Time‐dependent risk of fracture in adults with type 2 diabetes receiving anti‐diabetic drug: A one‐stage network meta‐analysis

Abstract Aims To assess the time‐dependent risk of fracture in adults with type 2 diabetes receiving anti‐diabetic drugs. Materials and Methods We searched MEDLINE, EMBASE, and Cochrane Library up to 18 November 2021, for randomized controlled trials (RCTs) and propensity‐score‐matched non‐randomized studies (NRSs) comparing all anti‐diabetic drugs with standard treatment or with each other on fracture in adults with type 2 diabetes. The study performed a one‐stage network meta‐analysis using discrete‐time hazard regression with reconstructed individual time‐to‐event data. Results This network meta‐analysis involved seven RCTs (65,051 adults with type 2 diabetes) with a median follow‐up of 36 months and three propensity‐score‐based NRSs (17,954 participants) with a median follow‐up of 27.3 months. Among anti‐diabetic drugs, thiazolidinediones increased the overall hazard of fracture by 42% (95% credible interval [CrI], 3%–97%) and almost tripled the risk after 4 years (hazard ratio [HR], 2.74; 95% CrI, 1.53–4.80). Credible subgroup analysis suggested that thiazolidinediones increased the hazard of fracture only in females (HR, 2.19; 95% CrI, 1.26–3.74) but not among males (HR, 0.81; 95% CrI, 0.45–1.40). Moderate certainty evidence established that thiazolidinediones increase 92 fractures in five years per 1000 female patients. We did not find the risk of fractures with other anti‐diabetic drugs including metformin, sulfonylureas, sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. Conclusions Long‐term use of thiazolidinediones elevates the risk of fracture among females with type 2 diabetes. There is no evidence eliciting fracture risk associated with other anti‐diabetic drugs.