Liraglutide to Improve corONary Haemodynamics During Exercise streSS

Study Overview
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Brief Summary
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A single-centre double-blind placebo-controlled crossover randomised controlled trial to determine the physiological basis of glucagon-like peptide-1 receptor activation on exercise haemodynamics, as manifest through specific electrophysiological parameters measured by serial exercise stress testing, in those patients with reversible myocardial ischaemia and obstructive coronary artery disease confirmed by a baseline exercise test and coronary angiography respectively.

Detailed Description
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Glucagon-like peptide-1 (GLP-1), an endogenous incretin hormone, is secreted by the gut in response to enteral nutrition and is responsible primarily for normal glucose homeostasis. There is a defective incretin effect in Type II diabetes mellitus such that meal-stimulated GLP-1 secretion is markedly impaired. However, a continuous infusion of exogenous GLP-1 can result in near normal insulin responses to a glucose load, suggesting preservation of insulinotropic activity. Liraglutide, a synthetic analogue that shares 97% structural homology to native GLP-1, is now a guideline-mandated antidiabetic therapy given as a once-daily subcutaneous injection. Evidence emerging from animal and latterly human studies suggest GLP-1, independent of its effect on glycemic control and weight loss, may protect the heart from myocardial ischaemia/reperfusion injury and could potentially modulate the metabolic and haemodynamic outcomes of patients with coronary artery disease and left ventricular systolic dysfunction. The investigators aim to determine whether chronic GLP-1 receptor occupancy has any effect on exercise haemodynamics in patients with known chronic stable angina, evidence of reversible ischaemia on exercise stress testing and angiographic evidence of obstructive coronary artery disease. Each study participant will be randomised to enter either a GLP-1 treatment arm or volume-matched saline placebo arm. Those randomised to GLP-1 will have a week's run-in phase with 0.6 mg Liraglutide followed by a week's course of 1.2 mg Liraglutide. At the end of Week 2, patients in the treatment arm will have their first exercise tolerance test (ETT). They will then be up-titrated to high dose 1.8 mg Liraglutide for another week before performing a Week 3 ETT. Patients in the placebo arm will have matched volume saline injections for the first two weeks before the Week 2 ETT and then another week of saline injections before the Week 3 ETT. At the end of Week 3 patients will crossover so that those in the GLP-1 treatment arm cross to the placebo arm and vice versa. By incorporating a run-in phase followed by a step-wise increase in Liraglutide therapy over a 3-week period the investigators aim to minimise the occurrence of adverse reactions and also hope to observe a dose-response effect on exercise haemodynamics. The crossover design will allow study participants to effectively act as their own controls.

Official Title
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The Physiological Effects of GLP-1 on Haemodynamics During Exercise in Patients With Ischaemic Heart Disease

Conditions
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Ischaemic Heart Disease, Coronary Heart Disease, Chronic Stable Angina

Intervention / Treatment
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* Drug: Liraglutide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18-80 Patients with a recent abnormal exercise tolerance test demonstrating >0.1 mV of planar or down-sloping ST-segment depression. Patients with known coronary artery disease and angiographic evidence of a >70% stenosis in a main epicardial artery, with or without coronary stenoses elsewhere. Patients must be able to walk confidently on a treadmill. Patients must have a normal resting electrocardiogram (ECG) in sinus rhythm without bundle branch aberration or other conduction disturbance. Patients must have normal left ventricular function. Exclusion Criteria: An abnormal resting ECG including atrial fibrillation, bundle branch aberration or other conduction disturbance. Pre-existing left ventricular systolic dysfunction. Pre-existing ischaemic or non-ischaemic cardiomyopathy. Pre-existing valvular heart disease. Inability to safely negotiate an exercise treadmill. Type I diabetes mellitus. Type II diabetes mellitus taking oral or subcutaneous anti diabetic therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br>Week 1 Run-In Phase = 0.6 mg (0.1 ml) Liraglutide once daily via subcutaneous injection Week 2 Low-Dose Phase = 1.2 mg (0.2 ml) Liraglutide once daily via subcutaneous injection Week 3 High-Dose Phase = 1.8 mg (0.3 ml) Liraglutide once daily via subcutaneous injection | Drug: Liraglutide<br>* GLP-1 receptor agonist administered via subcutaneous injection<br>* Other names: Victoza;|
| Placebo Comparator: Saline Placebo<br>Week 1 Run-In Phase = 0.1 ml normal saline once daily via subcutaneous injection Week 2 Low-Dose Phase = 0.2 ml normal saline once daily via subcutaneous injection Week 3 High-Dose Phase = 0.3 ml normal saline once daily via subcutaneous injection | Other: Placebo<br>* Volume-matched normal saline placebo administered via subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in rate pressure product at 0.1 mV ST-segment depression |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 
| Change in degree of ST-segment depression at peak exercise |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total exercise duration |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 
| Change in time to 0.1 mV ST-segment depression |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 
| Change in recovery time to 0.05 mV ST-segment depression |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 
| Evidence of hypoglycaemia | Monitored via twice daily home glucose monitoring and once weekly random serum glucose measurements | During 6-week study protocol | 
| Evidence of renal dysfunction | Monitored via once weekly measurement of serum creatinine, electrolytes and estimated glomerular filtration rate | During 6-week study protocol | 
| Evidence of acute pancreatitis | Monitored via once weekly measurement of serum amylase along with telephone and once weekly face-to-face interviews | During 6-week study protocol | 
| Change in time to maximum ST-segment depression |  | Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, Liraglutide, Ischaemic heart disease, Coronary heart disease, Chronic stable angina