GLP-1 and the heart: clinical and preclinical data
Clinical Data
In February 2004, a pilot study
reported the effect of acute GLP-1 administration in 10 human subjects with LV dysfunction and acute MI following
angioplasty. Native GLP-1 was
administered as a 72-hour infusion at a rate of 1.5 pmol/kg per
minute. Echocardiograms were obtained after reperfusion and after the
The ability of GLP-1 to control blood glucose while minimizing the risk of hypoglycemia, taken together with the putative inotropic and cardioprotective actions of GLP-1, have fostered efforts directed at understanding the potential role of GLP-1 therapy in subjects with established heart disease. A randomized study of conventional therapy vs continuous GLP-1 infusion in 20 human subjects undergoing CABG demonstrated that perioperative GLP-1 infusion beginning 12 hours before CABG and continuing for 48 hours resulted in improved glycemic control, less use of inotropic and vasoactive infusions and fewer arrhythmias in GLP-1-treated patients. See 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 Sep 1; 100(5):824-9. Epub 2007 Jun 14
A pilot study of continuous GLP-1 administration in human subjects with heart failure was reported by Sokos et et al. GLP-1 was administered by continuous subcutaneous infusion in 12 patients with NYHA Class II/IV heart failure for 5 weeks. GLP-1 increased quality of life and left ventricular ejection fraction in this group of diabetic and non-diabetic subjects. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure J Card Fail. 2006 Dec;12(9):694-9. However, a larger study of GLP-1 in heart failure carried out by Amylin Pharmaceuticals did not show a positive benefit.
Importantly, GLP-1 improves peripheral blood flow in short term studies in human subjects with type 2 diabetes Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15. Consistent with clinical findings that GLP-1 therapy may reduce blood pressure, a 3-h infusion of GLP-1 after an iv 9.9-g salt load produced a dose-dependent increase in urinary sodium excretion in healthy subjects whereas in obese men, the GLP-1 infusion significantly increased urinary sodium excretion, decreased urinary H(+) secretion and reduced the glomerular filtration rate. See Glucagon-like Peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004 Jun;89(6):3055-61
GLP-1 and the cardiovascular system
GLP-1 administered intravenously or by ICV injection increases heart rate and blood pressure in rats. See Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats. Am J Physiol. 1994 Mar;266(3 Pt 1):E459-66 and Sustained expression of exendin-4 does not perturb glucose homeostasis, beta-cell mass, or food intake in metallothionein-preproexendin transgenic mice. J Biol Chem. 2000 Nov 3;275(44):34471-7. These effects can be blocked by intravenous or ICV administration of the antagonist exendin(9-39) and bilateral vagotomy blocked the cardiovascular effects of ICV, but not peripherally administered GLP-1 Neural contribution to the effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure in rats. Am J Physiol. 1999 Nov;277(5 Pt 1):E784-91. Clinically significant effects of GLP-1 on heart rate and blood pressure in human studies have not yet been reported.
Nevertheless, infusion of wildtype recombinant GLP-1 into dogs with pacing-induced heart failure produces an improvement in myocardial function, LV stroke volume, cardiac output, increased cardiac insulin sensitivity and decreased LV end-diastolic pressure, heart rate, and systemic vascular resistance. See Recombinant Glucagon-Like Peptide-1 Increases Myocardial Glucose Uptake and Improves Left Ventricular Performance in Conscious Dogs With Pacing-Induced Dilated Cardiomyopathy. Circulation. 2004 Aug 16.
Central nervous system GLP-1R-dependent signals also appear to modulate peripheral blood flow. administration of exendin-4 into the lateral ventricles of mice reduced femoral arterial blood flow in a glucose-dependent manner via mechanisms that involve reactive oxygen species (ROS). See Brain GLP-1 regulates arterial blood flow, heart rate and insulin sensitivity. Diabetes. 2008 Jul 15. [Epub ahead of print]
Cardiovascular biology of GLP-1(9-36)amide
Remarkably, improvements in dog cardiovascular function in a canine model of pacing induced LV dysfunction have also been demonstrated using the truncated peptide GLP-1(9-36)amide, raising the possibility that a second functional receptor for GLP-1(9-36)amide may be critical for the cardiovascular actions of native GLP-1. See 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 Dec;289(6):H2401-8.
Moreover, emerging evidence suggests that the cardiovascular biology of GLP-1receptor agonists and GLP-1-derived peptides is increasingly complex and likely involves multiple distinct receptors and mechanisms. Classical GLP-1R agonists exert cardioprotective actions dependent on the knownGLP-1 receptor. However, GLP-1(9-36)amide also appears to be cardioprotective in the ischemic mouse heart when infused post-ischemia, and these actions are independent of the known GLP-1R. Moreover GLP-1(9-36) also appears to exert vasodilatory actions directly on murine blood vessels, increasing coronoary flow and vasodilation in mesenteric vessels. Furthermore, unexpectedly, even exendin-4 exerts some cardioprotective activity in a GLP-1R-independent manner. Hence, it is important to evaluate the existing GLP-1 cardiovascular literature in the context of understanding that some of the actions attributed to GLP-1 may be due in part to actions of GLP-1(9-36)amide; See 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 May 6;117(18):2340-50.
