Analysis of published and unpublished iraglutide studies in humans
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<strong>Unpublished and published liraglutide studies in humans - Completed before Jan 2011</strong> Unpublished (n=37): 68.5%<br>Published (n=17): 31.5% ----> 3.1 papers per registry ___________________________________________ Google Drive spreadsheet ---> Open Settings --> Anybody can post comments 5th URL __________________________________________ <em>"In the Novo Nordisk study, the rats treated with liraglutide showed increased ductal proliferation and acinar to ductal metaplasia. One rat treated with exenatide had a “hemorrhagic pancreas” at necropsy with 'moderate apoptosis-like necrosis, minimal inflammatory infiltration and slight hemorrhage/edema.”13Although the pancreases did not increase in weight, the incretin treated rats had “significantly higher” levels of pancreatic amylase. Three of the liraglutide treated animals died from a 'single erroneous dosing.'</em> <em>A spokeswoman from Novo Nordisk told the BMJ, 'Importantly, the study did not find any abnormalities in the pancreas associated with liraglutide treatment.'"</em> <strong>Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? BMJ 2013; 346.</strong> - 6th URL - Liraglutide findings in monkeys added to the fileset - Full paper available in this fileset ______________________________________<br> <strong>Fiona Godlee, editor, BMJ</strong> <em>"A slow moving, desert dwelling lizard that eats only a few times a year inspired a whole new class of diabetes drugs. Glucagon-like peptide-1 (GLP-1) agonists, developed initially from a peptide extracted from the Gila monster’s saliva, are now taken by millions of people around the world. Together with DPP-4 inhibitors, their apparent ability to reduce hyperglycaemia without causing weight gain is an important advance on older off-patent diabetes drugs, and has created a huge new market for the drug industry.</em> <em>But have clinicians and patients been adequately informed about safety concerns—specifically about possible increases in the risk of pancreatitis and pancreatic cancer? A BMJ investigation and linked editorials published this week suggest that they haven’t (doi:10.1136/bmj.f3680).</em> <em>After reviewing thousands of pages of regulatory and other documents obtained through freedom of information requests, Deborah Cohen has found that the drug manufacturers and regulators have had in their hands ample warning signs and chances to resolve some of the controversies. But the regulators have been slow to pursue safety concerns. Rather than insist on further independent research, they have allowed themselves to be reassured by the drugs’ manufacturers.</em> <em>Cohen has unearthed unpublished data from animal and human studies that point to pathological changes in the pancreas. These changes are consistent with the drugs’ mechanism of action, suggesting that unwanted proliferative effects could have been anticipated and properly investigated at an early stage. She has also uncovered attempts by drug companies to suppress scientific debate through pressure on academics and medical journals.</em> <em>As Thorvardur Halfdanarson and Rahul Pannala emphasise in their accompanying commentary (doi:10.1136/bmj.f3750), the observational studies available so far do not prove causality. Adverse event databases that rely on voluntary reporting are limited by the potential for reporting bias. Because of this, manufacturers and others say we should wait for the outcome of further clinical trials. But trials will have to be enormous to exclude an increased risk of pancreatic cancer, and unless the rules on openness of clinical trial data have changed radically by the time they are reported, most of the data will remain hidden from independent scrutiny. Meanwhile, as Sonal Singh asks in Cohen’s piece, “who bears the burden of the passage of time while these debates are settled?”</em> <em>So what should doctors and patients do? Victor Montori concludes that after careful reflection most patients and clinicians may opt to avoid using GLP-1 based drugs at all, or to avoid them early in the disease or for long periods (doi:10.1136/bmj.f3692).