Unpublished and published liraglutide studies in humans

Unpublished and published liraglutide studies in humans - Completed before Jan 2011 Unpublished (n=37): 68.5% Published (n=17): 31.5% ----> 3.1 papers per registry ___________________________________________ Google Drive spreadsheet ---> Open Settings --> Anybody can post comments 5th URL __________________________________________ "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.' A spokeswoman from Novo Nordisk told the BMJ, 'Importantly, the study did not find any abnormalities in the pancreas associated with liraglutide treatment.'" Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? BMJ 2013; 346. - 6th URL - Liraglutide findings in monkeys added to the fileset - Full paper available in this fileset ______________________________________ Fiona Godlee, editor, BMJ "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. 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). 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. 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. 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?” 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). 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). 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." Goodle F. Secrecy does not serve us well. 2013;346:f3819 __________________________________________ "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." 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. ____________________________________________ August 25, 2014 5 pm Bogotá time zone Sitagliptin (Januvia) ClinicalTrials.gov records completed before Jan 2011. Total number of records = 115 Expert search terms (PubMed): http://goo.gl/pIdDaQ Records not found = 85 Results = 40 Expert search terms of records not found nct00541450 OR nct00961480 OR nct00961857 OR nct01093794 OR nct01354990 OR nct00830076 OR nct01034111 OR nct01095991 OR nct00666848 OR nct01054118 OR nct00095056 OR nct00832624 OR nct00944450 OR nct00420511 OR nct00411554 OR nct00395343 OR nct00466518 OR nct00929201 OR nct00545584 OR nct00758069 OR nct01357148 OR nct00541775 OR nct00642798 OR nct00960453 OR nct00975052 OR nct00103857 OR nct00484419 OR nct01131182 OR nct00833027 OR nct00732121 OR nct00875394 OR nct00842556 OR nct01104532 OR nct00086515 OR nct00449930 OR nct00729326 OR nct00511108 OR nct00696826 OR nct00888238 OR nct00094757 OR nct00631488 OR nct00660075 OR nct00127192 OR nct00696982 OR nct00616811 OR nct00666458 OR nct00766441 OR nct00532935 OR nct00957060 OR nct00481663 OR nct00832390 OR nct00289848 OR nct00789191 OR nct00482079 OR nct01046110 OR nct00854035 OR nct00754988 OR nct00363519 OR nct00482729 OR nct00418366 OR nct00716092 OR nct00364377 OR nct00371007 OR nct01517321 OR nct00699322 OR nct00976261 OR nct00363844 OR nct00425490 OR nct00106704 OR nct01332370 OR nct00760344 OR nct00780715 OR nct01341795 OR nct00790348 OR nct00747383 OR nct01035879 OR nct00411411 OR nct01089790 OR nct00901979 OR nct00871507 OR nct00842400 OR nct00783549 OR nct00426413 OR nct01077323 OR nct00950534 _____________________________________