Semaglutide and Tirzepatide Significantly Reduce Fall and Femoral Fracture Risks in Older Adults with Type 2 Diabetes
Background
Older adults with type 2 diabetes (T2DM) and overweight or obesity face an elevated risk of falls and subsequent femoral fractures, leading to significant morbidity and mortality. Current T2DM management primarily focuses on glycemic control and weight, often overlooking musculoskeletal health. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a common treatment, but their impact on fracture risk is less clear. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) like semaglutide and GLP-1/GIP receptor co-agonists like tirzepatide, have shown benefits beyond glucose lowering, prompting investigation into their potential musculoskeletal protective effects.
Study Design
This retrospective cohort study utilized the TriNetX database (2018-2025) to compare outcomes in adults aged ≥65 with T2DM and BMI ≥25 kg/m2. Patients initiating semaglutide or tirzepatide were compared against those starting DPP-4 inhibitors using 1:1 propensity score matching to balance baseline characteristics. The study included 27,896 patients for the semaglutide comparison and 12,808 for the tirzepatide comparison. Primary and secondary outcomes were 1-year femoral fracture and falls, respectively, assessed via ICD-10 codes.
Results
Both semaglutide and tirzepatide demonstrated significantly lower risks of femoral fractures and falls compared to DPP-4 inhibitors over a 1-year period. For femoral fractures, semaglutide reduced incidence from 0.5% to 0.3% (HR 0.488; 95% CI 0.367-0.649; P<0.0001). Tirzepatide showed a similar reduction from 0.4% to 0.2% (HR 0.452; 95% CI 0.280-0.729; P=0.0008).
Fall risk was also substantially lowered by both agents: semaglutide reduced falls from 5.4% to 3.6% (HR 0.663; 95% CI 0.612-0.718; P<0.0001), and tirzepatide reduced falls from 5.7% to 3.6% (HR 0.664; 95% CI 0.591-0.747; P<0.0001). Subgroup analyses revealed consistent fall reduction across various patient categories. Fracture reduction was particularly pronounced in patients with BMI ≥30 kg/m2, suggesting a potential dose-response or weight-related mechanism for bone protection. These findings suggest musculoskeletal benefits beyond the established glycemic control and weight loss effects of these
GLP-1RandGIPRagonists.
Key Findings
- Semaglutide reduced 1-year femoral fracture risk by 51.2% (HR 0.488, P<0.0001) compared to DPP-4 inhibitors.
- Tirzepatide reduced 1-year femoral fracture risk by 54.8% (HR 0.452, P=0.0008) compared to DPP-4 inhibitors.
- Semaglutide reduced 1-year fall risk by 33.7% (HR 0.663, P<0.0001) compared to DPP-4 inhibitors.
- Tirzepatide reduced 1-year fall risk by 33.6% (HR 0.664, P<0.0001) compared to DPP-4 inhibitors.
- Femoral fracture reduction was more pronounced in patients with BMI ≥30 kg/m2.
Why It Matters
This study provides compelling evidence that semaglutide and tirzepatide offer significant musculoskeletal benefits in older adults with T2DM and overweight/obesity, specifically reducing the risk of falls and femoral fractures. For clinicians, this suggests that selecting these agents over DPP-4 inhibitors could improve patient safety and quality of life, especially in a vulnerable population prone to fracture-related complications. This expands the perceived utility of these peptides beyond metabolic control, highlighting their potential role in comprehensive geriatric care. While this is a retrospective study, the magnitude of the observed effect warrants consideration in treatment protocols, particularly for patients at high risk of falls or fractures. Further prospective studies are needed to confirm these findings and elucidate the underlying mechanisms.
semaglutide
tirzepatide
dpp-4-inhibitors
type-2-diabetes
falls
femoral-fractures