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Incretin Therapy: Role in Gallbladder and Bile Duct Diseases

Oct 8, 2016

Initiation of glucagon like peptide-1 agonists may increase risk of gallbladder or bile duct disease and cholecystectomy.

Glucagon like peptide-1 agonists (GLP-1RA) are effective glucose-lowering agents that can often aid in weight reduction, an important benefit for obese patients with type 2 diabetes (T2D). While substantial or rapid weight loss is associated with an increased risk of cholelithiasis, the registration trials for high-dose liraglutide (Saxenda) demonstrated a greater incidence of acute gallbladder disease in patients receiving the study drug compared with placebo, even after accounting for the degree of weight loss.1  The current study by  J.L. Faille, et-al, is a population-based cohort study designed to investigate the association between incretin-based therapy and acute gallbladder disease.2


The United Kingdom Clinical Practice Research Datalink and the Hospital Episodes Database were used to evaluate the occurrence of gallbladder and bile duct disease resulting in hospitalization in patients prescribed either a GLP-1RA, dipeptidyl peptidase-4 inhibitor (DPP4-I), or at least two non-incretin glucose-lowering agents. Secondary outcomes were cholecystectomy associated with incretin therapy, and the association of gallbladder or bile duct disease and duration of T2D or of uninterrupted incretin therapy.

Data was collected from January 1, 2007, when incretin therapy was first made available in the UK, to December 31, 2013. Patients included were 18 years or older and had at least 1 year of medical records in the database prior to initiation of hypoglycemic therapy. Newly diagnosed patients with T2D initiating therapy with insulin were excluded due to severity of their baseline diabetes. Patients with a history of polycystic ovarian syndrome, gestational diabetes, gallbladder and bile duct disease, biliary cancer or cirrhosis, HIV or AIDS, hemolytic disease, or taking ursodiol or ursodeoxycholic acid were excluded from the cohort.

Of the 71,369 patients included in the cohort, 693 were prescribed a GLP-1RA, 3,270 were prescribed a DPP4-I, and 67,406 were on non-incretin dual therapy. Baseline characteristics were similar amongst groups with the exception of increased prevalence of obesity, younger mean age, longer duration of diabetes and higher baseline A1c in the GLP-1RA arm compared with the other arms.

After adjusting for confounders (age, sex, BMI, smoking status, year of cohort entry, diabetic vascular complications, number of physician visits, history of gastric bypass, and the use of morphine or fibrate derivatives), there was a significant increase in the risk of hospitalization for gallbladder or bile duct disease in those patients in the GLP-1RA arm compared with the non-incretin dual-therapy arm (crude HR 1.89, adjusted HR 1.79; 95% CI, 1.21-2.67).  The risk of hospitalization was not statistically significantly different in the DPP4-I arm compared with the non-incretin dual-therapy arm. Significant secondary outcomes included: increased risk of hospitalization for gallbladder or bile duct disease in patients with duration of GLP-1RA therapy less than 180 days (adjusted HR, 2.01; 95% CI, 1.23-3.29), as well as a hospitalization resulting in a cholecystectomy in the GLP-1RA arm (adjusted HR, 2.08; 95% CI, 1.08-4.02). Duration of diabetes was not significant in either arm, and all secondary outcomes were insignificant in the DPP4-I arm.

This retrospective cohort study supports the association between GLP-1RA therapy and increased risk of hospitalization for gallbladder or bile duct disease and cholecystectomy in accord with results from randomized, controlled trials. However, the small number of patients identified for inclusion in the GLP-1RA group over the study period of 6 years may be an indicator of selection bias that minimized use of GLP-1RAs in the population studied, except for patients who had more significant duration of diabetes or higher baseline A1c. Additionally, this study was not designed to evaluate the effect of the rate of weight loss on the risk of development of acute gallbladder disease. Until further randomized, controlled trials are available to elucidate the mechanism of these outcomes, it is advised by the manufacturer of high-dose liraglutide to limit weight loss to no more than 1.5 kg per week and to pursue gallbladder studies and appropriate clinical follow up if cholelithiasis is suspected.

Practice Pearls:

  • GLP-1 receptor agonists were associated with a 79% increased risk of developing gallbladder or bile duct disease and an a 2-fold increased risk of cholecystectomy in a large, population-based cohort in the UK.
  • Therapy with DPP-4 inhibitors was not associated with an increased risk of acute gallbladder or bile duct disease.
  • Providers should closely monitor patients initiating GLP-1 agonist therapy especially in the first 6 months for rate of weight loss and signs of gallbladder or bile duct disease.GLP-1 receptor agonists were associated with a 79%




Saxenda (liraglutide)[package insert]. Novo Nordisk; Plainsboro (NJ): 2010.

Faillie JL, Yu OH, Yin H, Hillaire-Buys D, Barkun A, Azoulay L. Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus. JAMA Intern Med. 2016 Aug 1. doi: 10.1001/jamainternmed.2016.1531.


Researched and prepared by Iman Aberra, URI College of Pharmacy Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D, BCPS, BCACP, CDOE, CVDOE.