Pancreatitis and exenatide: What is the risk?

Post-marketing surveillance programs may be necessary to find potential risks and benefits.

Issue: February 2008

ByZachary T. Bloomgarden, MD, MACE, FASPC

Pancreatitis is common among patients with diabetes. In my personal clinical practice, of more than 1,500 patients followed during the past several years, 15 have had pancreatitis.

Diabetes is associated both with hypertriglyceridemia and with gallstones, both causes of pancreatitis. Diabetes doubles the likelihood of pancreatitis, with obesity and sulfonylureas as further risk factors. In a study of a Swedish population of approximately 1.4 million people, 2,453 had possible episodes of pancreatitis; 462 of those were documented first episodes. Known gallstones were present in an additional 390 cases, 180 people had gastrointestinal tract malignancy, 168 had undergone biliary tract endoscopy, and 509 had prior pancreatitis. A systematic review suggested an increase over the past four decades to approximately 20 cases per 100,000 population, of which approximately half are related to gallstones.

Zachary T. Bloomgarden, MD
Zachary T. Bloomgarden

The increased risk associated with sulfonylurea treatment may be explained by the involvement of an ATP-sensitive potassium channel in biliary smooth muscle contraction, with glyburide blocking gallbladder smooth muscle relaxation in vitro. The association of diabetes with pancreatitis may extend to the prediabetic state, as lean people with decreased gallbladder emptying show evidence of insulin resistance.

The pathogenesis of pancreatitis involves release of pancreatic exocrine secretions into the tissues of the pancreas, typically precipitated by situations involving decreased biliary tract motility, whether due to mechanical obstruction or functional abnormality, as seen in insulin resistance. The pancreatic digestive enzyme trypsin may be important in the genesis of pancreatitis. Gut hormones such as cholecystokinin mediate trypsin release. Cholecystokinin is stimulated by enteral nutrients delivered to the proximal small intestine, while nutrient in the mid-distal jejunum does not stimulate cholecystokinin or increase trypsin and is associated with stimulation of glucagon-like peptide (GLP)-1 secretion. Trypsin output correlates inversely with release of GLP-1 during ileal infusion of either lipid or carbohydrate. There is then no clear physiologic rationale for therapeutic GLP-1 receptor activation with exenatide leading to pancreatitis. Certainly the relationship between enteric hormones and biliary motor function is complex, with gastric distention stimulating sphincter of Oddi motility, a potential indirect mechanism for exenatide causing pancreatitis. GLP-1 has effects on vagal function, and cholinergic anti-inflammatory vagal pathways reduce pancreatitis severity, another potential mechanism.

Sulfonylureas, statins, fibrates, antihypertensive drugs and many other drugs may cause pancreatitis.

In this setting, the FDA report in October 2007 of 30 persons treated with exenatide who had developed pancreatitis is difficult to interpret. Given the .3 million prescriptions for exenatide by March 2007, the prevalence statistics cited above suggest tremendous underreporting. Exenatide causes weight loss, and rapid weight loss can induce gallstone formation by increasing bile saturation, which itself would increase pancreatitis incidence.

Certainly, pancreatitis must be considered in any person with diabetes and acute abdominal pain, and exenatide might slightly increase that clinical suspicion. More importantly, if such a relationship does exist, greater risk of pancreatitis might occur with use of more potent GLP-1 receptor agonists, acting for more sustained periods of time than exenatide. If such a risk exists, it is unlikely that standard phase-3 clinical trials enrolling no more than several thousand people will detect an increase in incidence of a condition affecting well below 1% of people with diabetes annually. Therefore it will be important to establish sturdy post-marketing surveillance programs to capture data more fully so that we will be able to understand potential risks, as well as benefits, of these important new agents.

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Zachary T. Bloomgarden, MD, is a Clinical Professor, Department of Medicine, Mount Sinai School of Medicine, New York, and he is a member of Endocrine Today’s Editorial Board.