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DIABETES & CARDIOVASCULAR RISK | DRUG REVIEW
Advances In Averting Cardiovascular Anomalies To Diabetes
Abdalla M. El-Mowafy, Mansoura University, Mansoura 35512, Egypt
Submission date: 06/09/2009, Revision date: 10/10/2009, Acceptance date: 10/10/2009
Keywords: CVD in diabetes, new drugs for diabetes, diabetes-evoked CVD
Cardiovascular disease (CVD) is a prime killer in patients with diabetes. Paradoxically, improvements
in fighting CVD have not tangibly been seen in patients with diabetes.1 This can be attributed to
multiple pathophysiological triggers of CVD in diabetes, shortcomings with current CV-treatments
or adverse reactions to drugs used to restore normoglycaemia (mainly hypoglycaemia). Therefore,
experts and regulatory authorities have suggested that new drugs for diabetes will need to
demonstrate cardiovascular safety before approval, either by not showing a signal for cardiovascular
risk or through long-term clinical trials. On the other hand, the role of tight glycaemic control in
reducing cardiovascular events and mortality in diabetes has not yet been firmly established, as
some recent clinical trials have yielded unexpected outcomes.1 Thus, recently, many clinical studies
have aimed to reveal the molecular underpinnings linking diabetes with cardiovascular disease in
most relevant tissues, hoping to develop new strategies against diabetes-evoked CVD. The newer
drugs that hold appreciable promise include:
1- Inhibitors of cross-linking (Advanced-
One way carnosine works is by scavenging for
glycation end-products; AGE-inhibitors):
free carbonyl groups. Carnosine is one of the
few cross-link inhibitors that is not only active
Advanced-glycation end-products (AGEs) are
against protein-to-protein cross-linking but also
carbonyl-protein cross-linked products that are
against protein-to-DNA cross-linking.4 Its mode
generated non-enzymatically in the diabetic
of action involves reacting with carbonylated
milieu, as a result of chronic hyperglycaemia
proteins (AGEs) to form carnosine-carbonyl-
and enhanced oxidative stress. They result in
the formation of large insoluble aggregates of
damaged proteins at many sites of the body
Conveniently, carnosine also stimulates and
including the heart and large blood vessels.2
enhances the process of proteolysis.5 Besides,
Further, AGEs, via direct and receptor (RAGE)-
carnosine has a direct antioxidant action, and it
also has a sparing effect on other antioxidants
promote the development and progression of
such as glutathione. It is also a strong chelator of
CVD through oxidative stress and inflammation
copper; thereby reducing the copper-mediated
via the NF-κB pathway and accumulation of
damage during AGE activity. At the clinical
extracellular matrix.2 These biological effects
level, carnosine reduced urinary products of
translate to accelerated vascular-plaque
free radical and glycosylation metabolism in
formation in diabetes as well as increased
cardiac fibrosis with consequent effects on
developments regarding carnosine is its ability
cardiac function. Strategies to reduce the ligation
to prevent and cure age-related cataract, and
of AGEs to their receptors include agents which
reduce AGE accumulation, soluble-RAGE which
eye conditions.7 In this instance, the form of
acts as a competitive antagonist to the binding
carnosine used is N-acetyl-carnosine. This
of AGEs to RAGE, and genetic deletions of RAGE;
curative action of carnosine is perhaps related
all appear to attenuate diabetes-evoked athero-
to its ability to stimulate proteolysis and thus
sclerosis. Specifically designed drugs, and luckily;
dissolve protein aggregates in the lens.
