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
Open accessAbstract
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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The association between semaglutide and gallbladder-related disorders has also been reported previously.
“The incidence of gallbladder-related disorders was higher with semaglutide than with placebo, an association that has also been reported previously. 27”
From Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (2023) · cites this paper as [27]
GLP-1 RA are associated with higher risks of gallbladder and biliary diseases.
“GLP-1 RA are also associated with higher risks of gallbladder and biliary diseases (172).”
A meta-analysis from 2022 of 76 RCTs involving 103,371 patients found a modestly elevated RR of 1.37 (95% CI 1.23-1.52) for gallbladder or biliary disease with GLP-1RA drugs.
“A meta‐analysis from 2022 of 76 RCTs involving 103 371 patients starting GLP‐1RA drugs for either T2D or weight loss, compared with placebo or non‐GLP‐1RA drugs, found a modestly elevated RR of 1.37 (95% CI 1.23–1.52) for gallbladder or biliary disease. 94”
A systematic review and meta-analysis of 76 RCTs demonstrated that GLP-1 RA therapy considerably elevated the probability of gallbladder and biliary disorders (pooled relative risk 1.37; 95% CI 1.23 to 1.52).
“A recent systematic review and meta-analysis encompassing 76 RCTs demonstrated that GLP-1 RA therapy considerably elevated the probability of gallbladder and biliary disorders (pooled relative risk, 1.37; 95% CI, 1.23 to 1.52) [39].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [39]
The augmented gallbladder/biliary risk with GLP-1 RAs is more pronounced in weight loss interventions than in diabetes management (P for interaction <0.001).
“This augmented risk was particularly pronounced in the context of weight loss interventions compared to diabetes management (P for interaction <0.001), when using higher rather than lower dosages (P for interaction=0.006), and with extended treatment duration compared to shorter intervals (P for interaction=0.030).”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [39]
The augmented gallbladder/biliary risk with GLP-1 RAs is more pronounced with extended treatment duration compared to shorter intervals (P for interaction=0.030).
“This augmented risk was particularly pronounced in the context of weight loss interventions compared to diabetes management (P for interaction <0.001), when using higher rather than lower dosages (P for interaction=0.006), and with extended treatment duration compared to shorter intervals (P for interaction=0.030).”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [39]
The augmented gallbladder/biliary risk with GLP-1 RAs is more pronounced with higher rather than lower dosages (P for interaction=0.006).
“This augmented risk was particularly pronounced in the context of weight loss interventions compared to diabetes management (P for interaction <0.001), when using higher rather than lower dosages (P for interaction=0.006), and with extended treatment duration compared to shorter intervals (P for interaction=0.030).”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [39]
GLP-1 RA treatment is associated with a modestly elevated risk of cholelithiasis (RR 1.27), cholecystitis (RR 1.36), and overall biliary disease (RR 1.55) compared to placebo or other active comparators.
“A meta-analysis of 76 RCTs, involving over 100,000 adults with overweight, obesity, or type 2 diabetes found that GLP-1 RA treatment, compared to placebo or other active comparators, was associated with a modestly elevated risk of cholelithiasis (RR: 1.27, 95% CI 1.10, 1.47), cholecystitis (RR: 1.36, 95% CI 1.14, 1.62), and overall biliary disease (RR: 1.55, 95% CI 1.08, 2.22), corresponding to an”
From The expanding role of GLP-1 receptor agonists: a narrative review of current evidence and future directions (2025) · cites this paper as [77]
Rapid weight loss with GLP-1 receptor agonists has been associated with an increased risk of cholelithiasis in prior studies.
“This represents a limitation of the current evidence, as rapid weight loss with GLP‐1 receptor agonists has been associated with an increased risk of cholelithiasis in prior studies [49].”
From Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta‐Analysis (2025) · cites this paper as [49]
GLP-1RA are known to be associated with an increased yet small risk of gallbladder and biliary-related disorders in patients treated for type 2 diabetes and obesity.
“which are known to be associated with an increased yet small risk of gallbladder and biliary-related disorders both in patients treated for type 2 diabetes and obesity [22].”
From The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database (2024) · cites this paper as [22]
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References 32 · Cited by 356
Research works printed but not linked: 2
- [20]20. Shaddinger BC, Young MA, Billiard J, Collins DA, Hussaini A, Nino A. Effect of albiglutide on cholecystokinin-induced gallbladder emptying in healthy individuals: a randomized crossover study. J Clin Pharmacol. 2017;57(10):1322-1329. doi:10. 1002/jcph.940
- [25]25. Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med. 2021; 384(18):1719-1730. doi:10.1056/NEJMoa2028198 · DOI · Paper page
- Authors
- He, L., Wang, J., Ping, F., Yang, N., Huang, J., Li, Y., Xu, L., Li, W., & Zhang, H.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Zhang, Huabing
- Venue
- JAMA Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2022-05-01
- Volume
- 182
- Issue
- 5
- Pages
- 513
- ISSN
- 2168-6106 (ISSN-L)
- PMC
- PMC8961394
- OpenAlex
- W4220972902
- Semantic Scholar
- 42e97b1bf6e4aee557aa8c6158894840b4d1887d
- Cited by
- 356
- References
- 32
- Citations by year
- 2026: 128 · 2025: 110 · 2024: 75 · 2023: 25 · 2022: 18
- FWCI
- 8.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Internal Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gallbladder and Bile Duct Disorders
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- GLP-1 receptor agonists, gallbladder disease, biliary tract diseases, gallstones, cholecystitis, cholecystectomy, biliary tract cancer, type 2 diabetes, drug safety, adverse drug reactions, randomized controlled trials, risk factors, anti-obesity drugs, cardiovascular risk reduction, glycemic control, risk of bias assessment
- MeSH terms
- Glucagon-Like Peptide-1 Receptor Agonists, Adult, Cholecystitis, Cholelithiasis, Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Weight Loss, Randomized Controlled Trials as Topic, Glucagon-Like Peptide 1
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