Common Therapeutic Modalities Against Diabetes and Associated Cardiovascular Disease

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Current Vascular Pharmacology, 2017, 15, 000-000 1

REVIEW ARTICLE

Common Therapeutic Modalities Against Diabetes and Associated Cardiovascular Disease

Nasimudeen R Jabir¹, Chelapram Kandy Firoz¹, Ghulam Md Ashraf¹, Syed Kashif Zaidi², Shazi Shakil^2,3, Mohammad Amjad Kamal^1,4,5 and Shams Tabrez*¹

1King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; ²Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; ³Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia;

4Enzymoics; ⁵Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW, Australia

A R T I C L E H I S T O R Y

Received: September 09, 2016 Revised: December 07, 2016 Accepted: December 07, 2016

DOI:

10.2174/15701611156661701051250 34

Abstract: Despite recent advances in medical research, the incidence of diabetes and cardiovascular disease (CVD)-induced fatal events is increasing. The literature point towards several co-occurring pathways that could lead to terminal complications related with these diseases. Different pathophysiological alterations such as hyperglycaemia, hyperinsulinaemia, insulin resistance, obesity, endothelial dysfunction and oxidative stress lead to the initiation and progression of atherosclerotic plaques. In view of the continuous rise in fatal events and overlapping pathological conditions associated with CVD and diabetes, there is a critical need to develop a common treatments against these diseases. The present review highlights the possible use of common drugs that could target diabetes and associated CVD.

Keywords: Cardiovascular disease, diabetes mellitus, glycaemic imbalance, obesity, oxidative stress.

INTRODUCTION

Due to the rise in incidence, diabetes-associated atherosclerosis has gained more attention in medical research lately. A clear relationship between diabetes and cardiovascular disease (CVD) has been established for decades. Epi- demiological evidence suggests hyperglycaemia and insulin resistance (IR) could lead to the development of atherosclerosis and CVD [1]. Moreover, type 2 diabetes mellitus (T2DM) has been suggested as an independent risk factor for coronary artery disease, where 75% of all hospitalized diabetic patients end up with CVD [2, 3]. Scientists have noted marked increase in the occurrence of CVD in diabetic patients during their life time [4]. Vascular inflammation and their associated inflammatory pathways are the potential driving force of diabetes that accelerates atherosclerosis [5- 7]. Moreover, diabetes has also been reported as an independent causative which promotes chronic atherosclerotic process in coronary arteries [8, 9]. Because of the mutually occurring pathological condition, there is a serious need to develop a common treatment for diabetes and associated atherosclerosis. The present review highlights the possible use of common drugs that could target both T2DM and CVD. Several overlapping pathways are targeted by these

*Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; E-mail: [email protected]

drugs (Fig. 1). In the following section, we have put forth the mechanistic linkage between CVD and diabetes and also discuss several drugs that could be used as anti-diabetic and atherosclerotic drugs.

HYPERGLYCAEMIA-CVD ASSOCIATION

Hyperglycaemia has been identified as the primary casual factor in the pathogenesis of diabetes and its complications.

Prolonged hyperglycaemia could trigger inflammatory responses which could lead to alterations in vascular tissue and endothelial dysfunction [1]. Moreover, activated inflammatory response further aggravates hyperglycaemic status via different pathological events such as IR and -cell dysfunction. These activated molecular pathways and resulting pathological events involved in endothelial dysfunction are collectively considered as the first step of atherogenesis [10, 11].

Scientific studies provide important insights on the vascular inflammatory process that took place through the different mechanism such as generation of advanced glycation end-products (AGEs), accumulation of diacylglycerol and activation of protein kinase C [12, 13]. Multiple biochemical pathways have also been suggested to link the adverse effects of hyperglycaemia with vascular complications [14].

A challenging goal in the management of patients with diabetes is to achieve blood glucose levels close to normal

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[15, 16]. Recent developments in diabetic research enable the medical practitioner to achieve this goal in a larger pro- portion of individuals. Anti-diabetic drugs reduce/prevent/

delay or reverse diabetic complications along with CVD have shown potential benefits to reduce diabetic morbidity and complications [17]. Several common anti-diabetic and anti-atherosclerotic drugs are listed below:

Targeting Therapies

Metformin: Classical anti-diabetic agents such as bigua- nides and thiazolidinediones have been reported for their benefits in glycaemic control by decreasing hepatic glucose production and absorption as well as increasing insulin- mediated glucose uptake [18]. Metformin is a well- established biguanide which has been used as a potent medi- cation for diabetes control. Large clinical trials indicated various benefits associated with metformin starting from glucose-lowering to enhanced cardiovascular protection in diabetic patients [19-21].

