Liraglutide to Improve corONary Haemodynamics During Exercise streSS (LIONESS)

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

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.

Study Overview

• Status: Completed
• Conditions: Coronary Heart Disease; Chronic Stable Angina; Ischaemic Heart Disease
• Intervention / Treatment: Drug: Liraglutide; Other: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE17EH
      • Guy's and St Thomas' NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Liraglutide; GLP-1 receptor agonist administered via subcutaneous injection; Other Names: Victoza
Placebo Comparator: 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	Other: Placebo; Volume-matched normal saline placebo administered via subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Guy's and St Thomas' NHS Foundation Trust
• Investigators: Principal Investigator: Michael Marber, PhD FRCP, King's College London; Principal Investigator: Simon Redwood, MD FRCP, King's College London

Publications and helpful links

General Publications

• 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.
• Myat A, Redwood SR, Arri S, Gersh BJ, Bhatt DL, Marber MS. Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS): a double-blind randomised placebo-controlled crossover trial. Diabetol Metab Syndr. 2021 Feb 12;13(1):17. doi: 10.1186/s13098-021-00635-6.

Helpful Links

• Trial rationale and protocol

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: November 10, 2014
• First Submitted That Met QC Criteria: December 9, 2014
• First Posted (Estimate): December 11, 2014

Study Record Updates

• Last Update Posted (Estimate): May 20, 2015
• Last Update Submitted That Met QC Criteria: May 19, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: GLP-1; Liraglutide; Coronary heart disease; Chronic stable angina; Ischaemic heart disease
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Ischemia; Angina, Stable; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: RJ112/N131; FS/11/70/28917 (Other Grant/Funding Number: British Heart Foundation)