Title: Use of GLP1-RAs in patients with a history of cholelithiasis
Author: Sarah Hughes, PharmD Candidate 2024 University of Rhode Island, School of Pharmacy
Reviewer: Courtney Cameron, PharmD, BCACP
Background
Cholelithiasis, also known as gallstones, are hardened collections of bile materials such as cholesterol or bilirubin that collect at the bottom of the gallbladder. The size of a gallstone can vary and most of the time, they do not cause an issue until they get loose and travel into the bile ducts. When a gallstone gets loose it can travel through the bile ducts to the liver or the small intestine causing an obstruction of bile flow which then forces the bile to back up into nearby organs leading to inflammation, pressure, and pain. In terms of GLP1-RA use, there is an increased risk of gallbladder and biliary disease such as cholelithiasis and cholecystitis especially when these drugs are used for weight loss. The risk is due to GLP1- RAs inhibiting gallbladder motility which then delays gallbladder emptying by suppressing the secretion of cholecystokinin, an enzyme that stimulates the gallbladder to contract and release bile into the small intestine. When cholecystokinin secretion is inhibited, gallstones are more likely to develop.
What is the real risk of gallstones?
The risk of developing gallstones is based on multiple factors. Gallstone formation is more commonly associated with those over the age of 40 and is more frequently seen in people assigned female sex at birth by a ratio of 3:1 due to the effects of feminine hormones. The two main hormones are estrogen, which is known to increase cholesterol, and progesterone, which slows down gallbladder contractions. Other risk factors include those of Native American or Mexican descent as well as those with metabolic syndromes such as obesity, hypertriglyceridemia, and insulin resistance. A meta-analysis was done that pooled 76 randomized clinical trials to evaluate the absolute risk of developing cholelithiasis in patients taking GLP1-RAs. Overall the absolute risk was around 40% when a GLP1-RA was specifically used to lose weight compared to around 27% when the drug was used for type II diabetes.
Should a history of gallstones be a contraindication for GLP1-RA or should a provider use caution?
When it comes to prescribing GLP1-RAs to patients with a history of gallstones, providers should use caution in order to make sure the benefits outweigh the risks. While studies in the meta-analysis described above excluded patients with a history of gallstones, clinical outcomes showed that higher doses and longer periods of use with GLP1-RAs have been associated with the greatest risk. In terms of which GLP1-RAs appear to have the highest risk of gallbladder or biliary disease, liraglutide, dulaglutide, and exenatide were at the top of the list. Subcutaneous semaglutide as well as oral semaglutide were not significantly linked to disease development.
Should patients with a history of gallbladder cancer or other gallbladder disorders take GLP1-RAs?
If patients have a history of gallbladder cancer or other gallbladder disorders it is important to note that taking a GLP1-RA can worsen their pre-existing condition or cause a new one. Recent trials stated acute short-term gallbladder disease was one of the most common adverse effects reported. However in relation to cancer development, the pooled meta-analysis showed no increased risk among those without a history of gallbladder disease when using a GLP1-RA (P= 0.86).
Conclusion
Overall, when it comes to prescribing GLP1-RAs for weight loss to patients with a history of cholelithiasis or other gallbladder disorders, providers should use caution. It is recommended that slow titration of a GLP1-RA is best in order to reduce the risk of developing gallstones in all patients who are using the drug specifically for weight loss. Providers could consider prescribing oral or subcutaneous semaglutide for approved indications if appropriate, since there was lack of evidence to support significant risk of cholelithiasis seen in one meta-analysis. At this time, further studies are needed in order to determine the role of gallstone prevention in patients using GLP1-RAs.
References:
1. GLP-1 Receptor Agonists: How Safe Are They for the Gallbladder? (2022, March 28). Www.medpagetoday.com. https://www.medpagetoday.com/endocrinology/diabetes/97895
2. He, L., Wang, J., Ping, F., Yang, N., Huang, J., Li, Y., Xu, L., Li, W., & Zhang, H. (2022). Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2022.0338
3. Cleveland Clinic. (2022). Gallstones: Treatment, Definition, Risk Factors & Symptoms. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/7313-gallstones