Aims: Most cardiac surgery patients, with or without diabetes, develop perioperative hyperglycaemia, for which intravenous insulin is the only therapeutic option. This is labour‐intensive and carries a risk of hypoglycaemia. We hypothesized that preoperative administration of the glucagon‐like peptide‐1 receptor agonist liraglutide reduces the number of patients requiring insulin for glycaemic control during cardiac surgery. Materials and methods: In this randomized, blinded, placebo‐controlled, parallel‐group, balanced (1:1), multicentre randomized, superiority trial, adult patients undergoing cardiac surgery in four Dutch tertiary hospitals were randomized to receive 0.6 mg subcutaneous liraglutide on the evening before surgery and 1.2 mg after induction of anaesthesia or matching placebo. Blood glucose was measured hourly and controlled using an insulin‐bolus algorithm. The primary outcome was insulin administration for blood glucose >8.0 mmol/L in the operating theatre. Research pharmacists used centralized, stratified, variable‐block, randomization software. Patients, care providers and study personnel were blinded to treatment allocation. Results: Between June 2017 and August 2018, 278 patients were randomized to liraglutide (139) or placebo (139). All patients receiving at least one study drug injection were included in the intention‐to‐treat analyses (129 in the liraglutide group, 132 in the placebo group). In the liraglutide group, 55 (43%) patients required additional insulin compared with 80 (61%) in the placebo group and absolute difference 18% (95% confidence interval 5.9–30.0, P = 0.003). Dose and number of insulin injections and mean blood glucose were all significantly lower in the liraglutide group. We observed no difference in the incidence of hypoglycaemia, nausea and vomiting, mortality or postoperative complications. Conclusions: Preoperative liraglutide, compared with placebo, reduces insulin requirements while improving perioperative glycaemic control during cardiac surgery.

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. By lowering blood glucose in a glucose-dependent manner, incretin-based therapies represent a novel and promising intervention to treat hyperglycaemia in hospital settings. We performed a systematic review of the literature for all current applications of incretin-based therapies in the peri-operative and critical care settings. We searched MEDLINE, the Cochrane Library, and Embase databases for all randomised controlled trials using exogenous GLP-1, GLP-1 receptor agonists, exogenous GIP and dipeptidyl peptidase IV inhibitors in the setting of adult peri-operative care or intensive care. We defined no comparator treatment. Outcomes of interest included blood glucose, frequency of hypoglycaemia and insulin administration. Of the 1190 articles identified during the initial literature search, 38 fulfilled criteria for full-text review, and 19 single-centre studies were subsequently included in the qualitative review. Of the 18 studies reporting glycaemic control, improvement was reported in 15, defined as lower glucose concentrations in 12 and as reduced insulin administration (with similar glucose concentrations) in 3. Owing to heterogeneity, meta-analysis was possible only for the outcome of hypoglycaemia. This revealed an incidence of 7.4% in those receiving incretin-based therapies and 6.8% in comparator groups (P = 0.94). In small, single-centre studies, incretin-based therapies lowered blood glucose and reduced insulin administration without increasing the incidence of hypoglycaemia. PROSPERO, CRD42017071926.

Aims/hypothesis: During hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations. Methods: This observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels. Results: Groups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol (p<0.001 and 0.036, respectively). Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels. Conclusions/interpretation: Hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities. Graphical

Sodium-glucose transporter-2 (SGLT2) inhibitors reduced the incidence of acute kidney injury in large cardiovascular outcome trials in patients with chronic heart and kidney failure. Acute kidney injury is a common complication following cardiac surgery. We hypothesized that perioperative SGLT2 inhibition could reduce kidney injury after cardiac surgery, measured with the biomarker neutrophil gelatinase-associated (NGAL). In this open-label phase IV, randomized, parallel-group, pilot study, adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were randomized to receive either an SGLT2 inhibitor, empagliflozin (10 mg; oral) once daily, from three days before surgery until postoperative day two, or standard-of-care. The primary outcome was the between-group difference of serum NGAL on the second postoperative day. Moreover, other biomarkers for acute kidney injury were measured, including serum kidney injury molecule-1 (KIM-1), hypoxia-inducible factor-1 alpha (HIF-1α), and urine NGAL/Creatinine and KIM-1/Creatinine ratios. Additional outcomes included acute kidney injury incidence within the first seven days following cardiac surgery according to Kidney Disease: Improving Global Outcomes criteria and metabolic parameters, including ketone body concentrations and glycemic control. Between 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. There were no significant between-group differences in serum and urine NGAL or KIM-1. However, empagliflozin significantly reduced the incidence of acute kidney injury (20 % vs 66.7 %; absolute difference 46.7 %, 95 % CI, -69.7 - -23.6; P < .001). A significant increase 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. In this pilot study, perioperative SGLT2 inhibition was not associated with lower NGAL levels. We observed that SGLT2 inhibition reduced the incidence of acute kidney injury in this small study population. As the results of this pilot study are hypotheses-generating, further validation is needed in a large-scale, double-blind, placebo-controlled, randomized trial, which is currently ongoing.