The literature also suggested a cardio-protective potential of metformin [22, 23]. The UK Prospective Diabetes Study (UKPDS) reported that early intervention with metformin in patients with T2DM significantly decreases the incidence of diabetes-related vascular endpoints, myocardial infarction, diabetes-related deaths and all-cause of mortality [24]. Intake of metformin by T2DM patients for 2-3 years leads to reduced carotid intima-media thickness [25]. This evidence supports metformin as a first-line therapy for T2DM, given its relative safety and beneficial effects on HbA1c, weight, and cardiovascular mortality [26]. Vasculoprotective effects of metformin in attenuating atherosclerosis and some of its underlying mechanisms have also been reported in mice model [27]. Its potential role in the decline of different atherosclerosis contributory components such as total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglyceride, and blood pressure has also been reported [28, 29]. However,

the data related to a metformin effect on blood pressure are variable [30]. In addition, metformin has also been reported to have additional cardio-protective effects such as short- term weight loss, moderate improvement in body mass in- dex, insulin sensitivity, fatty liver incidence and decreased visceral fat along with a reduction in alanine transaminase and gamma-glutamyl transferase activity [21, 31, 32]. Fur- thermore, treatment with metformin is associated with enhanced fibrinolysis, reduced platelet hyper-aggregation and chronic low-grade inflammation [28, 33, 34]. Metformin has also been suggested as an inhibitor of pro-inflammatory responses that take place via direct inhibition of NF-kB through blockage of PI3K-Akt pathway [21]. Scientific studies suggested metformin as a potent inhibitor of diabetes- induced oxidative stress in endothelial cells in newly diagnosed T2DM patients [23, 35, 36]. One study reported the suppressing potential of metformin in glucose-induced oxidative stress via inhibition of the PKC-NAD (P)H oxidase pathway [23]. Moreover, clinical evidence shows potential vascular protective effects of metformin and suggested it as an excellent choice for oral anti-diabetic therapy to provide cardiovascular protection in patients with T2DM [22].

Glucagon like peptide-1 (GLP-1) receptor agonists:

GLP-1 is produced in the entero-endocrine L cells, in response to food ingestion and exerts its effects through binding to the GLP-1 receptor (GLP-1R). On elevated glucose concentrations, GLP-1 stimulates insulin in pancreatic ß-cell and inhibits glucagon secretion [37]. Even though the exact mechanism associated with GLP-1-induced suppression of glucagon release is still ambiguous, protein kinase A - dependent and paracrine-mediated insulin independent mechanisms have been proposed [38]. In addition, GLP-1 lowers plasma concentrations of free fatty acids and slows down gastrointestinal motility [39, 40]. GLP-1 receptor agonists (GLP-1RA) represent a novel class of anti- hyperglycaemic agents which targets the incretin system, stimulate insulin secretion and improve IR [37]. These Fig. (1). Common regimen targeting the pathogenic pathways of T2DM and associated CVD.

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agents attain its therapeutic outcomes via improved glycaemic control along with other mechanisms such as reduced systolic blood pressure (SBP), increased insulin sensitivity, promote weight loss and anti-inflammatory effect [41].

Beyond the glycaemic control, GLP-1RAs also exert several cardiovascular benefits. GLP-1RAs have been reported for the beneficial effect against different cardiovascular risk factors such as overweight, lipids and hypertension [42]. Clinical trials with GLP-1RA treatment also demonstrated modest reductions in total cholesterol, LDL-C, triglycerides and apolipoprotein B levels [43, 44].Onestudy reported around 2 to 4 mmHg reductions in SBP when treated with the GLP-1RA, exenatide, in diabetic patients comparable with insulin or placebo [45]. Several other cardio-protective effects such as ischaemic conditioning and enhanced endothelial functioning have also been reported in diabetic patients treated with GLP-1RAs [45]. A preliminary study using GLP-1RAs showed promising results for the treatment of heart failure with preserved left ventricular (LV) function, enhanced myocardial glucose uptake and reduced apoptosis [46]. However, clinical studies reported conflicting findings. Considering the limitations of clinical trials, the use of GLP-1RAs still holds promise as a cardio-therapeutic agent. Both animal and a small series of patients with diabetes and coronary disease have been reported with improved vascular endothelial function in response to GLP-1RAs [47].

