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

Aung Myat, Satpal Arri, Deepak L Bhatt, Bernard J Gersh, Simon R Redwood, Michael S Marber, Aung Myat, Satpal Arri, Deepak L Bhatt, Bernard J Gersh, Simon R Redwood, Michael S Marber

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.

Figures

Figure 1
Figure 1
The LIONESS Trial study design.

References

    1. Elrick H, Stimmler L, Hlad CJ, Arai Y. Plasma insulin response to oral and intravenous glucose. J Clin Endocrinol Metab. 1964;24:1076–82. doi: 10.1210/jcem-24-10-1076.
    1. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest. 1967;46:1954–62. doi: 10.1172/JCI105685.
    1. Dupre J, Ross S, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973;37:826–8. doi: 10.1210/jcem-37-5-826.
    1. Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987;330:1300–4. doi: 10.1016/S0140-6736(87)91194-9.
    1. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215. doi: 10.1210/er.2011-1052.
    1. Myat A, Redwood S, Gersh B, Yellon D, Marber M. Diabetes, incretin hormones and cardioprotection. Heart. 2014;100:1550–61. doi: 10.1136/heartjnl-2012-303242.
    1. Nauck M, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab. 1993;76:912–7.
    1. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in Type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;2:46–52. doi: 10.1007/BF02427280.
    1. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002;45:1111–9. doi: 10.1007/s00125-002-0878-6.
    1. Elahi D, McAloon-Dyke M, Fukagawa NK, Meneilly GS, Sclater AL, Minaker KL, et al. The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects. Regul Pept. 1994;51:63–74. doi: 10.1016/0167-0115(94)90136-8.
    1. Nauck M, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–7. doi: 10.1172/JCI116186.
    1. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–30. doi: 10.1016/S0140-6736(02)07952-7.
    1. Rachman J, Gribble F, Barrow B, Levy J, Buchanan K, Turner R. Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7–36) amide in patients with NIDDM. Diabetes. 1996;45:1524–30. doi: 10.2337/diab.45.11.1524.
    1. Egan J, Meneilly G, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab. 2002;87:3768–73. doi: 10.1210/jcem.87.8.8743.
    1. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;225:1409–39. doi: 10.1152/physrev.00034.2006.
    1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–31. doi: 10.2337/diab.44.9.1126.
    1. Drucker DJ, Nauck M. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705. doi: 10.1016/S0140-6736(06)69705-5.
    1. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. SAVOR-TIMI 53 Steering committee and investigators. saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26. doi: 10.1056/NEJMoa1307684.
    1. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35. doi: 10.1056/NEJMoa1305889.
    1. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114:1788–803. doi: 10.1161/CIRCRESAHA.114.301958.
    1. Pyke C, Knudsen LB. The glucagon-like peptide-1 receptor–or not? Endocrinology. 2013;154:4–8. doi: 10.1210/en.2012-2124.
    1. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–75. doi: 10.1038/nm.3128.
    1. Richards P, Parker H, Adriaenssens A, Hodgson J, Cork S, Trapp S, et al. Identification and characterisation of glucagon-like peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes. 2014;63:1224–33. doi: 10.2337/db13-1440.
    1. Bose AK, Mm M, Carr RD, Cl B, Yellon DM. Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes. 2005;54:146–51. doi: 10.2337/diabetes.54.1.146.
    1. Poornima I, Brown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP. Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail. 2008;1:153–60. doi: 10.1161/CIRCHEARTFAILURE.108.766402.
    1. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz S-S, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117:2340–50. doi: 10.1161/CIRCULATIONAHA.107.739938.
    1. Sonne DP, Engstrøm T, Treiman M. Protective effects of GLP-1 analogues exendin-4 and GLP-1 (9–36) amide against ischemia-reperfusion injury in rat heart. Regul Pept. 2008;146:243–9. doi: 10.1016/j.regpep.2007.10.001.
    1. Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, et al. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013;127:74–85. doi: 10.1161/CIRCULATIONAHA.112.091215.
    1. Noyan-Ashraf M, Momen M, Ban K, Al-Muktafi S, Zhou Y, Riazi AM, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83. doi: 10.2337/db08-1193.
