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

Abstract

AbstractBackgroundCardiac 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-1α (HIF-1α) 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-1α 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/26563Identifier: NL9561Clinical perspectiveWhat Is New?In 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.The level of ketone bodies increased significantly during cardiac surgery, however, there was no additional effect of empagliflozin treatment.What Are the Clinical Implications?These results suggest that perioperative treatment with SGLT2 inhibitors might decrease the risk of cardiac surgery-associated (CSA)-AKI.These findings warrant validation in large-scale, double-blind, placebo-controlled, randomized trial, which is currently ongoing.