GLP-1 receptor agonists linked to increased risk of gallbladder, biliary diseases

A systematic review and meta-analysis of 76 randomized trials found that use of glucagon-like peptide-1 (GLP-1) receptor agonists was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

Use of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with increased risk of gallbladder or biliary diseases, a study found.

Researchers conducted a systematic review and meta-analysis of 76 randomized clinical trials comparing the use of GLP-1 receptor agonists with placebo or with non-GLP-1 receptor agonists in adults. The primary outcome was the composite of gallbladder or biliary diseases. The included studies had a combined total of 103,371 participants (mean age, 57.8 years; 40.5% women; mean body mass index, 32.6 kg/m2; mean HbA1c, 7.8%). Most participants had type 2 diabetes (84.4%). Results were published online March 28 by JAMA Internal Medicine.

Across all trials, randomization to GLP-1 receptor agonist treatment was associated with increased risks of gallbladder or biliary diseases (relative risk [RR], 1.37; 95% CI, 1.23 to 1.52). Relative risk was 1.27 (95% CI, 1.10 to 1.47) for cholelithiasis, 1.36 (95% CI, 1.14 to 1.62) for cholecystitis, and 1.55 (95% CI, 1.08 to 2.22) for biliary disease. Use of GLP-1 receptor agonists was also associated with increased risk of gallbladder or biliary diseases in trials where the drugs were used for weight loss (n=13; RR, 2.29 [95% CI, 1.64 to 3.18]) and for type 2 diabetes or other diseases (n=63; RR, 1.27 [95% CI, 1.14 to 1.45]; P<0.001 for interaction). Across all trials, GLP-1 receptor agonist use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36 to 1.78) versus lower doses (RR, 0.99 [95% CI, 0.73 to 1.33]; P=0.006 for interaction) and with longer (RR, 1.40; 95% CI, 1.26 to 1.56) versus shorter use (RR, 0.79 [95% CI, 0.48 to 1.31]; P=0.03 for interaction).

Information on biliary-related events may not have been fully reported because they were not a predefined safety outcome in most of the trials, the study authors noted. They added that the included trials were not specifically designed to evaluate the primary outcome, among other limitations.

An accompanying editorial comment offered two potential mechanisms behind the association between GLP-1 receptor agonist use and cholelithiasis or cholecystitis. “First, GLP-1 RAs [receptor agonists] may directly inhibit gallbladder and biliary duct motility, which may lead to sludging and stone formation,” the editorialists wrote. “Second, rapid weight loss associated with GLP-1 RA use may lead to supersaturation of cholesterol in the bile and gallstones.” They also noted: “Because GLP1-RA use increases the risk of gastrointestinal adverse effects, their use may be associated with more frequent imaging studies, such as abdominal ultrasonography or computed tomography, raising the possibility of surveillance bias.”

Still, it remains unclear whether the gallbladder and biliary complications observed in the review were directly attributable to the weight loss associated with the drug class or to other mechanisms, the editorial said. “Ultimately, the decision to start, continue, or change the dose of a GLP-1 RA should be reached through a collaborative and individualized discussion between a clinician and a patient,” the editorialists wrote.