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Understanding the Risks: Incretin-based Therapy

Aug 20, 2016

Can DPP-4 inhibitors and GLP-1 analogues cause bile duct and gallbladder complications?

The use of incretin-based therapy — DPP-4 inhibitors and GLP-1 analogues — in patients with T2DM has grown exponentially over the past few years. These agents are reserved as second or third line options, in adjunct to diet and exercise, in patients who are not able to achieve proper glycemic control. Additionally, their tolerability and low risk of hypoglycemia makes these agents a feasible option to manage T2DM and increase adherence. However, there are risks associated with their use. For example, post-marketing studies with Januvia (sitagliptin) have shown that the use of this DPP-4 inhibitor has been associated with an increased risk of pancreatitis. Other studies have linked the use of GLP-1 analogue, such as Byetta (exenatide) with the same risk. These findings have set the ground to elucidate other risks associated with the use of these agents. Recent studies have found that incretin-based therapies can also increase the risk of bile duct and gallbladder disease. Incretin-based therapy increases the activity and proliferation of cholangyocites, which possibly increases the risk of gallbladder stones, bile duct inflammation, and bile duct cancer.


A recent cohort study by Faillie, Jean-Luc et al., looked at the risk of bile duct and gallbladder disease in patients currently taking an incretin-based medication regimen for T2DM management. In this study, the researchers compiled a base cohort with patients who were 18 years old and older and were on non-insulin antidiabetic medications. From the base cohort they further examined those patients who received non-insulin antidiabetic medication since January 1, 2007. A cox proportional hazards regression model was utilized to assess the association of bile duct or gallbladder disease in patients utilizing incretins for diabetes management when compared to patients who utilize 2 or more other non-insulin antidiabetic drugs. A total of 71, 369 patients were included in the study and were followed for a mean of 3.2 years. From the total patients included in the study cohort, 693 patients were on GLP-1 analogues and 3,270 were on DPP-4 inhibitors, while the remaining 67,406 patients were on other non-insulin antidiabetic drugs.

Findings from the study suggest that there is a 79% increased risk of bile duct and gallbladder disease in those patients receiving therapy with GLP-1 analogues (adjusted HR, 1.79; 95% CI, 1.21-2.67), whereas those patients receiving therapy with DPP-4 inhibitors did not show any link with this risk (adjusted HR, 0.99; 95% CI, 0.75-1.32). It was also found that in addition to the risk of these diseases, the use of GLP-1 analogues was associated with a 2-fold increased risk of cholecystectomy. These results have a tied association with patients who are overweight and have a drastic weight reduction while on GLP-1 analogue therapy. It has been postulated that the high concentration of cholesterol during weight loss can accumulate in the bile, leading to formation of gallstones and ultimately causing obstruction. However, this finding has been linked with use of GLP-1 analogues for a time frame less than 180 days. This finding needs further research due to an unclear association between weight loss or the potential pharmacologic effects of GLP-1 analogues.

From these findings, further clinical trials and prospective studies are needed in order to assess the significance of these reported risks. The authors suggest taking into account the risk that diabetes itself poses for bile duct and gallbladder disease when assessing these adverse effects and potential complications with incretin-based therapy. Physicians should closely monitor patients receiving incretin-based therapy, especially those getting GLP-1 analogues. This data suggests that patients should be evaluated before initiating incretin-based therapy, as some of these may have predisposing conditions leading to these bile duct and gallbladder diseases. However, patients should be closely monitored for elevation of pancreatic enzymes and other enzymes as they are not indicative of gallbladder disease.

Practice Pearls:

  • Close monitoring should be done in patients receiving incretin-based therapy, especially in those patients at risk for developing bile duct or gallbladder disease.
  • Evaluate risk factors on case-by-case basis before initiating a patient in this therapy.
  • Incretin-based therapy has been associated with weight loss, improvements in β-cell function and cardiovascular risk. However, it can increase proliferation and activity of cholangyocites.

Faillie, Jean-Luc, Oriana H. Yu, Hui Yin, Dominique Hillaire-Buys, Alan Barkun, and Laurent Azoulay. Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus. JAMA Internal Medicine JAMA Intern Med (2016): E1-E8. Web. 02 Aug. 2016.

Nauck, M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab, 18: 203–216. (2016) Web. 02 Aug. 2016.

Pizzimenti, V et al., Incretin-based Therapy and Acute Cholecystitis: A Review of Case Reports and EudraVigilance Spontaneous Adverse Drug Reaction Reporting Database. J Clin Pharm Ther Journal of Clinical Pharmacy and Therapeutics 41.2 (2016): 116-18. Web. 02 Aug. 2016.


Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE