Why do Glucagon-like peptide-1 (GLP-1) receptor agonists increase the risk of gallstone formation?

GLP-1 Receptor Agonists and Gallstone Formation: Mechanisms

GLP-1 receptor agonists increase gallstone risk primarily through delayed gallbladder emptying and altered bile acid metabolism, not through direct effects on bile composition. The mechanism involves vagally-mediated inhibition of gallbladder contractility, leading to bile stasis and increased cholesterol supersaturation 1, 2.

Primary Mechanism: Impaired Gallbladder Motility

The dominant mechanism is delayed gallbladder emptying caused by vagal nerve inhibition. GLP-1 receptors located on the myenteric plexus activate nitrergic and cyclic adenosine monophosphate pathways that inhibit vagal activity throughout the gastrointestinal tract 3. This results in:

• Reduced gallbladder contractility and ejection fraction, allowing bile to remain stagnant for prolonged periods 1, 2
• Increased fasting gallbladder volumes, creating an environment conducive to cholesterol crystal precipitation 3
• Impaired postprandial gallbladder emptying, preventing the normal clearance of bile that would otherwise flush out cholesterol crystals 3

The vagal mechanism explains why these effects persist even with long-acting formulations, though some tachyphylaxis may develop over time 3.

Secondary Mechanism: Bile Acid Alterations

GLP-1 receptor agonists modify bile acid composition in ways that may promote gallstone formation:

• Liraglutide increases serum and fecal deoxycholic acid levels, suggesting alterations in intestinal microbiome and bile acid metabolism that could affect cholesterol solubility 4
• Changes in bile acid profiles may reduce the capacity to maintain cholesterol in solution, though this mechanism appears less significant than impaired motility 4

Importantly, one study found that liraglutide did not significantly affect gallbladder fasting volume or ejection fraction in a 12-week trial, suggesting individual variation or that longer exposure may be required for clinically significant effects 4.

Clinical Evidence of Increased Risk

GLP-1 analogues demonstrate a clear association with gallbladder disease in real-world data:

• GLP-1 analogues increase the risk of bile duct and gallbladder disease by 79% compared to dual oral antidiabetic therapy (adjusted HR 1.79; 95% CI 1.21-2.67) 5
• The risk of cholecystectomy is doubled with GLP-1 analogue use (adjusted HR 2.08; 95% CI 1.08-4.02) 5
• FDA labeling for both exenatide and liraglutide explicitly warns that acute gallbladder events such as cholelithiasis or cholecystitis have been reported in clinical trials and post-marketing surveillance 6, 7

Notably, DPP-4 inhibitors (which increase endogenous GLP-1 levels more modestly) do not show this association, suggesting a dose-dependent effect 5.

Pathophysiologic Sequence

The mechanism unfolds as follows:

1. GLP-1 receptor activation inhibits vagal tone to the gallbladder via myenteric plexus receptors 3, 1
2. Gallbladder contractility decreases, leading to bile stasis 1, 2
3. Prolonged bile retention allows cholesterol to precipitate and form crystals 8
4. Crystal aggregation progresses to gallstone formation over time 8
5. Altered bile acid metabolism may further reduce cholesterol solubility 4

Clinical Implications and Monitoring

Physicians should maintain heightened vigilance for gallbladder disease in patients on GLP-1 receptor agonists:

• If cholelithiasis is suspected, obtain gallbladder imaging and appropriate clinical follow-up as recommended by FDA labeling 6, 7
• The risk appears highest with GLP-1 analogues (exenatide, liraglutide) compared to DPP-4 inhibitors 5
• Tirzepatide (dual GLP-1/GIP agonist) may carry particularly high risk based on emerging data showing strong associations with gastric retention 9

The mechanism is fundamentally different from rapid weight loss-induced gallstones, as it involves direct pharmacologic effects on gallbladder motility rather than simply increased cholesterol mobilization 1, 8.