Evaluation of a POlypill and Colchicine for Risk Reduction in Patients With Established Atherosclerotic Cardiovascular Disease: The EPOCA Randomized Clinical Trial

The EPOCA study (Evaluation of a POlypill and Colchicine for risk reduction in patients with established Atherosclerotic cardiovascular disease) will be a randomized, superiority, parallel, 2x2 factorial, multicenter clinical trial which will include at least 7713 and up to a maximum of 10797 participants with established atherosclerotic cardiovascular disease.

开始日期2025-05-01

申办/合作机构-

NCT02596126

/ Completed临床3期IIT

Secondary Prevention of Cardiovascular Disease in the Elderly Trial

The purpose of this study is to evaluate the efficacy of a polypill strategy containing aspirin (100 mg), ramipril (2.5, 5 or 10 mgs), and atorvastatin (40 mgs) compared with the standard of care (usual care according to the local clinical practices at each participating country) in secondary prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and urgent revascularization) in elderly patients with a recent myocardial infarction.

开始日期2016-07-01

申办/合作机构

Istituto di Ricerche Farmacologiche Mario Negri

[+6]

NCT02791958

/ Unknown status临床2期

Pharmacodynamic Equivalence Study of Ramipril 10 mg and Atorvastatin 40 mg Administered as a Cardiovascular Fixed Dose Combination Pill AAR as Compared to Monotherapy With the Reference Products Altace® 10 mg and Lipitor® 40 mg

This study is to compare the pharmacodynamics of a Fixed Dose Combination Pill AAR (acetylsalicylic acid 100 mg, atorvastatin 40 mg and ramipril 10 mg) and the respective reference products, atorvastatin (Lipitor®) 40 mg and ramipril (Altace®) 10 mg.

开始日期2016-03-01

申办/合作机构

Ferrer Internacional SA

100 项与辛伐他汀/雷米普利/阿司匹林相关的临床结果

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100 项与辛伐他汀/雷米普利/阿司匹林相关的转化医学

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100 项与辛伐他汀/雷米普利/阿司匹林相关的专利（医药）

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项与辛伐他汀/雷米普利/阿司匹林相关的文献（医药）

2025-05-01·LANCET INFECTIOUS DISEASES

Albendazole–ivermectin co-formulation for the treatment of Trichuris trichiura and other soil-transmitted helminths: a randomised phase 2/3 trial

Article

作者: Bedane, Dereje ; Mwandawiro, Charles ; de Jesus, Áuria ; Messa, Augusto ; Gelaye, Woyneshet ; Kepha, Stella ; Algorta, Jaime ; Rono, Martin ; Gandasegui, Javier ; Mwahanje, Jusper ; Novela, Valdemiro ; Degarege, Dawit ; Mandomando, Inácio ; Muñoz, José ; Enbiale, Wendemagegn ; van Lieshout, Lisette ; Fleitas, Pedro E ; Krolewiecki, Alejandro

BACKGROUND:

Treatments for soil-transmitted helminthiases face challenges, especially in addressing Trichuris trichiura. Combination regimens, particularly of ivermectin and albendazole, are promising. We aimed to assess the safety, efficacy, and palatability of a combination tablet for the treatment of T trichiura, hookworm, and Strongyloides stercoralis infections among school-aged children in Ethiopia, Kenya, and Mozambique.

METHODS:

We conducted an adaptive phase 2/3, randomised, parallel-group, active-controlled, superiority trial in 15 schools in Ethiopia, Kenya, and Mozambique. Eligible participants for both phases were aged 5-18 years, weighed at least 15 kg, and were infected with T trichiura, hookworms, or S stercoralis. Participants were randomly assigned via a computer-generated sequence to either a single dose of a fixed-dose combination (FDC×1) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), three consecutive daily doses of an FDC (FDC×3) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), or a single dose of albendazole alone (400 mg) via block randomisation, stratified by soil-transmitted helminth species. Participants and those administering the treatments were not masked to treatment assignment, but those assessing the outcomes were masked. The primary outcome of phase 2 (conducted in Kenya only) was safety during the first 3 h after the intervention and for 7 days, and the primary outcome of phase 3 was efficacy (ie, the proportion of individuals cured at day 21 out of the total number infected at baseline) for T trichiura; both primary outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT05124691, and is terminated.

FINDINGS:

Between Jan 20, 2022, and March 24, 2023, 1001 participants were recruited (465 [46%] were female and 536 [54%] were male). 636 (64%) were infected with T trichiura, 360 (36%) with hookworm, and 104 (10%) with S stercoralis; 94 (9%) of 1001 participants had co-infections and were included in the analysis of each infecting species. A total of 243 participants were allocated to the albendazole group, 381 to the FDC×1 group, and 377 to the FDC×3 group. In both phase 2 and 3, gastrointestinal symptoms were the most common mild-to-moderate adverse events in the FDC groups, but resolved within 48 h without intervention. At least one treatment-related adverse event occurred in 34 (14%) of 243 participants in the albendazole group, 75 (20%) of 381 participants in the FDC×1 group, and 88 (23%) of 377 participants in the FDC×3 group. No serious adverse events occurred. For T trichiura, both FDC groups had a higher cure rate (97·2% [95% CI 95·2- 99·3] for FDC×3 and 82·9% [78·2-87·5] for FDC×1) than albendazole (35·9% [27·7-44·1]), with absolute differences of 61·3% (98% CI 50·2-71·2) and 47·0% (34·7-58·1), respectively. For hookworms, FDC×3 had a higher cure rate (95·0% [95% CI 91·1-98·9]) than albendazole (65·1% [56·0-74·2]), with absolute differences of 29·9% (98% CI 17·2-42·4), whereas FDC×1 had a similar cure rate (79·8% [72·8-86·9]) to albendazole. The sample size for efficacy evaluation of S stercoralis was not met.