Cardiovascular biology of GLP-1
Classical GLP-1 receptor signaling also modulates the function and survival of cardiomyocytes. See Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury. Diabetes. 2005 Jan;54(1):146-51 and The Direct Effects of Glucagon-Like Peptide-1 (GLP-1) on Myocardial Contractility and Glucose Uptake in Normal and Post-Ischemic Isolated Rat Hearts. J Pharmacol Exp Ther. 2006 Feb 17; [Epub ahead of print] and Myocardial Ischaemia-reperfusion Injury is Attenuated by Intact Glucagon Like Peptide-1 (GLP-1) in the In Vitro Rat Heart and may Involve the p70s6K Pathway. Cardiovasc Drugs Ther. 2007 May 31; This latter paper suggests that GLP-1 exerts its actions in a p70 S6 kinase-dependent manner and is only cardioprotective if intact and not degraded by DPP-4, suggesting that GLP-1(9-36) amide is not responsible for cardioprotection in this isolated rat heart model of experimental ischemia.
Analysis of direct GLP-1 actions on cardiac muscle cells was studied using cultures of rat cardiac myocytes. Although GLP-1 increased intracellular cAMP in cardiac myocytes, in contrast to the positive inotropic actions of isoproterenol, GLP-1 induced a decrease in contraction amplitude with no change in intracellular calcium transit. Furthermore, both isoproterenol and GLP-1 produced an intracellular acidosis. Hence, these findings demonstrate that coupling of cardiomyocyte GLP-1R signaling to cAMP generation produces distinct downstream signaling events when compared to adrenergic agonists. See Glucagon-Like Peptide-1 Increases cAMP but Fails to Augment Contraction in Adult Rat Cardiac Myocytes. Circ Res. 2001 Aug 31;89(5):445-452.
Even moderate doses of GLP-1 agonists infused at levels not sufficient to lower blood glucose result in activation of central sympathetic neurons and adrenal medullary chromaffin cells that produce catecholamines. Centrally and peripherally administered GLP-1R agonists including native GLP-1 and the lizard peptide exendin-4 dose-dependently increased blood pressure and heart rate in rats. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in AP neurons which express the GLP-1R, as shown in Glucagon-Like Peptide-1-Responsive Catecholamine Neurons in the Area Postrema Link Peripheral Glucagon-Like Peptide-1 with Central Autonomic Control Sites. J Neurosci. 2003 Apr 1;23(7):2939-2946.
These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in the rodent, and are consistent with previous reports demonstrating that GLP-1R systems function as a component of neural networks transducing the CNS response to aversive stimuli. See Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons J. Clin. Invest. 2002;110 43-52
The importance of cholinergic and nicotinic acid receptors for transduction of the central cardiovascular response to GLP-1 was determined in normal rats. The nicotinic receptor antagonist mecamylamine and the muscarinic receptor antagonist atropine prevented the stimulatory effect of GLP-1 on blood pressure whereas only mecamylamine blocked the GLP-1-dependent increase in heart rate. Intraarterial application of a V(1) receptor antagonist blocked the GLP-1 effects on blood pressure. See Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin. Regul Pept. 2004 Apr 15;118(1-2):33-8
GLP-1 may also exert direct effects on the peripheral vasculature and vascular tone, as outlined in Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005 Feb 15;125(1-3):173-7 and Effect of Glucagon-Like Peptide-1(7-36) and Exendin-4 on the Vascular Reactivity in Streptozotocin /Nicotinamide-Induced Diabetic Rats. Pharmacology. 2005 Mar 3;74(3):119-126.
In contrast to data suggesting that acute administration of GLP-1 may increase heart rate and blood pressure in rodents, chronic 14 day treatment of salt-sensitive rats on a high salt diet with recombinant GLP-1 reduced the development of hypertension, proteinuria and improved endothelial function with decreased renal and cardiac damage. The authors postulated that the protective effects of GLP-1 were attributable to increased urine flow and sodium excretion notable for the first 3 days following elevation in sodium intake. See Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003 Jun;21(6):1125-1135.
What
is the cardiac phenotype of mice born without the GLP-1 receptor?
GLP-1R-/- 2-month-old mice exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure and older (5 month old) mice demonstrate increased LV thickness. Although baseline hemodynamic parameters were normal, GLP-1R(-/-) mice displayed impaired LV contractility and diastolic function after insulin administration. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R(-/-) mice. See Cardiac function in mice lacking the glucagon-like peptide-1 receptor. Endocrinology. 2003 Jun;144(6):2242-52
A pilot study of continuous GLP-1 infusion examined the effect of GLP-1 on cardiac function in human subjects with heart failure. A 5 week infusion of GLP-1 significantly improved LV function and short term exercise capacity in both diabetic and non-diabetic subjects with Class II/IV heart failure. See Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006 Dec;12(9):694-9