Pharmacology & Pharmacy, 2013, 4, 647-650
Published Online December 2013 (http://www.scirp.org/journal/pp)
Open Access PP
Pleiotropic Effects of GLP-1. Cardiovascular Evidence of
Pedro Pujante Alarcón1, Ana Belén Hernández Cascales1, Alfonso López Ruiz2,
María Ángeles Ibañez Gil3, Alicia Hernández Torres4, María Dolores Hellín Gil1
1Endocrinology and Nutrition Service of the Hospital University Virgen de la Arrixaca, Murcia, Spain; 2Pharmaceutical Care
Research at the University of Granada, Granada, Spain; 3Health Center Mariano Yago, Yecla, Murcia, Spain; 4Infectious Internal
Medicine of the Hospital University Virgen de la Arrixaca, Murcia, Spain.
Received September 8th, 2013; revised October 16th, 2013; accepted October 29th, 2013
Copyright © 2013 Pedro Pujante Alarcón et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Patients with diabetes are characterized by the development of cardiovascular complications: nephropathy, retinopathy,
neuropathy, ischemia or hypertensive etc. Therefore, the cardiovascular involvement is the leading cause of death in
patients with Diabetes Mellitus type 2 (DM2). Despite intensive treatment on classical factors of cardiovascular disease
(blood pressure levels, LDL cholesterol, etc.), patients with diabetes have a high number of cardiovascular events and
the onset and prognosis of these are related to glycemic control parameters, glycosylated hemoglobin (HbA1c). On the
other hand, the question of the cardiovascular protective effect of some hypoglycemic treatments has been raised, ask-
ing what he has done to know more accurately about the safety and cardiovascular effects of the treatments we have
today. The two most important incretin hormones are GIP (gastric inhibitory polypeptide) and GLP-1 (glucagon-like
peptide-1). Treatment based on GLP-1 is a novel weapon in T2DM that achieves a reduction in HbA1c with other
metabolic effects: weight loss and extra effect in dyslipidemia and blood pressure. In the last years other beneficial ac-
tions such a protector effect against myocardium ischemia and other actions in basals were reported. In this article we
will try to explain the evidence of GLP-1 treatments and its cardiovascular effects.
Keywords: GLP-1; T2DM; Myocardium Ischemia
The incidence of type 2 diabetes is a health problem now
and with future prospects uncertain. It is estimated to
reach 300 million diabetic patients in the coming years
. Patients with diabetes are characterized by the de-
velopment of cardiovascular complications: nephropathy,
retinopathy, neuropathy, ischemia or hypertensive etc.
. Therefore, the cardiovascular involvement is the
leading cause of death in patients with Diabetes Mellitus
type 2 . Despite intensive treatment on classical fac-
tors of cardiovascular disease (blood pressure levels,
LDL cholesterol, etc.), patients with diabetes have a high
number of cardiovascular events and the onset and prog-
nosis of these are related to glycemic control parameters,
glycosylated hemoglobin (HbA1c) .
On the other hand, it has raised the question of the
cardiovascular protective effect of some hypoglycemic
treatments, rosiglitazone, [5,6] asking what he has done
to know more accurately about the safety and cardiovas-
cular effects of the treatments we have today.
The incretin effect is known as the amplification of the
insulin response that occurs after oral ingestion of glu-
cose in the administration of an equivalent amount intra-
venously. This effect is responsible for up to 60% of the
increase in insulin secretion after ingesta .
Incretins are intestinal peptides original in response to
intake. Among its effects include stimulation of insulin
production, suppression of glucagon thereby reducing
hepatic glucose production and inhibition of β-cell apop-
tosis . Nauck et al. , showed in 1986 that the in-
cretin effect was decreased in patients with type 2 diabe-
tes because they decrease in the concentrations of GLP-1
Pleiotropic Effects of GLP-1. Cardiovascular Evidence of Effectiveness
(and GIP), after ingestion. Its efficacy is mediated by its
action on GLP-1 receptor abundantly expressed in the
gastrointestinal tract but may be present also in pancre-
atic tissue, lung and stomach, nervous system, heart,
vascular smooth muscle cells and macrophages. For this
reason, besides the already mentioned hypoglycemic
effect, GLP-1 effects are attributed regulation about the
appetite, decreased gastric emptying, increased periph-
eral insulin sensitivity, as well as neuro and cardiopro-
tective effects [4,10]
Thus, treatments aimed at acquiring an incretin effect
have been for many years an attractive therapeutic target
that nowadays is part of our medical arsenal. Also we
have drugs GLP-1 analogues resistant to inactivation of
the enzyme DPP-4 (liraglutide), incretin mimetics resis-
tant to DPP-4 (exenatide) and inhibitors of the enzyme
DPP-4 (vildagliptin, siltagliptin, saxagliptin).
