Glucagon-like peptide-1-based therapies and cardiovascular

review

article

Diabetes, Obesity and Metabolism 13: 302–312, 2011.© 2011 Blackwell Publishing Ltdreview article

Glucagon-like peptide-1-based therapies and cardiovasculardisease: looking beyond glycaemic controlP. Anagnostis1, V. G. Athyros2, F. Adamidou1, A. Panagiotou1, M. Kita1, A. Karagiannis2

& D. P. Mikhailidis3

1Endocrinology Clinic, Hippokration Hospital, Thessaloniki, Greece2Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece3Department of Clinical Biochemistry (Vascular Prevention Clinic), Royal Free Hospital Campus, University College London Medical School, University College London (UCL),London, UK

Type 2 diabetes mellitus is a well-established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developedrecently based on the incretin phenomenon, such as the degradation-resistant incretin mimetic exenatide and the glucagon-like peptide-1(GLP-1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increasethe circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by aglucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actionsare mediated through GLP-1 receptors (GLP-1Rs), although GLP-1R-independent pathways have been reported. Except for the pancreatic islets,GLP-1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature,suggesting a pleiotropic activity of GLP-1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP-1and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growinglines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared withplacebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether theseagents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the roleof GLP-1 on the cardiovascular system and addresses the impact of GLP-1-based therapies on CVD outcomes.Keywords: adipose tissue, antidiabetic drug, cardiovascular disease, exenatide, GLP-1, incretins, lipid-lowering therapy, liraglutide

Date submitted 26 September 2010; date of first decision 27 October 2010; date of final acceptance 11 November 2010

IntroductionType 2 diabetes mellitus (T2DM) is a chronic disease character-ized by insulin resistance and progressive decline in pancreaticβ-cell function [1]. It has long been recognized that orallyadministered glucose is a stronger insulinotropic stimulus thanintravenous glucose, suggesting a modulation of plasma glucoseby the gastrointestinal system [2]. The mediators of this phe-nomenon are gut-derived hormones, termed incretins, whichare released in response to ingested nutrients, mainly glucose,and stimulate insulin secretion by β cells of the pancreas [3].The incretin effect seems to be significantly impaired in T2DMdue to a reduced secretion of these hormones, acceleratedmetabolism or defective responsiveness to their action [4].

The main members of the incretin family are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP). GLP-1 derives from the L cells of the distalintestine, while GIP is released from the K cells of the proximalintestine. They both stimulate insulin secretion by binding with

Correspondence to: Dr. Panagiotis Anagnostis, Endocrinology Clinic, Hippokration Hospital,49 Konstantinoupoleos Str, Thessaloniki 54 642, Greece.E-mail: [email protected]

specific receptors on β-pancreatic cells [3,5]. GIP and GLP-1seem to be responsible for about 50% of postprandial insulinsecretion [3]. Furthermore, GLP-1 has been shown to stimu-late proliferation and neogenesis of β cells and to inhibit theirapoptosis [3,5]. GLP-1 receptors (GLP-1Rs) are also present onα-pancreatic cells, whereas GIP receptors are expressed mainlyon β cells. GLP-1 suppresses glucagon secretion by α cells,while GIP stimulates it [3,6]. Apart from the pancreatic islets,GLP-1Rs are present in several other tissues including central(hypothalamus) and peripheral nervous systems, gastrointesti-nal tract, lung and heart [3,5,7]. As a result, GLP-1 exertsfurther beneficial actions on glucose metabolism by mediatingsatiety at the hypothalamic level leading to reduced food intakeand weight loss, and by delaying stomach emptying throughthe vagus nerve [3,5,7].

GLP-1 derives from the same gene that encodes glucagon,and is a product of the catalytic action of the protein convertasePC1/3 on proglucagon in the enteroendocrine cells [8]. In α-pancreatic cells, proglucagon is cleaved to glucagon via proteinconvertase PC2. However, under certain conditions, islet α cellsdo express PC1/3 and liberate GLP-1 from proglucagon [9].The active form of GLP-1 is GLP-1(7-36) [3,9]. GLP-1 is rapidlydegraded by the enzyme dipeptidyl dipeptidase-4 (DPP-4) to

DIABETES, OBESITY AND METABOLISM review articleinactive GLP-1(9-36), leading to the short circulating half-lifetime for GLP-1 of 2 min. The kidneys also play a role in theclearance of GLP-1 from the circulation [3,9,10].

