Download Impact of glucagon-like peptide-1 on endothelial function

ORIGINAL ARTICLE
doi: 10.1111/j.1463-1326.2009.01074.x
Impact of glucagon-like peptide-1 on endothelial function
Å. Sjöholm
Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institutet,
Stockholm, Sweden
Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals
with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance
and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as
glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and
induce slowing of gastric emptying and feelings of satiety – which result in reduced food intake and weight loss.
Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address
beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the
CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1
receptor–dependent and –independent mechanisms. If these initial findings are confirmed in larger clinical trials,
GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.
Keywords: cardiovascular, endothelial, glucagon-like peptide-1, incretin, type 2 diabetes
The Pathophysiology and Consequences of
Vascular Complications in Diabetes
Individuals with type 1 or type 2 diabetes are at significantly greater risk of cardiovascular (CV) and cerebrovascular disease, and vascular-related mortality, than
age-matched individuals without diabetes. Because of
the multisystem complications of atherosclerosis, which
primarily affects the coronary arteries, lower limb vasculature and extracranial carotid arteries, the overall
mortality rate among individuals with diabetes is approximately double that of non-diabetic people of the same age
[1]. Diabetes is associated with a two- to fourfold
increased risk of CV death and stroke [1], and a followup study to the World Health Organization Multinational Study of Vascular Disease in Diabetes, including
data from 4713 subjects, found CV disease to be the
most common underlying cause of mortality in adults
with diabetes, accounting for 44 and 52% of deaths in
individuals with type 1 and type 2 disease respectively
[2]. When vascular disease was excluded as a cause of
death in a cohort of subjects with diabetes in Edinburgh,
only 2% of deaths could be attributed directly to diabetes, in contrast to the >66% of individuals with diabetes
whose deaths were attributed to vascular disease [3].
While chronic hyperglycaemia is a core risk factor for
CV disease, individuals with diabetes frequently have
additional risk factors including obesity associated with
insulin resistance, dyslipidaemia and hypertension.
Three relevant factors that predispose arteries to atherosclerosis in individuals with diabetes are chronic hyperglycaemia, dyslipidaemia and insulin resistance [4]. Chronic
Correspondence:
Åke Sjöholm, MD, PhD, Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research,
Karolinska Institutet, SE-118 83 Stockholm, Sweden.
E-mail:
[email protected]
Conflicts of interest:
Professor Sjöholm has received research grants, speaker fees and consultancy honoraria for expert testimony from GlaxoSmithKline,
Schering-Plough, Roche Pharmaceuticals, Novo Nordisk, Eli Lilly, Novartis, sanofi-aventis, Bristol-Myers Squibb, Servier, Sankyo, Merck
Sharp & Dohme, Cynchron AB, Rheoscience, Johnson & Johnson, Pfizer, Boehringer Ingelheim, Selena Fournier, Roche Diagnostics,
Astra-Zeneca, Bayer, and Pharmacia. He is also on national and global advisory boards for Eli Lilly, Novartis, and Merck Sharp & Dohme.
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Impact of GLP-1 on endothelial function
hyperglycaemia differentially impairs cells that are unable
to reduce their internal glucose concentrations sufficiently in the face of hyperglycaemia, a deficit accounted
for through four main mechanisms: increased use of the
polyol pathway, increased production of advanced glycation end products (AGEs), activation of the enzyme protein kinase C (PKC) and increased utilization of the
hexosamine pathway [5]. Within the polyol pathway,
intracellular hyperglycaemia causes the enzyme aldose
reductase to reduce glucose to sorbitol, consuming cofactor NADPH in the process. As NADPH is essential for
regenerating the intracellular antioxidant reduced glutathione, reduced amounts of NADPH increase cellular vulnerability to oxidative stress. Increased synthesis of AGEs
damages cells by modifying intracellular proteins, alters
signalling between the extracellular matrix and the cell
itself and modifies proteins circulating in the blood.
These combined actions result in production of inflammatory cytokines and growth factors. Activation of PKC has
wide-ranging consequences, including increased vascular permeability, capillary occlusion and increased
proinflammatory gene expression [5] (figure 1). Lastly,
increased flow through the hexosamine pathway results
in alteration in gene expression that favours pathological
changes that damage the vasculature.
