Metabolic and renal outcomes in cardiac surgery patients receiving SGLT2 inhibitors

Rationale: Acute kidney injury is one of the most common complications after cardiac surgery. The new antidiabetic therapy, sodium glucose transport protein 2 inhibitors (SGLT2i) possess renoprotective properties and have been found to reduce acute kidney injury in large cardiovascular outcome trials in patients with diabetes mellitus.
Objective: To investigate the potential of empagliflozin to reduce the acute kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) on day 2 postoperatively in patients undergoing cardiopulmonary bypass surgery.
Study design: Single-center, open-label, randomized clinical trial.
Study population: Patients undergoing cardiac surgery with cardiopulmonary bypass, aged 18-90 years old.
Intervention: The intervention group receives once daily 10 mg empagliflozin starting 7 days before surgery to be continued until two days postoperatively. The control group will follow usual perioperative care.
Main study endpoint: The primary outcome of the study is the between group difference of Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentration in plasma measured on day 2 after surgery. Secondary outcomes are the between group differences in kidney injury markers (NGAL, KIM-1), kidney function (eGFR), perioperative glycaemia, the incidence of hypoglycaemia, perioperative ketonemia and the incidence of keto-acidosis.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For study purposes, an additional 28 ml of blood will be drawn. This will be taken from intravenous or intra-arterial catheters that have been inserted for clinical purposes. Adverse events with empagliflozin treatment are rare. Most often reported are genitourinary infections. While these are most common after prolonged use of SGLT2 inhibitors, for this study, subjects will receive empagliflozin for a period of maximum 10 days. Furthermore, there is a small risk of euglycemic ketoacidosis in the perioperative period related to fasting and surgical stress. Therefore, ketone levels will be measured from admission to the hospital until end of the study. In addition, all patient will receive a glucose-insulin infusion during surgery, to suppress ketone body production. Patient might benefit from this intervention by additional intensive monitoring of metabolic and renal function in the perioperative period. Empagliflozin might reduce the risk of perioperative acute kidney injury. In general, this study will provide more insight in the effect of empagliflozin on parameters of renal function and metabolism in the perioperative setting.

We hypothesize that preoperative initiation (7 days before surgery) and perioperative continuation (until day 2 after surgery) of empagliflozin 10 mg daily (10 days total) will reduce the postoperative concentration of NGAL in plasma on postoperative day 2 after cardiac surgery with cardiopulmonary bypass.

For NGAL, KIM-1, plasma ketones and incidence of keto-acidosis:
-On day of surgery:
• Before start of surgery (after placement of arterial line)
• At time of start of cardiopulmonary bypass (+/- 20 min)
• At the end of cardiopulmonary bypass (+/- 20 min)
• At time of transport to ICU (+/- 20 min)
-Postoperatively
• Measured daily, in the morning between 8:00 and 12:00 until postoperative day 2.
For eGFR (creatinine)
• Measured daily, in the morning between 8:00 and 12:00 until postoperative day 4.
For peak and average glucose and incidence of hypoglycaemia:
• any measurement occurring between start of surgery and end of study until postoperative day 4, as part of routine care.

Preoperative initiation (7 days before surgery) and perioperative continuation (until day 2 after surgery) of empagliflozin 10 mg daily (10 days total).