The recognition and better understanding of the physiol-ogy and pathophysiology of the incretin phenomenon has ledto the development of incretin-based therapeutic approachesto T2DM. These include the degradation-resistant GLP-1Ragonists and the inhibitors of DPP-4 activity [9]. There arecurrently two GLP-1R agonists that have been approved by theFood and Drugs Administration (FDA) and used clinically todate: exenatide and liraglutide. Exenatide is the synthetic formof exendin-4, an incretin mimetic that is present in the salivaof the Gila monster (Heloderma suspectum) [11]. Exenatidedisplays 53% sequence homology to mammalian GLP-1 andis resistant to DPP-4 action, due to the presence of glycine asthe second amino acid, resulting in a longer circulating half-life time (2.4 h) [12,13]. Experimental and clinical trials haveshown that exenatide exerts many of the glucoregulatory effectsof GLP-1, such as enhancement of glucose-dependent insulinrelease, inhibition of glucagon secretion and reduction of foodintake and satiety. It is administered subcutaneously and hasbeen associated with reductions in fasting and postprandial glu-cose concentrations, and haemoglobin A1c (HbA1c) (1–2% or11–22 mmol/mol), combined with weight loss [12,13]. Recentdata also suggest more beneficial effects of the long-actingrelease form of exenatide at a dose 2 mg once weekly in termsof glucose regulation with the same weight reduction comparedwith exenatide 10 μg BID [14] (Table 1).

Liraglutide has recently been approved for the treatmentof T2DM, expresses 97% homology to natural GLP-1 and itsresistance to degradation by DPP-4 is achieved through itsbinding to serum albumin, which prolongs its half-life timeto 12 h. It is administered subcutaneously once daily at adose of 0.6, 1.2 or 1.8 mg [9,12,15]. GLP-1R agonists can beadministered either as a monotherapy or adjuvant to met-formin, sulphonylureas or thiazolidinediones, when optimalglycaemic control is not achieved with these agents [16]. OtherGLP-1R agonists in development are albiglutide, taspoglutide(Ro1583), AVA0010, CJC-1134-PC, NN9535, LY2189265 andLY2428757 [12] (Table 1).

The DPP-4 inhibitors, including vildagliptin, sitagliptin,saxagliptin and the novel alogliptin, linagliptin and duto-gliptin, suppress the DPP-4 activity by 80% and cause atwofold increase in circulating bioactive GLP-1 and GIP levelsin humans [9,12,15,17,18]. They reduce fasting and postpran-dial plasma glucose, have neutral effect on weight and can beadministered either as monotherapy or in combination withother antidiabetic drugs. The benefit of DPP-4 inhibitors is theirease of administration, as they are taken orally, whereas cur-rently available GLP-1R agonists require injection [9,15,17,18](Table 1).

The present review considers the pleiotropic actions of GLP-1 on the cardiovascular system and the impact of GLP-1 agonistadministration on cardiovascular risk factors and outcomes.

GLP-1 and MyocardiumThe beneficial effect of glucose control on cardiovascular out-comes has long been shown by large randomized-controlled

studies, although mainly with regard to microvascular com-plications. In particular, the United Kingdom ProspectiveDiabetes Study (UKPDS) showed a 16% risk reductionfor myocardial infarction (MI) by intensive glucose controlin patients with T2DM (although of marginal significance,p = 0.052) [19], which remained significant (p = 0.01) inthe 10-year poststudy monitoring period [20]. In a similarway, two recent studies, the Action to Control CardiovascularRisk in Diabetes (ACCORD) and the Action in Diabetes andVascular Disease: Preterax and Diamicron Modified ReleaseControlled Evaluation (ADVANCE) evaluated the potentialbenefits of intensive glucose control [HbA1c targets ≤6% (or42 mmol/mol) and ≤6.5% (or 48 mmol/mol), respectively] oncardiovascular disease (CVD). In the ACCORD study, non-fatal MI occurred less often in the intensive glucose controlgroup, although the study was terminated early due to highermortality rates in this group of patients [21]. On the other hand,the ADVANCE trial showed a small but significant reductionin the incidence of both macro- and microvascular eventswith intensive glucose lowering [hazard ratio (HR), 0.90; 95%confidence interval (CI), 0.82–0.98; p = 0.01], mainly due toimprovement of nephropathy [22]. These studies indicated theimportance of the early intervention by achieving low glu-cose targets in patients with lower baseline HbA1c, no priorhistory of coronary artery disease (CAD) and shorter historyof diabetes. Moreover, in patients with type 1 DM strongerassociations between glucose control and reduction in the rateof CVD events (42%, p = 0.02) were shown in the DiabetesControl and Complications Trial (DCCT), followed-up fora mean 17-year period in the observational Epidemiology ofDiabetes Interventions and Complications (EDIC) study [23].

GLP-1R agonists affect not only fasting but also postprandialhyperglycaemia [12,13]. The effect of GLP-1 on postprandialblood glucose is mediated through its inhibition of gastricemptying and concomitant glucose absorption and by post-prandial insulin response [24]. Postprandial hyperglycaemiahas been strongly associated with CVD events and, in addi-tion, it is regarded as a more important CVD risk factorthan fasting glucose levels [25,26]. Many mechanisms for thisrelationship have been proposed, such as increased oxidativestress, abnormal vascular reactivity, hypercoagulability andendothelial dysfunction [27].

