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Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study.

Myat A, Arri S, Bhatt DL, Gersh BJ, Redwood SR, Marber MS - Cardiovasc Diabetol (2015)

Bottom Line: Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists.We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation.The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo.

Methods and design: The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3.

Discussion: The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.

Trial registration: National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001.

No MeSH data available.


Related in: MedlinePlus

The LIONESS Trial study design.
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Fig1: The LIONESS Trial study design.

Mentions: Both investigator and patient will be blinded to the study drug. Patients will be randomised to enter a GLP-1 treatment arm or matched-volume saline placebo arm. Following a 1-week run-in phase with 0.6 mg liraglutide followed by a 1-week course of 1.2 mg liraglutide, patients in the active intervention arm will have their first exercise tolerance test (ETT) at the end of Week 2. Patients will then be up-titrated to high-dose 1.8 mg liraglutide for another week before performing a Week 3 ETT. With a stepwise increase in liraglutide therapy over a 3-week period we hope to observe a dose–response effect on exercise haemodynamics. An initial 1-week run-in phase of once daily 0.6 mg liraglutide should also allow for improved gastrointestinal tolerability. Whilst in the placebo arm, patients 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. Patients will then crossover at this stage so that those in the treatment arm cross to the placebo arm and vice versa (please refer to Figure 1).Figure 1


Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study.

Myat A, Arri S, Bhatt DL, Gersh BJ, Redwood SR, Marber MS - Cardiovasc Diabetol (2015)

The LIONESS Trial study design.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358711&req=5

Fig1: The LIONESS Trial study design.
Mentions: Both investigator and patient will be blinded to the study drug. Patients will be randomised to enter a GLP-1 treatment arm or matched-volume saline placebo arm. Following a 1-week run-in phase with 0.6 mg liraglutide followed by a 1-week course of 1.2 mg liraglutide, patients in the active intervention arm will have their first exercise tolerance test (ETT) at the end of Week 2. Patients will then be up-titrated to high-dose 1.8 mg liraglutide for another week before performing a Week 3 ETT. With a stepwise increase in liraglutide therapy over a 3-week period we hope to observe a dose–response effect on exercise haemodynamics. An initial 1-week run-in phase of once daily 0.6 mg liraglutide should also allow for improved gastrointestinal tolerability. Whilst in the placebo arm, patients 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. Patients will then crossover at this stage so that those in the treatment arm cross to the placebo arm and vice versa (please refer to Figure 1).Figure 1

Bottom Line: Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists.We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation.The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo.

Methods and design: The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3.

Discussion: The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.

Trial registration: National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001.

No MeSH data available.


Related in: MedlinePlus