INTERPRETATION:

An FDC of albendazole plus ivermectin has a similar safety profile but superior efficacy to albendazole alone against T trichiura infection and hookworms. These findings open opportunities for control of all soil-transmitted helminth species of interest, including potentially S stercoralis. Evaluation of safety in larger populations and implementation scenarios are the next steps for this innovation to promote its incorporation into programmatic activities.

FUNDING:

European and Developing Countries Clinical Trials Partnership.

TRANSLATION:

For the Portuguese translation of the abstract see Supplementary Materials section.

2025-05-01·LANCET

Fixed-dose combination of obicetrapib and ezetimibe for LDL cholesterol reduction (TANDEM): a phase 3, randomised, double-blind, placebo-controlled trial

Article

作者: Davidson, Michael ; Kastelein, John ; Goldberg, Anne C ; Nicholls, Stephen J ; Hayden, Kierstyn ; Michos, Erin D ; Ditmarsch, Marc ; Stronczek, Amanda ; Mason, Denise ; Brennan, Danielle ; Neild, Annie L ; Tercek, Grace ; Sarraju, Ashish ; McGuire, Darren K ; Nissen, Steven E ; Kling, Douglas

BACKGROUND:

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe.

METHODS:

This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed.

FINDINGS:

Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0-73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were -48·6% (95% CI -58·3 to -38·9) versus placebo, -27·9% (-37·5 to -18·4) versus ezetimibe, and -16·8% (-26·4 to -7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo.

INTERPRETATION:

Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD.

FUNDING:

NewAmsterdam Pharma.

2025-04-22·JOURNAL OF MEDICAL MICROBIOLOGY

Targeted ‘knock out’ therapy with a combination antimicrobial regimen restores treatment options in the management of extensively drug-resistant carbapenemase-producing organisms

Article

作者: Donoghue, Orla ; McDermott, Sinead ; Ali, Saied

Introduction. Cefiderocol (FDC) and the combination of ceftazidime-avibactam and aztreonam (CZA+ATM) are emerging therapeutic options to combat carbapenemase-producing organisms (CPOs) that exhibit resistance due to multiple β-lactamases.Hypothesis/Gap Statement. Molecular diagnostics and specialized antimicrobial susceptibility testing (AST) are infrequently available in most clinical laboratories, and outputs from reference laboratories are not always timely. Practical methods must be explored to provide meaningful advice to treat infections due to CPOs in real time.Aim. To evaluate the in vitro efficacy of FDC and CZA+ATM against CPOs and to compare colistin (CST) MICs obtained locally with those from the reference laboratory.Methodology. CPOs isolated from 2017 to 2023 inclusive were retrieved. AST for FDC was performed using disc diffusion, CZA and ATM individually by E-tests and the E-test superposition method for the combination CZA+ATM. CST AST was performed locally using the VITEK2 system, and MICs were compared with those attained from the reference laboratory where manual broth microdilution is performed.Results. Fifty-eight CPOs were analysed. OXA-48 was the most frequently detected carbapenemase (37.9%, n=22). Co-existing β-lactamases of Ambler classes A and C were present for 79.3% of CPOs (n=46). Twenty-nine isolates (50%) were found to be susceptible to FDC. Fifty-seven isolates (98.3%) were susceptible to CST according to the VITEK2, compared to 44 of 47 tested isolates (93.6%) by the reference broth microdilution. Essential agreement was found to be 78.7%, and categorical agreement was 91.5% with one major error and three very major errors (VMEs) reported. CZA+ATM was tested against 26 CPOs, all of which harboured metallo-β-lactamases. Synergy was detected for all except one isolate where additivity was noted. Of the 32 isolates where combination therapy was not assessed, 29 (90.6%) possessed serine-β-lactamases and were susceptible to CZA monotherapy, whilst three (9.4%) possessed an isolated metallo-β-lactamase and were susceptible to ATM monotherapy.Conclusions. FDC appears to perform favourably against CPOs harbouring serine-β-lactamases, but not metallo-β-lactamases. The VITEK2 may provide presumptive categorical information for CST susceptibility, but MICs must be confirmed by broth microdilution as VMEs can lead to treatment failures. Moreover, our study confirms potent in vitro activity of CZA+ATM against CPOs expressing multiple β-lactamases.

