Meta-Analysis
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Meta-Anal. Dec 26, 2015; 3(6): 254-283
Published online Dec 26, 2015. doi: 10.13105/wjma.v3.i6.254
Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and meta-analysis of randomized trials
Hasan M Shihab, Tokunbo Akande, Kacie Armstrong, Sonal Singh, Yoon K Loke
Hasan M Shihab, Division of Acute Care Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Tokunbo Akande, Department of Pediatrics, Bronx-Lebanon Hospital Center, Bronx, NY 10457, United States
Kacie Armstrong, Sonal Singh, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Yoon K Loke, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, United Kingdom
Author contributions: Shihab HM designed study, extracted and analyzed data, and wrote manuscript; Akande T and Armstrong K contributed to study identification/extraction and edited manuscript; Singh S designed study, analysed data, contributed discussion and edited manuscript as corresponding author; Loke YK designed study, extracted and, analyzed data, and edited manuscript as corresponding author.
Conflict-of-interest statement: Sonal Singh had served as a consultant on the advisory board of Janssen Pharmaceuticals Inc. to comment on the safety of sodium glucose co-transporter inhibitor-2 (SGLT-2) canagliflozin. He was compensated for his time.
Data sharing statement: All available data has been presented in the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yoon K Loke, MD, Professor, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom. y.loke@uea.ac.uk
Telephone: +44-1603-591234 Fax: +44-1603-59752
Received: June 26, 2015
Peer-review started: June 28, 2015
First decision: September 17, 2015
Revised: October 13, 2015
Accepted: December 3, 2015
Article in press: December 4, 2015
Published online: December 26, 2015
Processing time: 181 Days and 2.8 Hours
Abstract

AIM: To systematically assess risk of pancreatic adverse events with glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor drugs.

METHODS: We searched PubMed, Embase, CINAHL, Cochrane review of clinical trials, pharmaceutical company clinical trials register, United States Food and Drug Administration website, European Medicines Agency website and ClinicalTrials.gov for randomized controlled trials from inception to October 2013. Randomized control trial studies were selected for inclusion if they reported on pancreatic complication events and/or changes in pancreatic enzyme levels (serum amylase and serum lipase) as adverse events or as serious adverse events for patients who were on GLP-1 receptor agonist and DPP-4 inhibitor drugs. Two independent reviewers extracted data directly. We performed Peto odds ratio (OR) fixed effect meta-analysis of pancreatic adverse events a, and assessed heterogeneity with the I2 statistic.

RESULTS: Sixty-eight randomized controlled trials were eligible. A total of 60720 patients were included in our analysis of the association of risk of pancreatic complication events with GLP-1 agents. A total of 89 pancreatic related adverse events occurred among the GLP-1 agents compared to 74 events among the controls. There was a statistically significant increased risk of elevation of pancreatic enzymes associated with GLP-1 agents compared with control (Peto OR = 3.15, 95%CI: 1.56-6.39, P = 0.001, I2 = 0%). There was no statistically significant difference in the risk of pancreatic adverse event associated with GLP-1 agent compared with controls (Peto OR = 1.00, 95%CI: 0.73-1.37, P = 1.00, I2 = 0%). There were a total of 71 pancreatitis events in patients on GLP-1 agents and 56 pancreatitis events occurred in the control patients. There were 36 reports of pancreatic cancer in these studies. Of these cases, 2 used linagliptin, 2 used alogliptin, 1 used vildagliptin, 7 used saxagliptin while 6 used sitagliptin. The remaining 18 cases occurred among controls.

CONCLUSION: Although GLP-1 based agents are associated with pancreatic enzyme elevation, we were unable to confirm a significant risk of pancreatitis or pancreatic cancer.

Keywords: Diabetes mellitus; Pancreatitis; Glucagon-like peptide-1 agonists; Dipeptidyl peptidase-4 inhibitors; Meta-analysis

Core tip: There is conflicting data on the risk of pancreatitis with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We performed a meta-analysis of 68 randomized controlled trials of 11 different GLP-1 or DPP-4 targeted drugs. The incidence of pancreatic adverse events in the trials was generally low and we did not find any definitive evidence for pancreatitis or pancreatic cancer amongst the trials. However, we found a significantly raised risk of elevated pancreatic enzymes in a small number of trials that reported such enzyme elevations.