some conventional drugs that are already in
use, were found to reduce AGEs formation and
produce clinically sound alleviations of diabetic
complications. Some examples of these drugs
It is a standard anti-diabetic drug (dimethyl-
biguanide) that is used worldwide both against
insulin-dependent and against non-insulin-
primarily to increase peripheral sensitivity to
A dipeptide (beta alanyl- L-histidine) that is
insulin and lower blood glucose, metformin has
naturally found in muscle and nervous tissue.3
several other important actions. Strikingly, in
It has multiple actions and as such it has been
virtue of its guanido group, it binds/deactivates
called a pluripotent agent. Carnosine has been
carbonyl groups in the tissues, thus blocking
shown as one of the most promising cross-link
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I | NOVEMBER 2009
ADVANCES IN AVERTING CARDIOVASCULAR ANOMALIES TO DIABETES
One prominent process that is enhanced by glycation, and inhibited
Remarkably, these drugs elicited substantial hypolipidaemic
by metformin, is fibrin-evoked thrombosis. Thus, metformin was
effects, and abated both atherogenesis and inflammation in the CV
evidently shown to attenuate the risk of myocardial infarction (MI)
system.17 Molecular targets involved MAPKs, TNF-α, NF-κB IL-6 and
and stroke.8 Accordingly, in diabetes, metformin has a dual effect.
IL-1.18 Clinical trials are ongoing (InteKrin is undergoing phase 2b
It lowers blood glucose, (a well-known and established activity)
plus, as new research is revealing, it inhibits cross-linking through
carbonyl trapping. Not surprisingly, therefore; many clinicians now
5- Exenatide-related drugs (Increting secreting agents):
recommend that everybody who is over the age of 40 should be
taking metformin, as a preventative anti-AGE drug.
Incretin is an intestinal peptide that stimulates insulin release in
response to food, and suppresses glucagon signalling.19 Incretin
c) Aminoguanidine, Pyridoxamine, and Acarbose
secretion is enhanced by using agonists of the GLP1 receptor, a
class of G-protein-linked receptors, such as the natural peptide
These are three different drugs with established anti-AGEs effects,
exenatide and its synthesised congeners. Exenatide, a reptile-
of which aminoguanidine has structural similarity to metformin,
derived peptide that was approved for the management of
and acarbose is an already anti-diabetic drug. Pyridoxamine, a
type-II diabetes, showed beneficial glucose-homeostatic responses,
vitamer of Vitamin B6, reduces the formation of AGEs by 25-50%
enhanced insulin secretion/sensitivity, and promoted gastric
and ameliorates diabetes-related kidney dysfunction, (it improves
emptying/satiety and weight loss. It activates (GLP-1) in the gastro-
albuminuria, plasma creatinine and hyperlipidemia). It works by
intestinal tract, pancreas and the heart. Not surprisingly, GLP1
trapping both reactive carbonyl groups9 and free-radical species.10
activators triggered favourable responses in patients with coronary
Further, it inhibits both methylglyoxal and glycoaldehydes which
ischaemia, MI and heart failure.19,20 Accordingly, new congeners
are most active following lipid peroxidation. The methylgly-
of exenatide were introduced. A prominent such examples is
oxal-pyridoxamine dimmers formed are inactive can easily be
exendin 4, a long-acting GLP-I agonist, which also demonstrated
vasodilatory and anti-oxidative effects.20,21
2- Resveratrol (a red-grape/wine polyphenol) and
6- VPAC2-agonists (pancreatic cAMP elevators):
The neuroendocrine and metabolic hormones; pituitary adenylate
They were recently shown, via SIRT1 (a member of the sirtuin
cyclase-activating polypeptide (PACAP) and vasoactive intestinal
family of NAD+-dependent protein deacetylases) to improve
peptide (VIP) act on three G-protein-and adenylate cyclase-linked
whole-body glucose homeostasis and insulin sensitivity, fight
receptors (PAC1, VPAC1 and VPAC2). VPAC2 is expressed in the
senescence, maintain the integrity of vascular endothelium
pancreatic islet β-cells and its activation increases insulin secretion.22
and antagonise atherogenic effects due to oxidative-stress or
Intriguingly, VPAC1 and VPAC2 were documented to be actively
engaged in regulation of the cardiovascular function and coronary
3- Statins (Simvastatin, Atorvastatin):
Conceivably, therefore; disruption of VIP levels or its interaction
The 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors
with receptors in the heart was observed in several cardiovascular
or statins primarily interrupt cholesterol synthesis in the liver. They
diseases, such as heart failure, cardiomyopathy and pulmonary
activate hepatocyte low-density lipoprotein (LDL) receptors to
hypertension.23 Furthermore, VPAC2 agonists, including PACAP,
produce consistent and predictable reductions in circulating LDL
demonstrated cardioprotective effects in rats, and elicited many
cholesterol.16 This entails improvements in cardiovascular risk by
beneficial effects on coronary flow and vascular haemodynamics
retarding or even regressing the march of atherosclerosis in all
in hypertensive animals as well.24 Collectively, VPAC2 agonists
major arterial trees (coronary, cerebral and peripheral). Clinical
are promising drug candidates that can act both to reduce blood
trials have demonstrated their capacity to further improve life
glucose and alleviate cardiovascular insults to diabetes mellitus.