    1. Timmers L, Henriques JPS, De Kleijn DPV, Devries JH, Kemperman H, Steendijk P, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009;53:501–10. doi: 10.1016/j.jacc.2008.10.033.
    1. Gros R, You X, Baggio L, Golam Kabir M, Sadi A, Mungrue I. Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003;144:2242–52. doi: 10.1210/en.2003-0007.
    1. Kavianipour M, Ehlers MR, Malmberg K, Ronquist G, Ryden L, Wikstrom G, et al. Glucagon-like peptide-1 (7–36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium. Peptides. 2003;24:569–78. doi: 10.1016/S0196-9781(03)00108-6.
    1. Zhao T, Parikh P, Bhashyam S. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317:1106–13. doi: 10.1124/jpet.106.100982.
    1. Nikolaidis L, Doverspike A, Hentosz T. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther. 2005;312:303–8. doi: 10.1124/jpet.104.073890.
    1. Nikolaidis LA, Elahi D, Shen Y-T, Shannon RP. Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005;289:H2401–8. doi: 10.1152/ajpheart.00347.2005.
    1. Ban K, Kim K-H, Cho C-K, Sauvé M, Diamandis EP, Backx PH, et al. Glucagon-like peptide (GLP)-1 (9–36) amide-mediated cytoprotection is blocked by exendin(9–39) yet does not require the known GLP-1 receptor. Endocrinology. 2010;151:1520–31. doi: 10.1210/en.2009-1197.
    1. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962–5. doi: 10.1161/01.CIR.0000120505.91348.58.
    1. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12:694–9. doi: 10.1016/j.cardfail.2006.08.211.
    1. Sokos GG, Bolukoglu H, German J, Hentosz T, Magovern GJ, Maher TD, et al. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am J Cardiol. 2007;100:824–9. doi: 10.1016/j.amjcard.2007.05.022.
    1. Halbirk M, Nørrelund H, Møller N, Holst JJ, Schmitz O, Nielsen R, et al. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. Am J Physiol Heart Circ Physiol. 2010;298:H1096–102. doi: 10.1152/ajpheart.00930.2009.
    1. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging. 2010;3:195–201. doi: 10.1161/CIRCIMAGING.109.899377.
    1. Read PA, Hoole SP, White PA, Khan FZ, O'Sullivan M, West NE, et al. A pilot study to assess whether glucagon-like peptide-1 protects the heart from ischemic dysfunction and attenuates stunning after coronary balloon occlusion in humans. Circ Cardiovasc Interv. 2011;4:266–72. doi: 10.1161/CIRCINTERVENTIONS.110.960476.
    1. Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagon-like peptide-1 in patients with coronary artery disease. Heart. 2012;98:408–13. doi: 10.1136/hrt.2010.219345.
    1. Lønborg J, Vejlstrup N, Kelbæk H, Bøtker HE, Kim WY, Mathiasen AB, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33:1491–9. doi: 10.1093/eurheartj/ehr309.
    1. McCormick LM, Kydd AC, Read PA, Ring LS, Bond SJ, Hoole SP, et al. Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease. Circ Cardiovasc Imaging. 2014;7:274–81. doi: 10.1161/CIRCIMAGING.113.000785.
    1. Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–16. doi: 10.1016/S0140-6736(09)61375-1.
    1. Edwards RJ, Redwood SR, Lambiase PD, Tomset E, Rakhit RD, Marber MS. Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals. Heart. 2002;88:604–10. doi: 10.1136/heart.88.6.604.
    1. Edwards RJ, Redwood SR, Lambiase PD, Marber MS. The effect of an angiotensin-converting enzyme inhibitor and a K+(ATP) channel opener on warm up angina. Eur Heart J. 2005;26:598–606. doi: 10.1093/eurheartj/ehi082.
    1. Lambiase PD, Edwards RJ, Cusack MR, Bucknall CA, Redwood SR, Marber MS. Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment. J Am Coll Cardiol. 2003;41:1174–82. doi: 10.1016/S0735-1097(03)00055-X.
    1. Lockie TPE, Rolandi MC, Guilcher A, Perera D, De Silva K, Williams R, et al. Synergistic adaptations to exercise in the systemic and coronary circulations that underlie the warm-up angina phenomenon. Circulation. 2012;126:2565–74. doi: 10.1161/CIRCULATIONAHA.112.094292.
    1. Williams RP, Manou-Stathopoulou V, Redwood SR, Marber MS. “Warm-up Angina”: harnessing the benefits of exercise and myocardial ischaemia. Heart. 2014;100:106–14. doi: 10.1136/heartjnl-2013-304187.
    1. Saha M, Redwood SR, Marber MS. Exercise training with ischaemia: is warming up the key? Eur Heart J. 2007;28:1543–4. doi: 10.1093/eurheartj/ehm187.
    1. Wellek S, Blettner M. Vom richtigen Umgang mit dem Crossover-Design in klinischen Studien: Teil 18 der Serie zur Bewertung wissenschaftlicher Publikationen. Dtsch Arztebl Int. 2012;109:276–81.

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