- In adults, GLP-1 receptor agonists have been linked to elevated risks of gallbladder and biliary disease.
- In a new study, retrospective data linked GLP-1 drug use in youth to higher risks of biliary colic and cholecystectomy.
- The researchers urged vigilance for biliary symptoms stemming from rapid weight loss and gallbladder dysmotility with GLP-1 drugs.
Use of GLP-1 receptor agonists was associated with increased cumulative gallbladder and biliary events in youths, according to a retrospective analysis of TriNetX data.
Among over 37,000 adolescents and young adults with overweight or obesity, GLP-1 drug use was associated with increased risks of biliary colic (RR 1.62, 95% CI 1.28-2.04, P<0.001) and cholecystectomy (RR 1.39, 95% CI 1.04-1.87, P=0.03) compared with matched controls, but not with cholecystitis, reported Josélio Rodrigues de Oliveira Filho, MD, of Mass General Brigham and Harvard Medical School in Boston, and colleagues.
Lag analyses and 12-month administrative censoring yielded similar results, the researchers wrote in a JAMA Pediatrics research letter. Time-to-event analyses showed higher effect estimates across all three biliary outcomes:
- Cholecystitis: HR 2.22, 95% CI 1.51-3.25, P<0.001
- Biliary colic: HR 2.92, 95% CI 2.29-3.71, P<0.001
- Cholecystectomy: HR 2.39, 95% CI 1.77-3.22, P<0.001
“The observed biliary risk likely reflects rapid weight loss, which predisposes to gallstone formation in children with obesity, compounded by GLP-1 receptor agonist-mediated gallbladder dysmotility,” the authors explained.
“These findings suggest vigilance for biliary symptoms is needed when prescribing GLP-1 receptor agonists to youths,” they advised.
This safety signal was first flagged in adolescents during the STEP TEENS trial, where 4% of participants in the semaglutide (Wegovy) arm developed acute gallbladder disease compared with none in the placebo arm. In contrast, the SCALE Teens and SCALE Kids trials of liraglutide (Saxenda) did not mention biliary events.
Biliary events have also been reported in adults using GLP-1 drugs, the authors added.
A 2022 meta-analysis of 76 randomized clinical trials in adults linked GLP-1 drug use to elevated risks of gallbladder and biliary disease, particularly when used at higher doses for weight loss. While this elevated risk was significant, the meta-analysis authors noted that the overall absolute risk increase was small, at only an additional 27 cases per 10,000 persons treated per year.
“Adult data suggest a pharmacologic mechanism,” Rodrigues de Oliveira Filho’s group noted.
For the current study, researchers evaluated patients ages 12 to 21 years diagnosed with overweight or obesity between January 2022 and May 2026 using ICD-10 codes. Propensity score matching yielded 18,759 individuals each in the GLP-1 drug and control groups. In the GLP-1 drug group, the mean age was 17.4 years, 63.0% were female, and median follow-up was 364 days.
The most commonly used GLP-1 agent was semaglutide (76.7%), followed by liraglutide (14.5%), dulaglutide (Trulicity; 8.6%), tirzepatide (Zepbound; 3.4%), and exenatide (Byetta, Bydureon; 0.6%).
In subgroup analyses, youths with class I or class II obesity (body mass index [BMI] 30-39.9) had elevated hazard rates over time for cholecystitis (HR 3.36), biliary colic (HR 2.78), and cholecystectomy (HR 2.93). Event counts were insufficient for meaningful analysis in the overweight (BMI 25-29.9) and class III obesity (BMI 40 or higher) subgroups.
The authors emphasized that the study’s retrospective design and reliance on diagnostic codes prevent establishing causality. Additionally, the data lacked details on GLP-1 drug dose, treatment duration, total weight loss, and gallbladder imaging.
“Prospective studies should clarify risk stratification, evaluate whether prophylactic strategies used in bariatric populations could be applied, and identify whether monitoring protocols can reduce biliary morbidity,” the authors recommended.
