Two incretin-based drugs linked to increased bile duct disease but not pancreatitis



At least two incretin-based drugs – glucagon-like peptide 1 agonists and dipeptidyl peptidase 4 inhibitors – do not appear to increase the risk of acute pancreatitis in individuals with diabetes but are associated with an increased risk of bile duct and gallbladder disease.

Two studies examining the impact on the pancreas of incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, have been published online August 1 in JAMA Internal Medicine.

Incretin-based drugs have been associated with increased risk of elevated pancreatic enzyme levels, while GLP-1 has been shown to increase the proliferation and activity of cholangiocytes, which have raised concerns of an impact on the bile duct, gallbladder, and pancreas.

The first study was an international, population-based cohort study using the health records of more than 1.5 million individuals with type 2 diabetes, who began treatment with antidiabetic drugs between January 2007 and June 2013.

Analysis of these data showed there was no difference in the risk of hospitalization for acute pancreatitis between those taking incretin-based drugs and those on two or more other oral antidiabetic medications (JAMA Intern Med. 2016 Aug 1. doi: 10.1001/jamainternmed.2016.1522).

The study also found no significant increase in the risk of acute pancreatitis either with DPP-4 inhibitors or GLP-1 agonists, nor was there any increase with a longer duration of use or in patients with a history of acute or chronic pancreatitis.

Most previous observational studies of incretin-based drugs and pancreatitis had reported null findings, but four studies did find a positive association. Laurent Azoulay, PhD, from the Lady Davis Institute at Montreal’s Jewish General Hospital, and his coauthors suggested this heterogeneity was likely the result of methodologic shortcomings such as the use of inappropriate comparator groups and confoundings.

“Although it remains possible that these drugs may be associated with acute pancreatitis, the upper limit of our 95% [confidence interval] suggests that this risk is likely to be small,” the authors wrote. “Thus, the findings of this study should provide some reassurance to patients treated with incretin-based drugs.”

Meanwhile, a second population-based cohort study in 71,368 patients starting an antidiabetic drug found the use of GLP-1 analogues was associated with a significant 79% increase in the risk of bile duct and gallbladder disease, compared with the use of at least two other oral antidiabetic medications.

When stratified by duration of use, individuals taking GLP-1 analogues for less than 180 days showed a twofold increase in the risk of bile duct and gallbladder disease (adjusted hazard ratio, 2.01; 95% CI, 1.23-3.29) but those taking the drugs for longer than 180 days did not show an increased risk.

The use of GLP-1 analogues was also associated with a two-fold increase in the risk of undergoing a cholecystectomy.

However, the study found no increased risk of bile duct or gallbladder disease with DPP-4 inhibitors (JAMA Intern Med. 2016 Aug 1. doi: 10.1001/jamainternmed.2016.1531).

Jean-Luc Faillie, MD, PhD, of the University of Montpellier (France) and his associates suggested that rapid weight loss associated with GLP-1 analogues may explain the association with bile duct and gallbladder disease, which would also account for the observation that the association did not occur in patients taking the drugs for a longer period of time.

“Weight loss leads to supersaturation of cholesterol in the bile, a known risk factor for gallstones,” the authors wrote.

DPP-4 inhibitors have different effects on the GLP-1 pharmacologic factors and a weaker incretin action, which the authors suggested may explain the lack of association with bile duct and gallbladder disease, as well as their lower incidence of gastrointestinal adverse events.

“Although further studies are needed to confirm our findings and the mechanisms involved, physicians prescribing GLP-1 analogues should be aware of this association and carefully monitor patients for biliary tract complications.”

The first study was enabled by data-sharing agreements with the Canadian Network for Observational Drug Effect Studies, which is funded by the Canadian Institutes of Health Research. Two authors declared consulting fees, grant support, or financial compensation from the pharmaceutical industry, but there were no other conflicts of interest declared.

The second study was funded by the Canadian Institutes of Health Research. No conflicts of interest were declared.

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