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.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 35344001 · doi:10.1001/jamainternmed.2022.0338
What was done
A systematic review and meta-analysis of randomized clinical trials (RCTs) searched MEDLINE/PubMed, EMBASE, Web of Science, Cochrane Library, and trial registries through mid-2021. Eligible studies compared GLP-1 receptor agonists (GLP-1 RAs) against placebo or non-GLP-1 RA active comparators in adults. Study quality was assessed with the Cochrane risk-of-bias tool, and evidence certainty was evaluated using GRADE. The primary outcome was a composite of gallbladder or biliary diseases; secondary outcomes included cholelithiasis, cholecystitis, biliary disease, cholecystectomy, and biliary cancer.
What was found
The meta-analysis included 76 RCTs with 103,371 participants (mean age 57.8 years; 40.5% women). GLP-1 RA use was associated with an increased risk of composite gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52), including 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). The risk was significantly higher in weight-loss trials (13 RCTs: RR, 2.29; 95% CI, 1.64-3.18) than in type 2 diabetes trials (63 RCTs: RR, 1.27; 95% CI, 1.14-1.43; P < .001 for interaction). Increased risk was also observed at higher doses (RR, 1.56; 95% CI, 1.36-1.78 vs lower doses: RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and longer treatment duration (RR, 1.40; 95% CI, 1.26-1.56 vs shorter: RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).
Why it matters
This review establishes a dose- and duration-dependent association between GLP-1 RA therapy and adverse gallbladder or biliary events. It highlights the need for clinical monitoring of biliary symptoms, particularly when prescribing high-dose GLP-1 RAs for weight management.
Limits
The abstract reports no numerical estimates for specific secondary outcomes such as cholecystectomy or biliary cancer. Gallbladder events were collected as secondary adverse events rather than pre-specified, systematically screened primary endpoints, and the confounding role of rapid weight loss itself on biliary lithogenesis was not isolated in the abstract.
Cited by
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