The Physiological Effects of GLP-1 on Haemodynamics During Exercise in Patients With Ischaemic Heart Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Change in rate pressure product at 0.1 mV ST-segment depression
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Liraglutide
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
干预措施: Liraglutide (Drug)
Saline Placebo
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
干预措施: Placebo (Other)
结局指标
主要结局
Change in rate pressure product at 0.1 mV ST-segment depression
时间窗: 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
时间窗: Following consecutive exercise treadmill tests performed at Week 2, Week3, Week 5 and Week 6 of a 6-week study protocol
次要结局
- 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)
- Evidence of renal dysfunction(During 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(During 6-week study protocol)
- Evidence of acute pancreatitis(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)