Acute Pancreatitis with Liraglutide – Background

An analysis of MedWatch adverse event reports submitted to the Food and Drug Administration in the first two years following approval

June 5, 2014

PART I: BACKGROUND

Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a widely used class of medications known as incretin mimetics developed for the treatment of type 2 diabetes mellitus. GLP-1 agonists directly activate GLP-1 receptors, while DPP-4 inhibitors block the degradation of endogenous GLP-1.[1]

GLP-1 reduces serum glucose both by stimulating insulin secretion by pancreatic islet (endocrine) beta cells and by inhibiting secretion of glucagon by pancreatic islet alpha cells.[2] Through these actions, incretin mimetics have been shown to be effective in reducing blood glucose levels.[3] However, concerns have been raised that chronic stimulation of GLP-1 receptors could have adverse effects on the pancreas, potentially through stimulation of GLP-1 receptors on the exocrine cells.[4],[5]

The Food and Drug Administration (FDA) issued safety communications in response to reports of acute pancreatitis associated with two incretin mimetics, exenatide (2007) and sitagliptin (2009),[6],[7] and warnings about acute pancreatitis are now present in the labels of all incretin mimetics currently on the market.[8]

Three previous analyses, limited to data contained in the FDA’s Adverse Event Reporting System (AERS) online database, reported markedly increased rates of acute and chronic pancreatitis associated with incretin mimetics compared with non-incretin diabetes drugs.[9],[10],[11] However, while these analyses, combined with the existence of a plausible mechanism, suggest an association between incretin mimetic drugs and pancreatitis, controversy remains as to whether the drugs actually cause an increase in pancreatitis above what would be expected in the general diabetic population.[12],[13]

This is the first study to analyze and systematically apply causality criteria to the additional clinical information in MedWatch case reports to determine the likelihood that the incretin mimetic drug liraglutide causes acute pancreatitis.

Next Page » Part II: Methods


[1] Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc 2009, 49(Suppl 1): S16-29.

[2] Ibid.

[3] Drab SR. Incretin-based therapies for type 2 diabetes mellitus: Current status and future prospects. Pharmacotherapy 2010, 30: 609-24.

[4] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[5] Gale EA. GLP-1-based therapies and the exocrine pancreas: more light, or just more heat? Diabetes 2012, 61: 986-8.

[6] FDA. Safety alert: Byetta (exenatide). FDA/CDER, Silver Spring; October 2007. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124712.htm. Accessed April 24, 2014.

[7] FDA. Safety alert: Januvia (sitagliptin). FDA/CDER, Silver Spring; September 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm. Accessed April 23, 2014.

[8] FDA. FDA-approved drug products. FDA/CDER, Silver Spring. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed April 17, 2014.

[9] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[10] Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterol 2011, 141: 150-156.

[11] Institute for Safe Medication Practices. Perspectives on GLP-1 Agents for Diabetes. QuarterWatch. April 18, 2013 ? Partial Data from 2012 Quarter 3. http://www.ismp.org/quarterwatch/pdfs/2012Q3.pdf. Accessed April 17, 2014.

[12] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[13] Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care 2013, 36: 2126-32.