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.Design Systematic review and meta-analysis.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.Eligibility criteria 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.Data collection and analysis 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

Is There a Link Between Liraglutide and Pancreatitis? A Post Hoc Review of Pooled and Patient-Level Data From Completed Liraglutide Type 2 Diabetes Clinical Trials

“…A systematic review and meta-analysis of 55 randomized clinical trials (33,350 patients) indicated an odds ratio (95% CI) for pancreatitis of 1.11 (0.57, 2.17) with incretinbased therapies versus control; estimates calculated by incretin therapy class (GLP-1 receptor agonists or DPP-4 inhibitors) showed similar results (23). In the same study, the authors described results of five observational studies without pooled analysis due to variation in outcome measures and data forms.…”

“…Four of these observational studies showed no increased risk of pancreatitis associated with incretin exposure, but one (19) linked exenatide or sitagliptin use with a significantly increased odds of acute pancreatitis (use within 2 years vs. no use 2.07 [1. 36,3.13]) (23).…”

Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice

“…Whereas no newly generated beta cells were detected by the activation of GLP-1 signalling alone, GLP-1 was able to facilitate beta cell neogenesis initiated by gastrin, although the reprogramming efficiency in our model was not as high as that of other mouse models [1,13]. It is noted that activation of GLP-1 signalling did not induce pancreatitis and pancreatic dysplasia, suggesting that these safety concerns, which have been reported in previous clinical cases and in vivo studies of incretin-based therapies [14][15][16], were abated in our models. The present findings point to possible future therapies for diabetes via these signalling pathways.…”

“…Activation of incretin signalling does not induce pancreatitis or pancreatic dysplasia The activation of incretin signalling was reported to possibly be associated with pancreatitis and pancreatic dysplasia both in humans and animal models, although recent studies support the safety of incretin-based drugs [14][15][16][34][35][36]. To test whether or not increased GLP-1 signalling in the pancreas results in undesired pathologies, pancreases from exo-Glp1r mice were examined microscopically.…”

Inkretintengelyen ható antidiabetikumok és a pancreas betegségei (pancreatitis, pancreascarcinoma)

“…A szerzők végkövetkeztetése szerint az inkretintengelyen ható gyógyszerek használata során a pancreatitis incidenciája igen alacsony, a gyógy-szer adása nem növeli a pancreatitis kockázatát. Mindazonáltal ez a vélemény nem tekinthető véglegesnek, a további adatgyűjtés még mindig indokolt [28].…”