title: Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials.
abstract: Glucagon-like peptide 1 receptor agonists (GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis.
  
  
  
  A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug.
  
  
  
  Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected.
  
  
  
  Presently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.
authors.affiliation: Department of Diabetology, Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy.
authors.forename: Matteo
authors.identifier: 0000-0001-9349-828X
authors.initials: M
authors.lastname: Monami
authors.affiliation: Department of Diabetology, Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy.
authors.forename: Besmir
authors.initials: B
authors.lastname: Nreu
authors.affiliation: Diabetology Unit, Osperdale San Donato Arezzo, Arezzo, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Scatena
authors.affiliation: Department of Diabetology, Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cresci
authors.affiliation: Diabetology Unit, Osperdale San Donato Arezzo, Arezzo, Italy.|Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Diabetology Unit, Osperdale San Donato Arezzo, Arezzo, Italy.|Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.affiliation: Department of Diabetology, Azienda Ospedaliero Universitaria Careggi and University of Florence, Florence, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Mannucci
mesh_terms: D001659:Biliary Tract / Q000187:drug effects*; D002769:Cholelithiasis / Q000139:chemically induced* / Q000150:complications / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D019317:Evidence-Based Medicine; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015994:Incidence; D010179:Pancreas / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012306:Risk; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: GLP-1 analogue; meta-analysis