Fracture risk associated with sodium-glucose cotransporter-2 inhibitors in adults with type 2 diabetes, chronic kidney disease, or heart failure: an updated systematic review and meta-analysis of randomized controlled trials

Abstract Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have transformed the management of type 2 diabetes (T2DM), chronic kidney disease (CKD), and heart failure (HF), but fracture risk concerns persist following the CANVAS trial signal. We conducted an updated systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating fracture risk associated with SGLT-2i across T2DM, CKD, and HF populations. We systematically searched PubMed/MEDLINE (inception to September 2026), supplemented by ClinicalTrials.gov and reference lists. Nine RCT cohorts from eight trials were included, comprising 62,583 participants and 2,606 fracture events. SGLT-2i were not associated with increased fracture risk (pooled RR 1.087, 95% CI 0.973–1.214; P = 0.141; I2 = 41.7%). Only CANVAS showed significantly increased fracture risk (RR 1.548, 95% CI 1.241–1.931); its exclusion eliminated the signal and heterogeneity (RR 1.033, I2 = 0%). Meta-regression confirmed that heterogeneity was not explained by age, follow-up duration, or baseline HbA1c. No fracture imbalance was observed in CKD or HF trials. Egger's test showed no publication bias (P = 0.166), and GRADE certainty was moderate. SGLT-2i as a class are not associated with increased fracture risk. The CANVAS signal is likely trial-specific rather than a class effect. These findings support the removal of fracture-related warnings and reassure that SGLT-2i cardiovascular and renal benefits are not offset by increased fracture risk.