2859-LB: Fracture Risk with Combined SGLT2 Inhibitors and GLP-1 Receptor Agonists in Patients with Type 2 Diabetes: A Target Trial Emulation

Introduction and Objective: While combining SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) provides synergistic cardiorenal benefits, their effect on skeletal safety remains unclear. We aimed to determine whether initiating combination therapy increases fracture risk compared to continuing either monotherapy in patients with type 2 diabetes (T2DM). Methods: We conducted a target trial emulation using a prevalent new-user design in the Tianjin Diabetes and Health Cohort. We included adults with T2DM and excluded those with prior major fractures or end-stage renal disease. Two parallel cohorts were constructed: 1) GLP-1RA background (adding SGLT2i vs. continuing GLP-1RA) and 2) SGLT2i background (adding GLP-1RA vs. continuing SGLT2i). Time-dependent propensity score matching (1:1) was used to balance baseline and time-varying covariates, including glycemic control, complications, and bone-active medications. The primary outcome was a composite of major fractures (hip, pelvis, humerus, or forearm). Hazard ratios (HRs) were estimated using stratified Cox proportional hazards models. Results: We matched 10,280 pairs in the GLP-1RA cohort and 13,664 pairs in the SGLT2i cohort, with mean ages of 54.2 and 57.3 years, respectively. Key covariates, including prior osteoporosis and use of bone-active medications, were well balanced between groups (SMD <0.1). In the GLP-1RA cohort, major fracture incidence was 1.08 per 1,000 person-years for combination therapy vs. 1.25 for monotherapy (HR 1.02; 95% CI 0.40-2.58). In the SGLT2i cohort, incidence was 1.19 vs. 0.82 per 1,000 person-years (HR 1.80; 95% CI 0.81-4.01). No significant differences were observed for secondary outcomes (other non-major fractures) in either cohort (P > 0.05). Conclusion: In this real-world study of T2DM, combined SGLT2i and GLP-1RA therapy was not associated with a significantly increased fracture risk compared to either monotherapy, supporting its relative skeletal safety in clinical practice. Disclosure X. Jia: None. J. Han: None. X. Guo: None. Y. Liu: None. H. Zhu: None. M. Li: None. Z. Song: None.