Evaluating the Safety of Sodium-Glucose Cotransporter-2 Inhibitors in a Nationwide Veterans Health Administration Observational Cohort Study.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are indicated in patients with or without type 2 diabetes mellitus atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. Postmarket surveillance data have identified many safety signals which warrants further investigation. We aimed to compare the safety of SGLT-2i and glucagon-like peptide-1 receptor agonists (GLP-1RA). Using the Veterans Health Administration nationwide database, patients with type 2 diabetes mellitus who were newly initiated on a SGLT-2i or GLP-1RA between April 1, 2013 and September 1, 2020 were identified. The primary outcome was the incidence of any amputation, below-knee amputation (BKA), all clinical fractures, hip fracture, Fournier gangrene, acute pancreatitis, diabetic ketoacidosis (DKA), serious urinary tract infections (UTIs), and venous thromboembolism (VTE). All outcomes were compared between the treatment groups. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs) for the comparative analysis. A total of 70,694 propensity-matched new users of SGLT-2i and GLP-1RA were identified. The use of SGLT-2 inhibitors, compared with GLP-1RA, was not associated with an increased rate of any amputation (aHR 1.02, 95% confidence interval [CI] 0.82 to 1.27), BKA (aHR 1.05, 95% CI 0.84 to 1.32), all clinical fractures (aHR 0.94, 95% CI 0.86 to 1.03), hip fractures (aHR 0.82, 95% CI 0.50 to 1.32), DKA (aHR 1.66, 95% CI 0.97 to 2.85), VTE (aHR 1.02, 95% CI 0.80 to 1.30), acute pancreatitis (aHR 1.02, 95% CI 0.80 to 1.30), and Fournier gangrene (aHR 0.92 95% CI 0.61 to 1.38). Lower rates of serious UTIs were observed in the SGLT-2i group than in the GLP-1RA group (aHR 0.74, 95% CI 0.64 to 0.84). This real-world study found that SGLT-2i use compared with GLP-1RA did not increase the rate of amputation, BKA, clinical fractures, hip fracture, Fournier gangrene, acute pancreatitis, DKA, serious UTIs, and VTE in veteran patients.