Cardioprotective Effects of GLP-1

Data From Animal Studies. Apart from this indirect effect ofGLP-1 on CVD outcomes through achievement of euglycaemia,accumulating evidence from both experimental and clinicalstudies suggests a direct influence on myocardium as well. Asmentioned earlier, GLP-1Rs have been detected in the rodentand human heart, as well as in regions of the brain involved inautonomic function, and, therefore, central or peripheral GLP-1R signalling may transduce direct and indirect cardiovasculareffects of circulating GLP-1 [28,29]. All these GLP-1Rs indifferent tissues have similar if not identical ligand-bindingcapacity and their sequence seems to be homologous to thesequences of the family of G-protein receptors for severalendocrine peptides such as glucagon, secretin, calcitonin,

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review article DIABETES, OBESITY AND METABOLISM

Table 1. Incretin-based therapies currently available or in development.

Compound Current status Structure Dosage

Exenatide Available 53% Sequence homology to mammalianGLP-1, glycine as a second amino acid

Twice daily, at doses of 5 or 10 μgLong-acting release form (onceweekly, at a dose of 2 mg)

Liraglutide Available 97% Sequence homology to humanGLP-1, with a single substitution ofarginine for lysine in position 34

Once daily at a dose of 0.6, 1.2 or1.8 mg

Albiglutide In development Two tandem-linked copies of a modifiedhuman

GLP-1 sequence within the large humanserum albumin

Molecule

30–50 mg once weekly

Taspoglutide (Ro1583) In development GLP-1-based molecule that containsaminoisobutyric acid substitutionsat positions 8 and 35

20–30 mg once weekly

AVA0010 In development Modified exendin-4 molecule withadditional lysine residues at thecarboxy terminal

5–30 μg once or twice daily

CJC-1134-PC In development Recombinant human serum albumin-exendin-4-conjugated protein

1.5–3 mg once or twice weekly

NN9535 In development GLP-1 analogue 0.1–1.6 mg once weeklyLY2189265 In development GLP-1 analogue 0.25–3 mg once weeklyLY2428757 In development Pegylated

GLP-1 molecule0.5–17.6 mg once weekly

Sitagliptin Available DPP-4 inhibitor 25–100 mg once dailyVildagliptin Available DPP-4 inhibitor 50 mg twice dailySaxagliptin Available DPP-4 inhibitor 5–10 mg once dailyAlogliptin In development DPP-4 inhibitor 12.5–25 mg once dailyLinagliptin In development DPP-4 inhibitor 2.5–5 mg once dailyDutogliptin In development DPP-4 inhibitor 200–400 mg once daily

DPP-4, dipeptidyl dipeptidase-4; GLP-1, glucagon-like peptide type-1.

growth hormone-releasing hormone (GHRH), parathyroidhormone and vasoactive intestinal peptide (VIP) [29].

In experimental rat studies, GLP-1 infusions resulted inincreased heart rate and blood pressure (BP). This inotropicand chronotropic effect is mediated through Fos-signallingin several autonomic control sites in the brain regions andin the adrenal medulla [30,31]. However, other investigatorsfailed to confirm such haemodynamic effects in pigs [32],while others reported negative inotropic effects of GLP-1 onrat cardiomyocytes in vitro [33]. On the other hand, it hasbeen shown that mice with genetic deletion of GLP-1R displayreduced heart rate, elevated left ventricular (LV) end-diastolicpressure and impaired LV contractility and diastolic func-tion after insulin administration, indicating a direct role ofGLP-1 on the myocardium [34]. Accordingly, 48-h infusion ofrecombinant GLP-1 (rGLP-1) in dogs with advanced dilatedcardiomyopathy led to significant improvements in LV func-tion (increased stroke volume and cardiac output and decreasedLV end-diastolic pressure) and systemic vascular resistance.This amelioration in LV dysfunction was associated withan increased insulin-independent myocardial glucose uptake,independent of the insulinotropic effects of GLP-1, as wellas decreased plasma norepinephrine and glucagon levels [35].The different haemodynamic effects of GLP-1 observed in thesestudies may be partly because of the differences in dose, methodof delivery or species.

Further animal studies showed additional benefits of GLP-1on myocardial metabolism in ischaemic conditions. In an open-chest porcine heart model, the infusion of rGLP-1 decreasedpyruvate and lactate concentrations both in normoxic condi-tions and during ischaemia and reperfusion. However, it did notsignificantly affect the extent of tissue necrosis [36]. In an in vivorabbit model of myocardial ischaemia/reperfusion, the GLP-1analogue fused to non-glycosylated human transferrin (GLP-1-Tf) limited myocardial loss, either given prior to myocardialischaemia or at the onset of reperfusion [37]. The results ofthis study suggest a cardioprotective effect of GLP-1 perhapsdue to antiapoptotic properties. Indeed, GLP-1 limits apoptosisin both β cells and myocytes via activation of cyclic adeno-sine monophosphate (cAMP) and phosphoinositide 3-kinase(PI3-K) by binding with GLP-1Rs [38,39]. PI3-K activationhas been associated with myocardial protection in the settingof ischaemic/reperfusion injury [40] and myocardial precon-ditioning [41]. The lack of GLP-1 effect on infarct size that wasobserved in the former study [36] may be attributed to the factthat the investigators did not employ an inhibitor of DPP-4,as GLP-1-Tf has a much longer half-life (27 h in rabbits) thannatural GLP-1 [37]. Indeed, the conjunction of GLP-1 withvaline pyrrolidide, a potent inhibitor of DPP-4, added beforemyocardial ischaemia in rats, reduced MI size both in vitroand in vivo [39]. Furthermore, 24-h continuous i.v. infu-sion of GLP-1 after coronary artery occlusion and subsequent

304 Anagnostis et al. Volume 13 No. 4 April 2011

DIABETES, OBESITY AND METABOLISM review articlereperfusion attenuated postischaemic regional contractile dys-function in normal conscious dogs [42]. GLP-1 seems also toreduce infarct size in rats, when given either prior to ischaemia(as a preconditioning mimetic) or directly at reperfusion [43].