The Incretin Hormone Glucagon-like Peptide-1
and Its Effects on Hyperglycaemia
The incretin hormones, including glucagon-like peptide-1
(GLP-1), are secreted from the gastrointestinal tract
within minutes of food intake, through a combination of
endocrine and neural mechanisms, causing the glucosedependent secretion of insulin as well as numerous other
A. Sjöholm
metabolic effects that reduce hyperglycaemia and induce
satiety [6–21] (table 1). In healthy individuals, up to
75% of postprandial insulin release may be attributable
to incretin hormones such as GLP-1, confirming their
central role in glucose homoeostasis [22]. Through its
ability to lower hyperglycaemia, GLP-1 is likely to have
indirect beneficial effects on endothelial cell function
through a reduction in the utilization of the polyol pathway in PKC activation and in AGE formation (figure 1).
Direct Effects of GLP-1 on the CV System
In addition to improving CV function through reduced
hyperglycaemia, food intake and weight loss, GLP-1 also
has direct effects on the CV system. Native GLP-1 and
GLP-1 receptor antagonists appear to exert a protective
effect on the myocardium, improve endothelial function,
reduce the expression of biomarkers associated with CV
risk and decrease blood pressure through improvements
in diuresis and natriuresis.
Effects of GLP-1 on the Myocardium
GLP-1 is known to induce antiapoptotic signalling pathways through phosphoinositide 3-kinase (PI3 kinase) and
mitogen-activated protein kinases. As these kinases are
known to afford protection against myocardial injury, it
would suggest that GLP-1 receptor agonists could have
direct protective effects on myocardial cells. One study
that supports this hypothesis demonstrated that
native GLP-1 protected against heart ischaemia/reperfusion injury in rats [23]. The study suggested GLP-1induced myocardial protection was mediated through
the GLP-1 receptor pathway (utilizing a cyclic AMP
Fig. 1 Hyperglycaemia has wide-ranging damaging consequences for vascular integrity and blood flow. Adapted and
reprinted with permission from Brownlee [5]. AGEs, advanced glycation end products; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; NF-kB, nuclear factor kB; PAI-1, plasminogen activator inhibitor; PKC, protein kinase C; ROS,
reactive oxygen species; TGF-b, transforming growth factor-b; VEGF, vascular endothelial growth factor.
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Table 1 Metabolic effects of glucagon-like peptide-1
Effects on glucose metabolism
Glucose-dependent stimulation
of insulin secretion
Restoration of the biphasic
insulin response
Enhanced incretin effect
Glucose-dependent suppression
of glucagon secretion
Effects on appetite and satiety
Slowed gastric emptying
Appetite suppression
Weight loss
Effects on beta cells
Increased pancreatic beta-cell mass
Sample supporting
references
[7–9]
[10,11]
[12,13]
[14,15]
[15,16]
[15,17–19]
[16,18]
[20,21]
(cAMP)-dependent signalling mechanism) and involved
the antiapoptotic signalling through PI3 kinase and
mitogen-activated protein kinases [23]. The protective
effect on myocardial cells following the addition of
exogenous GLP-1 required co-administration of a dipeptidylpeptidase-4 (DPP-4) inhibitor; however, administration of a DPP-4 inhibitor alone demonstrated no
protective effect on myocardial cells. These data suggest
that the myocardial protective effect of GLP-1 may require
the supraphysiological concentrations provided by GLP-1
analogues/mimetics rather than the physiological levels
provided by treatment with DPP-4 inhibitors; however,
this would need to be confirmed in further studies.
Liraglutide has also demonstrated a beneficial effect on
myocardial infarction in a mouse model [24], which was
associated with increased cardioprotective gene expression, reduced infarct size and cardiac rupture and
improved survival vs. the placebo group (80 vs. 40% survival, p ¼ 0.0001; figure 2) [25]. Again, GLP-1 induced
prosurvival kinases, in this case Akt (also known as protein kinase B) and glycogen synthase kinase 3b, and in
addition significantly downregulated the activity of
matrix metalloproteinase-9 in the infarct area (p ¼ 0.04).
In addition to animal studies, there has been one study
of GLP-1 in 10 patients following successful primary
angioplasty for acute myocardial infarction. Native GLP-1
administered intravenously for 72 h after successful
angioplasty improved left ventricular ejection fraction
and regional wall motion compared with 11 controls
[26]. In-hospital mortality was 27% (3/11) in the control group and 10% (1/10) in the GLP-1-treated group,
and hospital length of stay was significantly reduced
with GLP-1 (6.1 vs. 9.8 days, p < 0.02). The authors
felt that GLP-1 demonstrated significant benefits in
postmyocardial infarction and severe left ventricular
dysfunction, which warranted further study. In addi-
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Fig. 2 Liraglutide is associated with improved survival
and cardiac output in a mouse model of myocardial infarction. Adapted from Noyan-Ashraf et al. [25]. ns, not significant; PBS, phosphate-buffered saline; sham, myocardial
infarction not induced; **p ¼ 0.0001.
tion, they felt that it would be interesting to look at longer administration of GLP-1 following angioplasty for
myocardial infarction to see if additional clinical benefits could be conferred.
Effects of GLP-1 on Endothelial Function and CV
Risk Biomarkers
Individuals with type 2 diabetes generally show signs of
endothelial dysfunction; however, whether this is a
specific association or related to other co-morbidities
such as obesity, hypertension, hyperlipidaemia or insulin resistance has been the subject of debate. There
is evidence, however, of specific impairment of
endothelial-dependent vasodilation in type 2 diabetes
that was independent of obesity, suggesting the possibility of a specific association [27].
GLP-1 receptor antagonists may have beneficial effects
on endothelial function. Native GLP-1 improved endothelial-dependent vasodilation in patients with type 2
diabetes but not in healthy subjects [28]. In addition,
GLP-1 enhanced acetylcholine-induced vasodilation in
healthy, non-diabetic, normotensive non-smokers [29].
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Impact of GLP-1 on endothelial function
Interestingly, this beneficial effect on vasodilation was
abrogated by the sulphonylurea glibenclamide but not
by glimepiride. Further work is required on the clinical
benefits of GLP-1 receptor agonists on endothelial function and the potential impact of combination therapy
with sulphonylureas on this function.
In addition, to measuring blood flow and vascular reactivity to assess endothelial dysfunction, certain markers,
such as plasminogen activator inhibitor-1 (PAI-1) and
vascular cell adhesion molecule-1 (VCAM-1), are also
associated with endothelial dysfunction and increased
CV risk. In an in vitro human model, liraglutide inhibited the expression of hyperglycaemia-induced PAI-1
and VCAM-1 expression, suggesting the possibility of
a beneficial effect of liraglutide on endothelial dysfunction [30]. Similar data were reported by Courrèges et al.
[31], who examined the effect of liraglutide on CV risk
biomarkers as an exploratory end-point in a trial by
Vilsbøll et al. [32] in patients treated with various doses
of liraglutide compared with placebo. Liraglutide
(1.90 mg/day) improved PAI-1 (25%, p < 0.05),
B-type natriuretic peptide (38%, p < 0.01), C-reactive
protein (20%, p ¼ not significant) and triglycerides
(22%, p ¼ 0.01). In addition, a separate study demonstrated that the GLP-1 mimetic, exenatide, significantly
reduced triglycerides by 26% (p ¼ 0.01) and C-reactive
protein by 34% (p ¼ 0.05) [33]. These data suggest that
GLP-1 receptor agonists have the potential to benefit
endothelial function and CV risk.
Effects of GLP-1 on Systolic Blood Pressure
Vascular complications cause the majority of deaths and
complications in individuals with diabetes. Studies have
demonstrated that raised blood pressure increases
patients’ risk for CV events and mortality, and treatments
that reduce blood pressure can reduce these risks [34–36].
For example, a reduction of 5.6 mmHg in systolic blood
pressure and 2.2 mmHg in diastolic blood pressure has
been shown to result in an 18% reduction in deaths
from CV disease [36]. Liraglutide treatment in the six
Liraglutide Effect and Action in Diabetes trials resulted
in reductions in systolic blood pressure of between 2.50
and 6.58 mmHg, suggesting that GLP-1 receptor agonists
have clinically relevant effects on blood pressure in
individuals with diabetes [37–42] (table 2).
Proposed Dual Pathway of GLP-1 Action on
the CV System
Two recent studies in animal models have suggested a role
for the GLP-1 metabolite GLP-1 (9–36) in mediating CV
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effects independent of the GLP-1 receptor [43,44]. GLP-1
(9–36) is produced following the cleavage of GLP-1 by
DPP-4. These metabolites are unable to activate the
GLP-1 receptor and have no insulinotrophic activity. In
the Ban et al. study, the effects of GLP-1 and its metabolite [GLP-1 (9–36)] were investigated in wild-type and
GLP-1 receptor knockout mice [43]. The authors demonstrated GLP-1 receptor expression in cardiomyocytes,
endocardium, microvascular endothelium and coronary
smooth muscle cells but not in cardiac fibroblasts. In
wild-type mice, GLP-1, acting through the GLP-1 receptor, had an inotropic action on heart muscle by inducing
a increase in left ventricular diastolic pressure, induced
glucose uptake, increased functional recovery and cardiomyocyte viability after ischaemia/reperfusion injury and
had a mild vasodilatory function. In contrast, while the
GLP-1 metabolite, GLP-1 (9–36), did not appear to have
an inotrophic action, it did act through a GLP-1 receptor–
independent but nitric oxide/cyclic GMP–dependent
pathway to induce modest glucose uptake and had a positive effect on postischaemic recovery of cardiac function
and vasodilation.
