DOI: 10.6084/m9.figshare.1134664.v13
title: Analysis of published and unpublished liraglutide studies in humans

description: <strong>Unpublished and published liraglutide studies in humans - Completed before Jan 2011</strong> Unpublished (n=37): 68.5%<br>Published (n=17): 31.5% ----&gt; 3.1 papers per registry ___________________________________________ <strong>35 out of 39 ClinicalTrials.gov registers were retrospectively registered</strong> Median = - 250 days<br>Q1 = - 2128 days<br>Q3 = -18 days ___________________________________________ Google Drive spreadsheet ---&gt; Open (worldwide) Settings --&gt; 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>ClinicalTrials.gov study results: NCT00318461</strong> (1) "Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Novo Nordisk acknowledges the Investigator’s right to publish the entire results of the trial. Any such scientific paper, presentation, communication or other information concerning the investigation described in this protocol, must be submitted in writing to Novo Nordisk Trial Manager prior to submission for publication/presentation for comments. Comments will be given within four weeks from receipt of the manuscript." (2) Secondary outcome: change in bodyweight Baseline values for weight are not reported (only for BMI) (3) Race: limited external validity Race (NIH/OMB) [units: participants] American Indian or Alaska Native 0 Asian 98 Native Hawaiian or Other Pacific Islander 0 Black or African American 26 White 946 More than one race 0 Unknown or Not Reported 17 <strong>Jamaluddin JL, et al. Pancreatic gene variants potentially associated with dipeptidyl peptidase-4 inhibitor treatment response in Type 2 diabetes. Pharmacogenomics. 2014 Feb;15(2):235-49. doi: 10.2217/pgs.13.234.</strong> Abstract <em>"In the adult pancreas, the expression of the genes PAX4, KCNQ1, TCF7L2, KCNJ11, ABCC8, MTNR1B and WFS1 are mainly restricted to β cells to maintain glucose homeostasis. We have identified these genes as the main regulators of incretin-mediated actions, and therefore they may potentially influence the response of DPP-4 inhibitors. This review represents the first detailed exploration of pancreatic β-cell genes and their variant mechanisms, which could potentially affect the response of DPP-4 inhibitors in Type 2 diabetes. We have focused on the signaling pathways of these genes to understand their roles in gastrointestinal incretin-mediated effects; and finally, we sought to associate gene mechanisms with their Type 2 diabetes risk variants to predict the responses of DPP-4 inhibitors for this disease."</em> (4) Metformin monotherapy study arm (sample size) vs. other study arms (sample size) = <strong>1:2</strong> (5) Change in beta-cell function - Week 26: statistical significant differences only with liraglutide groups compared with metformin monotherapy. - Week 104: no statistically significant differences among the study groups. (6) History of changes: <br>- 7th URL below<br>- Image uploaded to this fileset<br>- No significant changes were detected in the study _______________________________________