In terms of pharmacological intervention, both GLP-1Ragonists and DPP-4 inhibitors have shown to exert cardiopro-tective effects on myocardial survival after MI in animal studies.Specifically, exenatide has shown strong infarct-limiting actionand improved systolic and diastolic cardiac functions afterischaemia–reperfusion injury in rat and porcine heart mod-els [44–47]. Furthermore, intraperitoneal administration ofliraglutide in mice before coronary artery occlusion reducedinfarct size and cardiac rupture and improved cardiac out-put [48]. However, others did not confirm these findings forliraglutide in a porcine ischemia–reperfusion model. In thisstudy, liraglutide was injected subcutaneously (as in humans)before ligation of the left anterior descending artery. Com-pared with controls, liraglutide had no effect on infarct sizenor on cardiac output and, in addition, the heart rate wassignificantly higher in liraglutide-treated pigs [49]. These dif-ferences may be attributed to the dosing regimen, the differentanalogue, the timing of treatment and the species to whichit was administrated. Larger animal models such as pigs areprobably more predictive of results in humans [50]. As far asDPP-4 inhibitors are concerned, sitagliptin seemed to improvefunctional recovery from ischaemia–reperfusion in mice andpresented similar cardioprotection with genetic deletion ofDPP-4 [51]. Sitagliptin has also been associated with a reduc-tion in infarct size in these experimental models [52].

Data From Human Studies. All these promising data have alsobeen reproduced in human studies. In particular, in a pilot studyof six patients with diabetes and New York Heart Association(NYHA) class II–III congestive heart failure of ischaemicaetiology, subcutaneous infusion of 3–4 pmol/kg/min of rGLP-1 for 72 h showed a trend towards improvement of systolic anddiastolic cardiac functions at rest and during exercise [53]. Inanother study of 12 patients with (NYHA) class III/IV heartfailure, a 5-week infusion of rGLP-1 (2.5 pmol/kg/min) addedto standard therapy improved variables of LV function, suchas ejection fraction, maximum myocardial ventilation oxygenconsumption and 6-min walk test, as well as quality of life [54].Similarly, i.v. infusion (1.5 pmol/kg/min) of rGLP-1 for 72 hin 11 subjects with LV dysfunction after MI and angioplastyled to reduced hospital stay and improved global and regionalLV wall motion scores. These favourable outcomes remaineddetectable even several weeks after hospital discharge [55] andwere noticed in patients with or without diabetes, indicatingthat GLP-1 may act on the cardiovascular system independentlyof glycaemic control [54,55]. In all these studies rGLP-1 waswell tolerated [53–55].

Similar benefits in terms of myocardial function were noticedin patients receiving GLP-1 (1.5 pmol/kg/min) before and aftercoronary artery bypass grafting (CABG). Compared with thecontrol group, they needed fewer inotropic and vasoactiveinfusions postoperatively to achieve the same haemodynamicresult and presented arrhythmias less frequently [56]. How-ever, these favourable outcomes were not confirmed in arecent study of 20 patients without diabetes and with NYHA

class II–III heart failure of ischaemic aetiology receiving 48-hrGLP-1 (0.7 pmol/kg/min). Despite the absence of major car-diovascular effects, minor increases in heart rate and diastolicBP during GLP-1 infusion were noticed [57]. In a recent largeretrospective study, exenatide twice daily was compared withother glucose-lowering agents in terms of their impact on CVDevents. Despite the higher rates of CAD, obesity, hyperlipi-daemia, hypertension and/or other comorbidities at baseline,exenatide-treated patients were less likely to have a CVDevent than non-exenatide-treated ones (HR: 0.81, 95% CI:0.68–0.95; p = 0.01). Furthermore, exenatide-treated patientsshowed lower rates of CVD-related hospitalization (HR: 0.88,95% CI: 0.79–0.98; p = 0.02) and all-cause hospitalization(HR: 0.94, 95% CI: 0.91–0.97; p < 0.001) than those nothaving received exenatide [58].

Emerging data also indicate a cardioprotective role of DPP-4inhibitors in humans. In particular, sitagliptin administrationat a single dose of 100 mg in patients with CAD and pre-served LV function enhanced LV response to stress, attenuatedpostischaemic stunning and improved global and regional LVperformance compared with placebo [59]. Encouraging resultshave also been published recently from an interim analysis ofa phase III randomized placebo-controlled trial regarding thegranulocyte colony-stimulating factor (G-CSF)-based stem cellmobilization in combination with sitagliptin in patients afteracute MI. During the first 6 weeks of follow-up, sitagliptin alongwith G-CSF seems to be quite safe and effective for myocardialregeneration and may constitute a new therapeutic option inthe future [60].

