龄为18岁或以上，患有HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E在有或没有钠 - 葡萄糖共转运蛋白-2抑制剂的稳定剂量的二甲双胍（≥1500mg或最大耐受）下，7·0-9·5％（53-80·3mmol \u002F mol）。\u003C\u002Fp\u003E\u003Cp\u003E参与者被随机分配（2：2：1），具有交互式网络反应系统，并按背景降糖药物和原产国分层，每日一次口服司美鲁肽（剂量递增至14 mg），每日一次皮下利拉鲁肽（剂量升高至1.8mg），或安慰剂52周。\u003C\u002Fp\u003E\u003Cp\u003E确定了两项估计：治疗政策（不论研究药物停药或救援药物）和试验产品（假设所有参与者均为研究药物，无需急救药物），所有参与者均被随机分配。治疗政策的主要原因是主要的因素。\u003C\u002Fp\u003E\u003Cp\u003E\u003Csub\u003E1c\u003C\u002Fsub\u003E（口服司美鲁肽优越性VS安慰剂和非劣效性[余量：0·4％]和优越性 VS皮下利拉鲁肽）和验证次要终点是从基线的变化至26周体重（口服司美鲁肽优越性 VS安慰剂和利拉鲁肽）。在接受至少一剂研究药物的所有参与者中评估安全性。\u003C\u002Fp\u003E\u003Cp\u003E该试验在Clinicaltrials.gov注册，编号为NCT02863419，欧洲临床试验注册编号为EudraCT 2015-005210-\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-4\"\u003E30\u003C\u002Fi\u003E。\u003C\u002Fp\u003E\u003Cp\u003EFINDINGS:Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA\u003Csub\u003E1c\u003C\u002Fsub\u003Eat week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E(estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA\u003Csub\u003E1c\u003C\u002Fsub\u003Ethan both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]).\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E结果：\u003C\u002Fstrong\u003E2016年8月10日至2017年2月7日期间，筛选了950名患者，其中711名符合条件，随机分配至口服司美鲁肽（n=285），皮下利拉鲁肽（n=284）或安慰剂（n=142）。\u003C\u002Fp\u003E\u003Cp\u003E711名参与者中有341名（48％）为女性，平均年龄为56岁（标准差10）。所有参与者至少服用一剂研究药物，口服司美鲁肽组277例（97％），利拉鲁肽组274例（96％），安慰剂组134例（94％）完成52周试用期。\u003C\u002Fp\u003E\u003Cp\u003EHbA\u003Csub\u003E1c\u003C\u002Fsub\u003E与基线的平均变化在第26周，口服司美鲁肽为-1·2％（SE 0·1），皮下利拉鲁肽为-1·1％（SE0·1），安慰剂为-0·2％（SE 0·1）。口服利马鲁肽在降低HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E方面不逊于皮下利拉鲁肽 （估计治疗差异[ETD] -0·1％，95％CI -0.3~0.0; p <0.0001）且优于安慰剂（ETD） -1·1％，-1·2至-0·9; p <0.0001）使用治疗政策目标。\u003C\u002Fp\u003E\u003Cp\u003E通过使用试验产品，口服semaglutide的HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E显着降低 皮下利拉鲁肽（ETD -0·2％，95％CI -0·3至-0·1; p=0,0056）和安慰剂（ETD-1％，-1·4~-1·0）第26周时，口服semaglutide导致体重减轻（-4·4 kg [SE 0·2]），而利拉鲁肽（-3·1 kg [SE 0·2]; ETD -1） ·2 kg，95％CI -1·9至-0·6; p = 0·0003）和安慰剂（-0.5 kg [SE 0·3]; ETD -3·8 kg，-4·7 to在第26周（治疗方针）-3·0; p <0·0001）。\u003C\u002Fp\u003E\u003Cp\u003E通过使用试验产品，第26周时口服利马鲁肽的体重减轻明显大于皮下利拉鲁肽（-1.5 kg，95％CI -2·2至-0.9;p<0.0001）和安慰剂（ETD -4·0 kg，-4·8至-3·2; p <0.0001）。