3. GLP-1 and Cardiovascular Risk Factors
Exenatide has shown a reduction of about 1% in HbA1c
in patients without prior treatment or with sulfonylureas
and metformin alone or in combination. It also adds a
beneficial effect on fasting blood glucose and postpran-
dial glucose [11-14], with a reduction in weight up to 5.3
kg in those studies for 3 years . Similarly Liraglutide
reduces HbA1c over 1% in patients with different com-
binations of antidiabetic orales [16-18] and even com-
pared to glargine insulin  with a beneficial effect on
weight. In those studies comparing the effect of liraglu-
tide vs. exenatide, liraglutide shows a greater reduction
in HbA1c (−1.12% vs. 0.79%, P < 0.05) with similar ef-
fect on weight loss (3 kg approximately) in 26 studies
Furthermore, liraglutide and exenatide have shown a
reduction in cardiovascular risk factors including dyslip-
idemia and blood pressure. In a meta-analysis of 6 stud-
ies performed more than 2000 patients exanatide showed
a reduction systolic (SBP) without changes in diastolic
blood pressure (DBP). This effect could not be explained
completely by weight loss . Liraglutide has demon-
strated in the 6 studies LEAD a reduction of 2.5 mmHg
SBP. This effect has been demonstrated in the first 2
weeks before the weight loss . Regarding the lipid
profile exenatide has demonstrated a decrease in the
concentration of triglycerides by 12%, 5% total choles-
terol, LDL 6% and increased HDL cholesterol by 24% in
studies conducted at 3 years.
In addition to these cardiovascular effects have been
reported in animal studies and human in vitro different
actions of analogues of GLP-1 on macrophages and
monocytes by decreasing their accumulation in athero-
sclerotic plaques and reducing production of inflamma-
tory mediators such as TNF-α or CD11b expression .
4. GLP-1 in the Cardiovascular System
Different studies in healthy patients have been con-
ducted to determine the effect of acute or chronic analogs
of GLP-1 in the endothelium. First, the acute treatment
has been shown to increase blood flow to endothe-
lium-dependent vascular level in non diabetic patients
 and in diabetics with stable coronary disease .
Moreover chronic treatment with GLP-1 analogs has
shown improvement in endothelial function and vaso-
constriction in rats diabetes induced with estreptozocine
. In addition, some studies suggest that this im-
provement in endothelial dysfunction provides vasodila-
tion and improved blood flow to areas distal, common
site for the development of complications associated with
diabetes . One of the potential mechanisms by which
GLP-1 analogs affect the vascular tree is due to the re-
duction of the toxic effect of glucose on the endothelial
cell. GLP-1 has been shown to decrease the deleterious
effect of advanced glycation products (AGE) in the en-
Most studies designed to determine the effect of
GLP-1 on cardiovascular function have focused on mod-
els of ischemia and reperfusion. Studies in vivo and in
vitro with cardiomyocytes in mice have shown that after
a period of ischemia and subsequent reperfusion, the
mice treated with GLP-1 analogs significantly reduce the
size of the infarct zone post-ischemia improve cardiac
contractility, systolic function and diastolic function .
Similar experiments have given similar results in canine
models of dilated cardiomyopathy  and porks . In
humans, a small, non-randomized study in patients, most
non-diabetics, who had undergone coronary revasculari-
zation after acute myocardial infarction and to which he
had been given an infusion of GLP-1 analogs for 72
hours, an improvement in ejection fraction and better left
ventricular myocardial contractility had been reported. In
this sense Sokos et al.  selected 20 patients who un-
derwent aortocoronary bypass and who infused GLP-1
analogues. Observed in the treated group that the use of
vasoactive or inoprotic drug was lower and there were
fewer arrhythmias. In additional studies, infusion of
GLP-1 analogs for 48 hours in patients non-diabetics and
heart failure reduced fasting glucose levels and insulin
levels increased compared to placebo associated with an
increased heart rate and blood pressure but no impact
The mechanism by which it acts is not clarified. It is
thought that the myocardium after ischemia increases
glucose uptake. This increase improves glucose oxida-
tion and producing more ATP than from the free fatty
acids. In addition to this increased supply of glucose to
Open Access PP
Pleiotropic Effects of GLP-1. Cardiovascular Evidence of Effectiveness 649
myocardial ischemia occurs a minor ischemic damage.
