A therapeutic approach to hyperglycaemia in the setting of acute myocardial infarction: spotlight on glucagon-like peptide 1

Abstract

Patients with acute myocardial infarction (AMI) frequently have abnormalities of glucose metabolism and insulin resistance, both of which are associated with a poor outcome. Glucagon-like peptide 1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties which not only controls glucose levels but also has potential beneficial actions on the ischaemic and failing heart. In this review we highlight the underlying pathophysiological mechanisms for the development of hyperglycaemia in AMI, speculate on the potential relationship between GLP-1 and sphingosine-1-phosphate, and review the literature on the role of GLP-1 as an important approach to treating hyperglycaemia in the setting of AMI.

Introduction

A rise in plasma glucose concentration is often observed in the early hours after the onset of acute myocardial infarction (AMI) both in patients with pre-existing diabetes mellitus and those without [Oswald et al. 1984]. Acute hyperglycaemia and diabetes mellitus are independently associated with adverse outcomes after AMI regardless of the method of revascularization (thrombolysis, percutaneous coronary intervention, or coronary artery bypass graft) [Goode et al. 2009; Lakhdar et al. 1984]. Furthermore, the presence of diabetes is associated with a worse prognosis in patients with heart failure, but only in patients with underlying ischaemic heart disease [Domanski et al. 2003; Goode et al. 2009].

Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted mainly by the enteroendocrine cells of the intestine in response to the presence of nutrients. It facilitates glucose-induced insulin release, and now, analogues of GLP-1 are a new class of drugs used in the management of type 2 diabetes. Emerging research studies suggest that GLP-1 not only control glucose levels but may also exert beneficial cardiovascular effects independent of its glucose-lowering actions [Inzucchi and McGuire, 2008]. In this review we highlight the underlying pathophysiological mechanisms for the development of hyperglycaemia in AMI, speculate on the potential relationship between GLP-1 and sphingosine-1-phosphate (S1P), and review the literature on the role of GLP-1 as an important approach to treating hyperglycaemia in the setting of AMI.

Hyperglycaemia after acute myocardial infarction: frequency and mechanisms

Raised serum glucose is a common feature early after AMI and abnormal glucose tolerance is common among patients with AMI who have no previous diagnosis of diabetes [Norhammar et al. 2002]. Norhammar and colleagues performed oral glucose tolerance tests (OGTTs) in patients without diabetes with AMI at hospital discharge and found that 31% had frank diabetes while a further 35% had impaired glucose tolerance (IGT) [Norhammar et al. 2002]. The Euro Heart Survey on diabetes and the heart reported that OGTTs identified diabetes in 22% and IGT in 36% of 923 patients without diabetes and with acute coronary syndrome [Bartnik et al. 2004].

Several mechanisms have been proposed to account for hyperglycaemia in patients with AMI (Figure 1). First, there may be pre-existing abnormalities in blood glucose metabolism that had previously been undetected. Second, serious illnesses including AMI are accompanied by a generalized stress reaction which includes activation of the hypothalamic–pituitary–adrenal (HPA) axis [Gauna et al. 2005]. As a result, blood glucocorticoids increase, and activation of the sympathetic nervous system results in catecholamine release [Van den Berghe, 2000]. The acute phase of AMI is accompanied by high levels of cortisol, growth hormone and catecholamines [Leor et al. 1993; Opie, 1975]. Increased stress hormones enhance glycogenolysis, gluconeogenesis, proteolysis and lipolysis, all resulting in increased glucose production [Barth et al. 2007; Seematter et al. 2004]. In addition, adrenaline inhibits glucose transport into cells by inhibiting the binding of insulin to its receptor: increased levels of circulating adrenaline can thus result in insulin resistance with hyperinsulinaemia [Gearhart and Parbhoo, 2006; Hunt and Ivy, 2002].

Figure 1.

Mechanisms leading to hyperglycaemia in patients with acute myocardial infarction (AMI). Three main mechanisms seem to underlie the occurrence of hyperglycaemia in patients with AMI: pre-existing abnormalities in blood glucose metabolism, an increased immune response and stimulation of the hypothalamic–pituitary–adrenal (HPA) axis. IL, interleukin; TNF, tumour necrosis factor.

Third, AMI is associated with an inflammatory response and the release of a wide range of cytokines [Frangogiannis et al. 2002]. Some cytokines, such as tumour necrosis factor, activate the HPA axis [Chrousos, 1995] and the activity of the cytokines is also associated with the development of insulin resistance [del Aguila et al. 1999].

