Background & aims Diabetes is known to increase the risk of gallstone disease. This study assesses the impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the incidence of biliary diseases, relative to sulfonylureas, in patients with type 2 diabetes mellitus (T2DM) and lithogenic diet (LD)-fed mice.

Methods A retrospective cohort analysis was performed on T2DM patient data who commenced SGLT2i or sulfonylurea therapy from January 1, 2017, to September 1, 2022-sourced from Nanjing Medical University’s database. They were matched using propensity scores (PS) and inverse probability of treatment weighting (IPTW). Follow-up for developing biliary diseases was conducted up to the earliest relevant end-point. Cox models, PS matching, and sensitivity analyses, including standard mortality ratio weighting (SMRW), were applied to determine hazard ratios (HRs) and confidence intervals (CIs). Parallelly, LD-fed C57BL/6J mice were administered SGLT2i or sulfonylureas to corroborate findings in animal models.

Results From the 1,901 patients analyzed over an average of 2.83 years, SGLT2i therapy correlated with a substantially lower risk of developing biliary diseases (HR 0.595, 95% CI 0.410-0.863), particularly among defined subgroups. A downward trend in risk was observed with extended use beyond two years. Concordant data from the mouse model pointed towards SGLT2i mitigating gallstone formation, with putative mechanisms including reduced liver injury and dyslipidemia, as well as improved gallbladder motility and bile acid production.

Conclusion SGLT2i potentially reduces the risk of biliary diseases compared to sulfonylureas, meriting further clinical investigation.

The authors have declared no competing interest.

The National Key Research and Development Program of China (Project Number: 2022YFA0806) and the National Natural Science Foundation of China (Project Approval Number: 82070849 and 82270871).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This cohort study was approved by Ethic Committee of Sir Run Run Hospital of Nanjing Medical University (2024-SR-040) and the animal study was approved by Institutional Animal Care and Use Committee (IACUC) of Nanjing medical university (IACUC-2308036).

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All data produced in the present study are available upon reasonable request to the authors