Cardiovascular disease (CVD) and type 2 diabetes (T2DM) are rapidly rising around the globe. Empirical researches demonstrated rapid increase in mortality and morbidity related to CVD and T2DM. Much of the diabetes-associated morbidity and mortality predominantly reflects its deleterious effect on macrovascular and microvascular diseases. The microvascular complications of T2DM include retinopathy, neuropathy and nephropathy and the macrovascular complications include ischemic heart disease, cerebrovascular disease and peripheral vascular diseases. Research indicates that coronary heart disease (CHD) is the major cause of mortality in people with T2DM. Herein, this chapter reviews relationship between CVD and T2DM, associated complications and effectiveness of relevant treatment modalities to treat/prevent diabetic macrovasculopthy. Macrovascular disease occur due to underlying obstructive atherosclerotic changes of major arteries which cause functional and structural abnormalities of blood vessels. The long-term complications can be controlled and prevented by controlling glycemia, maintaining normal lipid profiles, adopting a healthy lifestyle and using pharmacological interventions. Clinical trials have shown that lifestyle interventions help in prevention and reduction of CVD risk, but evidence for long-term CVD outcomes is lacking. A multidisciplinary approach involving patients, health professionals and researchers and governments should be undertaken to reduce the incidence and prevalence of diabetes-related cardiovascular complications.
- cardiovascular diseases
- type 2 diabetes
- macrovascular diseases
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with type 2 diabetes (T2DM) [1, 2], and coronary heart disease (CHD) is the most common cause of death among people with T2DM. It is estimated that up to 80% of the 200 million people suffering with T2DM globally die of CVD every year [3, 4]. In recent years, the pandemic of T2DM has emerged as a major and growing health problem. The cardiovascular (CV) complications associated with T2DM cause a considerable amount of disability, premature mortality, loss of productivity and tremendously increase burden on health care systems and economies worldwide [5–7]. Among the major complications, the development of CVD is two to four times higher in people with T2DM as compared with people without the condition [8, 9]. Thus, CVD and T2DM have become inseparable which need to be addressed by the global health initiatives.
T2DM acts as an independent risk factor for several forms of CVD (micro- and macrovascular diseases), and people with T2DM are more likely to develop CVD due to a variety of risk factors . Preclinical manifestations of macrovascular diseases are developed much earlier in newly diagnosed, never-treated T2DM patients , and such macrovascular changes are also observed even in normoglycemic and normotensive offspring of parents with T2DM [12, 13]. Furthermore, early manifestations of preclinical vasculopathy and development of macrovascular disease were potentially found to be at increased risk with impaired glucose tolerance (IGT) . The CV complications of T2DM have a significant impact on individuals, families, health systems, and economic development worldwide . According to the International Federation of Diabetes, $673 billion was spent on diabetes in 2015 which is 12% of global health expenditure . It is imperative to control the initiators of vasculopathy that ultimately develop into long-term CV complications by adopting a healthy lifestyle and using pharmacological interventions. This chapter reviews relationship between CVD and T2DM, associated complications and relevant treatment modalities to treat/prevent diabetic macrovasculopthy.
2. Cardiovascular disease risk in diabetes
CVD are the number one cause of death globally – more people die annually from CVD than from any other cause. Individuals at risk of CVD may demonstrate hypertension, hyperglycemia, and hyperlipidemia as well as overweight and obesity. According to World Health Organization :
Approximately 17.5 million people died worldwide from CVDs in 2012, representing 31% of all deaths.
Of all CVD deaths, an estimated 7.4 million were due to CHD and 6.7 million were due to stroke.
An estimated 75% of CVD deaths take place in low- and middle-income countries.
Of the 16 million deaths (≤70 years of age) as a result of non-communicable diseases 37% are caused by CVDs.
The main contributing factor in the increasing prevalence of CVD deaths is the increase in the cases of diabetes at very alarming rate, in particular, due to increasing prevalence of obesity, lifestyle choices, urbanization, aging, and genetic factors . According to the International Diabetic Federation :
In 2015, 415 million people had diabetes, and in 2040, 642 million people will develop diabetes worldwide.
At present, 3/4 of people with diabetes live in low and middle income countries.
In 2015, 1 in 11 adults had diabetes, and in 2040, 1 in 10 adults will have diabetes.
One in two adults with diabetes remains undiagnosed.
Every 6 s 1 person dies from diabetes.
Five million deaths occurred in 2015 as a result of diabetes.
3. Diabetes and macrovasculopthy: double trouble!
The alterations in vascular homeostasis that include anatomic, structural, and functional changes in blood vessels lead to multi-organ dysfunction and increase CV risk burden . Diabetic microvascular and macrovascular complications have similar pathogenetic mechanisms and characteristics. The microvascular complications include retinopathy, neuropathy and nephropathy and the macrovascular complications include ischemic heart disease, cerebrovascular disease and peripheral vascular diseases [19–21].