In a mouse model, GLP-1RAs demonstrated a decrease in vascular inflammatory markers and monocyte/macrophage accumulation in the arterial wall [48]. Animal models of myocardial ischemia also showed reductions in infarct size and preserved cardiac function treated with GLP-1 agonists [45]. A retrospective analysis database observed that diabetic patients treated with exenatide had lower rates of myocardial infarction, stroke, and coronary revascularization compared with patients treated with other glucose-lowering therapies [49]. In addition, structurally different GLP-1 receptor agonists (liraglutide and semaglutide) with anti-diabetic potential have also been reported for vascular protective effects . Liraglutide is approved for the treatment of T2DM for significant reduction in glycaemic variables [50, 51]. Recently, liraglutide has also been reported to reduce rates of cardiovascular events through reduced manifestation of multiple cardio-metabolic risk factors and increased cardiovascular safety in patients with type 2 diabetes [52]. Semaglutide is expected to be a next generation GLP-1 analogue from Novo Nordisk, currently in phase 3 clinical trial for the treatment of T2DM [53]. Its anti-diabetic potential and dose-dependent reduction in HbA1c have been reported earlier [54]. Re- cently, the SUSTAIN-6 trial also noted its potential in the significant reduction of cardiovascular events in patients with type 2 diabetes [55]. In view of above-mentioned literature, the scientific community believes that GLP-1RAs have the potential to reduce the risk of major cardiovascular events in patients with T2DM.

Ranolazine: Ranolazine,N(2,6dimethylphenyl)4(2 hydroxy3[2methoxyphenoxy]propyl)1piperazine acetamide dihydrochloride is an inhibitor of sodium and potassium ion channels [56]. It is currently approved for the management of chronic stable angina pectoris in the USA and Europe [57]. It has beneficial metabolic properties and does

not affect heart rate or blood pressure. During cardiac repo- larization, sodium current is considered as the critical mechanism that leads to decreased LV relaxation in response to ischemia and reperfusion [58]. In addition, ranolazine also plays a therapeutic role in potassium current. Its joint effect on sodium potassium current makes it clinically important in the anti-ischaemic and anti-anginal process. Different cardiovascular benefits of ranolazine have been reported in the literature. ₁ and ₁adrenergic antagonist role of ranolazine has been documented in a rat model [59]. As a therapeutic effector of sodium potassium current, ranolazine has also been reported to prolong QTc by 2-6 millisecs [60]. Multiple experimental and clinical studies reported its anti-arrhythmic efficacy [61-63]. Moreover, recent clinical studies revealed the efficacy of ranolazine in the management of different cardiovascular consequences such as acute coronary syndromes, atrial fibrillation after cardiac surgery, maintenance of sinus rhythm, ventricular tachycardia, and drug-refractory implant- able cardioverter defibrillator shocks [61, 64, 65].

In addition to its cardiovascular properties, ranolazine has been also reported for its beneficial role in the management of diabetes. Ranolazine has been reported to benefit the patients with diabetes and chronic angina despite their thera- peutically challenging co-occurrence [66]. Recent randomized, double-blind, placebo-controlled trial, TERISA (Type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina) reported relatively better efficacy of ranolazine in reducing the primary outcome of average weekly angina episodes and sublingual use of nitroglycerin [67].

Compared with placebo, the use of ranolazine monotherapy over 24 weeks, in T2DM patients significantly reduces HbA1c and other measures of glycaemic control [68]. The MERLIN trial also demonstrated the reduced levels of fasting plasma glucose and HbA1c in patients with cardiovascular disease and poorly controlled diabetic individuals in response to ranolazine [63]. Several researchers reported simi- lar results associated with ranolazine in reducing HbA1c values that indicates their therapeutic efficacy in the management of diabetes as well [67, 69, 70].

OBESITY

Obesity is a major health concern worldwide as it could lead to both diabetes and CVD. The cause of obesity is mul- tifaceted, brought about by an interaction between predispos- ing genetic, metabolic factors and rapidly changing modern environment [71]. Different classes of adipose tissue such as adipocytes, stromal pre-adipocytes, immune cells, and endo- thelium are extremely sensitive to the nutrient status [72].

Obesity dysregulates several physiological pathways such as endocrine, inflammatory, neural and cell-intrinsic [73]. It could also influence important causatives of diabetes such as IR and hyperinsulinaemia that result into hyperglycaemia [74]. Several studies have proposed different obesity- mediated mechanisms that lead to diabetes [73, 75, 76].