That has been regarded as a cardioprotective effect of the
myocardium with consequent smaller necrosis  zone.
What we do not known if this action is mediated by
GLP-1 receptor exclusively or by an intermediate me-
tabolites such GLP-1 (9 - 36), an antagonist receptor
have also shown beneficial effect after isquemia .
Therapies based on incretins, GLP-1 have proven to be
an effective treatment for glycemic control with very
beneficial effects on weight, blood pressure and lipid
profile. Moreover, although the results are preliminary,
we observe a beneficial effect on associated complica-
tions of DM2. The modifications to the atherosclerotic
plaques and improving endothelial dysfunction make us
foresee a very beneficial effect on cardiovascular disease
prevention. On the other hand, with the data in models of
ischemic heart disease, and the cardioprotective effect of
GLP-1, demonstrated in animal and human experiments,
we do consider the possibility of a beneficial effect be-
yond the treatment of cardiovascular risk factors. How-
ever, the data in the treatment in diabetes and heart fail-
ure are not as conclusive. In these patients, we must not
forget the side effects of current therapies against type 2
diabetes: the water retention of glitazons and insulin or
the contraindicated indication of metformin in patients
with renal failure. Although larger, prospective, random-
ized studies are needed in order to determine the safety
of GLP-1 analogs in heart failure, we can not discard
them when planning the best treatment for this kind of
 H. King, R. E. Aubert and W. H. Herman, “Global Bur-
den of Diabetes, 1995-2025: Prevalence, Numerical Es-
timates and Projections,” Diabetes Care, Vol. 21, No. 9,
1998, pp. 1414-1431.
 R. S. Clements Jr. and D. S. Bell, “Complications of
Diabetes. Prevalence, Detection, Current Treatment and
Prognosis,” American Journal of Medicine, Vol. 79, No. 5,
1985, pp. 2-7.
 Scandinavian Simvastatin Survival Study Group, “Ran-
domised Trial of Cholesterol Lowering in 4444 Patients
with Coronary Heart Disease: The Scandinavian Simvas-
tatin Survival,” Lancet, Vol. 344, No. S4, 1994, pp. 1383-
 M. Davidson, “Cardiovascular Effects of Glucagonlike
Peptide-1 Agonists,” American Journal of Cardiology,
Vol. 108, No. 3, 2011, pp. 33B-41B.
 The ADVANCE Collaborative Group, “Intensive Blood
Glucose Control and Vascular Outcomes in Patients with
Type 2 Diabetes,” New England Journal of Medicine, Vol.
358, No. 24, 2008, pp. 2560-2572.
 J. Hsai, J. D. Otvos, J. E. Rossouw, L. Wu, S. Was-
sertheil-Smoller, S. L. Hendrix, J. G. Robinson, B. Lund,
L. H. Kuller and Women’s Health Initiative Research
Group, “Lipoprotein Particle Concentrations May Explain
the Absence of Coronary Protection in the Women’s
Health Initiative Hormone Trials,” Arteriosclerosis, Throm-
bosis, and Vascular Biology, Vol. 28, No. 9, 2008, pp.
 M. J. Perley and D. M. Kipnis, “Plasma Insulin Re-
sponses to Oral and Intravenous Glucose: Studies in
Normal and Diabetic Subjects,” Journal of Clinical In-
vestigation, Vol. 46, No. 12, 1967, pp. 1954-1962.
 D. J. Drucker, “The Biology of Incretin Hormones,” Cell
Metabolism, Vol. 3, No. 3, 2006, pp. 153-165.
 M. Nauck, F. Stockmann, R. Ebert and W. Creutzfeldt.
“Reduced Incretin Effect in Type 2 (Non-Insulin-De-
pendent) Diabetes,” Diabetologia, Vol. 29, No. 1, 1986,
pp. 46-52. http://dx.doi.org/10.1007/BF02427280
 D. J. Grieve, S. C. Roslyn and B. D. Green, “Emerging
Cardiovascular Actions of the Incretin Hormone Gluca-
gon-Like Peptide-1: Potencial Therapeutic Benefits be-
yond Glycaemic Control?” British Journal of Pharma-
cology, Vol. 157, No. 8, 2009, pp. 1340-1351.
