Effect of sodium-glucose cotransporter-2 inhibitors on fracture risk in patients with type 1 diabetes receiving insulin-based therapy: a meta-analysis

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i), a novel class of antihyperglycemic agents, have raised concerns regarding bone safety. This meta-analysis aimed to evaluate the specific effect of adjunctive SGLT2i therapy on fracture risk in patients with type 1 diabetes mellitus (T1DM). Methods: We systematically searched four databases (PubMed, Embase, Cochrane Library and Web of Science Core Collection) to identifyall eligible randomized controlled trials (RCTs) investigating SGLT2i as adjunctive therapy to insulin in T1DM. Fracture risk was defined as primary outcome, while glycemic parameters, non-glycemic outcomes, and other safety index serving as secondary endpoints. Pooled ORs (95% CIs) were calculated, with dose-stratified subgroup analyses. Risk of bias was assessed using the Cochrane Collaboration Risk-of-Bias tool (RoB 2). Results: Our analysis included 10 RCTs comprising 6,731 T1DM patients. All included studies were deemed to be at low or moderate risk of bias. Pooled analysis revealed no significant association between SGLT2i use and fracture risk (OR 0.98, 95% CI [0.63-1.51]). This null finding remained consistent across subgroup analyses. Fracture odds ratios in the low-, moderate-, and high-dose subgroups were 0.78 (95% CI [0.11-5.58]), 1.08 (95% CI [0.55-2.11]), and 0.90 (95% CI [0.50-1.63]), respectively. SGLT2i significantly improved glycemic control, including HbA1c, fasting plasma glucose, and time in range. It also reduced body weight and blood pressure. However, SGLT2i treatment increased the risk of diabetic ketoacidosis (OR 3.52, 95% CI [2.16-5.71]) and genital tract infections (OR 3.69, 95% CI [2.85-4.78]). Conclusion: This meta-analysis provides reassuring evidence that adjunctive SGLT2 inhibitor use is not associated with increased fracture risk in insulin-treated patients with T1DM patients. Nonetheless, the substantially elevated risks of diabetic ketoacidosis and genital tract infections necessitate vigilant clinical monitoring and risk mitigation strategies to ensure safe use of these agents.