SUN-810 - Fragility Fracture Risk Associated with GLP-1 and Dual GLP-1/GIP RA Therapies in Older adults with Type 2 Diabetes

Background: Older adults, particularly females with type 2 diabetes (T2D), are at increased risk of fragility fractures. Potent glucagon-like peptide 1 (GLP 1) and glucose-dependent insulinotropic polypeptide (GIP) are increasingly prescribed for diabetes management and are associated with substantial weight loss. However, their effects on fragility fracture risk remain inconclusive.

Aims: To compare the effects of GLP 1 and GLP-1/GIP RA versus dipeptidyl peptidase 4 inhibitors (DPP 4i) on fragility fracture risk in older adults with T2D, using a large electronic health record database.

Methods: Using a target trial emulation framework with a new-user, active-comparator design, we compared the risk of fragility fractures between GLP 1 and GLP-1/GIP vs DPP-4i users in T2D population. In Epic Cosmos (2018–2025), GLP-1 RA were categorized as newer (semaglutide, tirzepatide) or older (other GLP-1 RAs) agents. The first prescription of the study medication was defined as an index date. We excluded patients with a history of cancer, end-stage renal disease (ESRD), or thiazolidinedione use prior to the index date. The primary endpoint was the first fragility fracture (identified using ICD-10 codes). Follow-up was censored at the earliest of death, the last EHR encounter, the study end (Dec 2025), or the occurrence of the primary endpoint. To ensure balance in baseline socio-demographics, comorbidities, laboratory values, and medications, 1:1 propensity score matching was employed. An intent-to-treatment analysis was conducted using Cox proportional hazards regression within the matched cohort.

Results: Newer GLP-1 and GLP-1/GIP RA initiators (n=241,524) and 144,770 older GLP-1 RA initiators were matched to 144,770 DPP-4i initiators. Newer GLP-1 and GLP-1/GIP RA were associated with significantly lower fracture risk overall (HR 0.904; 95% CI, 0.871–0.938), as were older GLP-1 RAs, though more modestly (HR 0.958; 95% CI, 0.923–0.993). Among patients aged ≥60, newer GLP-1 and GLP-1/GIP RA significantly reduced fracture risk (HR 0.904; 95% CI, 0.867–0.941), while older agents did not (HR 1.040; 95% CI, 0.997–1.085). Among older adults, men appear to be more protected against fragility fractures than older females (HR 0.856; 95% CI, 0.799-0.917 vs 0.925; 95% CI, 0.879-0.973). In older females (>60 years), newer GLP-1 and GLP-1/GIP RA consistently reduced fracture risk across BMI categories and fracture sites, with the strongest associations at HbA1c < 7% (HR 0.774; 95% CI, 0.700–0.855). Risk reduction persisted across modest 1-year weight loss strata (0–5%: HR 0.812; 5–10%: HR 0.759), suggesting an effect independent of weight loss.

Conclusion: Use of newer GLP1 and GLP 1/GIP RA is associated with a lower risk of fragility fractures among older adults with T2D. These findings might offer reassurance to millions of older adults taking these medications.

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