Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes

Aims: To evaluate the associations between semaglutide initiation and long-term skeletal outcomes in people with obesity, stratified by type 2 diabetes (T2D) status, using target trial emulation. Materials and Methods: This retrospective cohort study used the TriNetX federated electronic health record network. People with obesity initiating semaglutide were matched 1:1 via propensity score matching (215 covariates) to those initiating active comparators or usual care. The with-T2D cohort (n = 19 824–93 519 matched pairs per comparison) was followed for 3 years; the without-T2D cohort (n = 10 323–56 225 pairs) for 2 years. The primary outcome was major osteoporotic fracture (MOF). Secondary outcomes included osteoporosis diagnosis; exploratory outcomes included osteoarthritis and gout. Results: In the with-T2D cohort, semaglutide initiation was associated with a lower risk of MOF compared with empagliflozin (HR 0.69; 95% CI 0.61–0.77), glipizide (HR 0.72; 0.63–0.83) and usual care (HR 0.84; 0.76–0.93). In the without-T2D cohort, no significant associations with MOF were observed across any comparison (all p > 0.05). Osteoporosis risk did not differ significantly in most comparisons in either cohort. Exploratory analyses of osteoarthritis and gout showed inconsistent patterns across comparators. Conclusions: Among people with obesity and T2D, semaglutide initiation was associated with a lower risk of MOF over 3 years compared with other glucose-lowering agents and usual care. This association was not observed in people with obesity without T2D. These findings support further investigation of the skeletal effects of GLP-1 receptor agonists.