Is it safe to use GLP-1 (Glucagon-like peptide-1) agonists in patients with cholelithiasis?

From the Guidelines

GLP-1 receptor agonists can be used in patients with cholelithiasis, but caution is advised due to a potential increased risk of gallbladder-related issues, as noted in the most recent study from 2023 1.

Key Considerations

• Patients with existing gallstones can typically use GLP-1 agonists like semaglutide, liraglutide, dulaglutide, and tirzepatide with appropriate monitoring, as suggested by the 2023 study in Obesity Reviews 1.
• No dosage adjustments are specifically required for patients with gallstones, but careful monitoring is recommended, especially for those with symptomatic gallstones or a history of gallbladder disease, as indicated in the 2023 study in Diabetes Care 1.
• The mechanism behind the association between GLP-1 agonists and gallbladder issues may involve effects on gallbladder motility and bile composition, as well as weight loss-induced cholesterol mobilization and gallstone formation, as discussed in the context of weight management in the 2023 study in Obesity Reviews 1.

Monitoring and Precautions

• Patients should be informed about potential symptoms of gallbladder complications, including right upper quadrant pain, nausea, vomiting, and jaundice, and advised to seek medical attention if these develop, as a precautionary measure based on the potential risks outlined in the 2023 study in Diabetes Care 1.
• For patients with symptomatic gallstones or a history of gallbladder disease, more careful monitoring may be appropriate, and in some cases, prophylactic cholecystectomy might be considered before initiating treatment, particularly for higher-dose formulations used for weight management, as a consideration based on the information provided in the 2023 study in Obesity Reviews 1.

Medication-Specific Considerations

• Semaglutide, liraglutide, dulaglutide, and tirzepatide are examples of GLP-1 agonists that can be used in patients with cholelithiasis, with the understanding that each medication's specific safety profile and potential risks should be considered, as noted in the 2023 studies in Obesity Reviews 1 and Diabetes Care 1.

From the FDA Drug Label

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated [see Adverse Reactions (6.1)]. In a clinical study with exenatide, 1.9% of exenatide-treated patients and 1.4% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. The incidence of cholelithiasis was 0.3% in both liraglutide injection-treated and placebo-treated patients.

GLP-1 agonists and cholelithiasis: The use of GLP-1 agonists, such as liraglutide and exenatide, may be associated with an increased risk of acute gallbladder disease, including cholelithiasis.

• Key points:
  • Cholelithiasis has been reported in clinical trials and postmarketing with GLP-1 receptor agonists.
  • The incidence of cholelithiasis is similar between GLP-1 agonist-treated and placebo-treated patients in some studies.
  • Gallbladder studies and clinical follow-up are recommended if cholelithiasis is suspected.
• Clinical decision: It is not possible to conclude that GLP-1 agonists are safe to use in patients with cholelithiasis based on the available data.
  • Patients with cholelithiasis should be closely monitored for signs and symptoms of gallbladder disease if treated with GLP-1 agonists 2, 2, 3.

From the Research

Cholelithiasis and GLP-1 Agonists

• The use of GLP-1 agonists in patients with cholelithiasis is a topic of concern, with several studies investigating the association between GLP-1 receptor agonist use and the risk of gallbladder or biliary diseases.
• A systematic review and meta-analysis of randomized clinical trials found that GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases, specifically cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47) 4.
• Another meta-analysis of randomized controlled trials also found that GLP1-RA significantly increased the risk of cholelithiasis (MH-OR 1.28 [1.11,1.48]) 5.
• A comprehensive study mapping the effectiveness and risks of GLP-1 receptor agonists found that GLP-1RA use was associated with an increased risk of gastrointestinal disorders, including cholelithiasis, compared to usual care 6.

Safety Considerations

• The increased risk of cholelithiasis associated with GLP-1 agonist use may be dose-dependent, with higher doses associated with a greater risk (RR, 1.56; 95% CI, 1.36-1.78) compared to lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) 4.
• The duration of GLP-1RA use may also play a role, with longer durations associated with a greater risk of gallbladder or biliary diseases (RR, 1.40; 95% CI, 1.26-1.56) compared to shorter durations (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction) 4.
• While GLP-1 agonists have been shown to be effective in treating obesity and reducing cardiovascular risk, the potential increased risk of cholelithiasis must be carefully considered in patients with a history of gallbladder disease 7, 8.