title: Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies.
abstract: OBJECTIVE
  To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus.
  
  
  METHODS
  Systematic review and meta-analysis.
  
  
  METHODS
  Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.
  
  
  METHODS
  Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs.
  
  
  METHODS
  Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis.
  
  
  RESULTS
  60 studies (n=353,639), consisting of 55 randomised controlled trials (n=33,350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320,289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13).
  
  
  CONCLUSIONS
  The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.
authors.affiliation: Chinese Evidence-Based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Jiantong
authors.initials: J
authors.lastname: Shen
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Bala
authors.forename: Jason W
authors.initials: JW
authors.lastname: Busse
authors.forename: Shanil
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Per Olav
authors.initials: PO
authors.lastname: Vandvik
authors.forename: Lorena P
authors.initials: LP
authors.lastname: Rios
authors.forename: German
authors.initials: G
authors.lastname: Malaga
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wong
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sohani
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
mesh_terms: D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D054795:Incretins / Q000009:adverse effects / Q000627:therapeutic use*; D010195:Pancreatitis / Q000139:chemically induced*; D016032:Randomized Controlled Trials as Topic; D018027:Receptors, Glucagon / Q000819:agonists
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D018027:Receptors, Glucagon
references.citation: JAMA Intern Med. 2013 Apr 8;173(7):534-9
references.pmid: 23440284
references.citation: Diabetes Obes Metab. 2012 Nov;14(11):1032-9
references.pmid: 22690943
references.citation: Diabetes. 2009 Jul;58(7):1604-15
references.pmid: 19403868
references.citation: Diabetes Care. 2009 Oct;32(10):1880-6
references.pmid: 19592625
references.citation: Diabetes Obes Metab. 2012 Oct;14(10):927-36
references.pmid: 22583697
references.citation: Diabetes Obes Metab. 2012 Dec;14(12):1145-54
references.pmid: 22974280
references.citation: Diabetes Obes Metab. 2013 Apr;15(4):364-71
references.pmid: 23163910
references.citation: Endocr J. 2009;56(3):415-24
references.pmid: 19194050
references.citation: J Clin Endocrinol Metab. 2012 Jul;97(7):2370-9
references.pmid: 22539590
references.citation: Diabetes Care. 2013 Jul;36(7):2118-25
references.pmid: 23645885
references.citation: Obesity (Silver Spring). 2013 Feb;21(2):238-47
references.pmid: 23404788
references.citation: Diabetes Obes Metab. 2012 Oct;14(10):910-7
references.pmid: 22564709
references.citation: Diabetes. 2012 May;61(5):1243-9
references.pmid: 22338093
references.citation: Lancet. 2009 Feb 7;373(9662):473-81
references.pmid: 18819705
references.citation: Diabetes Care. 2013 Jul;36(7):2126-32
references.pmid: 23645884
references.citation: Diabetes Res Clin Pract. 2010 Sep;89(3):216-23
references.pmid: 20537746
references.citation: Diabetes Obes Metab. 2011 Jun;13(6):559-66
references.pmid: 21320263
references.citation: Lancet. 2012 Jun 16;379(9833):2270-8
references.pmid: 22683137
references.citation: Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E1076-86
references.pmid: 20923958
references.citation: Clin Ther. 2012 Jun;34(6):1247-1258.e22
references.pmid: 22608780
references.citation: Diabetes Care. 2012 Feb;35(2):252-8
references.pmid: 22210563
references.citation: Diabetologia. 2009 Oct;52(10):2046-55
references.pmid: 19688338
references.citation: Diabet Med. 2012 Nov;29(11):1412-8
references.pmid: 22416857
references.citation: Gastroenterology. 2013 Jun;144(6):1252-61
references.pmid: 23622135
references.citation: Diabetes Obes Metab. 2012 Jun;14(6):565-74
references.pmid: 22356132
references.citation: Diabetes Care. 2010 Nov;33(11):2349-54
references.pmid: 20682680
references.citation: Diabet Med. 2009 Mar;26(3):268-78
references.pmid: 19317822