\u003C\u002Fp\u003E\u003Cp\u003EINTERPRETATION:Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cstrong\u003E解释：\u003C\u002Fstrong\u003E在第26周时，口服利拉鲁肽在降低HbA\u003Csub\u003E1c\u003C\u002Fsub\u003E方面优于皮下利拉鲁肽，优于安慰剂，在降低体重方面优于利拉鲁肽和安慰剂。口服利马鲁肽的安全性和耐受性与皮下利拉鲁肽相似。\u003C\u002Fp\u003E\u003Cp\u003E口服semaglutide的使用可能导致在糖尿病治疗连续护理中更早开始GLP-1受体激动剂治疗。\u003C\u002Fp\u003E\u003Cp\u003E22-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial (译名：2厘米与4厘米手术切除边缘的原发性皮肤黑色素瘤厚度超过2毫米：多中心，随机试验的长期随访)\u003C\u002Fp\u003E\u003Cp\u003E3\u003Cstrong\u003EExpanding traditional tendon-based techniques with nerve transfers for the restoration of upper limb function in tetraplegia: a prospective case series(译名：扩大传统的肌腱技术与神经转移恢复四肢瘫痪的上肢功能：一个前瞻性病例系列)\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cp\u003E4Risankizumab compared with adalimumab in patients with moderate-to-severe plaque psoriasis (IMMvent): a randomised, double-blind, active-comparator-controlled phase 3 trial (译名：Risankizumab与中度至重度斑块状银屑病（IMMvent）患者中的阿达木单抗相比：一项随机，双盲，主动 - 比较对照控制的3期试验)\u003C\u002Fp\u003E\u003Cp\u003E5The public health control of scabies: priorities for research and action (译名：疥疮的公共卫生控制：研究和行动的优先事项)\u003C\u002Fp\u003E\u003Cp\u003E6Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study (译名：对于新诊断的多发性骨髓瘤（CASSIOPEIA），在自体干细胞移植之前和之后使用或不使用daratumumab的硼替佐米，沙利度胺和地塞米松：一项随机，开放标记的3期研究)\u003C\u002Fp\u003E\u003Cp class=\"\"\u003E7Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial (译名：中风后机器人辅助训练（RATULS）：一项多中心随机对照试验)\u003C\u002Fp\u003E\u003Cp\u003E《顶级医学期刊介绍系列》栏目\u003C\u002Fp\u003E\u003Cp\u003E该文章来自《顶级医学期刊介绍系列》栏目，本篇为第2期。《顶级医学期刊介绍系列》是知识银行推出的全新栏目，主要对世界顶级医学期刊做简单的介绍并对最新、最权威的论文做汇总集锦，旨在帮助大家了解最新期刊和论文学习，是一个学术交流的平台，每周发布在该\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-4\"\u003E微信\u003C\u002Fi\u003E平台，请大家持续\u003Ci class=\"chrome-extension-mutihighlight chrome-extension-mutihighlight-style-6\"\u003E关注\u003C\u002Fi\u003E。\u003C\u002Fp\u003E\u003Cimg src=\"http:\u002F\u002Fp9.pstatp.com\u002Flarge\u002Fpgc-image\u002FREQqWarBilUqDw\" img_width=\"1080\" img_height=\"61\" alt=\"顶级医学期刊《柳叶刀》：最新论文全文电子书限量领\" inline=\"0\"\u003E\u003Cp\u003E\u003Cstrong\u003E今日互动\u003C\u002Fstrong\u003E\u003C\u002Fp\u003E\u003Cp\u003E预测下，《柳叶刀》2019年的影响因子是多少？\u003C\u002Fp\u003E\u003Cp\u003E注： 以上翻译来自Google翻译；资料仅供内部学习交流，请勿用作商用。\u003C\u002Fp\u003E"'.slice(6, -6), groupId: '6715325499108753928