Does GLP-1 (Glucagon-like peptide-1) cause gallbladder contraction?

GLP-1 Receptor Agonists and Gallbladder Function

GLP-1 receptor agonists suppress cholecystokinin secretion, which inhibits gallbladder contraction and delays gallbladder emptying, potentially increasing the risk of gallbladder-related adverse events such as cholelithiasis and cholecystitis. 1, 2

Mechanism of Action on Gallbladder Function

• GLP-1 receptor agonists suppress the secretion of cholecystokinin (CCK) after meals, which attenuates gallbladder contractility and prolongs the gallbladder refilling phase 1
• This suppression of CCK-mediated gallbladder contraction appears to be part of a bile acid-TGR5-L cell-GLP-2 axis that serves to terminate meal-induced gallbladder contraction 2
• The effects on gallbladder motility contribute to the increased risk of gallbladder-related adverse events observed in clinical trials of GLP-1 receptor agonists 3

Clinical Evidence of Gallbladder Effects

• Meta-analyses of randomized clinical trials have shown that GLP-1 receptor agonist use is associated with a 37% increased risk of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52) 3
• Specific risks include increased rates of cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22) 3
• The American Gastroenterological Association clinical practice guideline notes that cholelithiasis and cholecystitis are among the serious adverse events reported with semaglutide use 4

Risk Factors for Gallbladder Complications

• Higher doses of GLP-1 receptor agonists are associated with greater risk of gallbladder or biliary diseases (RR, 1.56; 95% CI, 1.36-1.78) compared to lower doses (RR, 0.99; 95% CI, 0.73-1.33) 3
• Longer duration of GLP-1 receptor agonist use increases risk (RR, 1.40; 95% CI, 1.26-1.56) compared to shorter duration (RR, 0.79; 95% CI, 0.48-1.31) 3
• Use for weight loss carries a higher risk (RR, 2.29; 95% CI, 1.64-3.18) compared to use for type 2 diabetes or other conditions (RR, 1.27; 95% CI, 1.14-1.43) 3

Broader Effects on Gastrointestinal Motility

• GLP-1 receptor agonists delay gastric emptying through vagal nerve-mediated pathways, which contributes to their glucose-lowering and weight loss effects 5, 6
• These agents reduce phasic gastric contractions, delay gastric emptying, reduce gastric acid secretion, and increase both fasting and postprandial gastric volumes 4, 5
• The effects on gastric emptying are more pronounced with short-acting GLP-1 receptor agonists compared to long-acting formulations 4, 5

Clinical Implications and Monitoring

• Patients on GLP-1 receptor agonists should be monitored for symptoms of gallbladder disease, including right upper quadrant pain, nausea, and vomiting 4, 3
• Healthcare providers should be aware of the increased risk of gallbladder-related adverse events, particularly in patients using higher doses for weight loss and for longer durations 3
• The risk of gallbladder disease should be considered when weighing the benefits and risks of GLP-1 receptor agonist therapy, especially in patients with pre-existing gallbladder issues 4, 3

Hyperglycemia and Gallbladder Function

• Independent of GLP-1 effects, hyperglycemia itself can impair gallbladder contraction in response to cholecystokinin, which may further contribute to gallbladder dysfunction in patients with diabetes 7
• This suggests that patients with poorly controlled diabetes may have compounded risk when using GLP-1 receptor agonists 7

In summary, GLP-1 receptor agonists have a clear physiological effect on gallbladder function by suppressing cholecystokinin secretion, which inhibits gallbladder contraction. This mechanism explains the increased risk of gallbladder-related adverse events observed in clinical trials, particularly with higher doses, longer duration of use, and when used for weight loss rather than diabetes management.