Gallstones and GLP-1 Drugs
GLP-1 receptor agonists increase the risk of gallstone formation and related biliary complications, with liraglutide showing approximately 1.6-2.1 times higher risk compared to placebo or other diabetes medications. 1, 2, 3
Mechanism of Gallstone Risk
GLP-1 receptor agonists suppress cholecystokinin (CCK) secretion after meals, which reduces gallbladder contractility and emptying 4. This pharmacologic effect creates bile stasis, a known risk factor for gallstone formation. The suppression of CCK occurs in both healthy individuals and patients with diabetes, explaining the class-wide biliary adverse effects 4.
Additionally, liraglutide specifically increases serum and fecal levels of deoxycholic acid, suggesting alterations in intestinal microbiome and bile acid metabolism that may contribute to lithogenic bile 5.
Quantified Risk Data
The LEADER cardiovascular outcomes trial demonstrated the most robust evidence: liraglutide increased acute gallbladder or biliary disease events (141 of 4,668 patients vs. 88 of 4,672 on placebo; HR 1.60,95% CI 1.23-2.09, p<0.001) over 3.5-5 years 3. Cholecystectomy rates were also significantly higher (HR 1.56,95% CI 1.10-2.20, p=0.013) 3.
A UK population-based cohort study found GLP-1 analogues increased bile duct and gallbladder disease requiring hospitalization (6.1 vs 3.3 per 1000 person-years; adjusted HR 1.79,95% CI 1.21-2.67) and cholecystectomy risk (adjusted HR 2.08,95% CI 1.08-4.02) 2.
DPP-4 inhibitors do not share this risk (adjusted HR 0.99,95% CI 0.75-1.32), indicating this is specific to GLP-1 receptor agonism rather than incretin-based therapy generally 2.
FDA-Labeled Adverse Events
The FDA labels for both liraglutide and dulaglutide explicitly list cholelithiasis and cholecystitis as adverse reactions requiring cholecystectomy 1, 6. These are not theoretical risks but documented post-marketing events 1, 6.
For liraglutide specifically: cholelithiasis occurred in 0.3% of treated patients (same as placebo in controlled trials), but post-marketing surveillance revealed higher real-world rates requiring cholecystectomy 1.
For dulaglutide: cholecystitis and cholelithiasis requiring cholecystectomy are listed as post-marketing adverse reactions 6.
Clinical Categories of Biliary Events
The LEADER trial categorized gallbladder events into four groups, all showing increased risk with liraglutide 3:
- Uncomplicated gallbladder stones
- Complicated gallbladder stones
- Cholecystitis
- Biliary obstruction
The risk appeared consistent across all four categories, suggesting a broad biliary tract effect rather than isolated cholelithiasis 3.
Practical Clinical Implications
When prescribing GLP-1 receptor agonists, counsel patients about: 7, 1, 6
- Symptoms of acute cholecystitis (right upper quadrant pain, fever, nausea)
- The need for urgent evaluation if biliary symptoms develop
- The possibility of requiring cholecystectomy during treatment
Monitor for gastrointestinal symptoms, though these alone cannot determine gallbladder pathology 7. Approximately 57-59% of patients who develop gallbladder events will require cholecystectomy 3.
Consider baseline gallbladder ultrasound in high-risk patients (obesity, rapid weight loss anticipated, prior biliary symptoms) before initiating therapy, though this is not a guideline recommendation.
Perioperative Considerations
For patients on GLP-1 receptor agonists undergoing elective surgery, pulmonary aspiration risk from delayed gastric emptying is a concern, but the medications should generally be continued throughout the perioperative period 7. Point-of-care gastric ultrasound should be considered before anesthesia induction 7.
Balancing Risk Against Benefit
Despite the increased gallstone risk, GLP-1 receptor agonists remain recommended as preferred agents for patients with type 2 diabetes and established cardiovascular disease, heart failure, or chronic kidney disease due to their proven mortality and morbidity benefits 7. The cardiovascular and renal protective effects (MACE reduction, slowed CKD progression) outweigh the gallstone risk in appropriate patient populations 7, 8.
The dual GIP/GLP-1 receptor agonist tirzepatide also carries warnings about cholelithiasis and gallstone-related complications 7, suggesting this is a class effect extending beyond pure GLP-1 agonism.
Agent-Specific Considerations
Liraglutide has the strongest evidence for increased gallstone risk from the LEADER trial 3. Semaglutide and dulaglutide share similar FDA warnings 7, 6. Exenatide has additional renal clearance concerns and is not recommended with eGFR <30 mL/min/1.73 m² 7.