Increased caloric overload and fatty accumulation in liver develop hepatic IR that results in the failure of insulin to suppress liver glucose production [74]. CVD risks have also been documented in obese children [77]. Besides an altered metabolic profile, obesity could alter cardiac struc- ture and function due to excessive adipose tissue accumulation which ultimately promotes other cardiovascular risk

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factors such as dyslipidaemia, hypertension, glucose intoler- ance, inflammatory markers and a prothrombotic state [77].

In fact, successful control of obesity is imperative as it provides therapeutic benefit in prevention and control of both diabetes and CVD. Different therapeutic strategies have been used for the management of obesity which includes diet, physical activity, behavioural therapy and pharmacotherapy [78]. There is strong evidence in literature which indicates that weight loss in overweight and obese individuals reduces the risk of diabetes and CVD [4, 79].

The adipocyte hormone, leptin plays a role in the regulation of food intake and energy expenditure and therapeuti- cally targeted in obesity management. Its critical roles in the control of insulin-glucose axis, peripheral glucose, and insulin responsiveness have gained much attention. Reduced food intake and increased energy expenditure have been reported after the administration of leptin in animal models [80].

A pharmacological agent, orlistat can induce weight loss by blocking the action of pancreatic and gastric lipase and reducing absorption of fat [81]. Orlistat has been also reported to reduce the cumulative incidence of diabetes and decreases total cholesterol and LDL-C and increases HDL- C:LDL-C ratio [82]. Liraglutide, an anti-diabetic human GLP-1RA, has shown promising results in clinically mean- ingful weight loss in obese individuals [83]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are another class of anti-diabetic drugs which provides hope in the management of obesity and CVD [84]. Yousefzadeh and Wang [85] reported cardiovascular protective potential of DPP-4 in T2DM individuals in addition to their anti-diabetic actions. The up-regulation of cardio-protective genes and their protein products have been suggested as its possible mechanism of action [86]. Another study also demonstrated an improved heart function and coronary artery perfusion after sitagliptin (a DPP-4 inhibitor) treatment in patients with diabetes and CVD [84]. Velija- Asimi et al. [87] reported the combined effect of DPP-4 inhibitors and metformin, which was found to be associated with improved glycaemic control and a reduction in body weight in obese patients with T2DM. In another study, Vick- ers et al. [88] highlighted the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain. Re- cently, EMPA-REG trial reported the efficacy of an anti- diabetic drug (empagliflozin, a SGLT-2 inhibitor) in the significant reduction of cardiovascular events in diabetic patients [89]. This study reported a reduction in the primary major adverse cardiac event by 14% in T2DM patients.

Moreover, around 35% reduction in CVD mortality and hos- pitalization for heart failure were other noted benefits associated with the use of SGLT-2 inhibitors [90]. Vascular benefits linked with this inhibitor are the decrease in HbA1c level, body weight, blood pressure and an increase in HDL-C level. Moreover, SGLT-2 inhibitors have also been reported for their anti-obese potential and visceral adiposity in earlier studies [91, 92].

Frequent co-morbidity and combined effect of different vascular risk factors have specific expression pattern in T2DM and CVD. Consistent appearance of hypertension

along with other multiple risk factors such as abdominal obesity, hypertriglyceridaemia, low HDL-C and hyperglycaemia has been also observed in both diseases [68, 93]. A combined dose of angiotensin-converting enzyme (ACE) inhibitor and statin have been suggested to have beneficial vascular effects. Pravastatin and captopril (ACE inhibitor) combination showed atherosclerosis reduction in hyperlipidaemic hamsters [94]. In another study, Nazzaro et al. [95] reported beneficial vascular effects of simvastatin and enalapril. One study also reported better control of hypertension by an antihypertensive agent (enalapril and lisinopril) when they are used in combination with pravastatin or lovastatin [96].

Moreover, the combined use of statin and antihypertensive drugs have also been noted to reduce inflammation, arterial compliance and vascular smooth muscle cell proliferation mediated through angiotensin II type 1 receptors [97, 98].

Hypertension and IR are another co-existing condition in vascular complications. The antihypertensive agents such as angiotensin receptor and/or enzyme inhibitors have shown beneficial effects on glucose homeostasis. Large clinical trials reported the lower incidence of T2DM in hypertensive patients treated with ACE inhibitors [99, 100]. Moreover, treatment with angiotensin receptor inhibitors has also been reported to have the lower incidence of new-onset T2DM [101].

