Clinical trial NCT06324461: GLP-1 Receptor Agonist for Reduction of Myocardial Injury After Non-cardiac Surgery
Official title: Glucagon-like Peptide-1 Receptor Agonist for Reduction of Myocardial Injury After Non-Cardiac Surgery
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Myocardial Injury
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Research Grants Council, Hong Kong
First posted: 2024-03-22
Enrollment: 372
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-labelled, superiority randomized controlled trial
Primary purpose: PREVENTION

Brief summary: 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) 7 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 45 years
* Planned elective intermediate to high risk non-cardiac surgery under general anesthesia
* Anticipated to remain hospitalized for at least one night after surgery
* Voluntarily agrees to participate by providing written informed consent

Exclusion Criteria:

* History of symptomatic hypoglycemia within 1 month of recruitment
* History of pancreatitis
* Diabetic retinopathy
* Personal or family history of medullary thyroid carcinoma (MTC)
* Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
* Acute coronary syndrome, decompensated heart failure, cardiogenic shock, or myocarditis within 1 month of recruitment
* Stroke or transient ischemic attack within 1 month of recruitment
* Known severe liver disease (Child-Pugh B or C)
* Stage 5 chronic kidney disease (estimated glomerular filtration rate (eGFR) by Modified Diet in Renal Disease (MDRD) equation \< 15 mL/min)
* Recent use of GLP-1 RA within 1 month of recruitment
* Known allergy or hypersensitivity to GLP-1 RA
* Women of childbearing age who are not taking effective contraception, or who are pregnant or breast-feeding
* Use of Dipeptidyl peptidase-4 inhibitor(DPP4i)

Primary outcomes:
measure: Proportion of patients with MINS
timeFrame: Within 72 hours after surgery
Secondary outcomes:
measure: Proportion of patients with composite of non-fatal MINS, non-fatal stroke or cardiovascular mortality
timeFrame: Within 30 days of randomization
measure: Proportion of patients with MINS who do not fulfill the 4th universal definition of myocardial infarction
timeFrame: Within 30 days of randomization
measure: Proportion of patients with myocardial infarction according to the 4th universal definition of myocardial infarction
timeFrame: Within 30 days of randomization
measure: Proportion of patients with ischemic stroke
timeFrame: Within 30 days of randomization
measure: Proportion of patients with cardiovascular death
timeFrame: Within 30 days of randomization
measure: Proportion of patients with all-cause mortality
timeFrame: Within 30 days of randomization
measure: Mean days alive and out of hospital
timeFrame: Within 30 days of randomization
measure: Clinically important atrial fibrillation
timeFrame: Within 30 days of randomization
measure: Clinically significant hypoglycaemia
timeFrame: Within 30 days of randomization
measure: Mean peak troponin T concentration
timeFrame: During the period of index hospitalization up to 3 days
measure: Mean area under curve of troponin T concentration
timeFrame: During the period of index hospitalization up to 3 days
Other outcomes:
measure: Proportion of patients with coronary revascularization
timeFrame: Within 30 days of randomization
measure: Proportion of patients who require readmission for cardiovascular conditions
timeFrame: Within 30 days of randomization
measure: Proportion of patients with non-fatal cardiac arrest
timeFrame: Within 30 days of randomization
measure: Proportion of patients who require hospitalization for heart failure
timeFrame: Within 30 days of randomization
measure: Proportion of patients who develop pulmonary embolism and/or deep vein thrombosis
timeFrame: Within 30 days of randomization
measure: Proportion of patients with International Society on Thrombosis and Haemostasis (ISTH) major bleeding
timeFrame: Within 30 days of randomization
measure: Proportion of patients with bleeding independently associated with mortality following noncardiac surgery (BIMS)
timeFrame: Within 30 days of randomization
measure: Proportion of patients with infection or sepsis
timeFrame: Within 30 days of randomization
measure: Proportion of patients with acute renal failure fulfilling Kidney Disease Improving Global Outcomes (KDIGO) criteria
timeFrame: Within 30 days of randomization
measure: Proportion of patients with acute renal failure requiring dialysis
timeFrame: Within 30 days of randomization
measure: Proportion of patients requiring amputation
timeFrame: Within 30 days of randomization
measure: Mean length of stay
timeFrame: During index hospitalization up to 3 days
measure: Mean length of intensive care unit stay
timeFrame: During index hospitalization up to 1 week
measure: Mean days alive without need for intensive care support
timeFrame: During index hospitalization up to 3 days
Locations:
city: Hong Kong
country: China
facility: Queen Mary Hospital
state: Hong Kong SAR
Study officials:
affiliation: The University of Hong Kong
name: Chun Ka Wong, Clinical Assistant Professor
role: PRINCIPAL_INVESTIGATOR
References: