August 12, 2016
3 min read

Incretin-based diabetes drug linked to increased risk for bile duct, gallbladder diseases

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

Among incretin-based drugs for managing type 2 diabetes mellitus, glucagon-like peptide 1 agonists are associated with an increased risk for bile duct and gallbladder disease, but are not associated with an increased risk for acute pancreatitis compared with other oral antidiabetic drugs, according to study results published in JAMA Internal Medicine.

In addition, dipeptidyl peptidase 4 (DPP-4) inhibitors did not appear associated with an increased risk for any of these diseases.

Association with bile duct, gallbladder diseases

To determine whether DPP-4 inhibitors and glucagon-like peptide 1 (GLP-1) agonists are associated with an increased risk for bile duct and gallbladder diseases, researchers performed a population-based cohort study of 71,369 adults (227,994 person-years of follow-up) identified within the linked U.K. Clinical Practice Research Datalink and Hospital Episodes Statistics database.

Patients began taking an antidiabetic drug from 2007 through March 2014, and the researchers compared hospitalizations for cholelithiasis, cholecystitis, cholangitis, gallstone pancreatitis or other bile duct and gallbladder disorders between current users of DPP-4 inhibitors or GLIP-1 agonists and current users of at least two other oral antidiabetic drugs.

Throughout the study period, 853 patients were hospitalized for bile duct and gallbladder disease, for a corresponding incidence rate of 3.7 (95% CI, 3.5-4) per 1,000 person-years.

DPP-4 inhibitors were not associated with an increased risk for bile duct and gallbladder disease, but GLP-1 analogues were (6.1 per 1,000 person-years vs. 3.3 with 2 other oral antidiabetic drugs; adjusted HR = 1.79; 95% CI, 1.21-2.67).

Secondary analysis showed GLP-1 analogues were also associated with an increased risk for cholecystectomy (adjusted HR = 2.08; 95% CI, 1.08-4.02).

“While there was some biological evidence that incretin-based drugs may increase the risk of bile duct and gallbladder diseases, our study was conducted at a time when there was limited evidence for this possible association,” Laurent Azoulay, PhD, of the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital in Montreal, Canada, told Healio Gastroenterology. “Interestingly, our findings were recently corroborated in the large LEADER trial of liraglutide (a GLP-1 analogue), where there was a statistically significant imbalance in the number of acute gallstone events between the groups (liraglutide, 145 [3.1%] vs. placebo, 90 [1.9%]). This corroboration suggests that the association between GLP-1 analogues and bile duct and gallbladder disease is likely to be real, and that physicians should inform patients of this possible risk.”

Peter C. Butler, MD, of the David Geffen School of Medicine at University of California-Los Angeles, suggested two potential explanations for these effects associated with GLP-1 mimetics in a related editorial.

“The weight loss induced by the GLP-1 mimetics may promote gall stone formation,” he wrote. “Alternatively, GLP-1 mimetics may act pharmacologically on the gall bladder and biliary tree by decreasing gall bladder emptying and increasing cholangiocyte proliferation induced by GLP-1.”

Association with acute pancreatitis

In a separate study, researchers aimed to determine whether these drugs were associated with an increased risk for acute pancreatitis by performing a large population-based cohort study using combined health records from seven centers in Canada, the U.S. and the U.K.

They identified 1,532,513 patients with type 2 diabetes (51% men; mean age, 56.6 years; 3,464,659 person-years follow-up) who began using antidiabetic drugs from 2007 through June 2013, and were followed-up through June 2014. Then they performed nested case-control analyses of patients hospitalized with acute pancreatitis and up to 20 matched controls.

Throughout the study period, 5,165 patients were hospitalized for acute pancreatitis, for a corresponding incidence rate of 1.49 per 1,000 person-years. Neither incretin-based drug appeared associated with an increased risk for acute pancreatitis compared with current use of two or more oral antidiabetic drugs, and the risk did not vary by drug class or duration of use.

Conversely, the FDA adverse event reporting system “consistently shows a signal for acute pancreatitis with ... DPP-4 inhibitors and GLP-1 mimetics,” as well as a signal for pancreatic cancer with GLP-1 drugs, Butler wrote in his editorial.

“The absence of pancreatitis associated with GLP-1-based therapy in retrospective analyses, even in a large cohort, falls short of the gold standard, the [randomized clinical trial],” he added. “The same critique can be made of the retrospective cohort study by the same group, which found no association between pancreatic cancer and GLP-1-based therapy ... However, given the shortcoming of the FDA adverse event reporting system, and since it is not feasible to perform an RCT of sufficient size to address the potential for increased risks for relatively infrequent events such as pancreatic cancer, analyses of large patient cohorts after more prolonged drug exposure are required.” – by Adam Leitenberger


Butler PC. JAMA Intern Med. 2016;doi:10.1001/jamainternmed.2016.1523.

Disclosures: Azoulay reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Butler reports he is a member of the scientific advisory board for Semma Therapeutics.