Troubles ahead for the incretin therapies?
29 March 2013 (04:30 PM) - Hot Topics
Acute pancreatitis was first reported as a possible complication of treatment with exenatide in 2006, and has since caused concerns with all established GLP-agonist and DPP4-inhibitory agents, suggesting a possible class effect. Possible mechanisms have included disturbances of bile composition or flow, or hypertrophy of pancreatic duct cells causing obstruction of the smaller pancreatic ducts.
In defence of these agents it should be noted that animal studies have generated conflicting results, and that observational studies have reported a higher-than-expected background rate of pancreatitis in the diabetic population, with no excess for the incretin therapies as compared with other treatments for diabetes.
Two recent publications have re-opened the debate. In the first, Singh and colleagues from Johns Hopkins performed a large population-based matched case-control study comparing the risk of pancreatitis in patients starting on exenatide or sitagliptin with those on non-incretin based diabetes therapies. Current use (within 30 days) or recent past use (> 30 days but <2 years) of the GLP-1 based therapies was associated with a two-fold increase in the risk of acute pancreatitis (adjusted odds ratio for current use 2.24 [95% CI 1.36-3.68]; for recent use 2.01 [1.37-3.18]). Although this independent study has some of the limitations inherent in all pharmacoepidemiological studies, it is the largest and best-performed to date, and reopens the question of subclinical “silent” pancreatic damage in a much larger proportion of people on these therapies .
In the second study, Alexandra Butler and colleagues from UCLA examined pancreata from organ donors treated with exenatide (1 case) or sitagliptin (7 cases), as compared with 12 other donors with diabetes on other therapies, and 14 non-diabetic controls . Those on incretin therapy showed a 40% increase in pancreatic mass associated with exocrine proliferation and dysplasia (increased pancreatic intraepithelial dysplasia, a potentially pre-malignant change). Surprisingly, there was also marked proliferation of both alpha and beta islet cells. Beta cell mass was reduced by 60% in those with diabetes on other therapies, but was 6-fold greater in those on incretin therapy; unfortunately this had failed to reverse diabetes in the donors. The likely reason is that these cells were immature; a high proportion stained for both insulin and glucagon, a phenomenon normally seen only in foetal life. An unexpected finding was marked proliferation of alpha cells, associated with microadenomas in 3/7 treated with sitagliptin: one of these additionally harboured a neuroendocrine tumour. The authors point out that alpha cell proliferation has been reported in other situations associated with deficient glucagon secretion or action, and might represent a possible concern for all therapies based around glucagon inhibition. The FDA and EMA have been alerted to these new findings and are expected to report back shortly.
^ Singh S et al. Glucagonlike peptide-1 based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med 2013 Feb 25:1-6. doi: 10.1001/jamainternmed.2013.2720. [Epub ahead of print]
^ Butler AE et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumours. Diabetes [published online March 22nd 2013]