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Original Investigation
March 28, 2022

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Author Affiliations
  • 1Department of Endocrinology, Key Laboratory of Endocrinology of the National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
JAMA Intern Med. 2022;182(5):513-519. doi:10.1001/jamainternmed.2022.0338
Key Points

Question  What is the association of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) use with the risk of gallbladder or biliary diseases?

Findings  This systematic review and meta-analysis of 76 randomized clinical trials found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

Meaning  The findings of this systematic review and meta-analysis indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 RAs for treatment in clinical practice; future studies should report on associated gallbladder and biliary diseases.


Importance  Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.

Objective  To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.

Data Sources  MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.

Study Selection  Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.

Data Extraction and Synthesis  Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.

Main Outcomes and Measures  The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.

Results  A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, 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). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P  = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P  = .03 for interaction).

Conclusions and Relevance  This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

Trial Registration  PROSPERO Identifier: CRD42021271599

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    1 Comment for this article
    Possible confound
    David Karpf, MD | Stanford University School of Medicine
    It might be a little too soon to attribute the HR of 1.37 to the GLP-1 RAs. It has been known for some time that both obesity and significant weight loss increase the risk of gall bladder disease, including that of gallstones. See, for example, just a few references

    1. R L Weinsier, et al. Gallstone formation and weight loss. Obes Res. 1993 Jan;1(1):51-56.
    2. Gebhard RL, et al. The role of gallbladder emptying in gallstone formation during diet-induced rapid weight loss. Hepatology. 1996 Sep;24(3):544-548.
    3. Festi D, et al. Gallbladder motility and gallstone formation in
    obese patients following very low calorie diets. Use it (fat) to lose it (well). Int J Obes Relat Metab Disord. 1998 Jun;22(6):592-600.
    4. Festi D, et al. Review: low caloric intake and gall-bladder motor function. Aliment Pharmacol Ther. 2000 May;14 Suppl 2:51-53.
    5. Marks JW, et al. The sequence of biliary events preceding the formation of gallstones in humans. Gastroenterology. 1992 Aug;103(2):566-570.
    6. Hofmann AF. Et al. Primary and secondary prevention of gallstone disease: implications for patient management and research priorities. Am J Surg. 1993 Apr;165(4):541-548.

    It seems entirely plausible that at least some of the risk, if not all, can be attributed to the often profound and substantial weight loss due to the the GLP-1 RA therapy.

    David B. Karpf, MD
    Adj. Clinical professor of Endocrinology, Gerontology & Metabolism
    Stanford University School of Medicine