 T. J. Moretto, D. R. Milton, T. D. Ridge, et al., “Efficacy
and Tolerability of Exenatide Monotherapy over 24
Weeks in Antidiabetic Drug-Naive Patients with Types 2
Diabetes: A Randomized, Double-Blind, Placebo-Con-
trolled, Parallel-Group Study,” Clinical Therapeutics, Vol.
30, 2008, pp. 1448-1460.
 R. A. De Fronzo, R. E. Ratner, J. Han, D. D. Kim, M. S.
Fineman and A. D. Baron, “Exenatide (Exendín-4) on
Glycemic Control and Weight over 30 Weeks in Meth-
formin-Treated Patients with Type 2 Diabetes,” Diabetes
Care, Vol. 28, 2005, pp. 1092-1100.
 J. B. Buse, R. R. Henry, J. Han, D. D. Kin, M. S. Fine-
man and A. D. Baron, “Exenatide-113-Clinical Study
Group. Effects of Exenatide (Exendín-4) on Glycemic
Control over 30 Weeks in Sulfonylurea-Treated Patients
with Type 2 Diabetes,” Diabetes Care, Vol. 27, 2004, pp.
 D. M. Kendall, M. C. Riddele, J. Rosenstock, et al., “Ef-
fects of Exenatide (Exendín-4) on Glycemic Control over
30 Weeks in Patients with Type 2 Diabetes Treated with
Metformin and Sulfonylurea,” Diabetes Care, Vol. 28,
No. 5, 2005, pp. 1083-1091.
 D. M. Klonoff, M. C. Riddle, J. Rosenstock, et al.,
“Exenatide Effects on Diabetes, Obesity Cardiovascular
Risk Factors and Hepatic Biomarkers in Patients with
Open Access PP
Pleiotropic Effects of GLP-1. Cardiovascular Evidence of Effectiveness
Open Access PP
Type 2 Diabetes Treated for at Least 3 Years,” Current
Medical Research and Opinion, Vol. 24, 2008, pp. 275-
 A. Garber, R. Henry, R. Ratner, et al., “Liraglutide versus
Glimepiride Monotherapy for Type 2 Diabetes (LEAD-3
Mono): A Randomised 52 Weeks, Phase III, Double-
Blind, Paralle-Treatment Trial,” Lancet, Vol. 373, No.
9662, 2009, pp. 473-481.
 M. Nauck, A. Frid, K. Hermansen, et al., “Efficacy and
Safesty Comparison of Liraglutide, Glimpiride and Placebo
All in Combination with Metformin in Type 2 Diabetes,”
Diabetes Care, Vol. 32, No. 1, 2009, pp. 84-90.
 B. Zinman, J. Gerich, J. B. Buse, et al., “Efficacy and
Safety of the Human GLP-1 Analog Liraglutide in Com-
bination with Metformin and TZD in Patients with Type 2
Diabetes (LEAD-4-Met + TZD),” Diabetes Care, Vol. 32,
2009, pp. 1224-1230.
 D. Russell-Jones, A. Vaag, O. Schmitz, et al., “Liraglu-
tide vs Insulin Glargine and Placebo in Combination with
Metformin and Sulphonylurea Therapy in Type 2 Diabe-
tes Mellitus: A Randomised Controlled Trial(LEAD-5
met + SU),” Diabetología, Vol. 52, No. 10, 2009, p. 2046.
 J. Buse, J. Rosenstock, G. Sesti, et al., “A Study of Two
Glucagon-Like Peptide-1 Receptor Agonists for the
Treatment of Type 2 Diabetes: Liraglutide Once Daily
Compared with Exenatide Twice Daily in a Randomised
26 Weeks, Open-Label Trial(LEAD-6),” Lancet, Vol. 374,
2009, pp. 39-47.
 T. Okerso, P. Yan, A. Stonehouse and R. Brodows, “Ef-
fects of Exenatide on Systolic Lood Pressure in Subjects
with Type 2 Diabetes,” American Journal of Hyperten-
sion, Vol. 23, No. 3, 2010, pp. 334-339.
