Glucagon-like peptide-1-based therapies and cardiovascular

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

Glucagon-like peptide-1-based therapies and cardiovascular
disease: looking beyond glycaemic control
P. Anagnostis1 , V. G. Athyros2 , F. Adamidou1 , A. Panagiotou1 , M. Kita1 , A. Karagiannis2
& D. P. Mikhailidis3
1 Endocrinology Clinic, Hippokration Hospital, Thessaloniki, Greece
2 Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
3 Department 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 developed
recently 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 increase
the circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by a
glucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions
are 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-1
and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growing
lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared with
placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these
agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the role
of 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

Introduction specific receptors on β-pancreatic cells [3,5]. GIP and GLP-1
seem to be responsible for about 50% of postprandial insulin
Type 2 diabetes mellitus (T2DM) is a chronic disease character-
secretion [3]. Furthermore, GLP-1 has been shown to stimu-
ized by insulin resistance and progressive decline in pancreatic
late proliferation and neogenesis of β cells and to inhibit their
β-cell function [1]. It has long been recognized that orally
apoptosis [3,5]. GLP-1 receptors (GLP-1Rs) are also present on
administered glucose is a stronger insulinotropic stimulus than
α-pancreatic cells, whereas GIP receptors are expressed mainly
intravenous glucose, suggesting a modulation of plasma glucose
on β cells. GLP-1 suppresses glucagon secretion by α cells,
by the gastrointestinal system [2]. The mediators of this phe-
while GIP stimulates it [3,6]. Apart from the pancreatic islets,
nomenon are gut-derived hormones, termed incretins, which
GLP-1Rs are present in several other tissues including central
are released in response to ingested nutrients, mainly glucose,
(hypothalamus) and peripheral nervous systems, gastrointesti-
and stimulate insulin secretion by β cells of the pancreas [3].
nal tract, lung and heart [3,5,7]. As a result, GLP-1 exerts
The incretin effect seems to be significantly impaired in T2DM
further beneficial actions on glucose metabolism by mediating
due to a reduced secretion of these hormones, accelerated
satiety at the hypothalamic level leading to reduced food intake
metabolism or defective responsiveness to their action [4].
and weight loss, and by delaying stomach emptying through
The main members of the incretin family are glucagon-
the vagus nerve [3,5,7].
like peptide-1 (GLP-1) and glucose-dependent insulinotropic
GLP-1 derives from the same gene that encodes glucagon,
polypeptide (GIP). GLP-1 derives from the L cells of the distal
and is a product of the catalytic action of the protein convertase
intestine, while GIP is released from the K cells of the proximal
PC1/3 on proglucagon in the enteroendocrine cells [8]. In α-
intestine. They both stimulate insulin secretion by binding with
pancreatic cells, proglucagon is cleaved to glucagon via protein
convertase PC2. However, under certain conditions, islet α cells
do express PC1/3 and liberate GLP-1 from proglucagon [9].
Correspondence to: Dr. Panagiotis Anagnostis, Endocrinology Clinic, Hippokration Hospital,
49 Konstantinoupoleos Str, Thessaloniki 54 642, Greece. The active form of GLP-1 is GLP-1(7-36) [3,9]. GLP-1 is rapidly
E-mail: anagnwstis.pan@yahoo.gr degraded by the enzyme dipeptidyl dipeptidase-4 (DPP-4) to

DIABETES, OBESITY AND METABOLISM review article
inactive GLP-1(9-36), leading to the short circulating half-life studies, although mainly with regard to microvascular com-
time for GLP-1 of 2 min. The kidneys also play a role in the plications. In particular, the United Kingdom Prospective
clearance of GLP-1 from the circulation [3,9,10]. Diabetes Study (UKPDS) showed a 16% risk reduction
The recognition and better understanding of the physiol- for myocardial infarction (MI) by intensive glucose control
ogy and pathophysiology of the incretin phenomenon has led in patients with T2DM (although of marginal significance,
to the development of incretin-based therapeutic approaches p = 0.052) [19], which remained significant (p = 0.01) in
to T2DM. These include the degradation-resistant GLP-1R the 10-year poststudy monitoring period [20]. In a similar
agonists and the inhibitors of DPP-4 activity [9]. There are way, two recent studies, the Action to Control Cardiovascular
currently two GLP-1R agonists that have been approved by the Risk in Diabetes (ACCORD) and the Action in Diabetes and
Food and Drugs Administration (FDA) and used clinically to Vascular Disease: Preterax and Diamicron Modified Release
date: exenatide and liraglutide. Exenatide is the synthetic form Controlled Evaluation (ADVANCE) evaluated the potential
of exendin-4, an incretin mimetic that is present in the saliva benefits of intensive glucose control [HbA1c targets ≤6% (or
of the Gila monster (Heloderma suspectum) [11]. Exenatide 42 mmol/mol) and ≤6.5% (or 48 mmol/mol), respectively] on
displays 53% sequence homology to mammalian GLP-1 and cardiovascular disease (CVD). In the ACCORD study, non-
is resistant to DPP-4 action, due to the presence of glycine as fatal MI occurred less often in the intensive glucose control
the second amino acid, resulting in a longer circulating half- group, although the study was terminated early due to higher
life time (2.4 h) [12,13]. Experimental and clinical trials have mortality rates in this group of patients [21]. On the other hand,
shown that exenatide exerts many of the glucoregulatory effects the ADVANCE trial showed a small but significant reduction
of GLP-1, such as enhancement of glucose-dependent insulin in the incidence of both macro- and microvascular events
release, inhibition of glucagon secretion and reduction of food with intensive glucose lowering [hazard ratio (HR), 0.90; 95%
intake and satiety. It is administered subcutaneously and has confidence interval (CI), 0.82–0.98; p = 0.01], mainly due to
been associated with reductions in fasting and postprandial glu- improvement of nephropathy [22]. These studies indicated the
cose concentrations, and haemoglobin A1c (HbA1c) (1–2% or importance of the early intervention by achieving low glu-
11–22 mmol/mol), combined with weight loss [12,13]. Recent cose targets in patients with lower baseline HbA1c, no prior
data also suggest more beneficial effects of the long-acting history of coronary artery disease (CAD) and shorter history
release form of exenatide at a dose 2 mg once weekly in terms of diabetes. Moreover, in patients with type 1 DM stronger
of glucose regulation with the same weight reduction compared associations between glucose control and reduction in the rate
with exenatide 10 μg BID [14] (Table 1). of CVD events (42%, p = 0.02) were shown in the Diabetes
Liraglutide has recently been approved for the treatment Control and Complications Trial (DCCT), followed-up for
of T2DM, expresses 97% homology to natural GLP-1 and its a mean 17-year period in the observational Epidemiology of
resistance to degradation by DPP-4 is achieved through its Diabetes Interventions and Complications (EDIC) study [23].
binding to serum albumin, which prolongs its half-life time GLP-1R agonists affect not only fasting but also postprandial
to 12 h. It is administered subcutaneously once daily at a hyperglycaemia [12,13]. The effect of GLP-1 on postprandial
dose of 0.6, 1.2 or 1.8 mg [9,12,15]. GLP-1R agonists can be blood glucose is mediated through its inhibition of gastric
administered either as a monotherapy or adjuvant to met- emptying and concomitant glucose absorption and by post-
formin, sulphonylureas or thiazolidinediones, when optimal prandial insulin response [24]. Postprandial hyperglycaemia
glycaemic control is not achieved with these agents [16]. Other
has been strongly associated with CVD events and, in addi-
GLP-1R agonists in development are albiglutide, taspoglutide
tion, it is regarded as a more important CVD risk factor
(Ro1583), AVA0010, CJC-1134-PC, NN9535, LY2189265 and
than fasting glucose levels [25,26]. Many mechanisms for this
LY2428757 [12] (Table 1).
relationship have been proposed, such as increased oxidative
The DPP-4 inhibitors, including vildagliptin, sitagliptin,
stress, abnormal vascular reactivity, hypercoagulability and
saxagliptin and the novel alogliptin, linagliptin and duto-
endothelial dysfunction [27].
gliptin, suppress the DPP-4 activity by 80% and cause a
twofold increase in circulating bioactive GLP-1 and GIP levels
in humans [9,12,15,17,18]. They reduce fasting and postpran- Cardioprotective Effects of GLP-1
dial plasma glucose, have neutral effect on weight and can be
administered either as monotherapy or in combination with Data From Animal Studies. Apart from this indirect effect of
other antidiabetic drugs. The benefit of DPP-4 inhibitors is their GLP-1 on CVD outcomes through achievement of euglycaemia,
ease of administration, as they are taken orally, whereas cur- accumulating evidence from both experimental and clinical
rently available GLP-1R agonists require injection [9,15,17,18] studies suggests a direct influence on myocardium as well. As
(Table 1). mentioned earlier, GLP-1Rs have been detected in the rodent
The present review considers the pleiotropic actions of GLP- and human heart, as well as in regions of the brain involved in
1 on the cardiovascular system and the impact of GLP-1 agonist autonomic function, and, therefore, central or peripheral GLP-
administration on cardiovascular risk factors and outcomes. 1R signalling may transduce direct and indirect cardiovascular
effects of circulating GLP-1 [28,29]. All these GLP-1Rs in
different tissues have similar if not identical ligand-binding
GLP-1 and Myocardium capacity and their sequence seems to be homologous to the
The beneficial effect of glucose control on cardiovascular out- sequences of the family of G-protein receptors for several
comes has long been shown by large randomized-controlled endocrine peptides such as glucagon, secretin, calcitonin,

Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01345.x 303

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 mammalian Twice daily, at doses of 5 or 10 μg
GLP-1, glycine as a second amino acid Long-acting release form (once
weekly, at a dose of 2 mg)
Liraglutide Available 97% Sequence homology to human Once daily at a dose of 0.6, 1.2 or
GLP-1, with a single substitution of 1.8 mg
arginine for lysine in position 34
Albiglutide In development Two tandem-linked copies of a modified 30–50 mg once weekly
human
GLP-1 sequence within the large human
serum albumin
Molecule
Taspoglutide (Ro1583) In development GLP-1-based molecule that contains 20–30 mg once weekly
aminoisobutyric acid substitutions
at positions 8 and 35
AVA0010 In development Modified exendin-4 molecule with 5–30 μg once or twice daily
additional lysine residues at the
carboxy terminal
CJC-1134-PC In development Recombinant human serum albumin- 1.5–3 mg once or twice weekly
exendin-4-conjugated protein
NN9535 In development GLP-1 analogue 0.1–1.6 mg once weekly
LY2189265 In development GLP-1 analogue 0.25–3 mg once weekly
LY2428757 In development Pegylated 0.5–17.6 mg once weekly
GLP-1 molecule
Sitagliptin Available DPP-4 inhibitor 25–100 mg once daily
Vildagliptin Available DPP-4 inhibitor 50 mg twice daily
Saxagliptin Available DPP-4 inhibitor 5–10 mg once daily
Alogliptin In development DPP-4 inhibitor 12.5–25 mg once daily
Linagliptin In development DPP-4 inhibitor 2.5–5 mg once daily
Dutogliptin 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), parathyroid Further animal studies showed additional benefits of GLP-1
hormone and vasoactive intestinal peptide (VIP) [29]. on myocardial metabolism in ischaemic conditions. In an open-
In experimental rat studies, GLP-1 infusions resulted in chest porcine heart model, the infusion of rGLP-1 decreased
increased heart rate and blood pressure (BP). This inotropic pyruvate and lactate concentrations both in normoxic condi-
and chronotropic effect is mediated through Fos-signalling tions and during ischaemia and reperfusion. However, it did not
in several autonomic control sites in the brain regions and significantly affect the extent of tissue necrosis [36]. In an in vivo
in the adrenal medulla [30,31]. However, other investigators rabbit model of myocardial ischaemia/reperfusion, the GLP-1
failed to confirm such haemodynamic effects in pigs [32], analogue fused to non-glycosylated human transferrin (GLP-
while others reported negative inotropic effects of GLP-1 on 1-Tf) limited myocardial loss, either given prior to myocardial
rat cardiomyocytes in vitro [33]. On the other hand, it has ischaemia or at the onset of reperfusion [37]. The results of
been shown that mice with genetic deletion of GLP-1R display this study suggest a cardioprotective effect of GLP-1 perhaps
reduced heart rate, elevated left ventricular (LV) end-diastolic due to antiapoptotic properties. Indeed, GLP-1 limits apoptosis
pressure and impaired LV contractility and diastolic func- in both β cells and myocytes via activation of cyclic adeno-
tion after insulin administration, indicating a direct role of sine monophosphate (cAMP) and phosphoinositide 3-kinase
GLP-1 on the myocardium [34]. Accordingly, 48-h infusion of (PI3-K) by binding with GLP-1Rs [38,39]. PI3-K activation
recombinant GLP-1 (rGLP-1) in dogs with advanced dilated has been associated with myocardial protection in the setting
cardiomyopathy led to significant improvements in LV func- of ischaemic/reperfusion injury [40] and myocardial precon-
tion (increased stroke volume and cardiac output and decreased ditioning [41]. The lack of GLP-1 effect on infarct size that was
LV end-diastolic pressure) and systemic vascular resistance. observed in the former study [36] may be attributed to the fact
This amelioration in LV dysfunction was associated with that the investigators did not employ an inhibitor of DPP-4,
an increased insulin-independent myocardial glucose uptake, as GLP-1-Tf has a much longer half-life (27 h in rabbits) than
independent of the insulinotropic effects of GLP-1, as well natural GLP-1 [37]. Indeed, the conjunction of GLP-1 with
as decreased plasma norepinephrine and glucagon levels [35]. valine pyrrolidide, a potent inhibitor of DPP-4, added before
The different haemodynamic effects of GLP-1 observed in these myocardial ischaemia in rats, reduced MI size both in vitro
studies may be partly because of the differences in dose, method and in vivo [39]. Furthermore, 24-h continuous i.v. infu-
of delivery or species. sion of GLP-1 after coronary artery occlusion and subsequent

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

reperfusion attenuated postischaemic regional contractile dys- class II–III heart failure of ischaemic aetiology receiving 48-h
function in normal conscious dogs [42]. GLP-1 seems also to rGLP-1 (0.7 pmol/kg/min). Despite the absence of major car-
reduce infarct size in rats, when given either prior to ischaemia diovascular effects, minor increases in heart rate and diastolic
(as a preconditioning mimetic) or directly at reperfusion [43]. BP during GLP-1 infusion were noticed [57]. In a recent large
In terms of pharmacological intervention, both GLP-1R retrospective study, exenatide twice daily was compared with
agonists and DPP-4 inhibitors have shown to exert cardiopro- other glucose-lowering agents in terms of their impact on CVD
tective effects on myocardial survival after MI in animal studies. events. Despite the higher rates of CAD, obesity, hyperlipi-
Specifically, exenatide has shown strong infarct-limiting action daemia, hypertension and/or other comorbidities at baseline,
and improved systolic and diastolic cardiac functions after exenatide-treated patients were less likely to have a CVD
ischaemia–reperfusion injury in rat and porcine heart mod- event than non-exenatide-treated ones (HR: 0.81, 95% CI:
els [44–47]. Furthermore, intraperitoneal administration of 0.68–0.95; p = 0.01). Furthermore, exenatide-treated patients
liraglutide in mice before coronary artery occlusion reduced showed lower rates of CVD-related hospitalization (HR: 0.88,
infarct size and cardiac rupture and improved cardiac out- 95% CI: 0.79–0.98; p = 0.02) and all-cause hospitalization
put [48]. However, others did not confirm these findings for (HR: 0.94, 95% CI: 0.91–0.97; p < 0.001) than those not
liraglutide in a porcine ischemia–reperfusion model. In this having received exenatide [58].
study, liraglutide was injected subcutaneously (as in humans) Emerging data also indicate a cardioprotective role of DPP-4
before ligation of the left anterior descending artery. Com- inhibitors in humans. In particular, sitagliptin administration
pared with controls, liraglutide had no effect on infarct size at a single dose of 100 mg in patients with CAD and pre-
nor on cardiac output and, in addition, the heart rate was served LV function enhanced LV response to stress, attenuated
significantly higher in liraglutide-treated pigs [49]. These dif- postischaemic stunning and improved global and regional LV
ferences may be attributed to the dosing regimen, the different performance compared with placebo [59]. Encouraging results
analogue, the timing of treatment and the species to which have also been published recently from an interim analysis of
it was administrated. Larger animal models such as pigs are a phase III randomized placebo-controlled trial regarding the
probably more predictive of results in humans [50]. As far as granulocyte colony-stimulating factor (G-CSF)-based stem cell
DPP-4 inhibitors are concerned, sitagliptin seemed to improve mobilization in combination with sitagliptin in patients after
functional recovery from ischaemia–reperfusion in mice and acute MI. During the first 6 weeks of follow-up, sitagliptin along
presented similar cardioprotection with genetic deletion of with G-CSF seems to be quite safe and effective for myocardial
DPP-4 [51]. Sitagliptin has also been associated with a reduc- regeneration and may constitute a new therapeutic option in
tion in infarct size in these experimental models [52]. the future [60].
Data From Human Studies. All these promising data have also
been reproduced in human studies. In particular, in a pilot study Proposed Mechanisms
of six patients with diabetes and New York Heart Association The exact mechanisms underlying this cardioprotective effect
(NYHA) class II–III congestive heart failure of ischaemic of GLP-1 have not been fully elucidated. First of all, GLP-1
aetiology, subcutaneous infusion of 3–4 pmol/kg/min of rGLP- increases myocardial insulin sensitivity [35], as well as myocar-
1 for 72 h showed a trend towards improvement of systolic and dial glucose uptake independently of plasma insulin levels [61].
diastolic cardiac functions at rest and during exercise [53]. In Moreover, the survival of cardiac myocytes is mediated by
another study of 12 patients with (NYHA) class III/IV heart inhibition of apoptosis via cAMP and PI3-K pathways, after
failure, a 5-week infusion of rGLP-1 (2.5 pmol/kg/min) added binding with GLP-1Rs [38,39]. The next mediator is Akt,
to standard therapy improved variables of LV function, such a serine-threonine kinase, the activation of which has been
as ejection fraction, maximum myocardial ventilation oxygen shown to attenuate cardiomyocyte death, to restore regional
consumption and 6-min walk test, as well as quality of life [54]. wall thickening after myocardial ischaemia and to improve
Similarly, i.v. infusion (1.5 pmol/kg/min) of rGLP-1 for 72 h survival of preserved cardiomyocytes [62]. Furthermore, the
in 11 subjects with LV dysfunction after MI and angioplasty activation of the antioxidant gene, heme oxygenase-1 (HO-1),
led to reduced hospital stay and improved global and regional through GLP-1R [63] reduces fibrosis and LV remodelling and
LV wall motion scores. These favourable outcomes remained restores LV function after MI [64]. HO-1 acts via induction
detectable even several weeks after hospital discharge [55] and of nuclear factor-E2-related factor (Nrf)2 gene expression and
were noticed in patients with or without diabetes, indicating nuclear translocation and subsequent stimulation of Akt [65].
that GLP-1 may act on the cardiovascular system independently Other cardioprotective mediators are glycogen synthase kinase
of glycaemic control [54,55]. In all these studies rGLP-1 was (GSK)-3β, Bcl-2 family proteins [66] and PPARs-β and
well tolerated [53–55]. -δ [67].