OXIDATIVE STRESS

Diabetes mellitus is a multifactorial disease characterized by glucose imbalance and could lead to several complications. Although, the exact mechanism associated with this disease is still unclear but oxidative stress has been suggested to have a role in its development and progression [102]. Reactive oxygen species (ROS) act as signaling in- termediates at low concentrations and regulate fundamental cellular activities impacting growth and adaptive responses.

However, at higher concentrations, ROS can induce cell dysfunction, injury, and ultimate death [103, 104]. The role of oxidative stress in diabetes complications and its association with different hyperglycaemia-associated mechanisms such as IR and impaired insulin secretion and CVD are well documented [102, 105]. Moreover, hyperglycaemia-induced intracellular production of ROS and increased expression of NADPH oxidase are noted in diabetic individuals [105]. The increased ROS production is also observed in different causatives of diabetes including obesity. Clinical studies have also reported reduced antioxidant concentrations in plasma and erythrocytes of diabetic individuals [106].

Moreover, reduced superoxide dismutase (SOD) expression and total SOD activity have been noted in multiple tissues in various diabetic models [105, 107].

The increase in oxidative stress-induced chronic hyperglycaemia in diabetic individuals plays a key role in the genesis of atherosclerosis [5]. There is also report that hyperglycaemia could compromise natural antioxidant defences of the individual. Under normal circumstances, free radicals are rapidly eliminated by antioxidants such as reduced glutathione, vitamin C and vitamin E [108]. Moreover, reduced level of glutathione, vitamin C and E has been reported in diabetic patients compared with non-diabetic individuals [109-111]. Hyperglycaemia could also promotes oxidative stress pathways such as AGEs formation and protein kinase

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C (PKC) activation that could ultimately lead to vascular damage and endothelial dysfunction [13]. Glycoxidation products are formed by combined processes of glycation and oxidation that result in ROS release and up-regulation in oxidative stress response genes [112]. Moreover, hyperglycaemia-induced ROS activate PKC and results in the activation of the diacylglycerol-PKC pathway in vascular tissue [113].

Antioxidant therapy, achieved by supplementation with pharmaceutical preparations of antioxidant nutrients (phyto-

chemicals) and/or non-nutrients are believed to confer both cardiovascular and metabolic benefits in diabetic patients [114, 115]. This notion clearly indicates the possible role of oxidative stress in these diseases [116]. In fact, epidemiol- ogical data also provide strong evidence between the dietary intake of antioxidant nutrients and protection against CVD [117, 118].

Among antioxidant, plant-derived phytochemicals have gained increased attention lately [119]. Natural products hold several advantages as the identification of their efficacy doesn’t need much time, non-lengthy, inexpensive, reduces the significant challenges of drug discovery and compara-

Table 1. Mechanistic and drug commonalities against diabetes and associated cardiovascular disease.

Common Drugs Anti-Diabetic Effect Anti-CVD Effect

Metformin Decreases glucose output [18]

Decreases gluconeogenesis [19-21]

Increases insulin-mediated glucose uptake [18]

Vasculo-protective effects [27]

Reduces carotid intima-media thickness [25]

Reduces atherosclerosis contributory components [28, 29]

Decreases blood pressure [30]

Enhances fibrinolysis, reduces platelet hyper-aggregation and chronic low-grade inflammation [28, 33, 34]

Reduces diabetes-induced oxidative stress in endothelial cells [23, 35, 36]

GLP-1R agonists Improve IR [37]

Promote weight loss and anti-inflammatory effect [41]

Stimulates insulin in pancreatic ß-cell and inhibits glucagon secretion [37]

Reduces atherosclerotic lipids and hypertension [42]

Modest reduction in total cholesterol, LDL-C, triglycerides, and apolipoprotein B levels [43, 44]

Ischemic conditioning and enhanced endothelial functioning [45]

Enhances myocardial glucose uptake and reduces apoptosis [46]

Improve vascular endothelial function [47]

Decreases the levels of vascular inflammatory markers and monocyte/macrophage accumulation in the arterial wall [48]

Reduces infarct size and preserve cardiac function [45]

Ranolazine Reduces levels of fasting plasma glucose and HbA1c [63, 68]

Anti-ischaemic and anti-anginal process [58]

Works as 1 and 1adrenergic antagonist [59]

Prolong QTc [60]

Improve anti-arrhythmic efficacy [61-63]

Anti-obese agents Manage caloric overload [74]

Block action of pancreatic and gastric lipase [81]

Reduces absorption of fat [81]

Glycaemic control and reduces body weight [87]

Decreases total cholesterol, LDL-C and increases HDL-C:LDL- C ratio [82]

Improve several cardiometabolic risk factors [83]

Up-regulation of cardio-protective genes and their protein products [86]

Antioxidants Reduces antioxidant concentrations [106]

Reduces superoxide dismutase expression and its activity [105, 107, 128]

Decreases hyperglycaemia and hyperinsulinaemia [5]

Inhibit oxidative stress [5]

Prevents endothelial dysfunction [124]

Enhances endothelial eNOS [125]

Prevent eNOS uncoupling and NADPH oxidase activation [126].