项与辛伐他汀/雷米普利/阿司匹林相关的新闻（医药）

2025-02-09

·国际糖尿病idiabetes

大咖汇聚赋能基层，新版《中国糖尿病防治指南》全国巡讲正式启动！

点击“蓝字”关注我们编者按凝心聚力，乘“巳”而上。2025年2月9日，“《中国糖尿病防治指南(2024版)》发布暨赋能基层医路行项目”在南京正式启动。新版指南已于今年年初在线上发表，此次巡讲项目旨在深入解读新版指南，推动其在临床实践中的广泛应用，特别将焦点对准基层，力求通过这一系列巡讲，促进我国糖尿病诊疗与管理水平均质化发展。聚力启新章·赋能基层行朱大龙教授中华医学会糖尿病学分会主任委员、国家基层糖尿病防治管理办公室共同主任朱大龙教授在致辞中，首先对所有参与指南编写的专家作出的努力和贡献表示感谢。他表示，新版指南立足中国实践，与时俱进。不仅系统整合了国际前沿研究成果，收录了1000余篇最新文献，而且扩大了疾病覆盖范围。新版指南的发布为我国糖尿病防治工作指明了新方向，此次全国巡讲活动将有力推动其切实落地。同时，与之相应的英文版指南和基层版指南也即将问世，旨在向国际同行传递中国糖尿病领域的声音，或更好指导基层医生的规范化诊治工作。启动仪式新版指南[1]在多个方面进行了更新，主要有以下三大亮点： 01 治疗路径革新：强调个体化治疗，主张早期联合新版指南最大的亮点莫过于对“T2DM高血糖治疗路径”的革新，突出强调个体化治疗的重要性，血糖管理仍是基本策略；并特别指出，早期良好的血糖控制具有重要意义，早期联合是实现早期良好血糖控制的重要手段（A）。新版指南表示，早期强化血糖控制有利于远期获益。UKPDS 14年NHS监管下随访研究（2007-2021年）显示，与常规治疗组相比，强化治疗组心梗风险下降17%（P=0.002）、全因死亡风险下降10%（P=0.015）[2]。一项纳入7项RCT共40346例T2DM患者的荟萃分析显示，与常规治疗相比，强化降糖方案显著降低主要不良心血管事件（MACE）的发生风险达14%（P=0.007）[3]。 02 创新药物推荐：FRC首次纳入诊疗路径，获二联治疗和胰岛素起始推荐在早期联合治疗理念的驱动下，新版指南首次将FRC纳入诊疗路径，并将其作为HbA1c不达标的二联治疗推荐，以及口服药控制不佳T2DM患者胰岛素治疗的起始推荐。 FRC由基础胰岛素与GLP-1RA双组分组成，二者机制互补，可协同改善糖尿病八重奏中多达七重的病理生理机制；同时改善空腹和餐后血糖，促进全面血糖控制；在补充长效胰岛素的同时改善T2DM患者胰岛细胞功能。甘精胰岛素利司那肽注射液（简称甘精利司）作为代表性的FRC，在国内外T2DM人群中积累了丰富的循证证据，证实其可实现强效控糖，为二联治疗和胰岛素起始治疗提供更优的选择。 LixiLan-O-AP[4]研究纳入以中国人群为主的亚太地区成人受试者，经口服降糖药（OADs）治疗血糖控制不佳起始甘精利司治疗，HbA1c降幅高达1.9%，HbA1c达标率近80%，显著优于起始甘精胰岛素或利司那肽治疗组，且甘精利司胃肠道不良反应发生率低于起始利司那肽治疗组。 SoliD磐石研究[5]完全纳入口服降糖药血糖控制不佳的中国T2DM患者，与德谷门冬相比，甘精利司自基线至24周的HbA1c降幅达到了非劣效与优效，两组差值-0.2%，具有统计学意义。 03 覆盖人群扩大：新增T1DM章节，强调重视早筛指南新增“1型糖尿病”章节，并指出T1DM的发病率呈逐年上升趋势。中国1型糖尿病研究（CD1S）[6]显示，我国T1DM患者HbA1c达标率低，急慢性并发症比例高。另一项建模研究[7]显示，T1DM患者平均预期寿命减少。换言之，T1DM给家庭、社会带来了沉重负担，已成为不容忽视的重大公共卫生挑战。新版指南明确了T1DM的分期，即分为3期，1期为免疫紊乱期，2期为血糖异常期，3期为临床症状期，其中1期和2期为亚临床期（A）；强调重视对T1DM的筛查和监测，明确提出在高危人群（一级亲属等）中检测胰岛自身抗体筛查亚临床期T1DM，有助于早期诊断和降低糖尿病酮症酸中毒（DKA）的发病风险（A）。针对T1DM的管理，新版指南明确提出，T1DM患者需重视糖尿病自我管理教育与支持（DSMES）、营养与运动治疗及心理支持，并给予每日多次胰岛素注射或持续皮下胰岛素输注（CSII）进行治疗（A）。此外，对于8岁及以上2期T1DM患者还可考虑使用替利珠单抗（Teplizumab）以延缓T1DM进展至3期。替利珠单抗是首个且目前唯一被FDA批准用于延缓T1DM发病的疾病修饰疗法，适用于成年人和8岁及以上儿童2期T1DM患者[8]。2024年6月，该药获批先行先试临床急需进口药品，落地海南博鳌乐城先行区；8月进入国家药品审评中心优先审批流程，期待该药及更多新型T1DM预防及干预药物的诞生和获批应用。指南的更新无疑吸引了广泛关注，但与此同时，对经典药物的坚守同样引人瞩目。新版指南一如既往指出，2型糖尿病（T2DM）患者在生活方式和口服降糖药联合治疗的基础上，若血糖仍未达到控制目标，可以开始胰岛素或基础胰岛素/GLP-1RA固定比例复方（FRC）制剂治疗（A）。特别值得一提的是，今年恰逢甘精胰岛素在中国上市20周年，作为全球首个长效胰岛素类似物——甘精胰岛素U100的问世，开创了长效胰岛素时代，建立了“安全达标”的治疗理念。2020年，甘精胰岛素U300在中国上市，代表着向理想胰岛素的又一次完美进击。作为新一代超长效基础胰岛素，甘精胰岛素U300以独特的皮下储库微沉淀技术，带来更平稳的PK/PD，引领“稳态控糖”治疗理念。2023年，甘精胰岛素利司那肽的出现，在平稳控糖的同时，兼顾降低低血糖风险和体重管理，开启“优质达标”新时代。20年传承与突破，持续创新升级“中国方案”，累计造福近500万患者。 20周年庆典仪式大咖鞭辟入里·引领前沿观念 01 多措并举，提升基层防治贾伟平院士本次启动会还特别邀请到中国工程院院士、国家基层糖尿病防治管理办公室共同主任贾伟平教授发表讲话，她从“健康中国”战略高度出发，介绍了我国糖尿病防控现况、在基层糖尿病管理方面所做的工作以及取得的成效，并为未来基层的防治工作指明方向。糖尿病的防控需要全社会的共同参与，推动防治关口前移，夯实基层的防控基础，从而实现糖尿病治疗向全程健康管理转变。