Incretins and Questions About the PancreasPosted August 6, 2013 by Irl B. Hirsch, MD
Over the past six months we have had more questions than answers about the risk of incretin therapy (DPP-4 inhibitors and GLP-1 agonists) and the increased risks for both pancreatitis and pancreatic carcinoma. The discussion seems to have resolved to an interim and perhaps temporary conclusion based on the recent American Diabetes Association Scientific Sessions in Chicago in June.
At that conference Dr. Vanita Aroda from MedStar Health Research Institute in Hyattsville, Maryland reviewed the recent conference held on June 5th and 6th as part of an NIH workshop. She noted that type 2 diabetes itself increases the risk of pancreatitis and pancreatic cancer by 82%.1 Additionally, those recently diagnosed with diabetes (less than four years) have a 50% greater risk of pancreatic cancer compared to those with longer durations of diabetes.
The animal models have conflicting results on the effects of incretin therapy and the exocrine pancreas. Liraglutide did not result in pancreatitis in rats, mice, or monkeys at very high exposure rates (greater than 60 times the level in humans).2 However, another mouse model that is primed to develop pancreatitis and pancreatic cancer after 12 weeks of extended treatment produced expansion of the pancreatic duct glands. Additionally, premalignant pancreatic intraepithelial lesions were identified in these high-risk animals.
Many Unanswered Questions
When looking more closely at the clinical data now available, it seems there are simply more unanswered questions. The most referenced article on pancreatitis by Singh, et al 3 showed that the treatment group receiving incretins had a higher background rate of risk factors for pancreatitis such as obesity, alcohol use, and hypertriglyceridemia. This was an observational study that obviously could not control for other confounders or potential biases. This point is critical since we now have an increased awareness for the potential for pancreatitis with a DPP-4 inhibitor or a GLP-1 agonist; thus one has to wonder if a clinician is more apt to report this finding than if a similar patient was receiving a sulfonylurea or metformin.
Perhaps the study that has generated even more concern is that of Butler, et al.4 This report reviewed three groups of patients [those without diabetes (n=14), those with diabetes (n=12), and those with diabetes using an incretin-based therapy (n=8)]. It was a small study that was poorly matched for background treatment, diabetes duration, age, gender, and body-mass index. Specifically, those individuals with diabetes who did not receive incretin therapies were 18 years younger, mostly female (67%), and five were diagnosed with diabetes under the age of 20 years. Two in this group died of ketoacidosis suggesting that this “control group” had at least some individuals with type 1 diabetes. To me, that seems a bit odd for a comparator.
So far, more rigorous randomized controlled trials using incretin-based therapies have not detected any type of pancreatitis or pancreatic cancer signal. There have been three cases of pancreatic cancers reported with liraglutide, one in a patient treated with this GLP-1 agonist for 52 days, one treated for seven days and then diagnosed with advanced stage four pancreatic cancer, and one who was reported prior to randomization and never even received liraglutide. This suggests to me that really no pancreatic cancer signal has been seen to date with this agent.
Need for More Randomized, Controlled Clinical Studies
At the end of Dr. Aroda’s presentation, a question was asked by Dr. Bernard Zinman wondering if a patient receiving a GLP-1 agonist came to see you the next morning and expressed concerns about pancreatitis and pancreatic cancer based on the advertisements on television, what should the patient be told? Dr. Aroda then took an informal poll of the audience and asked how many would tell the patient not to take the GLP-1 agonist. Not one individual in this auditorium of 1,000 that I could see raised their hand. She then asked how many would try to educate the patient on balancing risk and continue the medication and almost every hand was raised. This was then met with applause.
I find this response quite interesting after also attending the American College of Physicians meeting held earlier in the spring in San Francisco. At that meeting, the Butler results had just been released, and there was quite a bit of concern based on news reports and quite a bit of internet attention. It was quite clear to me that with this different population of physicians, almost all general internists and some internal medicine subspecialists, there was a general concern about ever using an incretin-based therapy, especially with so many unanswered medical-legal questions left to be answered with late-night lawyer advertisements just starting. While I would like to think more physicians have had time to review the evidence, we would all admit no clear conclusions can be made now (despite the informal vote at the ADA session) suggesting the concern I noted in San Francisco has remained.
The good news about all of this is that over the next few years we will obtain more rigorous and robust data from randomized, controlled human trials. These trials will include a variety of cardiovascular outcome studies for both DPP-4 inhibitors and GLP-1 agonists (there are currently eight trials now under way with a total of 76,362 patients). In addition this topic will be also assessed as part of the GRADE study which is now just starting. 5 I should also point out that on July 26, 2013 there was a press release from European drug regulators, and after careful evaluation they found no new safety concern with any of the incretin-based therapies. We know that the US Food and Drug Administration is of course studying the drugs’ safety.
This entire discussion of events over the previous few months has been fascinating to watch. This is all occurring during a time period where it is now acknowledged that some of our concerns about rosiglitizone were overstated. And of course the fiasco with glargine and cancer was resolved with the publication of the ORIGIN trial. 6 The point is, observational studies simply cannot definitively answer these types of clinical questions. It is obviously easy in our litigious society to overreact to reports about the potential for drug safety. The good news is all of the major endocrine and diabetes organizations in the United States and elsewhere in addition to the regulators are watching this closely and obviously are well attuned about judging the quality of these various reports.
I will continue to watch this story with great interest until we get more definitive data, not only on these potential side effects, but any potential benefit (or lack thereof) of these drugs in the large cardiovascular outcome trials that are now underway. In the meantime, I will continue to use these various drugs in the most appropriate fashion possible. For the GLP-1 agonists, I feel comfortable in using these drugs in patients with type 2 diabetes who are obese. I also have no safety concern about DPP-4 inhibitors, particularly in older patients with whom I have greater concerns about hypoglycemia. Obviously, as more data become available my thoughts could change.
I would be curious about your thoughts on this issue.
1. Huxley, et al. Type II diabetes and pancreatic cancer: A meta-analysis of 36 studies British J Cancer2005;92:2076–2083.
2. Nyborg, NC, et al. The human GLP-1 analog liraglutide and the pancreas: Evidence for the absence of structural pancreatic changes in three species. Diabetes 2012;61:243–1249.
3. Singh, S et al. Glucagonlike peptide I-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;173:534-539.
4. 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 tumors. Diabetes 2013;62:2595-2604.
5. Nathan DM, et al. GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Diabetes Care 2013;36:2254-2261.
6. ORIGIN Trial Investigators: Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-328.