SGLT2 inhibitors improved clinical outcomes on biliary diseases beyond glycemic control in patients with type 2 diabetes

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.