Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Abstract

Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon‐like peptide (GLP)‐1 receptor agonists and dipeptidyl peptidase (DPP)‐4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta‐analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP‐1 receptor agonists and DPP‐4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient‐years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP‐1 receptor agonists and DPP‐4 inhibitors. Neither data on individual CVOTs of GLP‐1 receptor agonists nor their meta‐analysis [rate ratio: 1.05 (0.78–1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP‐4 inhibitors displayed a non‐significant trend towards an increased risk of acute pancreatitis, which was significant in the meta‐analysis [1.75 (1.14–2.70); P = 0.01]. Neither GLP‐1 receptor agonists nor DPP‐4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo‐controlled, prospective cardiovascular outcomes studies with GLP‐1 receptor agonists and DPP‐4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta‐analysis of DPP‐4 inhibitor CVOTs.

No effects of a 6‐week intervention with a glucagon‐like peptide‐1 receptor agonist on pancreatic volume and oedema in obese men without diabetes

“…Others have reported an increased protein synthesis rather than DNA synthesis to be responsible for enlargement of the pancreas 18 . Chronic administration of GLP‐1 in mice, rats and monkeys did not induce any structural changes (neoplasia or signs of inflammation) of the pancreatic tissue, 19 in line with the recent meta‐analyses from the cardiovascular outcome trials which, as mentioned, did not show differences in the incidence of pancreatitis or pancreatic cancer between subjects treated with GLP‐1RAs or placebo 11 . The effects of the GLP‐1RA liraglutide on pancreas volume, oedema and DNA synthesis have, to our knowledge, not been investigated in humans.…”

“…Initially, there was fear that the rises were signs of pancreatitis 9 . However, an association between the use of GLR‐1RAs and incidence of acute pancreatitis or pancreatic cancer has not been confirmed, neither in preclinical safety studies nor in the large, long‐duration cardiovascular outcome trials with GLP‐1RAs 2,9–12 …”

Pathological Mechanisms in Diabetes of the Exocrine Pancreas: What’s Known and What’s to Know

“…However, rather than the main cause leading to T2DM, the deficiency of incretin was more often considered as a results of deteriorating glucose homeostasis in T2DM ( Knop et al, 2007b ; Knop, 2010 ). Incretin-based pharmacotherapy has been suggested to be correlated with increased risk of AP in T2DM patients ( Azoulay et al, 2016 ; Ueberberg et al, 2016 ; Tseng et al, 2017 ) although more recent and thorough studies have suggested that incretin-based treatment does not increase pancreatitis risk ( Wang et al, 2015 , 2018 ; Abd El Aziz et al, 2020 ). The GLP-1 receptor may activate PSCs, changes pancreatic gene, and enhances pancreatic mass, therefore inducing pancreatic injury ( Koehler et al, 2009 ; Yang et al, 2013 ).…”

“…Due to potential differences in symptoms and etiology between DMs, personalized hyperglycemia solutions should pay special attention to drug indications and contraindications. For example, although being preferred selections for DM treatment in many situations, incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists have been suggested to be associated with increased pancreatitis risk ( Buse et al, 2017 ; Abd El Aziz et al, 2020 ). Although more thorough studies have suggested that incretin-based treatment did not increase pancreatitis risk ( Wang et al, 2015 , 2018 ; Abd El Aziz et al, 2020 ), it is still suggested to be used with vigilance ( Buse et al, 2017 ; Abd El Aziz et al, 2020 ).…”

Gut-Based Strategies to Reduce Postprandial Glycaemia in Type 2 Diabetes

“…Unfortunately, in the majority of studies these have been assessed by participant self-report which is known to be unreliable (118) iii) the insulinotropic actions of GLP-1-based therapy necessitates adequate endogenous insulin secretory capacity iv) GLP-1 agonists are contraindicated in the rare case of medullary thyroid carcinoma. While recent observational studies and meta-analyses have failed to establish a causal relationship between GLP-1 agonists and acute pancreatitis, this remains potential issue (94,119). A post-hoc analysis of the LEADER trial showed that the GLP-1 receptor agonist, liraglutide, to have an increased risk of gallbladder or biliary tract related events compared with placebo (120).…”