Do Incretin-based Therapies Increase the Risk of Developing Acute Pancreatitis in Patients with Diabetes?

Despite the promise shown by incretin-based therapies for the treatment of type 2 diabetes, concerns remain that incretins may increase the risk of pancreatitis in this patient population. However, several epidemiological studies on this topic have produced conflicting results.

Speaking at a session Sunday at the American Diabetes Association’s 74th Scientific Sessions, held June 13-17, 2014, in San Francisco, CA, Reimar Thomsen, MD, PhD, from the Department of Clinical Epidemiology at Aarhus University Hospital, Denmark, reported on a major epidemiological study conducted in that country investigating links between incretin therapy for type 2 diabetes and the development of pancreatitis.

This inquiry into associations between the use of GLP-1 receptor analogs and DPP-4 inhibitors and risk of developing acute pancreatitis included all hospitals in Denmark and is the largest population-based, case-control study on the link between incretin therapy and pancreatitis conducted to date.

Characterizing the limitations of this epidemiological study, Thomsen said, “There is a lack of exact data on diabetes duration and severity. However, incretin therapy usually is associated with more advanced diabetes and increased comorbidity.”

He added, “The choice of confounder variables is critical. Some factors may be intermediate variables, such as use of glucose-lowering drugs, rather than true confounders, such as gallstones. Another issue can arise from incompletely measured, unmeasured, or even unknown confounders.” Thomsen offered obesity as an example, where this variable might be more completely registered in data on users of glucose-lowering drugs (including incretin therapies) compared with non-users. Thomsen added that, in general, their database had limited information on lifestyle factors.

The Danish study included 12,868 patients with a first-time hospitalization for acute pancreatitis along with 128,680 matched population controls from a period spanning 2005 to 2012. Adjustments were made for various confounding factors including development of gallstones, alcoholism, obesity, and other pancreatitis-associated comorbidities and drug treatments related to these pathologies. From this cohort, a total of 89 pancreatitis patients (0.69%) and 684 controls (0.53%) were found to have used incretins at least once; 54 (0.42%) and 482 (0.37%), respectively, were being treated with incretins at the time of the study.

Although patients with acute pancreatitis were 1.17 times more likely than matched controls to be current users of incretins, they were 1.35 times more likely to be current users of other anti-hyperglycemic drugs (AHDs). Odds ratios (ORs) were estimated for development of acute pancreatitis associated with use of incretins and other AHDs.

Risk of acute pancreatitis was not increased among current incretin users, based on adjusted OR=0.81 (95% CI, 0.60-1.10), compared with non-users of any AHDs. In breaking this incretin group down, current DPP-4 inhibitor users displayed an adjusted OR=0.78 (95% CI, 0.53-1.16) compared to non-users of AHDs, while current GLP-1 receptor analog users had an adjusted OR=0.84 (95% CI, 0.53-1.34) compared to non-users of AHDs. The adjusted OR for acute pancreatitis among current users of non-incretin AHDs compared with non-users of AHDs was actually higher: OR=0.99 (95% CI, 0.91-1.08).

In offering an interpretation of the results, Thomsen said, “Patients with acute pancreatitis are about 40% more likely to be users of glucose-lowering drugs than the general population, whether these drugs are incretins or not. After adjusting for the available confounding factors, we do not believe that the use of incretin-based therapies is associated with an increased risk of pancreatitis. Our null-results are also consistent with two recent meta-analyses of randomized clinical trials involving incretin therapy and with the overwhelming majority of the approximately 10 observational studies that have been conducted on this topic to date.”