Diabetes, obesity & metabolism · 2026
Associations of Semaglutide With Skeletal Outcomes in People With Obesity, With and Without Type 2 Diabetes: A Target Trial Emulation.
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Huang Yu-Nan, Tsou Min-Yu, Li Pin-Hung, Chen Jo-Ching, Chen Shao-Chia, Hsieh Hao-I, Meyerowitz-Katz Gideon, Liu Yen-Liang, Su Pen-Hua
Аннотация
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.
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.