从国家层面，包括制定防控政策、打造支持环境、调动社会力量、促进主动健康；从行业层面，包括提供新理论、新技术、新方法，特别是适合基层的适宜技术。 (1) 2024年7月，14部委联合下发《关于印发健康中国行动-糖尿病防治行动实施方案(2024-2030年)的通知》，强调“坚持预防为主，以基层为重点”，从9个部分提供了24条措施，为进一步改善基层的糖尿病防治工作给出明确指导。 (2) 新版指南的发布为医务工作者带来了新的参考。在广泛推广指南的过程中，首要任务是确保基层实践的同质化；其次，推广措施需直接触及基层；再者，内容务必更加科普化，以便于理解和应用；最终目标是教会基层医生如何切实有效地运用指南。 02 以人为本，实现CKM共管陈莉明教授天津医科大学朱宪彝纪念医院陈莉明教授指出，糖尿病合并心肾风险的现象普遍存在，近年来国际上提出“心血管-肾脏-代谢综合征(CKM)”新概念，强调糖心肾共管的重要性，充分满足“以患者为中心”的管理需求。新版指南强调血糖管理与心肾风险管理并重，选择降糖疗效确切、心肾获益的治疗方案有助于实现糖尿病管理 Treat to success。 (1) 良好的血糖控制会降低并发症发生风险，以GLP-1RA为基础的治疗方案具有良好的降糖效果；同时GLP-1RA改善肥胖症能带来心血管获益。 (2) GLP-1RA与SGLT-2抑制剂可减少T2DM合并心血管风险患者的MACE发生风险；推荐合并ASCVD或其高风险的患者，可单药起始GLP-1RA或SGLT2抑制剂；如HbA1c不达标，二联治疗可直接联合起始选择FRC/FDC。 (3) GLP-1RA和SGLT-2抑制剂具有肾脏保护作用，推荐eGFR>20 ml·min-1·(1.73 m2)-1合并CKD 的T2DM患者选择有肾脏保护作用证据的SGLT-2抑制剂或GLP-1RA。 (4) SGLT-2抑制剂对心力衰竭（HF）有明确的获益，推荐T2DM合并HF患者首选SGLT-2抑制剂。 03 早期联合，早期良好控糖苏青教授上海交通大学医学院附属新华医院苏青教授表示结合国内外最新研究证据，新版指南着重强调了早期联合治疗的重要性，并就早期良好控糖的意义和临床如何做，进一步分享了他的真知灼见。在临床意义方面，从UKPDS[2]到糖尿病和增龄研究[9]均显示，早期良好的血糖控制具有极为重要的意义，不仅有助于保护β细胞功能，利于远期血糖控制，还可通过代谢记忆或遗留效应减少远期并发症，改善患者预后。针对临床如何做，一是关注降糖目标，进行更为严格的控糖；二是尽量选用新型药物，例如基础胰岛素与GLP-1RA的复方制剂FRC、超长效基础胰岛素等，从而避免过去传统胰岛素强化治疗带来的低血糖风险、体重增加等问题；三是注重个体化治疗，基于患者的临床特征和病理生理特点进行精细化管理。此外，除早期良好控糖外，还应加强长期管理，获得终生血糖良好控制以及其他代谢危险因素的控制。在“巅峰对话”环节，各位专家围绕新版指南在基层实践的具体应用问题展开，特别针对T1DM和青少年糖尿病在日常工作中的诊断与管理挑战，进行了细致入微的分享。（左）李小英教授主持（右）巅峰对话：苏青教授、朱大龙教授、陈丽教授、包玉倩教授指南如明灯，照亮前行路，论道映霞光，智慧共飞扬。本次会议上，专家们不仅围绕新版指南进行了全方位、深层次、多角度解读，而且还就“糖尿病与跨学科发展”议题进行了深度探讨，包括从全面达标看中国T2DM患者的降糖策略优选、对糖尿病认知功能障碍的深度思考、非酒精性脂肪性肝炎（NASH）的临床干预策略前沿进展、特殊类型糖尿病的疑难病例分享以及基层糖尿病护理质量提升策略与实践等内容，为全面优化基层糖尿病的防治提供了前瞻性的指导和启示。李晓牧教授、臧丽教授、杨雁教授、张惠杰教授、张宁教授（左右滑动查看更多）研讨聚名医，交流谋良策。在圆桌讨论环节，专家们围坐在一起，面对面共商基层糖尿病防治良策，深入剖析了当前基层糖尿病防治的现状与存在的挑战，并从各自专业角度出发，提出了切实可行的解决方案与独到见解，为基层糖尿病防治工作提供了诸多实用且宝贵的建议。（左）马建华教授主持（右）圆桌讨论：潘泉教授、陈继芳教授、钟绍教授总结新元肇启，《中国糖尿病防治指南（2024版）》全国巡讲启动会盛大召开，吸引了内分泌领域的众多顶尖专家参与。通过深入解读新版指南，并围绕糖尿病与跨学科发展的前沿议题展开精彩纷呈的交流，为我国基层糖尿病管理的未来发展指明了方向。期待通过指南巡讲活动，能够助力我国糖尿病管理事业不断攀登新的高峰。参考文献：（上下滑动查看更多） [1]中华医学会糖尿病学分会. 中国糖尿病防治指南（2024版）. 中华糖尿病杂志，2024，17(00):16-139. DOI:10.3760/cma.j.cn115791-20241203-00705 [2]Adler AI, et al. Lancet. 2024 Jul 13;404(10448):145-155 [3]Prattichizzo F, et al. Metabolism. 2020 Sep;110:154308. [4]Yang W, et al. Diabetes Obes Metab 2022;24: 1522–33 [5]Liu M, et al. Diabetes Obes Metab. 2024 Sep;26(9):3791-3800 [6]Deng C, et al. Diabetes Metab Res Rev. 2024 Mar;40(3):e3796. [7]Gregory GA, et al.Lancet Diabetes Endocrinol. 2022 Oct;10(10):741-760. [8]https://www.fda.gov/media/164864/download [9]Laiteerapong N,et al. Diabetes Care. 2019 Mar;42(3):416-426. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 MAT-CN-2502536 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《国际糖尿病》编辑部）版权声明版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

