Medication Follies: The Story of New-Line Diabetes Medications and Pancreatitis

Since the discovery of the incretins of the small intestine in the 1970s, academics and pharmaceutical companies studying the effects of DPP-4 as well as methods to block the physiological actions associated with the enzyme. In 2006 or 2007, Merck Co. received FDA approval for Januvia (Sitagliptin), a DPP-4 inhibitor that was able to suppress glucagon while increasing insulin secretion. Due to the epidemic of diabetes and obesity, clinicians were ecstatic on its action and lack of drug-drug interaction. However, after use, clinicians and professors were concerned. They were unsurprised with the typical side effects of any diabetes medication (mainly because patients' lowered blood glucose levels and weight-neutral appearance), but were concerned about the incidences of acute pancreatitis.  From the AACE PSE.

Pancreatitis is, simply put, an inflammation of the pancreas.  Prior to the appearance of DPP-4 inhibitors and GLP-1 agonists, it was typically associated with infection by viruses, fungi, parasites or even bacteria.  A physical examination will reveal only abdominal pain, and the diagnosis can be confirmed by a laboratory measure of pancreatic amylase OR lipase.  Imaging studies are typically done to confirm pancreatitis, find a cause, or even rule out diseases with similar presentations (such as DKA, gallstones, and fatty liver disease).  Treatment is not really direct, but mainly supportive.  Patients are not allowed to eat, but given intravenous infusion of nutrition and saline as well as oxygen via a mask or a nasal cannula.  If pancreatitis becomes severe (which is rare with DPP-4 inhibitors), patients are admitted to an Intensive Care Unit to address hypovolemia (shock) and other underlying causes.

But, first, we need to describe what is Dipeptidyl-Peptidase-IV (DPP-4) and Glucagon-like Peptide 1 (GLP-1). During a meal, cells in the small intestine secrete incretins, namely GLP-1 and glucose-dependent gastric inhiitory peptide (GIP), into the bloodstream. GLP-1 is utilized to stimulate insulin synthesis in the pancreas, suppress glucagon secretion, and decrease the rate of gastric emptying. However, GLP-1 and GIP is inactivated relatively quickly by DPP-4.  The following video can visually clarify the mechanism:

There are two ways to tackle this problem: (1) Increase the concentration of GLP-1 and GIP in the bloodstream, or (2) Help increase the half-lives of GIP and GLP-1 already present. Pharmacists, chemists, and physicians theorized that inhibition of DPP-4 will allow GLP-1 and GIP to remain active in the bloodstream and consequently lengthen the beneficial effects. GLP-1 agonists (first milked and isolated freshly from Arizona's own Gila Monsters) help increase production of the incretins from the small intestines.   Unfortunately, by postulated (but still unknown) mechanisms (Olansky, Cleveland Clinic), it is difficult to explain why pancreatitis is occurring with these drugs.

However, with the incidence of acute pancreatitis, there is now debate on what these drugs are doing. Professors, clinicians, pharmaceutical companies, and researchers are constantly debating the issue almost in the manner of the "chicken or the egg" controversies.  The problem, according to physicians, is associated with the incretin-stimulation.  Dr. Peter Butler at the Hillblom Islet Research Center observed that the sitagliptin, when administered alone in transgenic rats, found higher rates of cellular production in the pancreas, while finding pancreatitis and ductal metaplasia in the minority of his research subjects.  In addition, they found that when Metformin (a front-line biguanide/diabetic medication) was administered with DPP-4 Inhibitors, they found a synergistic effect and minimization of metaplasia in the pancreas.  (Hillblom Islet Press Release)  However, the problem with associating GLP-1 agonists and DPP-4 inhibitors with pancreatitis is that diabetics are already at risk of acute pancreatitis due to the cellular apoptosis in the pancreas, though there is repeated correlation of exenatide usage and incidences of pancreatitis.  (Medscape Article)  A second issue with associating pancreatitis with such an association is the relatively low incidences that can't fully establish the correlation.  Physicians, having to weigh the therapeutic and adverse effects, is given a lot of choices with the plethora of medications, but can revert back to standard operating procedure (SOP): If the patient is experiencing an adverse effect, stop the drug and look for other approaches.  Pharmaceutical companies, in an effort to avoid legal nightmares and civil lawsuits, have began posting advisory notices and warnings.  But to avoid another public scare, physicians have been able to produce advisory notices to patients as well as colleagues.



So, why do you think that DPP-4 inhibitors and GLP-1 agonists have these new symptoms?  Should physicians be forced to discontinue the medication because of these adverse effects?  Does this reinforce the idea that diet management and exercise, in conjunction with these medications, can help minimize the disease's effects and even a drug's adverse effects?