The relationship between diabetes and CVD is complex and multifactorial . Studies demonstrated the following macrovascular complications in T2DM patients:
T2DM is considered to be one of the six major controllable risk factors for CVD .
T2DM and IGT are related to increased risk of CV problems .
People with T2DM also have high rates of hypertension, lipid abnormality, and obesity, which contribute to their high rates of CVD .
Approximately 7% of people with T2DM have had a stroke at time of diagnosis and, indeed, stroke is the second major cause of death in T2DM .
It was also demonstrated that 18% of diabetic patients have evidence of coronary heart disease at diagnosis, and the risk of a fatal myocardial infarction is increased 2–4 times in people with T2DM .
Fatal cardiovascular events were 70 times more common than deaths from microvascular complications .
Peripheral vascular disease (PVD) is estimated to be the most costly complication of diabetes in relation to inpatient care.
PVD greatly increases the risk of intermittent claudication, foot ulcers, gangrene, infection and amputation .
Lower extremity amputations are at least 10 times more common in people with diabetes than in non-diabetic individuals in developed countries and more than half of all non-traumatic lower limb amputations are due to T2DM .
4. Pathophysiology of diabetic macrovasculopathy
Atherosclerotic vascular disease mainly occurs due to endothelial dysfunction [35, 36], which is the failure of the vascular endothelium to subserve its normal role in vasodilatation and/or vascular homeostasis. The physiological impairment that causes diabetic vasculopathy includes endothelial dysfunction, platelet hyper-reactivity, smooth muscle cell (SMC) dysfunction, impaired fibrinolysis coupled with a tendency for thrombosis and coagulation, and increased inflammation [37, 38]. Endothelial dysfunction links each of these pathological manifestations to develop macrovasculopathy . The main regulatory function of endothelium stimulation includes vasodilatation; other mechanisms include vasoconstriction, and antiplatelet and anticoagulant effects . Endothelial dysfunction lead to morphologic and structural vascular changes . Capillary endothelium rapidly disappears , intercellular junctions weaken causing increased vascular permeability , protein synthesis is dysregulated and expression of adhesion glycoproteins on endothelial cells is altered [42–45], thereby triggering adherence of monocytes and leucocytes and their increased transendothelial migration .
The characteristic feature of diabetic complications includes the progression of atherosclerotic lesion or alteration of vasculature, which is a major cause of CVD development . It was shown that diabetes accelerates these processes by stimulating the atherogenic activity of vascular SMC and these considered as the integral part in the development of atherosclerosis . The process begins as a response to chronic minimal injury to the endothelium leading to it being dysfunctional. Fewer vascular SMCs are also found in patients with diabetes with advanced atherosclerotic lesions . Diabetes alters vascular smooth muscle function in ways that promote atherosclerotic lesion formation, plaque instability and clinical events. Platelet aggregation and adhesion are seen in diabetic patients [48–51]. The process involves an increase in intrinsic platelet activation and decrease endogenous inhibitors of platelet activity . Platelets exhibit enhanced platelet aggregation activity in the early disease state that may precede the development of CVD [48–54]. T2DM also brings about some changes in coagulation of blood. A procoagulant state has been shown in people having diabetes [55–57]. It was demonstrated that there is an increase in plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), fibrinogen, factor VII and thrombin–antithrombin complexes in macrovascular diseases and poor glycemic control [55–61].
5. Pathogenesis of vasculopathy
It is now well-established that metabolic, humoral and hemodynamic factors contribute to the characteristic dysfunction in diabetic vasculopathy. Prolonged hyperglycemia is considered as a major factor in the pathogenesis of diabetic vasculopathy [62–64]. Hyperglycemia together with several other factors accelerates the progression of atherosclerosis. In particular, hypoglycemia increases oxidative stress ; enhances leucocyte–endothelial interaction , and glycation of protein, lipoproteins, apolipoproteins and clotting factors, which cumulatively enhance vasomotor tone, vascular permeability, growth and remodeling [42–45]. Moreover, hyperglycemia delays endothelial cell replication, increases cell death [42, 45, 67–70] and potentially accelerates the atherosclerotic process. Glucose-induced damage occurs through advanced glycation, activation of protein kinase C (PKC), and sorbitol accumulation [71, 72]. Early glycated products on collagen, intestinal tissues and blood vessels undergo a series of chemical rearrangement to form irreversible AGE. AGE product promotes atherosclerotic effect by receptor-mediated biological activities e.g. monocyte emigration, release of cytokines and growth factors from macrophages and increase in endothelial permeability and procoagulant activity .