2024-11-29

·国际糖尿病idiabetes

CDS2024｜糖尿病治疗的协同创新——固定复方制剂的突破与展望

CDS微专辑扫描二维码可查看更多内容编者按：在糖尿病管理理念的不断变迁中，个性化医疗的重要性愈发显著。固定复方制剂（FDC）的问世，为实现精准治疗提供了新的途径，以全面满足糖尿病患者的多元化治疗需求，并有效提升血糖控制效果。在本届中华医学会糖尿病学分会第二十六次学术会议（CDS2024）期间，糖尿病领域专家对FDC在糖尿病治疗中的重要作用展开了讨论。本刊荣幸邀请到南京市第一医院马建华教授、上海市东方医院（同济大学附属东方医院）冯波教授、哈尔滨医科大学附属第一医院匡洪宇教授以及浙江大学医学院附属邵逸夫医院周嘉强教授，请他们就FDC的应用和发展分享了深刻的见解和宝贵的经验。《国际糖尿病》我国糖尿病患者血糖达标率低，而治疗依从性不佳是阻碍血糖达标的重要因素之一。请问哪些因素影响治疗依从性？应如何提高依从性？马建华教授：糖尿病患者血糖达标率不高是由多种因素共同作用的结果。首先，医生的诊疗水平有待提升。近年来我国政府推出的“健康中国2030”计划，就致力于提高社区医生的能力，以便为患者提供更全面的诊断和治疗服务。这不只是关注血糖升高问题，还应关注其他需要同时治疗的健康问题。其次，治疗方案的合理性同样重要，比如，对于β细胞功能尚可的患者，长期注射胰岛素可能会导致高胰岛素血症和血糖波动大。因此，治疗方案不合理也是血糖达标率低的原因。患者治疗依从性差也是一个多因素问题。首先，部分糖尿病患者仅降糖就需要双药、三药联合治疗，且此类患者可能同时患有高血压、高血脂等疾病，需要多种药物联合治疗，因此患者经济负担更重。于我国而言，患者支付能力和医保覆盖范围都是有限的，使得高昂的药物费用成为限制患者用药的一个重要因素。此外，部分患者可能因为药物不良反应如胰岛素导致的低血糖、胰高糖素样肽-1受体激动剂（GLP-1RA）引起的胃肠道反应等，自行减少剂量或停止用药。尽管大多数口服降糖药的副作用相对较小，但药物的有效性、安全性、经济性和便利性仍然是提高患者依从性的关键。只有当这些条件都得到满足时，患者的依从性才能明显提高，进而提升血糖达标率。《国际糖尿病》 DPP-4i有效降糖且安全性良好，请您谈谈其在糖尿病管理中的地位和优势？瑞格列汀作为国内首款创新DPP-4i，具有哪些优势？冯波教授：二肽基肽酶4抑制剂（DPP-4i）作为降糖药物的一种，因其确切的降糖效果和较低的低血糖风险，在临床使用中显示出显著优势，尤其在老年患者和易发生低血糖的人群中更为安全。近年来，DPP-4i在多个指南中的地位逐渐提升，但仍建议在二甲双胍的基础上使用。目前我们的降糖策略是当患者不存在动脉粥样硬化性心血管疾病（ASCVD）及其高危因素、心衰和慢性肾脏病（CKD）时，应考虑降糖的有效性以及对体重的改善。DPP-4i降糖效果确切、对体重的中性效果和较少的低血糖反应，使其在指南中被广泛推荐，并作为一线联合治疗方案。对于特殊人群，如最新老年糖尿病管理指南中，DPP-4i也被推荐作为一线用药，与二甲双胍并列使用；而在社区人群中，DPP-4i的独特性尤为显著。目前中国约70%的糖尿病患者在社区接受管理，而社区管理的质量直接影响糖尿病的达标率，此时如果社区医生能妥善使用DPP-4i，将极大提高糖尿病的有效控制率。在过去十年间，我国使用的DPP-4i主要来自外企，但随着瑞格列汀的脱颖而出，我们有了首个国产原研的DPP-4i，这一突破使我们摆脱了完全依赖外国进口DPP-4i的历史。瑞格列汀在临床上的表现与进口DPP-4i降糖效果一致，低血糖风险低，对体重影响中性，联合用药时也显示出良好的安全性。此外，瑞格列汀价格相对便宜，且作为国产药物，供应稳定，不受外部政治、经济因素的影响。近年来，我国医保政策也在不断优化，推动“价廉质优”降糖药的普及。因此，瑞格列汀以其价格优势和优良品质，成为政策的受益者和突出代表。《国际糖尿病》请问需要联合降糖药物治疗的患者采用FDC方案有哪些优势？匡洪宇教授：2型糖尿病（T2DM）患者在糖尿病患者中占比最高，其发病机制复杂多样，因此治疗上需要综合考虑多种机制以实现长期有效的血糖控制。当前的治疗指南推荐以二甲双胍为基础治疗，若血糖未达标，则考虑联合治疗。DISCOVER研究显示，在二甲双胍一线治疗后，仍有很多患者需要联合治疗。强化治疗与更高的血糖达标率和血糖持久达标相关，同时对体重管理和并发症获益也有积极影响。因此，从简化、方便性方面而言，科学合理地选择FDC，兼顾降糖疗效和安全性，更符合临床经济性和便利性需求，在糖尿病治疗中展现更多优势，符合早期和持久降糖的治疗理念。