quality by retarding the progression of diabetes mellitus and
chronic renal disease and by enhancing central and peripheral
7- Sergliflozin-analogs (the SGLT-2-inhibitors):
blood flow. In cardiovascular end-point trials they have proven
ability to help prevent myocardial infarction and to reduce the
The kidney membrane transporters (SGLT-2 proteins) were recently
likelihood of its recurrence in those who do succumb. They are
shown to associate with hyperglycaemia, glucosuria and some
effective at all levels of cardiovascular risk, whether caused by
cardiovascular anomalies of diabetes. Thus, their inhibition has
hypercholesterolemia, hypertension, cigarette smoking, diabetes
been lately targeted by specific drugs like sergliflozin and dapa-
mellitus or the metabolic syndrome. Their most important potential
gliflozin.25 This category of drugs was documented to prevent
side-effect can be limited myopathy, or elevation of liver enzymes.16
the progression of diabetic nephropathy, the proliferation of the
glomerular mesangial area and the proteinuria, commonly seen
4- Pioglitazone and newer selective PPAR
in diabetes.26 It is thought that such drugs may well cut down the
deleterious cytotoxic-effects of glucose and their ramifications.
modulators (PPAR- γ agonists): The insulin sensitisers
Beyond that, SGLT-2-inhibitors were shown to reduce infarct size,
ischaemia, and improve stroke outcomes in experimental animals.
The selective peroxisome proliferators activating receptor agonists
The link to humans is yet to be delineated, especially that SGLT
(selective PPAR modulators (SPPARMs); e.g InteKrin) favourably
proteins were demonstrated in human cardiac tissues.27
interact with PPAR- γ to elicit the beneficial effects of PPARγ
agonists while avoiding the common side-effects, edema,
increased preload and lipogenesis that were evident with
conventional thiazolidinone agonists (Pioglitazone, Rosiglitazone).
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I | NOVEMBER 2009
HEALTHCARE BULLETIN | DIABETES & CARDIOVASCULAR RISK
8- Rimonabant-like drugs
El-Mowafy AM, Alkhalaf M, Nassar NN. Resveratrol reverses
(The Cannabinoid antagonists):
ET-1-evoked mitogenic effects in human coronary arterial cells by
activating the kinase-G to inhibit ERK-enzymes. Int. J. Cardiol. 2009,
The tetrahydrocannabinol (THC) is a main active compound of
cannabis, which turned out to act on specific G-protein-linked
El-Mowafy AM, Alkhalaf M, Elkashef H. Resveratrol reverses
receptors; namely CB1 (mostly central, yet also exists in the CV
hydrogen peroxide-induced proliferative effects in human coronary
system and adipocytes) and CB2 (mostly peripheral). CB1
smooth muscle arterial cells: A novel signaling mechanism.
inhibitors, such as rimonabant, suppressed appetite and showed
glucose-modulating effects in humans,28 and decreased serum
triglycerides, plasma glucose and glycated haemoglobin A1c. Many
Shepherd J. Who should receive a statin these days?
other favourable responses were reported on key diabetes and CV
Lessons from recent clinical trials. J Intern Med. 2006,260(4),305-19.
risk factors.29 Likewise, CB1 blockade produced anti-inflammatory
Balint BL, Nagy L. Selective modulators of PPAR activity as new
and antiatherogenic effects. Adverse reactions to rimonabant
therapeutic tools in metabolic diseases. Endocr. Metab. Immune
involved some CNS disruption and depressive moods,30 which
Disord. Drug Targets.2006,6,33–43.