Dysregulation of Lipid metabolism underlies pathogenesis of macrovascular diseases of diabetes origin . Diabetic dyslipidemia causes increase in total cholesterol and low-density lipoprotein (LDL) and -decrease in high-density lipoprotein (HDL) and high triglyceride levels [74, 75]. LDL and other lipoproteins enter the endothelial cells by vascular transport and may get modified by oxidation, glycation, aggregation, association with proteoglycans or incorporation to immune-complexes [76–78].
Insulin resistance is a common feature associated with T2DM and development of CVDs. Insulin resistance precedes the development of overt T2DM and leads to endothelial dysfunction and increases blood plasma levels of endothelin and vWF . Furthermore, insulin resistance may cause increase in arterial blood pressure by triggering several mechanisms, such as, activation of sympathetic nervous system, increase in renal sodium retention, alteration in transmembrane cation transport, augmentation of growth-promoting actions of SMCs and vascular hyperactivity [80–82].
Increased expression and action of various cytokines and growth factors in T2DM may induce macrovascular injury via activation of proliferative cytokines epidermal growth factor  and platelet-derived growth factor (PDGF) . Metabolic and hemodynamic factors interact to stimulate the expression of cytokines and growth factors in the various vascular trees, which contribute to the characteristic dysfunction observed in diabetic vasculopathy .
Intracellular hyperglycemia has been implicated in the pathogenesis of diabetic complications through the activation of PKC, an intracellular second messenger system [85, 86]. PKC appears to be activated in a range of diabetic tissues including heart and aorta . The beta isoform of PKC is involved in abnormalities of endothelial-dependent vasodilatation in diabetes by promoting superoxide ions (O2−) to react with nitric oxide to produce peroxynitrate (ONOO−), which damages tissues and activates monocyte macrophages . Diabetic vasculopathy is characterized by early migration of monocytes into the arterial wall . Monocytes differentiate into macrophages to form foam cells which secrete growth factors and metalloproteinases. The growth factors stimulate cell proliferation and matrix production, and the metalloproteinases cause matrix degeneration .
Another major factor involved in the pathogenesis of vasculopathy is oxidative stress [89–91]. Increased oxidative stress in T2DM induces generation of free radicals that cause vascular tissue damage. In the pathogenesis of diabetic vasculopathy, white blood cells (WBCs) play a potential role. High WBC count predicts a decrease in insulin action and development of T2DM . Inflammation is a primary risk factor for CVD , and proinflammatory cytokines and C-reactive protein are found to be linked to the development of diabetes. Increased WBC count, in particular, increase in activated neutrophils is a major contributing factor in development of CVD . Activation of neutrophils leads to altered rheological properties of blood, increases blood corpuscular adhesion, and damages endothelium with cytotoxic reactive oxygen species and proteolytic enzymes . These changes trigger activity of granulocytes and monocytes in endothelial injury site and result in atherogenesis. Besides, leucocyte adhesiveness/aggregation is found to be slightly increased in those who have had concomitant diabetes .
6. Diagnosis of vasculopathy
Increased arterial stiffness is a dysfunctional property of the arterial circulation that leads to CVD. The stiffening of aorta and other central arteries is a potential risk factor for increased CV morbidity and mortality . Arterial stiffness can be measured by a number of methods. Some of these are more widely used in the clinical settings as these are simple, accurate and, reproducible and thus can easily be applied for the evaluation of CV risk. . Most of them are complex or need sophisticated technical equipment, which limits their application in clinical practice. Among the non-invasive and simple methods of evaluating arteries, pulse wave velocity (PWV)  and augmentation index (AI) [100–103] measurement are widely used as indexes of large artery elasticity and stiffness.
7. Treatment modalities of diabetic vasculopathy
CVD is a major complication and the leading cause of early death among people with T2DM . Much of the diabetes-associated morbidity and mortality predominantly reflects its deleterious effect on macrovascular and microvascular diseases [119, 120]. As T2DM is a complex metabolic disorder characterized by hyperglycemia, hypertension, hypercoagulability, and dyslipidemia, the diabetic patients with CVD require therapy for each of these metabolic abnormalities to reduce atherogenesis and prevent CV complications . The main strategies for an effective therapy are to reverse insulin resistance, restore beta cell function, and control hepatic glucose output. The key treatment modalities include lifestyle modification and pharmacological interventions.
7.1. Lifestyle management
Lifestyle management is an essential part of management of T2DM and CVD in diabetic patients. Dietary restriction is recommended to achieve weight loss and reduce the risk factors for CVD in T2DM. Calorie restriction and weight loss bring down the blood pressure to normal limits and improves blood lipid profile, especially triglycerides and very low-density lipoprotein cholesterol. Exercise improves glycemic control, reduces certain CV risk factors, and increases psychological wellbeing . In addition, physical training has been shown to reverse insulin resistance by increasing the number of skeletal muscle glucose transporters, which may reduce the need for hypoglycemic agents .
