Glucagon-Like Peptide-1 Receptor Agonists and Fragility Fracture Risk in Type 2 Diabetes

Importance: Obesity, type 2 diabetes (T2D), and weight loss are associated with increased fragility fracture risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, yet their effects on skeletal outcomes remain uncertain. Objective: To evaluate the association between GLP-1 RA initiation and 3-year fragility fracture risk compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) initiation among adults with T2D. Design, Setting, and Participants: This comparative effectiveness study using retrospective target trial emulation examined data from the TriNetX Research Network (January 1, 2015, to December 31, 2022), a multicenter US electronic health record database. Adults aged 50 to 90 years with T2D who newly initiated a GLP-1 RA or DPP-4i were followed up for up to 3 years. A separate cohort stratified by T2D status was also analyzed. The database was queried on January 26, 2026, to generate a line-level analytic dataset. Exposures: Initiation of GLP-1 RAs vs DPP-4is. Main Outcomes and Measures: The primary outcome was incident fragility fracture, defined as fractures after low-energy trauma (eg, fall from standing height). Cohorts were propensity score matched. Time-varying mediation analyses were used to evaluate the contribution of changes in body mass index and hemoglobin A1c. Results: After matching, 133 606 patients (66 803 per group; GLP-1 RA vs DPP-4i: mean [SD] age 63.2 [8.1] vs 63.8 [8.5] years; 35 195 [52.7%] vs 36 098 [54.0%] male) were included. Initiation of GLP-1 RA was associated with lower fragility fracture risk compared with DPP-4i initiation (hazard ratio [HR], 0.79 [95% CI, 0.76-0.83]; absolute risk reduction, 0.79% [95% CI, 0.60%-0.99%]; number needed to treat, 126 [95% CI, 101-168]). The largest risk reductions were observed with vertebral (HR, 0.68 [95% CI, 0.63-0.73]) and hip or femur (HR, 0.70 [95% CI, 0.63-0.79]) fractures. In a sensitivity analysis stratified by diabetes status, fracture risk reduction was observed among patients with T2D (HR, 0.91 [95% CI, 0.88-0.95]) but not among those without T2D (HR, 1.13 [95% CI, 1.04-1.23]; interaction P < .001). Mediation analyses showed that the direct association between GLP-1 RA use and lower fracture risk persisted (HR, 0.81 [95% CI, 0.76-0.86]). Conclusions and Relevance: This target trial emulation study of adults with T2D found that initiation of a GLP-1 RA was associated with lower 3-year fragility fracture risk compared with initiation of a DPP-4i, independent of changes in body mass index and hemoglobin A1c. Prospective studies are needed to establish causality and define long-term skeletal effects.