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Higgins LS, Mantzoros CS. The development of INT131 as a selective
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Nikolaidis, L. A. et al. Glucagon-like peptide-1 limits myocardial
stunning following brief coronary occlusion and reperfusion in
conscious canines. J. Pharmacol. Exp. Ther. 2005, 312, 303-308.
Demssie YN, Soran H, Younis N. Tight glycaemic control and
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Cabou, C. et al. Brain glucagon-like peptide-1 regulates arterial blood
flow, heart rate, and insulin sensitivity. Diabetes. 2008, 57, 2577–2587.
Suzuki D, Miyata T, Kurokawa K. Carbonyl Stress.
Sokos, G. G. et al. Effect of glucagon-like peptide-1(GLP-1) on
glycemic control and left ventricular function in patients undergoing
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Borboni, P. et al. Molecular and functional characterization of
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Hipkiss A, Brownson C. Carnosine reacts with protein carbonyl groups:
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system. Endocrinology. 1999, 140,5530–5537.
Hipkiss A, Brownson C et al. Reaction of carnosine with aged proteins.
Dvorakova, M. C. Cardioprotective role of the VIP signaling system.
Drug News Perspect. 2005, 18, 387–391.
Kyriazis M. Low dose L-carnosine. Antiaging Bull 2001, 4(11):19-24
Gardiner, S. M. et al. Regional hemodynamic responses to pituitary
adenylate cyclase-activating polypeptide and vasoactive intestinal
Babizhayev M, Deyev A, Yermakova V. Efficacy of N-acetylcarnosine in
polypeptide in conscious rats. Br. J. Pharmacol. 1994,111, 589-597.
the treatment of cataracts. Drugs RD 2002, 3(2):87-103.
Idris, I. & Donnelly, R. Sodium-glucose co-transporter-2 inhibitors:
Stendeven K, Ariens RE et al. The effects of dimethylbiguanide on
an emerging new class of oral antidiabetic drug. Diabetes Obes.
thrombin activity, FXIII activation, fibrin polymerisation and fibrin clot
formation. Diabetes 2002, 51(1):189-197.
Vemula, S. et al. A functional role for sodium dependent glucose
Voziyan PA et al. A post Amadori inhibitor pyridoxamine.
transport across the blood-brain barrier during oxygen glucose
deprivation.J. Pharmacol. Exp. Ther. 2009,328, 487–495.
10 Jain SK, Lim G. Pyridoxin and Pyridoxamine inhibit superoxide
Zhou, L. et al. Human cardiomyocytes express high level of Na+/
radicals and prevent lipid peroxidation and protein glycosylation.
glucose cotransporter 1 (SGLT1) .J. Cell. Biochem. 2003, 90, 339–346.
Nissen, S. E. et al. Effect of rimonabant on progression of
11 Nagaraj RH et al. Effect of pyridoxamine on chemical modification
atherosclerosis in patients with abdominal obesity and coronary
of protein carbonyls in diabetic rats. Arch Biochem Biophys 2002,
artery disease: the STRADIVARIUS randomized controlled trial.
12 Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics
Sugamura, K. et al. Activated endocannabinoid system in coronary
for the treatment of type 2 diabetes. Nature 2007, 450, 712–716.
artery disease and antiinflammatory effects of cannabinoid 1
receptor blockade on macrophages. Circulation.2009,119, 28–36.
13 Yoshizaki, T. et al. SIRT1 exerts anti-inflammatory effects and improves
insulin sensitivity in adipocytes. Mol. Cell. Biol. 2008,29, 1363–1374.
Mitchell, P. B. & Morris, M. J. Depression and anxiety with rimonabant.
EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I | NOVEMBER 2009
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