</em> <em>Edwin Gale concludes that the drugs’ fate has yet to be determined, but that, once again the current regulatory procedures have been shown to be inadequate, especially for so called shotgun drugs—those, like the GLP-1 based drugs, that act on many targets. “Similar scenarios will play out again while secrecy rules and companies control access to the data” (doi:10.1136/bmj.f3617).</em> <em>Science thrives on open challenge and objective debate. Patients will not receive safe and effective care in an environment characterised by commercial secrecy, bullying of academics and journal editors, or reliance on overstretched regulators."</em> <strong>Goodle F. Secrecy does not serve us well. 2013;346:f3819</strong> <strong>__________________________________________</strong> <em>"In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk."</em> <strong>Butler and colleagues. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013 Jul;36(7):2118-25.</strong> <strong>____________________________________________</strong> <strong>August 25, 2014</strong> <strong>5 pm Bogotá time zone</strong> Ramirez, Jorge H (2014): Sitagliptin. figshare.<br>http://dx.doi.org/10.6084/m9.figshare.1150354<br>Retrieved 22:29, Aug 25, 2014 (GMT) _____________________________________ <strong><br></strong>
<strong>2011年1月前完成的未发表及已发表人类利拉鲁肽(liraglutide)研究</strong> 未发表研究（n=37）：占比68.5%<br>已发表研究（n=17）：占比31.5% ——＞ 每注册库平均3.1篇论文 ___________________________________________ Google Drive电子表格 ——＞ 打开设置 → 允许所有人发表评论 第5个链接 __________________________________________ <em>"在诺和诺德(Novo Nordisk)的该项研究中，接受利拉鲁肽(liraglutide)治疗的大鼠表现出导管增生及腺泡-导管化生现象增强。1只接受艾塞那肽(exenatide)治疗的大鼠在尸检时呈现“出血性胰腺”，伴有“中度凋亡样坏死、轻度炎症浸润及轻微出血/水肿”<sup>13</sup>。尽管胰腺重量未出现增加，但接受肠促胰岛素(incretin)治疗的大鼠其胰腺淀粉酶水平“显著升高”。3只接受利拉鲁肽治疗的动物因“单次给药失误”死亡。"</em> <em>"诺和诺德(Novo Nordisk)的一位发言人在接受《英国医学期刊》(BMJ)采访时表示：“重要的是，该研究未发现与利拉鲁肽治疗相关的胰腺异常。”"</em> <strong>Cohen D. 胰高血糖素抑制类糖尿病药物造成的胰腺损伤是否被低估了？BMJ 2013; 346.</strong> —— 第6个链接 —— 猴源利拉鲁肽(liraglutide)研究结果已添加至该数据集 —— 完整论文可在本数据集中获取 ______________________________________<br> <strong>Fiona Godlee，《英国医学期刊》(BMJ)主编</strong> <em>"一种仅每年进食数次的慢节奏沙漠蜥蜴，催生了全新一类糖尿病药物。最初从钝尾毒蜥唾液中提取的肽类开发而来的胰高血糖素样肽-1(GLP-1)受体激动剂，目前已被全球数百万患者使用。与二肽基肽酶-4(DPP-4)抑制剂一道，这类药物在不引发体重增加的前提下降低高血糖的显著优势，是已过专利保护期的老旧糖尿病药物的重要进步，也为制药行业创造了庞大的全新市场。"</em> <em>"但临床医生与患者是否充分了解了安全性隐患——具体而言是胰腺炎与胰腺癌风险的潜在升高？本周发表的《英国医学期刊》(BMJ)调查与相关社论表明，他们并未充分知晓（doi:10.1136/bmj.f3680）。"</em> <em>"在审阅了通过信息自由法案获取的数千页监管文件与其他资料后，Deborah Cohen发现，药物制造商与监管机构早已掌握大量警示信号，本有机会解决部分争议。但监管机构在跟进安全性隐患方面行动迟缓。他们并未坚持开展进一步的独立研究，反而接受了药物制造商的安抚说辞。"</em> <em>"Cohen揭露了来自动物与人体研究的未发表数据，这些数据指向胰腺的病理变化。这类变化与该类药物的作用机制相符，提示人们本可在早期阶段预见到此类不良增殖效应并开展恰当的研究。她还揭露了制药企业通过向学者与医学期刊施压来压制科学讨论的行为。"</em> <em>"正如Thorvardur Halfdanarson与Rahul Pannala在其配套评论（doi:10.1136/bmj.f3750）中所强调的那样，目前已有的观察性研究无法证明因果关系。依赖自愿上报的不良事件数据库受报告偏倚的潜在影响而存在局限。正因如此，制造商与其他相关方称我们应等待进一步临床试验的结果。但要排除胰腺癌风险升高的可能性，试验规模必须极其庞大；且除非临床试验数据的公开规则在试验结果发布时发生了根本性改变，否则绝大多数数据仍将无法接受独立审查。与此同时，正如Sonal Singh在Cohen的报道中所提出的那样：“在这些争论得到解决的过程中，谁来承担时间流逝带来的负担？”"</em> <em>"那么医生与患者该何去何从？Victor Montori得出的结论是，经过审慎思考后，大多数患者与临床医生可能会选择完全避免使用基于GLP-1的药物，或是在疾病早期或长期疗程中避免使用（doi:10.1136/bmj.f3692）。"</em> <em>"Edwin Gale认为，这类药物的命运尚未定论，但监管程序再次被证明存在不足，尤其是针对所谓的“散弹药物”——即像GLP-1类药物那样作用于多个靶点的药物。“只要保密规则与企业掌控着数据获取渠道，类似的场景还会再次上演”（doi:10.1136/bmj.f3617）。"</em> <em>"科学的蓬勃发展离不开公开的质疑与客观的辩论。在以商业保密、恐吓学者与期刊编辑，或是依赖不堪重负的监管机构为特征的环境中，患者无法获得安全有效的诊疗。"</em> <strong>Goodle F. 保密并非益事。2013;346:f3819</strong> <strong>__________________________________________</strong> <em>"在下文的正面论述中，Butler博士及其同事分享了他们对现有数据的观点与综述，并指出鉴于潜在风险的日益加剧以及对药物作用机制更清晰的理解，我们需要重新审视基于肠促胰岛素(incretin)的治疗方案。在Butler博士及其同事的论述之后的反面论述中，Nauck博士为基于肠促胰岛素的治疗方案进行了辩护，称其获益显然远超任何风险担忧。"</em> <strong>Butler及同事. 基于肠促胰岛素治疗的临床应用批判性分析：GLP-1类疗法是否安全？Diabetes Care. 2013 Jul;36(7):2118-25.</strong> <strong>____________________________________________</strong> <strong>2014年8月25日</strong> <strong>波哥大时区下午5点</strong> Ramirez, Jorge H (2014): 西格列汀(sitagliptin). figshare.<br>http://dx.doi.org/10.6084/m9.figshare.1150354<br>检索时间：2014年8月25日22:29（GMT） _____________________________________ <strong><br></strong>
