Abstract
<title>Abstract</title> <p>Purpose GLP-1 receptor agonists (GLP-1 RAs) are widely used for type 2 diabetes mellitus (T2DM) and obesity and have been linked to gallstone disease. Whether gallstone occurrence translates into clinically significant biliary disease, and whether this signal is driven by diabetes or obesity, remains unclear. Methods We performed a retrospective propensity-matched cohort study using the TriNetX network. Adults aged 18 to 65 with T2DM or obesity and recorded body mass index (BMI) were grouped by GLP-1 RA exposure and matched one to one on 20 covariates, including BMI. Six biliary outcomes were followed for five years. We reported odds ratios for cumulative occurrence, Cox hazard ratios and Kaplan-Meier survival for event timing, phenotype subgroups, and E-values for confounding. Results We matched 721,898 pairs. GLP-1 RA use was associated with slightly higher odds of cholelithiasis (OR 1.11) and choledocholithiasis (OR 1.14), and lower odds of cholecystitis (0.94), cholangitis (0.51), cholecystectomy (0.62), and ERCP (0.46). Hazard ratios were below 1 for all outcomes, including stones, and five-year cholelithiasis incidence was nearly identical. Higher stone odds appeared only in obesity without diabetes and were absent in T2DM-only and combined groups. Inverse associations for inflammatory and procedural outcomes appeared in every subgroup. E-values were large for inverse associations and small for stone associations. Conclusions Increased gallstone occurrence with GLP-1 RAs was modest, limited to obesity without diabetes, and not evident after accounting for event timing. It did not correspond to more clinically significant biliary disease. Inverse findings should be interpreted as associations, not benefit.</p>