GLP-1 Receptor Agonists and Cholelithiasis Risk
GLP-1 receptor agonists do not worsen pre-existing cholelithiasis, but they do increase the risk of developing new gallstones and gallbladder disease. The mechanism involves delayed gastric emptying and suppression of cholecystokinin (CCK) secretion, which reduces gallbladder contractility and bile flow, creating conditions favorable for stone formation 1.
Magnitude of Risk
The evidence consistently demonstrates an increased risk of cholelithiasis with GLP-1 receptor agonists:
- Meta-analysis data shows a 28-46% increased risk of cholelithiasis compared to placebo or other antidiabetic therapies (OR 1.28-1.46) 2, 3.
- The 2025 American Diabetes Association guidelines specifically warn that GLP-1 RAs "may cause cholelithiasis and gallstone-related complications" 1.
- Real-world data demonstrates relative risks of 1.2-1.4 across different GLP-1 RAs, with liraglutide showing the highest risk (RR 1.2, NNH 17.25), followed by semaglutide (RR 1.4, NNH 10.96) and dulaglutide (RR 1.3, NNH 14.69) 4.
Risk Varies by Agent and Dose
Liraglutide carries the highest risk of symptomatic cholelithiasis (81.1% of patients with stones become symptomatic), compared to semaglutide (68%) and dulaglutide (44%) 4. The 2019 American Heart Association statement lists cholelithiasis as a common side effect of GLP-1 receptor agonists 1.
Higher doses and weight-loss formulations appear to confer greater risk, though subgroup analyses did not reach statistical significance 2. The risk is more pronounced in patients using GLP-1 RAs for weight loss rather than diabetes management alone 4.
Mechanism of Gallstone Formation
The pathophysiology involves two key mechanisms:
- GLP-1 suppresses CCK secretion after meals, which normally stimulates gallbladder contraction and bile flow 5.
- Reduced gallbladder motility and emptying creates bile stasis, promoting cholesterol supersaturation and stone formation 5.
- This effect occurs in both normal subjects and patients with diabetes 5.
Clinical Management Algorithm
Before initiating GLP-1 therapy:
- Evaluate for existing gallbladder disease with history focused on right upper quadrant pain, postprandial symptoms, and prior biliary colic 1.
- Avoid GLP-1 RAs in patients with active symptomatic cholelithiasis or recent cholecystitis 1.
- Consider baseline ultrasound in high-risk patients (obesity, rapid weight loss history, female sex, age >40) 1.
During GLP-1 therapy:
- Educate patients to report right upper quadrant pain, nausea after fatty meals, or fever 1.
- If cholelithiasis is suspected, obtain gallbladder ultrasound and appropriate clinical follow-up 1, 6, 7.
- Discontinue GLP-1 RA if acute cholecystitis develops 1.
For patients who develop gallstones:
- Asymptomatic stones do not require GLP-1 discontinuation, but monitor closely 4.
- Symptomatic cholelithiasis warrants cholecystectomy evaluation and consideration of alternative diabetes therapy 6, 7, 8.
- The FDA labels for liraglutide and exenatide specifically note increased risk of cholecystitis and cholelithiasis requiring cholecystectomy 6, 7.
Important Caveats
GLP-1 RAs are not contraindicated in patients with asymptomatic gallstones, but use caution and enhanced monitoring 1. The absolute risk increase translates to approximately 2 additional cases per 1000 patients treated 2.
The cardiovascular and metabolic benefits often outweigh gallbladder risks in appropriate patients, particularly those with established atherosclerotic cardiovascular disease 1, 9. However, the American Heart Association notes that adverse effects including cholelithiasis have "slowed their uptake in clinical practice" 1.
Population-based cohort data shows GLP-1 analogues increase hospitalization risk for bile duct and gallbladder disease (adjusted HR 1.79,95% CI 1.21-2.67) and cholecystectomy (adjusted HR 2.08,95% CI 1.08-4.02) compared to other oral antidiabetic drugs 8.