Effect of glucagon-like peptide 1

Overview

GLP-1 analogues are a new class of drugs used in the management of type 2 diabetes. GLP-1 is a hormone secreted after oral glucose administration. It stimulates (pro)insulin biosynthesis, which might explain (at least in part) why there is a greater insulin response to an oral glucose load than to an intravenous glucose load. GLP-1 also lowers glucagon concentrations and slows gastric emptying. In addition, it reduces food intake after intra-cerebroventricular administration in animals [Nauck et al. 1997].

These GLP-1 effects are mediated by binding to the GLP-1 receptor, which is a G-coupled receptor linked to adenylate cyclase via a stimulatory G protein and is expressed in pancreatic islet cells and in the kidney, lung, brain, gastrointestinal tract, and heart [Holst, 2007]. The half life of GLP-1 (7-36) in circulation is very brief (1–2 min), as in addition to undergoing renal excretion, it is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV) to generate an NH₂ terminally truncated metabolite GLP-1 (9-36), which does not act at the GLP-1 receptor [Holst, 2007]. Importantly, as an antidiabetic agent, GLP-1 does not cause hypoglycaemia, as both its stimulatory effect on insulin secretion and its inhibitory action on glucagon release are inhibited in the presence of plasma glucose levels at or below fasting levels [Holst, 2007].

The use of GLP-1 as a clinical therapy, however, is hampered by the need to administer it as an infusion because it is rapidly broken down in plasma by DPP-IV. Therefore, as a therapeutic antidiabetic strategy, synthetic analogues of GLP-1 (such as exenatide and liraglutide) that are resistant to the degradative actions of DPP-IV have been developed. In addition, pharmacological inhibitors of DPP-IV that are capable of augmenting endogenous levels of GLP-1, such as sitagliptin and vildagliptin, are in clinical use.

The side effects of GLP-1 are predominantly gastrointestinal. Nausea is a common adverse effect of exenatide but is generally mild to moderate in intensity and wanes with the duration of treatment [Buse et al. 2004; DeFronzo et al. 2005; Kendall et al. 2005; Zinman et al. 2007]. Exenatide may also cause dose-dependent and progressive weight loss [Amori et al. 2007]. There have been 36 postmarketing reports of acute pancreatitis and 78 reported cases of acute renal failure or renal insufficiency in patients taking exenatide [US Food and Drug Administration, 2012; Elashoff et al. 2011]. Therefore, exenatide should not be used in patients with a creatinine clearance below 30 ml/min. In patients with moderate renal impairment (creatinine clearance 30–50 ml/min), monitoring of serum creatinine is warranted when initiating therapy and after the usual dose increase from 5 to 10 µg [US Food and Drug Administration, 2012].

Emerging research studies suggest that GLP-1 not only controls glucose levels but may also exert beneficial cardiovascular effects independent of its glucose-lowering actions [Inzucchi and McGuire, 2008].

Effect on acute myocardial infarction

The GLP-1 receptor is widely expressed in the heart [Wei and Mojsov, 1995]. The GLP-1 receptor is a G-protein–coupled receptor and is a distinct member of the glucagon-secretin receptor super family which has been shown to function by causing intracellular calcium influx in addition to upregulating cyclic adenosine monophosphate (cAMP) [Holz et al. 1995]. Interestingly, cAMP has been demonstrated to protect against apoptosis in several cell types other than myocardial [Hui et al. 2003; Kwon et al. 2004]. However, of specific interest is the fact that GLP-1 has also been shown to promote the activity of phosphoinositide 3 kinase (PI3K) in β cells which has been clearly associated with myocardial protection in the setting of ischaemia–reperfusion injury as well as myocardial preconditioning [Buteau et al. 1999; Hausenloy and Yellon, 2004; Mocanu et al. 2002; Tong et al. 2000]. GLP-1 can directly act on cardiac myocytes and protect them from hypoxia-reoxygenation injury mainly by inhibiting their apoptosis [Xie et al. 2008]. When added to standard therapy, GLP-1 infusion improved regional and global left ventricular function in patients with AMI and severe systolic dysfunction after successful primary angioplasty [Nikolaidis et al. 2004].

