Incretin mimetics: liraglutide (Victoza) unpublished studies (ClinicalTrials.gov, EudraCT, and UMIN) → 69%

I. Background

Unpublished and published liraglutide studies in humans – Completed before Jan 2011
Unpublished (n=37): 68.5%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

35 out of 39 ClinicalTrials.gov registers were retrospectively registered
Median = – 250 days
Q1 = – 2128 days
Q3 = -18 days


“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.


 

“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.


 II. ClinicalTrials.gov study results: NCT00318461

(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

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.

Abstract

“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.”

(4) Metformin monotherapy study arm (sample size) vs. other study arms (sample size) = 1:2

(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: No significant changes were detected in the study


Acknowledgments

Lorena Hoyos — undergraduate medical student at the University of Valle — for reminding me about incretin mimetics.


To be continued...

Chaos Theory and Pharmacology

 

Background: “Novo Nordisk replies to BMJ investigation on incretins and pancreatic damage” – Re: let’s start this discussion again

  • Unpublished & published liraglutide studies in humans – Completed before Jan 1, 2011 –

    – Unpublished (n=37): 68.5%
    – Published (n=17): 31.5% → 3.1 papers per published study record.


Incretin Mimetics Database  WHO ICTRP ClinicalTrials.gov PubMed EMBASE - Search Date  MM DD YYYY   03 05 2014 - Google Sheets (7)


90% of the studies (35 / 39) were retrospectively registered
Median (Interquartile range: Q1 – Q3) = – 250 days (– 2128 to -18)


Database of ClinicalTrials.gov and WHO ICTRP downloaded registries of incretin mimetics (i.e.,liraglutide, exenatide, sitagliptin, others) is Open (worldwide) via figshare & Google Drive Spreadsheet (raw data).


More information:
Ramirez, Jorge H (2014): Analysis of published and unpublished liraglutide studies in humans. figsharehttp://dx.doi.org/10.6084/m9.figshare.1134664

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