周嘉强教授：FDC在糖尿病治疗中相较于多药自由联合确实展现出更多优势，尤其是在提升患者依从性方面。由于许多糖尿病患者需要联合用药来控制血糖，FDC简化了治疗方案，减少了患者服药的片数，使得患者更容易接受，从而提高治疗依从性。其次，FDC通常联合了不同作用机制的药物，能够更全面地覆盖T2DM的病理生理机制，使血糖控制疗效更佳。FDC还有助于克服临床惰性，使得医生和患者在糖尿病管理过程中更积极地调整治疗方案。此外，FDC可能更具经济性，因为相比于单独购买两种或更多药物，FDC的费用可能更低，长期来看有助于减少患者的经济负担。《国际糖尿病》目前临床上常用的联合降糖方案是SGLT2i+二甲双胍，恒格列净二甲双胍复方缓释片于去年年底获批上市。您认为它具有哪些特点？在临床使用中您有哪些建议？马建华教授：在口服降糖药物中，二甲双胍和SGLT2i（列净类药物）因其在血糖控制、心血管和肾脏保护方面的显著效果而被广泛使用。这两种药物各有优势，可通过不同的机制来控制血糖，联合使用可以增强疗效。对于单一药物治疗效果不佳的患者，联合用药是常见的选择。FDC（恒格列净二甲双胍复方缓释片）将两种药物做成一片，减少了服药片数，改善了患者的服药体验；同时降低了长期用药成本，改善患者的依从性。此外，使用FDC时我们不能仅考虑适合哪类患者或使用后的获益，也需要注意可能的副作用。在长期使用FDC治疗时，应尤其关注其潜在注意事项，如使用二甲双胍时需要定期检查肾功能（每年1~2次），而SGLT2i可能增加泌尿生殖器感染的风险，尤其是在女性糖尿病患者中。因此，在处方这些药物前，应进行必要的检查，如尿常规等以筛查是否存在感染，并在用药期间提醒患者注意个人卫生和多饮水，以减少不良反应的发生。《国际糖尿病》 HR17031是恒瑞医药研发的一款基础胰岛素类似物和 GLP-1RA的FDC，在今年美国糖尿病协会（ADA）年会上公布的Ⅱ期临床研究结果显示，HR17031显著降低T2DM患者的HbA1c达2.4%，且安全性好。请问这种FDC的优势是什么？周嘉强教授：与传统的每日多次注射方案相比，HR17031*能够显著减少注射频率，这不仅减轻了患者的痛苦，也提高了患者注射治疗的满意度，进而提高依从性。此外，最新公布的数据显示HR17031能将HbA1c降低2.4%，远超一般认为降幅为1%~2%的优良降糖效果，显示出极强的降糖能力。基础胰岛素与GLP-1RA的联合使用，不仅作用机制互补，还能减少各自药物的剂量，从而降低胰岛素可能带来的低血糖和体重增加风险，甚至可能带来轻微的体重和腰围改善。因此，我们都很期待这类药物上市后，能有更多的临床数据来验证其对患者血糖控制和生活质量的影响。 *HR17031是恒瑞研发的一款是基础胰岛素类似物（INS068）和 GLP-1 受体激动剂（SHR20004）的固定复方制剂，在今年ADA年会上公布其在T2DM患者中的Ⅱ期临床研究结果显示，HR17031组HbA1c较基线降低幅度达2.4% ，并优于单药治疗，且低血糖发生率与单药组相似。《国际糖尿病》恒瑞医药在代谢性疾病的产品管线布局处于国内领先地位，未来还会推出DPP-4i+二甲双胍、SGLT2i+DPP-4i+二甲双胍固定复方制剂。您对这种全面布局的策略有什么见解？匡洪宇教授：在选择糖尿病治疗方案时，需要综合考虑患者的年龄、体重指数（BMI）、病程、并发症、饮食偏好等多种因素，进行个体化考量。其中不仅需要评估药物是否适合患者，还要考虑药物的可及性和经济性等重要因素。糖尿病治疗的核心是以患者为中心，因此，提供多样化的药物选择，尤其是FDC，使患者各取所需，能够更好地满足不同患者的需求，实现精准化的个体化治疗。此外，未来多样化FDC的布局将更有助于解决不同患者的血糖控制问题，这是非常值得提倡的，也受到医生和患者的广泛青睐。结语在糖尿病治疗领域，FDC正逐渐成为个体化治疗的重要工具。随着对糖尿病病理生理机制的深入理解，FDC通过联合不同作用机制的药物，不仅提高了血糖达标率，还简化了治疗方案，提高患者治疗依从性。随着对FDC的进一步研究和临床应用，我们期待这些制剂能够在未来的糖尿病治疗中发挥更大的作用，帮助患者实现更好的血糖控制，提高“糖友”的生活质量。声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！（来源：《国际糖尿病》编辑部）版权声明版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

