Effect of SGLT2i and GLP-1RAs on fracture risk: analysis of a large retrospective population-based

Introduction: Type 2 diabetes (T2D) medications have been linked to increased risk of fragility fracture. However, results are conflicting and lacking specifically designed RCTs. This study aims to evaluate whether with newer diabetes treatments (DPP-4i, GLP-1 RA, and SGLT-2i) are associated to fragility fractures in a large retrospective population-based cohort in Lombardy (Italy). Methods: Using data from the regional healthcare utilization databases, the 94,923 diabetes patients aged over 40 years who, between 2015 and 2020, were newly treated with SGLT-2i (n=11,062), DPP-4i (n=21,420), GLP-1 RA (n=12,335), or sulfonylureas (n=50,106) were selected. Patients were followed-up from the date of treatment start until a hospital admission with ICD-9-CM diagnostic code of bone fracture, migration or 31/12/2022. Results: During an average follow-up of 4.3 years, fragility fracture occurred in 1934 patients (4.73/1000 persons-year). In adjusted (age, gender, MSC score, osteoporosis, previous fractures, stroke, rheumatological diseases, chronic kidney disease and heart failure in the two years preceding the treatment start) multivariate Cox model, both SGLT-2i and GLP-1 RA, compared to DPP-4i, showed statistically significant fracture risk reduction, respectively 34% (HR=0.66; 95%CI 0.52-0.85) and 41% lower (HR=0.59; 95%CI 0.45-0.77). Sulfonylureas did not significantly affect fracture risk compared to DPP-4i (HR=1.02; 95%CI 0.92-1.13). When comparing SGLT-2i use to GLP-1 RA use, no increased fracture risk was found (HR=1.13; 95%CI 0.80-1.58). These results were consistent in sensitivity analyses using multivariate Fine&Gray model and High Dimensional Propensity Score, albeit with statistical significance loss. Conclusions: In our large cohort, SGLT-2i and GLP-1 RA use was not associated with increased fragility fracture risk in T2D patients, compared to DPP-4i, supporting their safety. However, to draw clear conclusions, more large-scale studies should be specifically performed.