 L. Blonde and D. Russell-Jones, “The Safety and Efficacy
of Liraglutide with or without Oral Antidiabetic Drug
Therapy in Type 2 Diabetes: An Overview of the LEAD
1-5 Studies,” Diabetes, Obesity and Metabolism, Vol. 11,
Suppl. 3, 2009, pp. 26-34.
 M. Arakawa, T. Mita, K. Azuma, C. Ebato, H. Goto, T.
Nomiyama, Y. Fujitani, T. Horise, R. Kawamori and H.
Watada, “Inhibition of Monocyt Adhsion to Endothelial
Cells and Attenuation of Atherosclerotic Lesion by a
Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4,”
Diabetes, Vol. 59, No. 4, 2010, pp. 1030-1037.
 A. Basu, N. Charkoudian, W. Schrage, R. A. Rizza, R.
Basu and M. J. Joyner, “Benefial Effects of GLP-1 on
Endothelial Function in Humans: Dampening by Gly-
buride but Not by Glimepiride,” Endocrinology and Me-
tabolism—American Journal of Physiology, Vol. 293,
2005, pp. E1289-E1295.
 T. Nyström, M. K. Gutniak, F. Zhan, J. J. Holst, B. Ahrén
and A. Sjöholm, “Effects of Glucagon-Like Peptide-1 on
Endothelial Function in Type 2 Diabetes Patients with
Stable Coronary Artery Disease,” Endocrinology and
Metabolism—American Journal of Physiology, Vol. 287,
2004, pp. E1209-E1215.
 S. Ozyazgan, N. Kutluta, S. Afsar, S. B. Ozdas and A. G.
Akkan, “Effect of Glucagon-Like Peptide-1(7-36) and
Exendin-4 on the Vascular Reactivity in Streptozotocin/
Nicotinamide-Induced Diabetic Rats,” Pharmacology, Vol.
74, No. 3, 2005, pp. 119-126.
 Y. Ishibashi, T. Matsui, M. Takeuchi and S. Yamagishis,
“Glucagon-Like Peptide-1 (GLP-1) Inhibits Advance
Glycation End Product (AGE)-Induced Up-Regulation of
VCAM-1 mRNA Levels in Endothelial Cells by Sup-
pressing AGE Receptor (RAGE) Expression,” Bioche-
mical and Biophysical Research Communications, Vol.
391, No. 3, 2010, pp. 1405-1408.
 D. P. Sonne, T. Engstrom and M. Treiman, “Protetive
Effects of GLP-1 Analogues Exendin-4 and GLP-1 (9-36)
Amide against Ischemiareperfusion Injury in Rat Heart,”
Regulatory Peptides, Vol. 146, No. 1-3, 2008, pp. 243-
 L. A. Nikoladis, D. Elahi, Y. T. Shen and R. P. Shannon,
“Active Metabolite of GLP-1 Mediates Myocardial Glu-
cose Uptake and Improve Left Ventricular Performance
in Conscious Dogs with Dilated Cariomyopathy,” Heart
and Circulatory Physiology—American Journal of Physi-
ology, Vol. 289, 2005, pp. H2401-H2408.
 L. Timmer, J. P. Henriques, D. P. De Klein, J. H. Devries,
H. Kemperman, P. Steendijk, et al., “Exenatide Reduces
Infarcts Size and Improves Cardiac Function in a Porcine
Model of Ischemia and Reperfusion Injury,” Journal of
the American College of Cardiology, Vol. 53, No. 6, 2009,
pp. 501-510. http://dx.doi.org/10.1016/j.jacc.2008.10.033
 G. G. Sokos, H. Bolukoglu, J. German, T. Hentosz, G. J.
Magovern, T. D. Maher, D. A. Dean, S. H. Bailey, G.
Marrone, D. H. Benckart, D. Elaine and R. P. Shannon,
“Effect of Glucagon-Like Peptide-1 (GLP1) on Glycemic
Control and Left Ventricular Function in Patients Under-
going Coronary Artery Bypass Grafting,” American Jour-
nal of Cardiology, 2007, pp. 824-829.
 M. H. Noyan-Ashraf, M. A. Momen, K. Ban, A. M. Sadi,
Y. Q. Zhou, A. M. Riazi, L. L. Baggio, R. M. Henkelman,
M. Husain and D. J. Drucker, “GLP-1R Agonist Liraglu-
tide Activates Cytoprotective Pathways and Improves
Outcomes after Experimental Myocardial Infaction in
Mice,” Diabetes, Vol. 58, No. 4, 2009, pp. 975-983.