GLP-1 (7-36) therapy is capable of limiting AMI reperfusion injury, as evidenced by a reduction in myocardial infarct size in both the isolated and in situ murine heart when GLP-1 (7-36), coadministered with a DPP-IV inhibitor, is given to the heart before a period of sustained ischaemia followed by reperfusion [Bose et al. 2005a]. Dokken and colleagues have recently shown that GLP-1 may decrease myocardial infarct size in rodents, probably through attenuation of neutrophil-mediated reperfusion injury [Dokken et al. 2011]. Consistently, albiglutide, a novel GLP-1 analogue with a long half life, may reduce myocardial infarct size and improved postischaemic cardiac function and energetics following myocardial ischaemia–reperfusion injury [Bao et al. 2011]. In addition, GLP-1 (7-36) is protective against myocardial ischaemia–reperfusion injury when given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model [Bose et al. 2005b]. Furthermore, exenatide administered prior to reperfusion increased myocardial salvage in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention [Lønborg et al. 2011].

The mechanism underlying this cardioprotective effect is independent of any effect on glucose and has been linked to GLP-1 receptor activation and recruitment of intracellular prosurvival signalling pathways as well as the downstream phosphorylation and inhibition of the proapoptotic protein BAD [Bose et al. 2005a, 2005b].

Interestingly, recent studies suggest that GLP-1 (9-36), the metabolite that is generated by DPP-IV, is also capable of increasing myocardial glucose uptake, improving left ventricular contractile function in a canine model of pacing-induced dilated cardiomyopathy, improving postischaemic myocardial injury and left ventricular contractile function, and inducing vaso relaxation through a mechanism that involves nitric oxide [Ban et al. 2008; Nikolaidis et al. 2005].

Ongoing clinical trials with different GLP-1 analogues will provide further important information as to whether GLP-1 may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with AMI and type 2 diabetes [Scholte et al. 2011; Scirica et al. 2011].

Effect on sphingosine-1-phosphate signalling

S1P is a circulating bioactive lipid metabolite which has been shown to promote several cellular responses, including cellular proliferation and migration, smooth muscle contraction, and intracellular calcium mobilization [Egom et al. 2010b]. The concentration of S1P in plasma ranges from 0.2 to 0.9 μM. It is tightly associated with albumin and lipoproteins, particularly high-density lipoprotein. S1P may be involved in ischaemic preconditioning-mediated intracellular signalling processes [Egom et al. 2010b]. The protective effect of ischaemic preconditioning can be mimicked by exogenous administration of S1P [Egom et al. 2010b]. We found that the S1P receptor agonist, FTY720, a new generation of S1P receptor modulator in phase III clinical trials as an immunosuppressant agent for the treatment of autoimmune diseases and in organ transplantation [Budde et al. 2006], can prevent ischaemia–reperfusion damage in isolated heart and sino-atrial (SA) nodes in the rat [Egom et al. 2010a]. We also showed that FTY720 reduces ischaemia-induced ventricular arrhythmias and SA nodal dysfunction via activation of p21-activated kinase, a Ser/Thr kinase downstream of small G proteins, and Akt [Egom et al. 2010a, 2010b].

Stimulation of endothelial differentiation gene (EDG) receptors in islets and insulinoma cell lines with S1P inhibits GLP-1-stimulated cAMP production and thus reduces insulin secretion in a concentration-dependent manner [Laychock et al. 2003]. Both EDG receptors and GLP-1 receptors are subclasses of G-protein-coupled receptors, and there may be some cross talk or nonspecific signalling between these receptors. Ban and colleagues have recently shown that GLP-1 increases functional recovery and cardiomyocyte viability after ischaemia–reperfusion injury of isolated hearts and dilated preconstricted arteries from GLP-1 receptor knockout mice [Ban et al. 2008]. Furthermore, GLP-1 (9-36), a by product of GLP-1 metabolism, gives protection against ischaemia–reperfusion injury and induces vasodilation via a mechanism that does not require a functional GLP-1 receptor [Ban et al. 2008]. It is therefore possible that GLP-1 analogues compete for the same receptor as S1P and that their cardiovascular protective effects may be mediated via increased S1P signalling.

Conclusions

The ability of GLP-1 to confer cardioprotection, probably via a mechanism that involves S1P signalling, makes it a suitable candidate for the treatment of hyperglycaemia in patients with AMI as not only does it combat hyperglycaemia but it also appears to improve the cardiovascular outcomes in this clinical setting.

Clearly, further experimental and clinical studies are needed to determine whether synthetic GLP-1 analogues and DPP-IV inhibitors are able to reproduce their direct cardioprotective effect in humans.