Similar benefits in terms of myocardial function were noticed Liraglutide has been shown to enhance the activity of Akt
in patients receiving GLP-1 (1.5 pmol/kg/min) before and after and to suppress GSK-3β, an Akt substrate. It may also increase
coronary artery bypass grafting (CABG). Compared with the the levels of PPAR-β/δ and Nrf2 in the mouse heart [48].
control group, they needed fewer inotropic and vasoactive Furthermore, in this animal model, liraglutide induced mRNA
infusions postoperatively to achieve the same haemodynamic and protein levels of HO-1 and reduced cleaved caspase 3 [48],
result and presented arrhythmias less frequently [56]. How- a type of aspartate-specific cysteine protease, the activation of
ever, these favourable outcomes were not confirmed in a which is also associated with the induction of cardiac cell apop-
recent study of 20 patients without diabetes and with NYHA tosis [68]. Exenatide seems also to use the same pathways in



Table 2. Proposed pathogenic mechanisms for glucagon-like peptide GLP-1(9-36) improved LV function and increased myocar-
(GLP)-1 cardioprotection. dial glucose uptake [71]. Noticeably, another experimental rat
model evaluating the effects of GLP-1(7-36) on the cardiovascu-
lar system and elucidating the role of GLP-1(9-36) showed that
Pathogenic mechanisms GLP-1(7-36) infusion was characterized by regional haemody-
Achievement of fasting and postprandial euglycaemia namic effects including tachycardia, hypertension, renal and
Increased myocardial glucose uptake mesenteric vasoconstriction, whereas GLP-1(9-36) did not
Activation of cAMP and concomitant PIK-3 and PKA display any cardiovascular actions [72].
antiapoptotic pathways
Activation of Akt
Activation of antioxidant gene HO-1
Nrf2 gene expression (through HO-1) GLP-1 and Atherosclerosis (Vasculature,
Activation of PPAR-β and -δ Endothelium, Inflammation)
Suppression of GSK-3β
Inhibition of caspase-3 It is well documented that diabetes is associated with endothelial
GLP-1R-independent pathway role of GLP-1(9-39) dysfunction [73]. Emerging lines of evidence show an addi-
Beneficial effects on endothelium tional benefit of GLP-1 on the endothelium. Indeed, except
Increased activity of NO. for cardiomyocytes, GLP-1R expression has been detected
NO-independent vasodilation through GLP-1 on endothelial and vascular smooth muscle cells (SMCs),
Inhibition of monocyte/macrophage accumulation
as well as on macrophages and monocytes [70,74]. Previ-
Anti-inflammatory effects
Inhibition of atherosclerosis ous animal studies have shown that GLP-1 can induce an
endothelial-dependent relaxation of pulmonary artery vessel
cAMP, cyclic adenosine monophosphate; GLP-1R, GLP-1 receptor; GSK, rings [75,76], an effect that is NO dependent [76]. NO is a
glycogen synthase kinase; HO-1, heme oxygenase-1; NO, nitric oxide; Nrf2, well-known vasodilatory endothelium-derived factor [77]. Of
nuclear factor-E2-related factor; PI3-K, phosphoinositide 3-kinase; PKA,
note, GLP-1(9-36) appeared to improve the survival of human
protein kinase A; PPAR, peroxisome proliferator-activated receptor.
aortic endothelial cells after ischaemia–reperfusion [69]. These
actions were also exerted through the NOS pathway [68]. Nev-
ertheless, some investigators observed a vasodilatory effect of
order to exert its cardioprotective action. Specifically, exenatide
GLP-1 independently of NO, indicating clearly a direct action
treatment increases myocardial phosphorylated Akt and Bcl-2
on vascular SMC via its GLP-1R [78] (Table 3).
expression levels and inhibits the expression of active caspase
Another pathogenic link between diabetes and atheroscle-
3 [44]. In terms of DPP-4 cardioprotective pathways, sitagliptin
rosis is the increased formation of advanced glycation-end
seems to reduce infract size in ischaemia–reperfusion animal
products (AGEs). AGEs and their receptors play a key role
models via cAMP-dependent activation of protein kinase A
in the vascular damage in patients with diabetes [79]. On the
(PKA) [52] (Table 2).
other hand, GLP-1 may have an impact on this process as
Remarkably, these effects of GLP-1 were not shown in
it has been shown to protect from the deleterious effects of
animals with genetic deletion of GLP -1R, a fact that in
AGEs on human umbilical vein endothelial cells, through the
combination with the increased cAMP and reduced apop-
inhibition of AGE receptor gene expression on these cells [80].