A second study in a rat model of ischaemia/reperfusion injury also suggested that GLP-1 receptor may have
a dual action through a GLP-1 receptor–dependent and
–independent pathway [44]. Exendin-4, a GLP-1 receptor agonist, showed a significant effect on reducing
infarct size (33.2 vs. 14.5%, p < 0.05), and this beneficial effect was abolished by a GLP-1 receptor antagonist. In contrast, GLP-1 (9–36) had no effect of
infarct size but did have an inotropic action on heart
muscle as did extendin-4 [44].
Although further work is required to identify the receptor for GLP-1 (9–36) in cardiac tissue, these studies provide an interesting initial insight into a potential dual
mechanism of action for GLP-1 that may make it a potentially useful preconditioning and/or postconditioning
agent in clinical setting such as acute myocardial infarction treatment or coronary bypass grafting.
Conclusions
In vitro studies, animal models and clinical studies suggest that native GLP-1 and GLP-1 receptor agonists such
as liraglutide and exenatide have beneficial effects on
endothelial dysfunction and cardiac function and can
reduce systolic BP. In addition, GLP-1 metabolites such
as GLP-1 (9–36) have demonstrated GLP-1 receptor–
independent effects on CV function. It will be of great
interest to observe whether these promising data will
translate into a proven CV benefit for GLP-1 receptor
antagonists.
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Table 2 SBP reductions associated with liraglutide treatment
Liraglutide
Comparator
Reduction in
SBP (mmHg)
Study
Dose (mg)
LEAD-1 [37], all subjects received glimepiride
1.8
LEAD-2 [38], all subjects received metformin
LEAD-5 [41], all subjects received metformin and glimepiride
1.2
1.8
1.8
1.2***
1.8****
1.8
2.56
2.81
2.81*
2.29*
3.64**
6.71
5.65
3.97***
LEAD-6 [42], all subjects received metformin and/or a sulphonylurea
1.8
2.51
LEAD-3 [39]
LEAD-4 [40], all subjects received metformin and rosiglitazone
Dose
Reduction in
SBP (mmHg)
Rosiglitazone (4 mg)
0.93
Glimepiride (4 mg)
þ0.41
Glimepiride (4 mg)
Placebo
0.69
1.11
Insulin glargine [titrated to
achieve 5.5 mmol/l
(100 mg/dl) FPG target]
Exenatide (10 mg twice daily)
þ0.54
2.00
FPG, fasting plasma glucose; LEAD, Liraglutide Effect and Action in Diabetes ; SBP, systolic blood pressure.
p values for liraglutide vs. comparators: *p < 0.05, **p ¼ 0.0117, ***p < 0.0001, ****p ¼ 0.0009.
Acknowledgements
I gratefully acknowledge the effort, intellectual input
and creative stimulation by my associates at the KISÖS
Unit for Diabetes Research, in particular Drs Thomas
Nyström, Qimin Zhang, David Nathanson, Özlem
Erdogdu, Hanna Dahlin, Ulrika Löfström, Carin Cabrera, Caroline Simberg, Marie Guldstrand, Björn Rathsman and Anna Kernell. Financial support for our own
work cited herein was provided through the regional
agreement on medical training and clinical research
between Stockholm county council and the Karolinska
Institutet and also financially supported by Stiftelsen
Olle Engkvist Byggmästare, an unrestricted medical
school grant from Merck Sharp & Dohme, a European
Foundation for the Study of Diabetes/Servier research
grant, the Juvenile Diabetes Research Foundation, Karolinska Institutet, the Janne Elgqvist Family Foundation, the Swedish Society of Medicine, the Sigurd and
Elsa Golje Memorial Foundation, Svenska Försäkringsföreningen, Svenska Diabetesstiftelsen, Åke Wiberg’s
Foundation, Trygg-Hansás Research Foundation and
Tore Nilson’s Foundation for Medical Research and is
gratefully acknowledged. Novo Nordisk A/S provided
financial support for this publication. Editorial assistance was provided by Watermeadow Medical on behalf
of Novo Nordisk A/S.
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