2024-09-27

·Business Wire

Final Real-World Results from MILOS German Cohort Demonstrate Strong Increase in LDL-C Goal Achievement With Addition of Bempedoic Acid

MUNICH--( BUSINESS WIRE )--For EU media only Daiichi Sankyo Europe, (hereafter, Daiichi Sankyo) today announced final 2-year follow-up data from the German cohort of the multinational, European observational MILOS study. 1 The study evaluated the real-world use of bempedoic acid, marketed as NILEMDO ® ▼ and its FDC with ezetimibe, NUSTENDI ® ▼, in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The results, presented in Hamburg, Germany at DGK Hertztage 2024, demonstrated the effectiveness and safety profile of bempedoic acid, both alone and in combination with other lipid-lowering therapies (LLTs) in clinical practice. 1 Raised LDL-C is a key modifiable contributor to risk of major cardiovascular events, with studies showing that every 1 mmol/L reduction in LDL-C is associated with a 22% reduction in major cardiovascular events after one year. 5,6 The German cohort of MILOS study comprising 973 patients from 125 sites in Germany, is one of the most comprehensive assessments of bempedoic acid in a real-world clinical setting to-date in Germany. 1 Patients were followed-up for two years, with LDL-C levels assessed at pre-treatment, one year (1Y) and two years (2Y). Overall, 638 of 973 patients (65.6%) completed 2Y follow up, with LDL-C values at pre-treatment, 1Y and 2Y available for 451 patients. In these 451 patients, a mean reduction of LDL-C levels from 3.1 mmol/L (121.4 mg/dL) at pre-treatment, to 2.0 mmol/L (77.2 mg/dL) was observed, representing an average relative reduction of 30.3% in the overall population. 1 Additionally, the percentage of patients reaching their LDL-C goals increased from 4.9% at pre-treatment to 35.3% at the 2Y follow-up – an approximately 7-fold increase. 1 The proportions of high-risk and very high-risk patients reaching LDL-C goals increased from 5.6% to 32.5%, and 3.6% to 35.2%, respectively. 1 Overall, more than 80% of patients received bempedoic acid in combination with other LLTs at pre-treatment and 2Y, including statins and ezetimibe. The safety profile of bempedoic acid in this real-world population was assessed at 1Y and 2Y and was consistent with that observed in the CLEAR clinical trial programme. 2,3,4 “By significantly lowering LDL-C levels toward guideline goals, we are taking a vital step in reducing the risk of cardiovascular events, which can have a profound impact on a person’s long-term health and quality of life,” said Professor Ioanna Gouni-Berthold, University of Cologne, Center for Endocrinology, Diabetes, and Preventive Medicine and Executive Board Member of the International Atherosclerosis Society . “Cardiovascular disease remains Europe’s leading cause of death, yet the majority of premature CV events are preventable,” 7,8 said Dr. Stefan Seyfried, Vice President Medical Affairs, Specialty Medicines, at Daiichi Sankyo Europe GmbH . “ The findings from this cohort reinforce the benefit provided by bempedoic acid for reducing LDL-C levels. Our long-term goal is to empower the medical community with real-world insights to improve CVD prevention and, ultimately, improve patient care.” -ENDS- About MILOS MILOS (NCT04579367) is an ongoing, multinational, European observational study in adult patients diagnosed with primary hypercholesterolaemia or mixed dyslipidaemia. The aim is to evaluate the real-world use of bempedoic acid and bempedoic plus ezetimibe FDC. Patients in the German cohort were recruited from 125 sites between January 2021 and January 2022 and were followed up for 2 years after baseline measurements. 1 Change in LDL-C levels and the proportion of patients achieving LDL-C goal were assessed in patients at pre-treatment, 1Y and 2Y visits. Analyses were stratified by investigator-assessed CV risk, based on the ESC/EAS dyslipidaemia guidelines. 1 Beyond Germany, MILOS has sites in Austria, Belgium, Italy, the Netherlands, Spain, Switzerland and the UK. 9 About Bempedoic Acid and its Fixed-Dose Combination with Ezetimibe Bempedoic acid (NILEMDO ® ) is a first-in-class, oral, once-daily treatment to lower cholesterol, and can be combined with other oral treatments to help lower cholesterol even further. 10 Bempedoic acid inhibits ATP citrate lyase (ACL), an enzyme which is involved in the production of cholesterol in the liver. 10 Bempedoic acid acts on the well-known cholesterol synthesis pathway, upstream of the statin target in the liver, which allows additional LDL-C lowering when added to statin or other LDL-C-lowering therapies. 11 Bempedoic acid is not activated in skeletal muscle. 10 Bempedoic acid is indicated in adults with primary hypercholesterolaemia (heterozygous familial and nonfamilial) or mixed dyslipidaemia, as an adjunct to diet: 10 in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or, 10 alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. 10 Bempedoic acid is indicated in adults with established or at high risk for atherosclerotic CV disease to reduce CV risk by lowering LDL-C levels, as an adjunct to correction of other risk factors: 10 in patients on a maximum tolerated dose of statin with or without ezetimibe or, 10 alone or in combination with ezetimibe in patients who are statin-intolerant, or for whom a statin in contraindicated. 10 The bempedoic acid / ezetimibe FDC (NUSTENDI ® ) combines two complementary ways of reducing cholesterol in a once-daily tablet. Bempedoic acid / ezetimibe FDC is indicated in adults with primary hypercholesterolaemia (heterozygous familial and nonfamilial) or mixed dyslipidaemia, as an adjunct to diet: 12 in combination with a statin in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe, 12 alone in patients who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone, 12 in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin. 12 Bempedoic acid / ezetimibe FDC is indicated in adults with established or at high risk for atherosclerotic CV disease to reduce CV risk by lowering LDL-C levels, as an adjunct to correction of other risk factors: 12 in patients on a maximum tolerated dose of statin and not adequately controlled with additional ezetimibe treatment or, 12 in patients who are either statin-intolerant, or for whom a statin in contraindicated, and not adequately controlled with ezetimibe treatment or, 12 in patients already being treated with the combination of bempedoic acid and ezetimibe as separate tablets. 12 Daiichi Sankyo Europe has licensed exclusive commercialisation rights to bempedoic acid and its FDC with ezetimibe (marketed as NILEMDO ® and NUSTENDI ® ) in the European Economic Area, UK, Turkey and Switzerland from Esperion and is the full Marketing Authorisation Holder in these territories. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops, and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular, and other diseases with high unmet medical need. For more information, please visit https://www.daiichi-sankyo.eu/ ▼ This medicinal product is subject to additional monitoring. References 1 DGK Hertztage 2024 Abstract. Real-world effectiveness and safety of bempedoic acid in Europe: final 2-year results from the MILOS German cohort. Gouni-Berthold, I et al. 2 Nissen SE, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med . 2023;388:1353–64 3 Ray KK, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med . 2019; 380:1022–32 4 Ballantyne CM, et al . Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol . 2020; 27(6): 593–603 5 Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet. 2010. 376(9753): 1670–1681 6 NHS England. Improving lipid management to reduce cardiovascular disease and save lives. Available at: https://www.england.nhs.uk/long-read/improving-lipid-management-to-reduce-cardiovascular-disease-and-save-lives/#:~:text=Raised%20LDL%20cholesterol%20is%20one,vascular%20events%20after%201%20year . Last accessed September 2024. 7 Eurostat. (2023) Causes of death statistics. Available at: https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Causes_of_death_statistics#Major_causes_of_death_in_the_EU_in_2020 . Last accessed September 2024. 8 World Heart Federation. Prevention. Available at: https://world-heart-federation.org/what-we-do/prevention/#:~:text=An%20estimated%2080%25%20of%20cardiovascular,and%20“knowing%20your%20numbers ”. Last accessed September 2024 9 ClinicalTrials.gov. Treatment With Bempedoic Acid and/or Its Fixed-dose Combination With Ezetimibe in Primary Hypercholesterolemia or Mixed Dyslipidemia (MILOS). Available at: https://clinicaltrials.gov/study/NCT04579367#contacts-and-locations . Last accessed September 2024. 10 European Medicines Agency. Nilemdo – Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/nilemdo-epar-product-information_en.pdf . Last accessed September 2024. 11 Pinkosky, S.L., et al . Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun . 2016. 7: 13457. 12 European Medicines Agency. Nustendi –Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/nustendi-epar-product-information_en.pdf . Last accessed September 2024 HQ/BIL/09/24/0001

