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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
DOI: 10.5083/ejcm.20424884.05

Cardiovascular disease (CVD) is a prime killer in patients with diabetes. Paradoxically, improvements
CORRESPONDENCE
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 b) Metformin
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- a) Carnosine
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):
other SIRT1-activators.
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.
limited its pharmaceutical production, yet encouraged research in this direction; hoping to come up with specific analogs that would Higgins LS, Mantzoros CS. The development of INT131 as a selective PPARγ modulator: approach to a safer insulin sensitizer. 26 Aug 2008 Nikolaidis, L. A. et al. Glucagon-like peptide-1 limits myocardial REFERENCES
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Demssie YN, Soran H, Younis N. Tight glycaemic control and cardiovascular disease in type-2 diabetes. Br J Hosp Med (Lond). 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 coronary artery bypass grafting. Am. J. Cardiol. 2007, 824–829 (100).
Gariballa A., Sinclair A. Carnosine: Physiological properties and therapeutic potential. Age Aging 2000, 29:207-210 Borboni, P. et al. Molecular and functional characterization of pituitary adenylate cyclase activating polypeptide (PACAP-38)/ Hipkiss A, Brownson C. Carnosine reacts with protein carbonyl groups: vasoactive intestinal polypeptide receptors in pancreatic beta-cells another possible role for the antiaging peptide? Biogerontology and effects of PACAP-38 on components of the insulin secretory 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.
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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.
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13 Yoshizaki, T. et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol. Cell. Biol. 2008,29, 1363–1374.
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