SGLT2 Inhibitors and Cardiovascular Outcomes in Patients With Fabry Disease: Observations From a Federated Research Network.

BACKGROUND AND AIM: Fabry disease (FD) is frequently complicated by renal impairment and cardiovascular events; however, evidence on sodium-glucose cotransporter-2 inhibitors (SGLT2i) in this population is scarce. Accordingly, we assessed the association between SGLT2i exposure and cardiovascular outcomes in adults with FD. METHODS: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with Fabry disease and eGFR ≥ 20 mL/min/1.73 m2, excluding Type 1 diabetes. Patients were stratified by SGLT2 inhibitor exposure. The primary outcome was a composite of all-cause death, acute myocardial infarction and acute or acute-on-chronic heart failure at 2 and 5 years; secondary outcomes included individual components and progression to advanced kidney disease. Patients with prior non-fatal outcomes were excluded from the respective analyses. Propensity score matching (1:1) and Cox proportional hazards models were used. Sensitivity analyses included alternative follow-up periods, restriction to Fabry disease diagnosed from 2013 onwards and a stricter Fabry disease definition requiring ≥ 2 diagnoses; subgroup analyses were performed by sex and age. RESULTS: Among 14 940 FD patients, 1028 (6.9%) had recorded exposure to SGLT2 inhibitors (mean age: 65.5 ± 12.0 years; 53.0% male), who were older and had a higher comorbidity burden and worse baseline renal profile than non-exposed patients. After PSM, 732 patients per group (exposed and non-exposed patients) were available for analysis. At 2 years, SGLT2i exposure was associated with a lower risk of the composite outcome (HR 0.61; 95% CI 0.38-0.97) and all-cause death (HR 0.56; 95% CI 0.33-0.95). At 5 years, results were consistent for the composite outcome (HR 0.56; 95% CI 0.39-0.79) and all-cause death (HR 0.62; 95% CI 0.42-0.93), with reduced myocardial infarction risk (HR 0.53; 95% CI 0.30-0.90). CONCLUSIONS: In a large real-world FD cohort, SGLT2i exposure was associated with lower cardiovascular risk and mortality, supporting further prospective investigation.