Proposed Mechanisms

The exact mechanisms underlying this cardioprotective effectof GLP-1 have not been fully elucidated. First of all, GLP-1increases myocardial insulin sensitivity [35], as well as myocar-dial glucose uptake independently of plasma insulin levels [61].Moreover, the survival of cardiac myocytes is mediated byinhibition of apoptosis via cAMP and PI3-K pathways, afterbinding with GLP-1Rs [38,39]. The next mediator is Akt,a serine-threonine kinase, the activation of which has beenshown to attenuate cardiomyocyte death, to restore regionalwall thickening after myocardial ischaemia and to improvesurvival of preserved cardiomyocytes [62]. Furthermore, theactivation of the antioxidant gene, heme oxygenase-1 (HO-1),through GLP-1R [63] reduces fibrosis and LV remodelling andrestores LV function after MI [64]. HO-1 acts via inductionof nuclear factor-E2-related factor (Nrf)2 gene expression andnuclear translocation and subsequent stimulation of Akt [65].Other cardioprotective mediators are glycogen synthase kinase(GSK)-3β, Bcl-2 family proteins [66] and PPARs-β and-δ [67].

Liraglutide has been shown to enhance the activity of Aktand to suppress GSK-3β, an Akt substrate. It may also increasethe levels of PPAR-β/δ and Nrf2 in the mouse heart [48].Furthermore, in this animal model, liraglutide induced mRNAand protein levels of HO-1 and reduced cleaved caspase 3 [48],a type of aspartate-specific cysteine protease, the activation ofwhich is also associated with the induction of cardiac cell apop-tosis [68]. Exenatide seems also to use the same pathways in



Table 2. Proposed pathogenic mechanisms for glucagon-like peptide(GLP)-1 cardioprotection.

Pathogenic mechanisms

Achievement of fasting and postprandial euglycaemiaIncreased myocardial glucose uptakeActivation of cAMP and concomitant PIK-3 and PKAantiapoptotic pathwaysActivation of AktActivation of antioxidant gene HO-1Nrf2 gene expression (through HO-1)Activation of PPAR-β and -δSuppression of GSK-3β

Inhibition of caspase-3GLP-1R-independent pathway role of GLP-1(9-39)Beneficial effects on endothelium

Increased activity of NO.NO-independent vasodilation through GLP-1Inhibition of monocyte/macrophage accumulationAnti-inflammatory effectsInhibition of atherosclerosis

cAMP, cyclic adenosine monophosphate; GLP-1R, GLP-1 receptor; GSK,glycogen synthase kinase; HO-1, heme oxygenase-1; NO, nitric oxide; Nrf2,nuclear factor-E2-related factor; PI3-K, phosphoinositide 3-kinase; PKA,protein kinase A; PPAR, peroxisome proliferator-activated receptor.

order to exert its cardioprotective action. Specifically, exenatidetreatment increases myocardial phosphorylated Akt and Bcl-2expression levels and inhibits the expression of active caspase3 [44]. In terms of DPP-4 cardioprotective pathways, sitagliptinseems to reduce infract size in ischaemia–reperfusion animalmodels via cAMP-dependent activation of protein kinase A(PKA) [52] (Table 2).

Remarkably, these effects of GLP-1 were not shown inanimals with genetic deletion of GLP -1R, a fact that incombination with the increased cAMP and reduced apop-tosis in cardiomyocyte cultures indicates a GLP-1R-dependentaction [46]. Nevertheless, GLP-1 action is also mediatedthrough GLP-1R-independent pathways. In particular, as men-tioned earlier, under the influence of DPP-4, GLP-1(7-36)amide is degraded to the inactive N-terminally truncatedmetabolite GLP-1(9-36) amide, which does not interact withthe known GLP-1R [3,69]. Data from isolated mouse heartmodels show that GLP-1(9-36) exerts a vasodilatory effectthrough a GLP-1R-independent mechanism via the formationof cyclic guanosine monophosphate (cGMP) by nitric oxide(NO) which, in turn, is produced under the action of nitricoxide synthase (NOS) [70]. In this study, native GLP-1, as wellas the synthetic analogue exendin-4 [which is DPP-4 resis-tant and therefore cannot be metabolized to GLP-1(9-36)],improved LV functional recovery after ischaemia–reperfusioninjury. However, for animals lacking GLP-1Rs, this action wasevident only for GLP-1 and not for exendin-4 [70]. Moreover,GLP-1 and not GLP-1(9-36) displayed a direct inotropic actionvia GLP-1R in the mouse heart and vasculature [70]. TheGLP-1R-independent role of GLP-1(9-36) for the cardiovascu-lar system was further indicated from a study of consciousdogs with dilated cardiomyopathy, in which infusions of

GLP-1(9-36) improved LV function and increased myocar-dial glucose uptake [71]. Noticeably, another experimental ratmodel evaluating the effects of GLP-1(7-36) on the cardiovascu-lar system and elucidating the role of GLP-1(9-36) showed thatGLP-1(7-36) infusion was characterized by regional haemody-namic effects including tachycardia, hypertension, renal andmesenteric vasoconstriction, whereas GLP-1(9-36) did notdisplay any cardiovascular actions [72].