references.citation: Lancet Diabetes Endocrinol. 2014 Feb;2(2):111-5
references.pmid: 24622714
references.citation: Diabet Med. 2010 Sep;27(9):1024-32
references.pmid: 20722676
references.citation: Diabetes Obes Metab. 2011 May;13(5):418-25
references.pmid: 21251180
references.citation: Diabetes Obes Metab. 2013 Mar;15(3):204-12
references.pmid: 22985213
references.citation: Diabetes Obes Metab. 2010 Apr;12(4):341-7
references.pmid: 20380655
references.citation: BMJ. 2012 Jan 10;344:d7771
references.pmid: 22236411
references.citation: Diabetes Care. 2009 May;32(5):762-8
references.pmid: 19196887
references.citation: Diabetes Res Clin Pract. 2012 Nov;98(2):271-84
references.pmid: 23010561
references.citation: Lancet. 2012 Aug 4;380(9840):475-83
references.pmid: 22748821
references.citation: Diabetes Care. 2012 Mar;35(3):485-7
references.pmid: 22301126
references.citation: BMJ. 2013 Jun 11;346:f3782
references.pmid: 23757752
references.citation: BMJ. 2012 Mar 12;344:e1369
references.pmid: 22411919
references.citation: Diabetes Care. 2012 Jun;35(6):1225-31
references.pmid: 22432104
references.citation: Diabetes Obes Metab. 2014 Jan;16(1):48-56
references.pmid: 23837679
references.citation: Diabetes Obes Metab. 2011 Jan;13(1):81-8
references.pmid: 21114607
references.citation: J Clin Epidemiol. 2012 Mar;65(3):262-7
references.pmid: 22200346
references.citation: Diabet Med. 2012 Oct;29(10):1260-7
references.pmid: 22804250
references.citation: BMJ. 2012 May 08;344:e3259
references.pmid: 22570213
references.citation: Diabetes Metab Res Rev. 2012 Mar;28(3):268-75
references.pmid: 22081481
references.citation: Curr Med Res Opin. 2012 Sep;28(9):1465-74
references.pmid: 22816729
references.citation: Curr Med Res Opin. 2009 Apr;25(4):1019-27
references.pmid: 19278373
references.citation: N Engl J Med. 2012 Apr 5;366(14):1319-27
references.pmid: 22475595
references.citation: Lancet. 2010 Jun 26;375(9733):2234-43
references.pmid: 20609969
references.citation: Diabet Med. 2013 Jan;30(1):109-13
references.pmid: 22937895
references.citation: JAMA. 2000 Apr 19;283(15):2008-12
references.pmid: 10789670
references.citation: Clin Ther. 2012 Sep;34(9):1892-908.e1
references.pmid: 22884767
references.citation: Diabetes Care. 2012 Jun;35(6):1364-79
references.pmid: 22517736
references.citation: Curr Med Res Opin. 2010 May;26(5):1013-22
references.pmid: 20199137
references.citation: Diab Vasc Dis Res. 2011 Apr;8(2):125-35
references.pmid: 21562064
references.citation: BMJ. 2009 Jul 21;339:b2535
references.pmid: 19622551
references.citation: BMJ. 2013 Jul 30;347:f4838
references.pmid: 23900829
references.citation: Diabetes Obes Metab. 2009 Dec;11(12):1145-52
references.pmid: 19758359
references.citation: Diabetes. 2009 Sep;58(9):2148-61
references.pmid: 19509017
references.citation: Gastroenterology. 2011 Jul;141(1):150-6
references.pmid: 21334333
references.citation: Diabetes Technol Ther. 2011 Jan;13(1):27-32
references.pmid: 21175268
references.citation: Diabetes Obes Metab. 2013 Mar;15(3):234-40
references.pmid: 22958426
references.citation: Diabetologia. 2010 Jan;53(1):153-9
references.pmid: 19756486
references.citation: Diabetes Care. 2014 Jan;37 Suppl 1:S14-80
references.pmid: 24357209
references.citation: BMJ. 2013 Jun 10;346:f3750
references.pmid: 23751908
references.citation: Ann Intern Med. 2011 Jan 18;154(2):103-12
references.pmid: 21138825
references.citation: Diabetes. 2012 May;61(5):1250-62
references.pmid: 22266668
references.citation: BMJ. 2013 Jun 07;346:f3680
references.pmid: 23748128
references.citation: Diabetes Care. 2009 Jul;32(7):1237-43
references.pmid: 19366970
references.citation: Diabetes Care. 2009 Jul;32(7):1224-30
references.pmid: 19289857
references.citation: BMJ. 2013 Jun 17;346:f3900
references.pmid: 23775889
references.citation: Diab Vasc Dis Res. 2011 Apr;8(2):150-9
references.pmid: 21562067
references.citation: Diabetes Technol Ther. 2012 Oct;14(10):904-11
references.pmid: 22845701
references.citation: Lancet. 2010 Aug 7;376(9739):431-9
references.pmid: 20580422
references.citation: BMJ. 2013 Jun 10;346:f3617
references.pmid: 23751905
references.citation: Stat Med. 2007 Jan 15;26(1):53-77
references.pmid: 16596572