tosis in cardiomyocyte cultures indicates a GLP-1R-dependent
Remarkably, in T2DM patients with CAD, rGLP-1 infusions
action [46]. Nevertheless, GLP-1 action is also mediated
through GLP-1R-independent pathways. In particular, as men-
tioned earlier, under the influence of DPP-4, GLP-1(7-36) Table 3. Glucagon-like peptide (GLP)-1 and atherosclerosis.
amide is degraded to the inactive N-terminally truncated
metabolite GLP-1(9-36) amide, which does not interact with Related tissues Proposed mechanisms
the known GLP-1R [3,69]. Data from isolated mouse heart
Endothelium Expression of GLP-1 receptors
models show that GLP-1(9-36) exerts a vasodilatory effect NO-dependent action
through a GLP-1R-independent mechanism via the formation Upregulation of NOS
of cyclic guanosine monophosphate (cGMP) by nitric oxide Inhibition of AGE receptor gene
(NO) which, in turn, is produced under the action of nitric expression
oxide synthase (NOS) [70]. In this study, native GLP-1, as well Inhibition of expression of TNF-α,
VCAM-1 and PAI-1
as the synthetic analogue exendin-4 [which is DPP-4 resis-
Vascular smooth muscle cells Expression of GLP-1 receptors
tant and therefore cannot be metabolized to GLP-1(9-36)], Increased flow-mediated vasodilation
improved LV functional recovery after ischaemia–reperfusion Macrophages Expression of GLP-1 receptors
injury. However, for animals lacking GLP-1Rs, this action was Inhibition of macrophage accumulation
evident only for GLP-1 and not for exendin-4 [70]. Moreover, through cAMP/PKA pathways
GLP-1 and not GLP-1(9-36) displayed a direct inotropic action Monocytes Expression of GLP-1 receptors
via GLP-1R in the mouse heart and vasculature [70]. The AGE, advanced glycation-end product; cAMP, cyclic adenosine monophos-
GLP-1R-independent role of GLP-1(9-36) for the cardiovascu- phate; NO, nitric oxide; NOS, nitric oxide synthase; PAI-1, plasminogen
lar system was further indicated from a study of conscious activator inhibitor type-1; PKA, protein kinase A; TNF-α, tumour necrosis
dogs with dilated cardiomyopathy, in which infusions of factor-α; VCAM-1, vascular cell adhesion molecule-1.


(at a dose of 2 pmol/kg/min) significantly increased flow- GLP-1 and Arterial Hypertension
mediated vasodilation (FMD) in the brachial artery compared
Conflicting data exist with respect to the effects of GLP-1
with placebo [81]. FMD highly correlates with endothelial
on BP in rats. Although some studies have showed mod-
dysfunction in the coronary circulation [82] and is also con-
sidered to be NO mediated [83]. Furthermore, GLP-1 infusion est increases in BP and heart rate [30,31], in salt-sensitive
enhanced acetylcholine-mediated vasodilation in non-diabetic, rodent models GLP-1 treatment has shown antihypertensive,
normotensive non-smokers, an effect that was abolished after cardioprotective and renoprotective actions [95,96]. The main
co-administration of glyburide (but not glimepiride). These mechanism for the latter seems to be a natriuretic and diuretic
data indicate also a potential modulatory role of sulphony- effect of GLP-1, due to inhibition of Na+ reabsorption in the
lurea receptor subunit on GLP-1Rs in the endothelial cells proximal tubule [97] or attenuation of angiotensin II-induced
and a selectivity of KATP channel inhibition amongst different phosphorylation of extracellular signal-regulated kinase-1/2
sulphonylurea agents [84]. in renal cells [96]. Noticeably, increased cardiac output with
There are also data about the impact of GLP-1R agonists and no BP changes has also been reported in rats, suggesting
DPP-4 inhibitors on endothelial function and CVD biomarkers. that GLP-1 may cause peripheral vasodilatation [98]. As men-
Exendin-4 has been shown to prevent homocysteinaemia- tioned earlier, endothelial-dependent vasorelaxation by GLP-1
induced endothelial dysfunction in rats with diabetes [85]. in experimental studies comprises another mechanism of BP
Exenatide may also attenuate intimal hyperplasia of carotid lowering [75,76]. This vasorelaxation may be mediated through
artery (a surrogate marker of CVD [86]) in insulin-resistant NO pathways or may be NO independent and mediated via
rats independently of glucose regulation and food intake. In cAMP/PKA-mediated hyperpolarization [99]. In calves, GLP-
this study, exenatide was associated with a non-significant 1 was haemodynamically neutral [100], whereas in isolated
upregulation of NOS and reduction of the proinflammatory porcine ileal arteries it produced a dose-dependent vasodilatory
transcriptional nuclear factor-κB (NF-κB) [87]. In another effect [101]. Antihypertensive, cardioprotective and renopro-
experimental model, it also reduced monocyte/macrophage tective effects have also been reported for exenatide analogue
accumulation in the arterial wall, by inhibiting the inflam- AC3174 in a salt-sensitive rat model [102].