GLP-1 and Atherosclerosis (Vasculature,Endothelium, Inflammation)It is well documented that diabetes is associated with endothelialdysfunction [73]. Emerging lines of evidence show an addi-tional benefit of GLP-1 on the endothelium. Indeed, exceptfor cardiomyocytes, GLP-1R expression has been detectedon endothelial and vascular smooth muscle cells (SMCs),as well as on macrophages and monocytes [70,74]. Previ-ous animal studies have shown that GLP-1 can induce anendothelial-dependent relaxation of pulmonary artery vesselrings [75,76], an effect that is NO dependent [76]. NO is awell-known vasodilatory endothelium-derived factor [77]. Ofnote, GLP-1(9-36) appeared to improve the survival of humanaortic endothelial cells after ischaemia–reperfusion [69]. Theseactions were also exerted through the NOS pathway [68]. Nev-ertheless, some investigators observed a vasodilatory effect ofGLP-1 independently of NO, indicating clearly a direct actionon vascular SMC via its GLP-1R [78] (Table 3).

Another pathogenic link between diabetes and atheroscle-rosis is the increased formation of advanced glycation-endproducts (AGEs). AGEs and their receptors play a key rolein the vascular damage in patients with diabetes [79]. On theother hand, GLP-1 may have an impact on this process asit has been shown to protect from the deleterious effects ofAGEs on human umbilical vein endothelial cells, through theinhibition of AGE receptor gene expression on these cells [80].Remarkably, in T2DM patients with CAD, rGLP-1 infusions

Table 3. Glucagon-like peptide (GLP)-1 and atherosclerosis.

Related tissues Proposed mechanisms

Endothelium Expression of GLP-1 receptorsNO-dependent actionUpregulation of NOSInhibition of AGE receptor gene

expressionInhibition of expression of TNF-α,

VCAM-1 and PAI-1Vascular smooth muscle cells Expression of GLP-1 receptors

Increased flow-mediated vasodilationMacrophages Expression of GLP-1 receptors

Inhibition of macrophage accumulationthrough cAMP/PKA pathways

Monocytes Expression of GLP-1 receptors

AGE, advanced glycation-end product; cAMP, cyclic adenosine monophos-phate; NO, nitric oxide; NOS, nitric oxide synthase; PAI-1, plasminogenactivator inhibitor type-1; PKA, protein kinase A; TNF-α, tumour necrosisfactor-α; VCAM-1, vascular cell adhesion molecule-1.


DIABETES, OBESITY AND METABOLISM review article(at a dose of 2 pmol/kg/min) significantly increased flow-mediated vasodilation (FMD) in the brachial artery comparedwith placebo [81]. FMD highly correlates with endothelialdysfunction in the coronary circulation [82] and is also con-sidered to be NO mediated [83]. Furthermore, GLP-1 infusionenhanced acetylcholine-mediated vasodilation in non-diabetic,normotensive non-smokers, an effect that was abolished afterco-administration of glyburide (but not glimepiride). Thesedata indicate also a potential modulatory role of sulphony-lurea receptor subunit on GLP-1Rs in the endothelial cellsand a selectivity of KATP channel inhibition amongst differentsulphonylurea agents [84].

There are also data about the impact of GLP-1R agonists andDPP-4 inhibitors on endothelial function and CVD biomarkers.Exendin-4 has been shown to prevent homocysteinaemia-induced endothelial dysfunction in rats with diabetes [85].Exenatide may also attenuate intimal hyperplasia of carotidartery (a surrogate marker of CVD [86]) in insulin-resistantrats independently of glucose regulation and food intake. Inthis study, exenatide was associated with a non-significantupregulation of NOS and reduction of the proinflammatorytranscriptional nuclear factor-κB (NF-κB) [87]. In anotherexperimental model, it also reduced monocyte/macrophageaccumulation in the arterial wall, by inhibiting the inflam-matory response in macrophages through cAMP/PKA path-ways [74]. In this study, exenatide attenuated the mRNAexpression of tumour necrosis factor (TNF)-α, and mono-cyte chemoattractant protein-1 (MCP-1), which have alsobeen associated with atherosclerosis [74]. Of note, indirectanti-inflammatory effects for exenatide can be also speculatedby its effect on adiponectin, a well-known insulin-sensitizingand antiatherogenic adipokine [88]. In particular, in cultures ofadipocytes, exenatide increased adiponectin mRNA expressionvia the GLP-1R–PKA pathway [89] (Table 3).

