Liraglutide to Improve corONary Haemodynamics During Exercise streSS

Coronary Heart Disease Clinical Trial

— LIONESS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02315001
• Other study ID #: RJ112/N131
• Secondary ID: FS/11/70/28917
• Status: Completed
• Phase: Phase 2
• First received: November 10, 2014
• Last updated: May 19, 2015
• Start date: January 2014
• Est. completion date: March 2015

Study information

• Verified date: May 2015
• Source: King's College London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics CommitteeUnited Kingdom: National Health ServiceUnited Kingdom: Department of Health
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Men and women aged 18-80

2. Patients with a recent abnormal exercise tolerance test demonstrating >0.1 mV of planar or down-sloping ST-segment depression.

3. Patients with known coronary artery disease and angiographic evidence of a >70% stenosis in a main epicardial artery, with or without coronary stenoses elsewhere.

4. Patients must be able to walk confidently on a treadmill.

5. Patients must have a normal resting electrocardiogram (ECG) in sinus rhythm without bundle branch aberration or other conduction disturbance.

6. Patients must have normal left ventricular function.

Exclusion Criteria:

1. An abnormal resting ECG including atrial fibrillation, bundle branch aberration or other conduction disturbance.

2. Pre-existing left ventricular systolic dysfunction.

3. Pre-existing ischaemic or non-ischaemic cardiomyopathy.

4. Pre-existing valvular heart disease.

5. Inability to safely negotiate an exercise treadmill.

6. Type I diabetes mellitus.

7. Type II diabetes mellitus taking oral or subcutaneous anti diabetic therapy.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor)

Related Conditions & MeSH terms

• Angina, Stable
• Chronic Stable Angina
• Coronary Artery Disease
• Coronary Disease
• Coronary Heart Disease
• Heart Diseases
• Ischaemic Heart Disease
• Ischemia
• Myocardial Ischemia

Intervention

Drug:
• Liraglutide
GLP-1 receptor agonist administered via subcutaneous injection

Other:
• Placebo
Volume-matched normal saline placebo administered via subcutaneous injection

Locations

Country	Name	City	State
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London	Greater London

Sponsors (2)

Lead Sponsor	Collaborator
King's College London	Guy's and St Thomas' NHS Foundation Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

Myat A, Arri S, Bhatt DL, Gersh BJ, Redwood SR, Marber MS. Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study. Cardiovasc Diabetol. 2015 Feb 19;14:27. doi: 10.1186/s12933-015-0193-4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Evidence of hypoglycaemia	Monitored via twice daily home glucose monitoring and once weekly random serum glucose measurements	During 6-week study protocol	Yes
Secondary	Evidence of renal dysfunction	Monitored via once weekly measurement of serum creatinine, electrolytes and estimated glomerular filtration rate	During 6-week study protocol	Yes
Secondary	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	Yes
Secondary	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	No

External Links

•   Trial rationale and protocol