matory response in macrophages through cAMP/PKA path- In humans, small pilot studies in patients with heart failure
ways [74]. In this study, exenatide attenuated the mRNA showed a slight increase in diastolic blood pressure (DBP) after
expression of tumour necrosis factor (TNF)-α, and mono- GLP-1 infusions [53,57], despite a trend towards a decrease
cyte chemoattractant protein-1 (MCP-1), which have also in systolic blood pressure (SBP) [53]. On the other hand,
been associated with atherosclerosis [74]. Of note, indirect in a study of patients with T2DM, GLP-1 (at a dose of 2.4
anti-inflammatory effects for exenatide can be also speculated pmol/kg/min, for 48-h continuous infusion) showed a ten-
by its effect on adiponectin, a well-known insulin-sensitizing dency to decrease both SBP and DBP compared to saline, with
and antiatherogenic adipokine [88]. In particular, in cultures of no significant effect on heart rate [103]. However, these studies
adipocytes, exenatide increased adiponectin mRNA expression were too small for safe conclusions.
via the GLP-1R–PKA pathway [89] (Table 3). Nonetheless, encouraging data have emerged from larger
Beneficial effects on markers of endothelial dysfunction and studies with GLP-1 analogues. A double-blind 24-week
increased CVD risk have also been observed for liraglutide. placebo-controlled trial in T2DM patients na¨ve to antidiabetic
ı
Specifically, in cultured human vascular endothelial cells, drugs showed a significant reduction in both SBP and DBP with
liraglutide inhibited the expression of TNF-α and the exenatide (5 or 10 μg BID) compared with placebo [104]. Exe-
hyperglycaemic-mediated induction of expression of vascular natide (5 μg BID for 4 weeks followed by 10 μg BID) showed
cell adhesion molecule-1 (VCAM-1) and plasminogen activator also a trend towards lowering 24-h, day-time and night-time
inhibitor type-1 (PAI-1) [90,91]. Noticeably, in another study SBP, with a neutral effect on DBP and heart rate, when added
of cultured human umbilical vein endothelial cells, liraglutide to metformin and/or thiazolidinedione for 12 weeks in another
increased NO production and suppressed NF-κB activation. placebo-controlled trial of T2DM [105]. Studies of longer dura-
Liraglutide also reduced TNF-α-induced MCP-1, VCAM-1 tion of exenatide (at a dose of 10 μg BID for 82 weeks up to
and intercellular adhesion molecule-1 (ICAM-1) mRNA 3.5 years while continuing other antidiabetic medications such
expression. These effects were mediated by the AMP-activated as metformin and/or sulphonylurea) suggest also improve-
protein kinase, which occurs through a signalling pathway ments in DBP [106] or both SBP and DBP [107]. A recent
independent of cAMP [92]. study pooling data from six trials, including 2171 subjects with
An additional effect of liraglutide on inflammatory process a follow-up of at least 6 months, tried to compare the effects of
has emerged, as it tended to reduce the levels of high-sensitivity exenatide on BP with those of insulin or placebo. The authors
C-reactive protein (hsCRP) in patients with T2DM in a dose- showed greater reductions in SBP with exenatide than with
dependent way [91]. It is well known that elevated hsCRP has placebo mainly in patients with abnormally high baseline SBP
been associated with an increased risk for atherosclerosis and levels. No differences between these groups were noticed in
CVD [93]. Similar inhibitory effects on VCAM-1 and hsCRP terms of DBP [108]. The main mechanism for this antihyper-
have also been reported for exenatide [74,94]. Favourable tensive effect of exenatide seems to be related to weight loss (as it
effects on endothelial function have also been reported for is well known that weight reduction exerts beneficial outcomes
sitagliptin, mainly through induction of NOS activity, and to a on hypertension [109]) notwithstanding the aforementioned
greater extent compared with pioglitazone [52] (Table 3). natriuretic and vasodilatory effects of GLP-1.