Beneficial effects on markers of endothelial dysfunction andincreased CVD risk have also been observed for liraglutide.Specifically, in cultured human vascular endothelial cells,liraglutide inhibited the expression of TNF-α and thehyperglycaemic-mediated induction of expression of vascularcell adhesion molecule-1 (VCAM-1) and plasminogen activatorinhibitor type-1 (PAI-1) [90,91]. Noticeably, in another studyof cultured human umbilical vein endothelial cells, liraglutideincreased NO production and suppressed NF-κB activation.Liraglutide also reduced TNF-α-induced MCP-1, VCAM-1and intercellular adhesion molecule-1 (ICAM-1) mRNAexpression. These effects were mediated by the AMP-activatedprotein kinase, which occurs through a signalling pathwayindependent of cAMP [92].

An additional effect of liraglutide on inflammatory processhas emerged, as it tended to reduce the levels of high-sensitivityC-reactive protein (hsCRP) in patients with T2DM in a dose-dependent way [91]. It is well known that elevated hsCRP hasbeen associated with an increased risk for atherosclerosis andCVD [93]. Similar inhibitory effects on VCAM-1 and hsCRPhave also been reported for exenatide [74,94]. Favourableeffects on endothelial function have also been reported forsitagliptin, mainly through induction of NOS activity, and to agreater extent compared with pioglitazone [52] (Table 3).

GLP-1 and Arterial HypertensionConflicting data exist with respect to the effects of GLP-1on BP in rats. Although some studies have showed mod-est increases in BP and heart rate [30,31], in salt-sensitiverodent models GLP-1 treatment has shown antihypertensive,cardioprotective and renoprotective actions [95,96]. The mainmechanism for the latter seems to be a natriuretic and diureticeffect of GLP-1, due to inhibition of Na+ reabsorption in theproximal tubule [97] or attenuation of angiotensin II-inducedphosphorylation of extracellular signal-regulated kinase-1/2in renal cells [96]. Noticeably, increased cardiac output withno BP changes has also been reported in rats, suggestingthat GLP-1 may cause peripheral vasodilatation [98]. As men-tioned earlier, endothelial-dependent vasorelaxation by GLP-1in experimental studies comprises another mechanism of BPlowering [75,76]. This vasorelaxation may be mediated throughNO pathways or may be NO independent and mediated viacAMP/PKA-mediated hyperpolarization [99]. In calves, GLP-1 was haemodynamically neutral [100], whereas in isolatedporcine ileal arteries it produced a dose-dependent vasodilatoryeffect [101]. Antihypertensive, cardioprotective and renopro-tective effects have also been reported for exenatide analogueAC3174 in a salt-sensitive rat model [102].

In humans, small pilot studies in patients with heart failureshowed a slight increase in diastolic blood pressure (DBP) afterGLP-1 infusions [53,57], despite a trend towards a decreasein systolic blood pressure (SBP) [53]. On the other hand,in a study of patients with T2DM, GLP-1 (at a dose of 2.4pmol/kg/min, for 48-h continuous infusion) showed a ten-dency to decrease both SBP and DBP compared to saline, withno significant effect on heart rate [103]. However, these studieswere too small for safe conclusions.

Nonetheless, encouraging data have emerged from largerstudies with GLP-1 analogues. A double-blind 24-weekplacebo-controlled trial in T2DM patients naıve to antidiabeticdrugs showed a significant reduction in both SBP and DBP withexenatide (5 or 10 μg BID) compared with placebo [104]. Exe-natide (5 μg BID for 4 weeks followed by 10 μg BID) showedalso a trend towards lowering 24-h, day-time and night-timeSBP, with a neutral effect on DBP and heart rate, when addedto metformin and/or thiazolidinedione for 12 weeks in anotherplacebo-controlled trial of T2DM [105]. Studies of longer dura-tion of exenatide (at a dose of 10 μg BID for 82 weeks up to3.5 years while continuing other antidiabetic medications suchas metformin and/or sulphonylurea) suggest also improve-ments in DBP [106] or both SBP and DBP [107]. A recentstudy pooling data from six trials, including 2171 subjects witha follow-up of at least 6 months, tried to compare the effects ofexenatide on BP with those of insulin or placebo. The authorsshowed greater reductions in SBP with exenatide than withplacebo mainly in patients with abnormally high baseline SBPlevels. No differences between these groups were noticed interms of DBP [108]. The main mechanism for this antihyper-tensive effect of exenatide seems to be related to weight loss (as itis well known that weight reduction exerts beneficial outcomeson hypertension [109]) notwithstanding the aforementionednatriuretic and vasodilatory effects of GLP-1.



Similar favourable effects on both SBP and DBP have alsobeen reported for liraglutide, either as a monotherapy (at asingle dose of 0.65, 1.25 or 1.9 mg) [110] or in combination withmetformin and thiazolidinediones (1.2 or 1.9 mg daily) [111],compared with placebo [110,111] or with sulphonylurea (1.2or 1.9 mg daily) [112]. Regarding the role of DPP-4 inhibitorson BP, sitagliptin (at a dose of 50 or 100 mg BID) has beenassociated with small but significant reductions (2–3 mmHg)in 24-h ambulatory SBP and DBP compared with placebo,although this study involved patients without diabetes [113].However, the exact effect of DPP-4 inhibitors on BP needsto be better elucidated, as experimental data suggest also anenhancement of the vasoconstrictor role of angiotensin II inkidneys by sitagliptin [114].

