Incretin-based therapies and pancreatitis risk: myth or reality

Abstract

Incretins are gastrointestinal hormones secreted in response to food intake that modify biological mechanisms of glucose homeostasis in the body. Approximately 70 % of insulin secretion by pancreatic b-cells is under the control of two incretin molecules, namely glucose-dependent intestinal polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) [1]. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) to an inactive molecule that terminates its incretin effect. Research on the pharmacological manipulation of GLP-1 and DPP-4 molecules resulted in the development of multiple drugs in recent years, which are very useful for the treatment of type 2 diabetes mellitus (T2DM). These drugs, the GLP-1 analogues and DPP-4 inhibitors, form the incretin-based therapies in the management of T2DM, collectively termed as incretin mimetics or incretin analogues. With a modest effect on haemoglobin A1c, favourable effects on body weight and relatively low risk of hypoglycaemia [2], these drugs gained much popularity in the past few years. Incretin-based therapies are recommended by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) as second-line agents for the management of T2DM [2,3].The meal-related insulin release from pancreas results from the binding of GLP-1 to b-cell GLP-1 receptors (GLP-1R). Because of the very short biological half-life, endogenously produced GLP-1 does not possess sustained effects on the pancreas. However, incretin mimetic drugs result in continued stimulation of GLP-1R with a potential for pleotropic effects on the pancreatic tissues [4].Experimental data from animal models showed conflicting results with some studies showing evidence of pancreatic damage from incretin mimetics [5,6], whereas the others demonstrating protective effects [7,8]. Concerns were raised about the risk for pancreatic damage from incretinbased therapies based on multiple case reports and recent data from the United States Food and Drug Administration (FDA) adverse events reporting system. These prompted the FDA and other international agencies to caution the global medical fraternity about the potential harm related to the use of this new class of medications which were deemed to be promising in the management of T2DM, especially in obese individuals.The warnings from different global agencies evoked a hot international debate on the safety of incretin-based therapies in 2013 [4,9]. Several reports from the FDA and other international agencies also added chaos to the discussion although none has resolved the uncertainty completely. A systematic review and meta-analysis addressing this issue published early this year concluded that evidence for increased incidence of pancreatitis in T2DM patients taking incretin mimetics is inadequate, and that incretinbased therapies do not increase pancreatitis risk [10]. The studies analysed in this paper provided robust data from a total patient population of 33,350 cases treated for a median duration of 26 wee...

Extra Glycemic Impacts of GLP-1 Receptor Agonists: Benefits of a Class Effect?

“…Pancreatitis cases have been reported in animals and in humans treated with agents of this class. Exenatide and Liraglutide are associated with reported cases of acute pancreatitis, whereas lixisenatide has not, so far [64]. Studies show an average incidence of 1.6 cases of acute pancreatitis per 1000 patients/years of exposure, as for Liraglutide [65].…”

Use of incretin agents and risk of acute and chronic pancreatitis: A population‐based cohort study

“…One observational study found that current use of sitagliptin or exenatide was significantly associated with risk of hospitalization for acute pancreatitis; however, a systematic review and meta‐analysis, including 9 studies, with >1.3 million individuals and an average follow‐up of 0.7 to 1.4 years, found that incretin‐based therapy did not increase the risk of pancreatitis . Multiple observational studies have assessed the association between incretin‐based therapy and pancreatitis . Given the controversy, the European Medicines Agency and the US Food and Drug Administration have called for additional studies …”

“…13 Multiple observational studies have assessed the association between incretin-based therapy and pancreatitis. [14][15][16][17] Given the controversy, the European Medicines Agency and the US Food and Drug Administration have called for additional studies. [18][19][20] Furthermore, in contrast to the risk of acute pancreatitis, the risk of chronic pancreatitis with incretin use has not been investigated in an observational setting.…”