Similar favourable effects on both SBP and DBP have also significantly decreased TG, TC, LDL-C, non-HDL and total-
been reported for liraglutide, either as a monotherapy (at a to-HDL cholesterol (9–16%), although it led to a smaller
single dose of 0.65, 1.25 or 1.9 mg) [110] or in combination with increase in HDL cholesterol (+4 vs. +9%) [123]. No data exist
metformin and thiazolidinediones (1.2 or 1.9 mg daily) [111], on the effect of sitagliptin on postprandial lipaemia in humans.
compared with placebo [110,111] or with sulphonylurea (1.2 However, it must be stated that in an animal model sitagliptin
or 1.9 mg daily) [112]. Regarding the role of DPP-4 inhibitors reduced postprandial apoB48 and triacylglycerol accumulation
on BP, sitagliptin (at a dose of 50 or 100 mg BID) has been to a similar extent than exendin-4 [124]. The exact mecha-
associated with small but significant reductions (2–3 mmHg) nisms underlying the postprandial lipid reduction by DPP-4
in 24-h ambulatory SBP and DBP compared with placebo, inhibitors and GLP-1R agonists are not clarified. It seems,
although this study involved patients without diabetes [113]. however, that GLP-1R signalling plays a key role in the con-
However, the exact effect of DPP-4 inhibitors on BP needs trol of intestinal lipoprotein synthesis and secretion, beyond
to be better elucidated, as experimental data suggest also an weight reduction [124]. Finally, in an open-label prospective
enhancement of the vasoconstrictor role of angiotensin II in trial assessing the LDL-C-lowering effects of sitagliptin, cole-
kidneys by sitagliptin [114]. sevelam and rosiglitazone, sitagliptin (as well as rosiglitazone),
in contrast to colesevelam, did not exert any beneficial effect
on LDL-C [125].
GLP-1 and Lipid Metabolism
Three placebo-controlled studies tried to evaluate the impact Conclusions
of exenatide on lipid parameters [total cholesterol (TC), low-
density lipoprotein cholesterol (LDL-C), high-density lipopro- Emerging evidence suggests some pleiotropic actions of GLP-1
tein cholesterol (HDL-C) and triglycerides (TG)] in patients on the cardiovascular system, either directly through GLP-
on metformin alone [115], sulphonylurea alone [116] or met- 1Rs on the myocardium, endothelium and vasculature or via
formin plus sulphonylurea [117]. At week 30, no significant the GLP-1R-independent actions of GLP-1(9-36). Experimen-
differences were observed in these studies for either the exe- tal data from animal and human studies indicate inotropic
natide group or placebo in terms of TC, LDL-C, HDL-C, TG and vasodilatory effects of GLP-1, increased myocardial glu-
or apolipoprotein B (apoB) concentrations [115–117]. Never- cose uptake, improvement of endothelial function, reduction
in infarct size (when given either prior to injury or at the
theless, in an open-label 82-week extension of these studies,
point of reperfusion), as well as potential anti-inflammatory
exenatide treatment at 10 μg BID led to significant improve-
and antiatherogenic actions. Based on these data, the GLP-1R
ments in HDL-C (mean increase of 4.6 mg/dl from baseline)
agonists seem to exert a cardioprotective role either directly
and TG levels (mean reduction of 38.6 mg/dl from baseline).
via the aforementioned pathways or indirectly by improving
The greatest improvements in lipid profile were observed in
CVD risk factors beyond hyperglycaemia, such as hypertension
subjects with the greatest weight reduction [107]. Furthermore,
and dyslipidaemia. These mechanisms deserve further research.
when a subset of this cohort was followed-up for 3.5 years,
Although the exact mechanisms have not been fully elucidated,
exenatide as adjunctive therapy to metformin and/or sulpho-
these encouraging lines of evidence remain to be verified in large
nylurea significantly ameliorated all lipid parameters compared
prospective randomized placebo-controlled trials with optimal
with baseline. In particular, it resulted in 12% reduction in TG,
doses of GLP-1R agonists and possibly DPP-4 inhibitors in
5% reduction in TC and 6% in LDL-C, whereas it induced
order to determine their impact on CVD risk and associated
an increase in HDL-C of 24% [106]. Exenatide has also been
variables.
associated with a decrease in postprandial TG and apoB48
levels (a component of chylomicrons, rich in triacylglycerol
and produced after fat ingestion [118]) compared with insulin Conflict of Interest
glargine [119] or placebo [120]. Postprandial lipaemia is highly
This review was written independently. The authors did not
associated with insulin resistance and leads LDL-C and HDL-C
receive financial or professional help with the preparation of the
metabolism to a more atherogenic direction in patients with
manuscript. The authors have given talks, attended conferences
T2DM [118]. Significant reductions in TG and TC and in
and participated in advisory boards and trials sponsored by
insulin dosage requirement have also been reported retrospec-
various pharmaceutical companies. P. A., V. G. A., A. K. and
tively for exenatide (5 μg BID) when added to insulin or oral
D. P. M. designed the study. F. A. and A. P. conducted and
hypoglycaemic agents [94,121].
collected data. F. A., M. K. and D. P. M. analysed the study.
Regarding the impact of liraglutide on lipids, it has been
P. A. wrote the manuscript.
associated with a significant reduction in TG levels (up to 22%
All the authors have no competing interest to disclose.
at the dose of 1.9 mg daily, compared with placebo), although it
did not exert any significant change on TC, LDL-C, HDL-C and
apoB [110]. Few data exist for the effect of DPP-4 inhibitors on References
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