GLP-1 and Lipid MetabolismThree placebo-controlled studies tried to evaluate the impactof exenatide on lipid parameters [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipopro-tein cholesterol (HDL-C) and triglycerides (TG)] in patientson metformin alone [115], sulphonylurea alone [116] or met-formin plus sulphonylurea [117]. At week 30, no significantdifferences were observed in these studies for either the exe-natide group or placebo in terms of TC, LDL-C, HDL-C, TGor apolipoprotein B (apoB) concentrations [115–117]. Never-theless, in an open-label 82-week extension of these studies,exenatide treatment at 10 μg BID led to significant improve-ments in HDL-C (mean increase of 4.6 mg/dl from baseline)and TG levels (mean reduction of 38.6 mg/dl from baseline).The greatest improvements in lipid profile were observed insubjects with the greatest weight reduction [107]. Furthermore,when a subset of this cohort was followed-up for 3.5 years,exenatide as adjunctive therapy to metformin and/or sulpho-nylurea significantly ameliorated all lipid parameters comparedwith baseline. In particular, it resulted in 12% reduction in TG,5% reduction in TC and 6% in LDL-C, whereas it inducedan increase in HDL-C of 24% [106]. Exenatide has also beenassociated with a decrease in postprandial TG and apoB48levels (a component of chylomicrons, rich in triacylglyceroland produced after fat ingestion [118]) compared with insulinglargine [119] or placebo [120]. Postprandial lipaemia is highlyassociated with insulin resistance and leads LDL-C and HDL-Cmetabolism to a more atherogenic direction in patients withT2DM [118]. Significant reductions in TG and TC and ininsulin dosage requirement have also been reported retrospec-tively for exenatide (5 μg BID) when added to insulin or oralhypoglycaemic agents [94,121].

Regarding the impact of liraglutide on lipids, it has beenassociated with a significant reduction in TG levels (up to 22%at the dose of 1.9 mg daily, compared with placebo), although itdid not exert any significant change on TC, LDL-C, HDL-C andapoB [110]. Few data exist for the effect of DPP-4 inhibitors onlipids. There is evidence that vildagliptin (50 mg BID) reducespostprandial plasma TG and chylomicron apoB48 comparedwith placebo, through reduction of intestinally derived TG.However, in this study it presented minimal effects on fastinglipid levels [122]. Compared with rosiglitazone, vildagliptin

significantly decreased TG, TC, LDL-C, non-HDL and total-to-HDL cholesterol (9–16%), although it led to a smallerincrease in HDL cholesterol (+4 vs. +9%) [123]. No data existon the effect of sitagliptin on postprandial lipaemia in humans.However, it must be stated that in an animal model sitagliptinreduced postprandial apoB48 and triacylglycerol accumulationto a similar extent than exendin-4 [124]. The exact mecha-nisms underlying the postprandial lipid reduction by DPP-4inhibitors and GLP-1R agonists are not clarified. It seems,however, that GLP-1R signalling plays a key role in the con-trol of intestinal lipoprotein synthesis and secretion, beyondweight reduction [124]. Finally, in an open-label prospectivetrial assessing the LDL-C-lowering effects of sitagliptin, cole-sevelam and rosiglitazone, sitagliptin (as well as rosiglitazone),in contrast to colesevelam, did not exert any beneficial effecton LDL-C [125].

ConclusionsEmerging evidence suggests some pleiotropic actions of GLP-1on the cardiovascular system, either directly through GLP-1Rs on the myocardium, endothelium and vasculature or viathe GLP-1R-independent actions of GLP-1(9-36). Experimen-tal data from animal and human studies indicate inotropicand vasodilatory effects of GLP-1, increased myocardial glu-cose uptake, improvement of endothelial function, reductionin infarct size (when given either prior to injury or at thepoint of reperfusion), as well as potential anti-inflammatoryand antiatherogenic actions. Based on these data, the GLP-1Ragonists seem to exert a cardioprotective role either directlyvia the aforementioned pathways or indirectly by improvingCVD risk factors beyond hyperglycaemia, such as hypertensionand dyslipidaemia. These mechanisms deserve further research.Although the exact mechanisms have not been fully elucidated,these encouraging lines of evidence remain to be verified in largeprospective randomized placebo-controlled trials with optimaldoses of GLP-1R agonists and possibly DPP-4 inhibitors inorder to determine their impact on CVD risk and associatedvariables.

Conflict of InterestThis review was written independently. The authors did notreceive financial or professional help with the preparation of themanuscript. The authors have given talks, attended conferencesand participated in advisory boards and trials sponsored byvarious pharmaceutical companies. P. A., V. G. A., A. K. andD. P. M. designed the study. F. A. and A. P. conducted andcollected data. F. A., M. K. and D. P. M. analysed the study.P. A. wrote the manuscript.

All the authors have no competing interest to disclose.

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Glucagon-like peptide-1-based therapies and cardiovascular

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