CVD: Cardiovascular disease; IR: Insulin resistance; LDL-C: Low density lipoprotein cholesterol; GLP-1R: Glucagon-like peptide 1 receptor; HbA1c: Glycosylated heamoglobin;

QTc: Corrected QT interval; HDL-C: High density lipoprotein cholesterol; eNOS: Endothelial nitric oxide synthase; NADPH: Nicotinamide adenine dinucleotide phosphate

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tively have fewer side-effects. The biological activity of these natural products mainly depends upon their multi- target mechanism of action [120]. Different phytochemicals such as polyphenols, alkaloids, terpenoids, organosulfur and phytosterols had shown potential anti-obesity and anti-CVD effects [121]. They have been reported to reduce atherogenic cholesterol, prevent lipid accumulation and oxidation, decreases food intake and increases energy expenditure [122].

Several fruits and fruit derived phytochemicals such as nar- ingin, resveratrol, plorizin, epicatechin, anthocyanin, pome- granate and cherry have also been reported for their anti- diabetic activities including reduction in oxidative stress, modulation in insulin and glucose metabolism. In addition, vegetables and spices have also shown important anti- diabetic activities [123]. Researchers have also reported the consumption of natural dietary phytochemicals from fruit, vegetables, grains and spices and their strong association with reduced risk of diabetes and cardiovascular disease.

There has been report of improved endothelial dysfunction by anti-diabetic drug (gliclazide) with antioxidative potential. Moreover, gliclazide has also been reported to decrease hyperglycaemia, hyperinsulinaemia, and inhibits oxidative stress mediated vascular complications in diabetic individuals [5]. A clinical study also reported amelioration in endothelial dysfunction by rosiglitazone therapy other than glucose control in T2DM patients [124]. Cheang et al. [125]

reported a vascular benefit by AVE3085, an endothelial nitric oxide synthase (eNOS) enhancer, in preserving endothelial function in diabetic mice. This study suggested eNOS and NO production targeted therapy to combat diabetic vas- culopathy. In another study, Schuhmacher et al. [126] reported the beneficial role of pentaerithrityl tetranitrate (an organic nitrate) with potent antioxidant properties in improving endothelial dysfunction in diabetic through the prevention of eNOS uncoupling and NADPH oxidase activation.

Wang et al. [127] suggested AMP-activated protein kinase, an important target for treating cardiovascular complications in diabetic individuals. The mechanistic and drug commonalities against diabetes and associated cardiovascular disease have been summarized in Table 1.

SUMMARY AND CONCLUSIONS

Co-existing mechanism of CVD and diabetes provide several opportunities to develop a common therapeutic strategies for their prevention and control. Various candidate drugs that are already in use for diabetes also showed promising outcome against CVD or its causative and vice-versa.

In addition, management of overlapping mechanisms such as obesity and oxidative stress could also reduce the diabetic and cardiovascular complications. The above-mentioned evidence provides hope in the treatment of atherosclerosis and diabetes together. However, further studies are required that could target common overlapping pathways for the treatment of diabetes and associated CVD which will facili- tate the significant reduction of these disease burden from the globe.

LIST OF ABBREVIATIONS

ACE = Angiotensin-converting enzyme CVD = Cardiovascular disease

DPP4 = Dipeptidyl peptidase-4 eNOS = Endothelial nitric oxide synthase GLP-1 R = Glucagon like peptide-1 receptor HbA1c = Glycosylated heamoglobin HDL-C = High density lipoprotein cholesterol

IR = Insulin resistance

LDL-C = Low density lipoprotein cholesterol NADPH = Nicotinamide adenine dinucleotide

phosphate PKC = Protein kinase C QTc = Corrected QT interval SBP = Systolic blood pressure SOD = Superoxide dismutase

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge the research facility provided by the King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Ara- bia. Thanks are also due to Mohammad S Gazdar (Librarian, KFMRC) for providing assistance with the literature.

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