Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes: A Target...

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.

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.

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.

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.