Exenatide for Stress Hyperglycemia

Study Overview
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Brief Summary
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Stress hyperglycemia is a common phenomenon in cardiac surgery that concerns diabetic and non diabetic patients. It has been shown that perioperative hyperglycemia is an independent risk factor of postoperative mortality and morbidity. The Leuven et al.'s study suggested that strict glycemic perioperative control using an intensive insulin therapy could reduce mortality and morbidity in surgical intensive care's patients. This study included a majority of cardiac surgery patients. Others studies have suggested that the beneficial effect of insulin-based tight perioperative glycemic control might be hampered by iatrogenic hypoglycemia. Moreover, insulin therapy failed to obtain perioperative glycemic stability in most patients. Exenatide (Byetta ®) is an incretin mimetic, characterized by an anti-hyperglycemic effect that depends on the blood glucose level. We hypothesize that continuous intravenous infusion of exenatide could improve perioperative glycemic control and stability and could reduce the risk of iatrogenic hypoglycemia compared to a conventional insulin therapy during the perioperative period of cardiac surgery.

Detailed Description
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The phase II of the study will assess the safety and the efficacy of a continuous intravenous infusion of exenatide for the management of post operative stress hyperglycemia after planned coronary artery graft bypass (CABG) surgery. A nested cohort study will concern the 24 first patients included in the study (12 patients/group) to assess the impact of a continuous intravenous infusion of exenatide on post operative glycemic variability after planned CABG surgery. The aim of the phase III of the study will compare the efficacy of a continuous intravenous infusion of exenatide to the gold standard treatment, i.e the intravenous infusion of short-acting insulin, for the management of post operative stress hyperglycemia after planned CABG surgery.

Official Title
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Intravenous Exenatide (Byetta®) Versus Insulin for Perioperative Glycemic Control in Cardiac Surgery: the Open-labeled Randomized Phase II/III ExStress Study

Conditions
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Stress Hyperglycemia

Intervention / Treatment
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* Drug: Exenatide
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age over 18. Patient consent. Non insulin requiring type 2 diabetic patients. Non diabetic patients. Planned coronary artery bypass graft (CABG) surgery. ASA (American Society of Anesthesiologists) score 1, 2, or 3. Exclusion Criteria: Pregnancy and breast feeding. Pancreatectomy. Acute pancreatitis. Chronic pancreatitis. Type 1 diabetic patients. Insulin requiring type 2 patients. HbA1c>8% Ketoacidosis. Hyperosmolar coma. Preoperative blood glucose level above 300 mg/dl [21]. Insulin or exenatide contraindication. History of renal transplantation or currently receiving renal dialysis or creatinine clearance below 60 ml/min. Emergency surgery. Planned non CABG cardiac surgery.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide group<br>Exenatide. Exenatide: bolus of 0.05 µg/min infused during the 1st hour of treatment, followed by a continuous infusion of 0.025 µg/min until the end of treatment. The exenatide therapy will begin as soon as a blood glucose level is above 140 mg/dl will be measured. A of exenatide will be intravenously . The treatment will be administrated during the first postoperative 48 hours in the intensive care unit or until intensive care unit discharge if this event occurs earlier. | Drug: Exenatide<br> <br> * Other names: Incretin;|
| Active Comparator: Insulin group<br>Insulin: Humalog (insulin lispro human analog). The insulin therapy will begin as soon as a blood glucose level is above 140 mg/dl will be measured. The dose of insulin intravenously infused will be adapted to blood glucose measurements, following the insulin therapy protocol used in our department. The insulin therapy protocol used in our department and prescribed as the benchmark treatment in the present study has been validated in a previous study. It has been derived from the protocol validated by Goldberg et al. | Drug: Insulin<br> <br> * Other names: Humalog Insulin Lispro Human Analog;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients spending more than 50 % of the time in the glycemic target range (100 to 140 mg/dl) | The percentage of time spent achieving blood glucose control is defined as the ratio between the total time spent achieving blood glucose control and the total time under treatment. Blood glucose measurement will be done hourly. Blood glucose control is considered to be achieved between 2 blood glucose measurements if the first blood glucose value measured belongs to blood glucose target interval, defined as blood glucose level between 100 mg/dl l and 140 mg/dl l. | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycemia | Hypoglycemia is defined as blood glucose level less than 80 mg/dl. | 48 hours | 
| Severe hypoglycemia | Severe hypoglycemia is defined as blood glucose level less than 40 mg/dl. | 48 hours | 
| Number of patients needing rescue to insulin therapy protocol |  | 48 hours | 
| Number of adverse events occuring in the exenatide group | As the safety of exenatide has never been assessed in the perioperative period in cardiac surgery, all adverse events will be reported, in particular: known adverse events (diarrhea, nausea, vomiting) et severe adverse events (pancreatitis, acute renal failure, death, cardiac arrest). | Day 30 | 
| Mortality |  | Day 30 | 
| Postoperative morbidity | Postoperative morbidity is defined as: neurological complications: stroke. renal complication: acute renal failure requiring dialysis. cardiac complication: cardiogenic shock, arrhythmia, myocardial infarct. vasopressive drug support in postoperative intensive care unit. length of postoperative mechanical ventilation. infectious complication: deep sternal infection. | Day 30 | 
| The mean (GluAve) and standard deviation (GluSD) of blood glucose |  | 48 hours | 
| The coefficient of variability (GluCV) of blood glucose level | GluCV = GluSD*100/GluAve | 48 hours | 
| Mean number of blood glucose measured |  | 48 hours | 
| Mean difference between each blood glucose measurement and 120 mg/dl |  | 48 hours | 
| Perioperative cardiac mortality |  | Day 30 | 
| Perioperative non cardiac mortality |  | Day 30 | 
| Length of stay in intensive care unit |  | Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stress Hyperglycemia, Perioperative glycemic control, Cardiac surgery, Coronary artery bypass surgery