MON-664 - Association of Semaglutide Versus SGLT2-Inhibitors with Risk of Falls and Major Osteoporotic Fractures in Older Adults with Type 2 Diabetes

Importance: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, are increasingly prescribed to older adults for type 2 diabetes (T2D) and weight management. However, concerns persist regarding the potential for skeletal fragility due to rapid weight loss-induced sarcopenia, compared with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have established safety profiles but theoretical risks of fall-related injuries due to volume depletion.

Objective: To compare the risk of falls and major osteoporotic fractures between older adults initiating semaglutide versus SGLT2 inhibitors.

Design, Setting, and Participants: This retrospective, propensity score-matched cohort study utilized data from the TriNetX global health research network, which aggregates electronic medical records from large healthcare organizations. The study identified adults aged 65 years or older with T2D who were new users of either semaglutide or an SGLT2 inhibitor (canagliflozin, empagliflozin, or dapagliflozin) between January 1, 2019, and June 1, 2025.

Exposures: Initiation of semaglutide vs. SGLT2 inhibitors. Patients with prior use of either class were excluded.

Main Outcomes and Measures: The primary outcomes were the risk of falls and composite major osteoporotic fractures (fractures of the femur, thoracic/lumbar vertebrae, humerus, or forearm) at 1-year and 3-year follow-up intervals. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models after 1:1 propensity score matching (PSM). Negative control outcomes (ingrowing nail, herpes zoster) were analyzed to detect residual bias.

Results: After matching, 41,592 patients were included (20,796 per group; mean age 70.7 years; 54.5% female). Baseline characteristics were well-balanced (Standardized Mean Differences < 0.1). At 1 year, there was no significant difference between semaglutide and SGLT2 inhibitors in the risk of fractures (HR, 1.14 [95% CI, 0.89-1.47]) or falls (HR, 1.12 [95% CI, 0.94-1.33]). These findings persisted at 3 years for both fractures (HR, 1.09 [95% CI, 0.91-1.31]) and falls (HR, 1.07 [95% CI, 0.94-1.21]). A statistically significant signal in the negative control outcome at 3 years (HR, 1.39 [95% CI, 1.10-1.77]) suggested potential surveillance bias in the semaglutide group, though this did not translate to an elevated risk in the primary safety outcomes.

Conclusions and Relevance: In older adults with T2D, the initiation of semaglutide was not associated with an increased risk of falls or major osteoporotic fractures compared with SGLT2 inhibitors. These real-world data provide reassurance regarding the skeletal safety of semaglutide in this vulnerable population, supporting its use for cardiometabolic indications without excess concern for fracture risk.

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