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适应症	最高研发状态	国家/地区	公司	日期
急性心肌梗塞	临床3期	捷克	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	法国	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	德国	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	匈牙利	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	意大利	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	波兰	Ferrer Internacional SA	2016-07-01
急性心肌梗塞	临床3期	西班牙	Ferrer Internacional SA	2016-07-01
ST段抬高心肌梗死	临床3期	阿根廷	Ferrer Internacional SA	2012-01-01
ST段抬高心肌梗死	临床3期	巴西	Ferrer Internacional SA	2012-01-01
ST段抬高心肌梗死	临床3期	意大利	Ferrer Internacional SA	2012-01-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02596126 (SECURE, CTgov)	临床3期	心肌梗塞 \| 急性心肌梗塞	2,499	Treatment Prevention for Secondary CV (Treatment Prevention for Secondary CV)	艱鹹簾衊遞簾願醖製廠 = 鹹鏇鏇顧觸醖醖夢選壓糧鬱鏇構築構願憲鑰壓 (遞蓋繭鏇憲膚餘築範製, 獵觸遞襯憲醖餘範遞網 ~ 繭蓋範蓋蓋憲醖願壓顧) 更多	-	2025-05-23
NCT02596126 (SECURE, CTgov)	临床3期	心肌梗塞 \| 急性心肌梗塞	2,499	Cardiovascular Polypill (Cardiovascular Polypill)	艱鹹簾衊遞簾願醖製廠 = 鬱蓋餘鬱廠製衊醖醖願糧鬱鏇構築構願憲鑰壓 (遞蓋繭鏇憲膚餘築範製, 壓夢夢壓醖獵衊艱壓糧 ~ 齋積網顧積鑰衊鬱鹽窪) 更多	-	2025-05-23
Pubmed \| Arch Med Res	临床4期	-	1,193	CNIC-Ferrer polypill	觸淵醖構襯鏇構簾廠獵(衊顧獵襯製鹽鏇鑰襯觸) = 網夢壓鹽憲遞鹽醖蓋鹽蓋淵選醖獵齋願壓餘鹽 (鬱蓋範鑰夢選製壓壓選 ) 更多	积极	2019-01-01
NCT01004705 (CTgov)	临床2期	高脂蛋白血症	36	simvastatin	齋衊鹽製顧鬱網鏇積網(選鏇築鹽獵選願艱蓋鬱) = 鹹鹹簾憲遞膚選觸獵製膚選遞網範構醖壓鏇糧 (網製積製艱鹽餘夢鏇積, 32.597) 更多	-	2012-08-31