SGLT2 inhibition reduces cardiac surgery-associated acute kidney injury: An open-label randomized study

BackgroundCardiac surgery-associated acute kidney injury (CSA-AKI) is a common postoperative complication. Currently, no effective preventative strategies exist to mitigate CSA-AKI. Sodium-glucose transporter-2 (SGLT2) inhibitors reduced acute kidney injury (AKI) incidence in large, randomized placebo-controlled, cardiovascular and kidney outcome trials conducted in patients with chronic kidney disease. We hypothesized that perioperative SGLT2 inhibition could also reduce CSA-AKI. MethodsIn this open-label phase IV, randomized, parallel-group, pilot study, adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were randomized to receive the SGLT2 inhibitor, empagliflozin (10 mg; oral), once daily three days prior to surgery and continued to two days after surgery compared with standard-of-care. Biomarkers for acute kidney injury (AKI), including serum and urinary neutrophil gelatinase-associated lipocalin (NGAL), serum and urinary kidney injury molecule-1 (KIM-1), and serum hypoxia-inducible factor-1 (HIF-1) were measured. Additional outcomes included AKI incidence according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria as well as metabolic parameters, including ketone body concentrations and glycemic control. ResultsBetween March 2022 and April 2023, 55 patients were included (sex: 73% male, age: 66 {+/-} 10 years, BMI: 28 {+/-} 4 kg/m2, empagliflozin n = 25, control n = 30) in the intention-to-treat analysis. Empagliflozin significantly reduced the incidence of AKI (20% vs 66.7%; absolute difference 46.7%, 95% CI, -69.7 - -23.6; P=.001). Following surgery, urinary NGAL, and KIM-1 were found to increase in both arms, whereas a significant increment in serum HIF-1 after surgery was solely observed in the control group. We observed no between-group differences in the incidence of (euglycemic) ketoacidosis or hypoglycemic events. ConclusionsPerioperative SGLT2 inhibition, compared with standard of care, significantly reduced the incidence of CSA-AKI. These findings warrant validation in large-scale, double-blind, placebo-controlled, randomized trials. Trial Registryhttps://onderzoekmetmensen.nl/en/trial/26563 Identifier: NL9561 Clinical perspective What Is New?O_LIIn this open-label, randomized, controlled, pilot trial perioperative use of sodium glucose transporter-2 (SGLT2) inhibition with empagliflozin significantly reduced the incidence of acute kidney injury (AKI) by 46.7% (95% CI, -69.7 - -23.6; P=.001) compared to the control group. C_LIO_LIThe level of ketone bodies increased significantly during cardiac surgery, however, there was no additional effect of empagliflozin treatment. C_LI What Are the Clinical Implications?O_LIThese results suggest that perioperative treatment with SGLT2 inhibitors might decrease the risk of cardiac surgery-associated (CSA)-AKI. C_LIO_LIThese findings warrant validation in large-scale, double-blind, placebo-controlled, randomized trial, which is currently ongoing. C_LI