GLP-1 Receptor Agonist for Reduction of Myocardial Injury After Non-cardiac Surgery

Overview

This is an investigator initiated, multi-center, open-labelled, superiority randomized controlled trial of 372 patients undergoing elective non-cardiac surgery. Recruited patients will be randomized in a 2:1 ratio to receive single subcutaneous dose of Glucagon-like Peptide-1 Receptor Agonist (GLP-1 RAs) 1 to 14 days prior to surgery or receive routine care. Dulaglutide (Trulicity; Eli Lilly, USA) is chosen as GLP-1 Receptor Agonists investigational drug for this study. Apart from peri-operative routine care, all recruited subjects will undergo physical, respiratory and cardiac assessments including electrocardiography and blood check including cardiac enzymes. Myocardial injury, cardiovascular outcomes and safety will be assessed and evaluated for efficacy and safety of this prophylactic measurement for the reduction of myocardial injury after non-cardiac surgery.

Myocardial injury following non-cardiac surgery (MINS) is increasingly recognized as a major cause of peri-operative morbidity and mortality worldwide. MINS is defined as post-operative cardiomyocyte injury that can be detected by high-sensitive troponin assays, which may or may not be associated with symptoms or changes on electrocardiogram (ECG). Globally, it was found that 35.5% patients had MINS with elevated troponin level in the early post-operative period. Post-operative troponin T level strongly correlated with peri-operative mortality. It was demonstrated that elevated troponin T level to 14-20 ng/L after surgery significantly increased 30-day mortality with hazard ratio of 9.11. As the global volume of non-cardiac surgeries continues to increase, there is an urgent need to identify effective strategies to minimize MINS. To date, no pharmacological intervention has been shown to safely reduce MINS. This study will evaluate the effect of pre-operative glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on MINS. GLP-1 is a peptide hormone produced by intestinal epithelial endocrine L-cells that stimulates insulin secretion and inhibits glucagon secretion. GLP-1 RAs have been used to treat both diabetic and non-diabetic conditions. In landmark cardiovascular outcome trials, GLP-1 RAs were shown to reduce major adverse cardiovascular events (MACE) when compared with placebo. GLP-A RAs exert beneficial effects by stabilizing atherosclerotic plaques. Animal studies revealed that a GLP-1 RAs attenuate activation and recruitment of monocytes and macrophages to the arterial wall by suppressing expression of interleukin 6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2), vascular cell adhesion molecule 1 (VCAM-1), and E- selectin (SELE). GLP-1 RAs also suppress vascular smooth muscle cell proliferation and migration via the Cyclic adenosine monophosphate (cAMP) or protein kinase A (PKA) pathway. Another key advantage of using GLP-1 RA in the context of surgery is intra-operative stabilization of glycemic level. It is well established that intra-operative hyperglycemia is associated with increased risk of MINS. Prospective studies have revealed that GLP-1 RA infusion during the peri-operative period resulted in better glycemic control among diabetic and non-diabetic patients without significantly increasing hypoglycemia risk. The "Glucagon-like Peptide-1 Receptor Agonist for Reduction of Myocardial Injury after Non-Cardiac Surgery" (GLUMINS) trial is an investigator initiated, multi-center, open-labelled Randomized Controlled Trial that will determine the effect of pre-operative GLP-1 RAs on MINS. The study hypothesis is that pre-operative GLP-1 RAs will reduce myocardial injury in patients undergoing non-cardiac surgery. Critically needed new knowledge will be generated about the effectiveness of GLP-1 RAs as a peri-operative intervention to reduce MINS, which may fundamentally alter peri-operative management in non-cardiac surgeries.