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Liraglutide Linked to Gallbladder Complications

Sep 24, 2019
 
Editor: Steve Freed, R.PH., CDE

Author: Nadeen Ayad, BCPS, PharmD Candidate, Skaggs School of Pharmacy, University of Colorado

GLP-1 receptor agonist liraglutide linked to gallbladder issues in secondary analysis of the LEADER trial to investigate the safety of the drug in patients with type 2 diabetes. 

Although metformin is the mainstay of initial therapy, treatment with a glucagon-like-peptide-1 (GLP-1) receptor agonist is now regularly used as an add-on approach to achieve proper glycemic control. Liraglutide is an analog of human GLP-1 approved for use in patients with type 2 diabetes. It is administered subcutaneously once daily. In addition to glycemic control, it also promotes weight loss which could be favorable in patients with obesity and type 2 diabetes.

 

However, development of gallstones may be a common side effect in patients that are on liraglutide for the treatment of their type 2 diabetes. The aim of this study is to investigate the association between liraglutide and gallbladder and biliary tract related events in patients receiving liraglutide for the treatment of type 2 diabetes compared with placebo. The researchers aimed to perform a secondary analysis of the LEADER trial, a randomized, double blind, placebo controlled trial, which investigated the differences in incidence of cardiovascular death, myocardial infarction and stroke between adults who received liraglutide or placebo for the treatment of type 2 diabetes. The sample size was 9,340 participants.

Participants with type 2 diabetes were randomized 1:1 to receive either 1.8 mg liraglutide (n= 4,668) or placebo (n= 4,672). The outcome of interest was the development of an acute gallstone disease. The median follow-up time was 3.8 years. Gallstone diseases were categorized into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction.

The researchers observed an increased risk of acute gallbladder or biliary disease with liraglutide vs. placebo (HR 1.60; 95% CI 1.23-2.09, P< 0.001). Specifically, 16 patients in the liraglutide group had uncomplicated gallbladder stones vs five patients in the placebo group, 52 participants in the liraglutide group had complicated gallbladder stones vs. 40 patients taking placebo, 51 participants taking liraglutide had cholecystitis vs. 33 receiving placebo. Furthermore, 25 patients had a biliary obstruction in the liraglutide group vs.16 in the placebo group. Cholecystectomy rates were higher in the liraglutide group (HR 1.56, 95% CI 1.1-2.2).

With regard to weight loss, patients taking liraglutide who experienced a complication of the gallbladder or biliary tract lost an average of 5.3 kg compared with an average of 3 kg in those who did not experience any complications and took the medication. In the placebo group, patients who had a complication lost an average of 3.3 kg compared with 0.6 kg in those who did not have a complication. The researchers stated that complications were 4% more likely for every 1 kg lost in weight.

The researchers concluded that the mechanism by which liraglutide causes gallbladder complications is unknown, but may involve altered bile acid production and secretion, decreased gallbladder emptying, weight loss or a combination of all these. Although the LEADER was not initially designed to assess acute gallbladder or biliary disease, the results demonstrate an increased risk of gallbladder complications across the four categories in the liraglutide group compared with placebo. Further studies are needed to investigate the relevant mechanisms.

Practice Pearls:

  •  Liraglutide also promotes weight loss which may be a preferred outcome in patients with obesity and type 2 diabetes.
  • The researchers performed a secondary analysis of the LEADER trial to investigate the occurrence of gallbladder complications as a side effect for liraglutide.
  • There was an increased risk of gallbladder or biliary disease with liraglutide vs placebo ( HR= 1.60, 95% CI 1.23-2.09 P< 0.001).

Reference for “Liraglutide Linked to Gallbladder Complications”:

Nauck MA, et al. Effects of Liraglutide compared with placebo on events of Acute Gallbladder or Biliary Disease in patients with type 2 diabetes at High risk for Cardiovascular events in the LEADER Randomized trial. Diabetes Care. 2019 Aug; 42(9).

Nadeen Ayad, BCPS, PharmD candidate, Skaggs school of Pharmacy, University of Colorado.