What are the recommendations for managing the risk of cholelithiasis in patients taking tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist)?

Managing Cholelithiasis Risk in Patients Taking Tirzepatide

Tirzepatide may cause cholelithiasis and gallstone-related complications, requiring monitoring and appropriate clinical follow-up if cholelithiasis is suspected. 1

Risk Assessment and Monitoring

• Tirzepatide is associated with an increased risk of gallbladder/biliary diseases (RR = 1.52; 95% CI: 1.17-1.98) and specifically cholelithiasis (RR = 1.67; 95% CI: 1.14-2.44) compared to placebo or other treatments 2
• The FDA label for tirzepatide specifically notes that acute gallbladder disease such as cholelithiasis or cholecystitis has been reported in GLP-1 receptor agonist trials and postmarketing surveillance 1
• In clinical trials, gallbladder/biliary disease was reported in 0.6% of tirzepatide-treated patients compared to 0% in placebo-treated patients 1
• The risk appears to be present across all doses of tirzepatide, with no clear dose-response relationship identified in subgroup analyses 2

Recommendations for Management

Baseline Assessment

• Before initiating tirzepatide, assess patients for existing gallbladder disease or risk factors for cholelithiasis 3
• Consider avoiding use in patients at high risk for biliary disease when possible 3

During Treatment

• Monitor patients for signs and symptoms of gallbladder disease, including:
  • Right upper quadrant pain
  • Nausea and vomiting
  • Fever
  • Jaundice 1
• If cholelithiasis is suspected, promptly perform appropriate diagnostic studies (e.g., gallbladder ultrasound) 1
• Provide appropriate clinical follow-up for patients with confirmed gallbladder disease 1

Patient Education

• Inform patients about the potential risk of gallbladder disease before starting tirzepatide 3
• Educate patients on recognizing symptoms of gallbladder disease that warrant medical attention 3
• Counsel patients on dietary modifications that may help mitigate gastrointestinal side effects:
  • Reduction in meal size
  • Mindful eating practices
  • Decreasing intake of high-fat or spicy foods 3

Special Considerations

• The risk of gallbladder disease appears to be a class effect seen with GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists 3
• While the incidence of cholelithiasis is increased with tirzepatide, severe complications such as acute cholecystitis remain rare (≤1%) 4
• The mechanism behind increased gallstone formation with tirzepatide and other GLP-1 receptor agonists likely relates to delayed gastric emptying and alterations in gallbladder motility 3
• Weight loss itself, which is a primary effect of tirzepatide, can independently increase the risk of gallstone formation 3, 5

Management of Diagnosed Cholelithiasis

• If cholelithiasis is diagnosed in a patient taking tirzepatide, management should follow standard clinical guidelines for gallstone disease 1
• For symptomatic gallstones, consider referral for surgical evaluation (cholecystectomy) based on symptom severity and patient factors 1
• For asymptomatic gallstones discovered incidentally, continued monitoring may be appropriate while maintaining tirzepatide therapy, with treatment decisions based on individual risk assessment 1
• In patients with recurrent or severe biliary symptoms, consider discontinuation of tirzepatide and switching to an alternative glucose-lowering or weight management medication with lower risk of biliary complications 3

By implementing these monitoring and management strategies, clinicians can help mitigate the risk of gallbladder disease while allowing patients to benefit from the significant glycemic control and weight loss benefits that tirzepatide offers.