Patients with T2DM who do not show improvements in blood glucose levels with diet therapy are generally prescribed
Sulfonylureas act by promoting insulin secretion from the pancreatic islet beta cells and may improve insulin resistance in muscle and liver by improving insulin sensitivity in these target tissues. Metformin is the most commonly used biguanide and is suggested as the first-line drug of choice. It reduces hepatic glucose output, primarily by decreasing gluconeogenesis, and to a lesser extent, by enhancing insulin sensitivity in hepatic and peripheral tissues. Alpha-glucosidase inhibitors such as acarbose, miglitol, and voglibose inhibit the α-glucosidase enzyme which is essential for the release of glucose from more complex carbohydrates and is found in the brush border of enterocytes of small intestine. Thus, α-glucosidase inhibit the absorbance of carbohydrates in the gut and help in prevention of hyperglycemia . Rosiglitazone and pioglitazone belong to the group of thiazolidinediones. The thiazolidinediones enhance insulin sensitivity in the peripheral target tissues such as muscle and adipose tissue, and inhibit hepatic glucose production to some extent, but have no effect on insulin secretion. When used in combination with other antidiabetic drugs, the thiazolidinediones achieve significant improvement in insulin resistance. Importantly, the thiazolidinediones have also been shown to improve the dyslipidemia in patients with T2DM.
A recent advance in the management of T2DM has been the development and clinical use of incretin-based therapies, i.e., glucagon-like peptide-1 (GLP-1) receptor analogs (e.g., exenatide) and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin) [128–131]. GLP-1 receptor agonists mimic the action of GLP-1 and increase the incretin effect in patients with T2DM, stimulating the release of insulin. DPP-4 inhibitors prevent degradation of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide, thereby helping in glycemic control .
8. Clinical trials on prevention strategies and therapeutic approaches for diabetic vasculopathy
Growth of overweight and obese population due to diet and life-style changes worldwide correlates with the global T2DM epidemic . However, majority of the studies focusing on diabetes prevention were not designed to assess CV outcomes . There is a need for studies to explore the effect of exercise and diet on quality of life, morbidity, and mortality, with a special focus on CV outcomes.
Clinical trials examining the effect of
Diabetic vasculopathy can be improved by
Clinical trials e.g. CARDS (the Collaborative Atorvastatin Diabetes Study) , LIPID (Long-term Intervention with Pravastatin in Ischemic Disease) , 4S (Scandinavian Simvastatin Survival Study)  and HPS (the Heart Protection Study) , demonstrated that statin significantly reduced the incidence of stroke in diabetic patients.
Subgroup analysis of the Helsinki Heart Study , and VA-HIT (Veterans Affairs High-density lipoprotein Intervention Trial) [172, 173] provided evidence for the potential benefit of fibrate therapy in reducing CVD in T2DM. However, FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study  failed to show similar benefits. The lipid arm of the ACCORD study examined combination therapy of statin and fibrate and failed to support the effectiveness to reduce CV risk as compared with statin alone .
In a subgroup analysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study, patients with T2DM taking clopidogrel seem to derive enhanced benefit from clopidogrel compared with aspirin [181, 182]. The subgroup analysis of PRISMPLUS (Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) trial showed that triple therapy (aspirin, heparin, tirofiban) significantly reduced the incidence of myocardial infarction or death as compared with aspirin plus heparin .
9. Conclusion and recommendations
CV complications are the major causes of morbidity and mortality in patients with T2DM. Macrovascular complications are more common, and most diabetic patients develop or die of macrovascular diseases, predominantly by developing CVD.
The initiators of vasculopathy that ultimately develop into long-term complications can be controlled and avoided by strict glycemic control, maintaining normal lipid profiles, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions. Studies have shown that lifestyle interventions help in prevention and reduction of CV risk factors; however, there is a lack of studies investigating effects of lifestyle modifications on long-term CV outcomes that need to be addressed. Similarly, because the intensive glycemic control in T2DM patients did not show consistent beneficial effects on CV events, such a strict glycemic control needs to be revisited. Contrary to the disappointing results of intensive glucose control in prevention of CVD, intensive control of blood pressure using anti-hypertensive drugs, normalization of lipid profiles using lipid-lowering agents, and prevention of atherosclerosis and vascular thrombosis with antiplatelet therapy have been found to be beneficial.
Health promotion and patient education should be given priority to combat CV complications in T2DM patients. A multidisciplinary approach involving patients, health professionals, and researchers should be undertaken to reduce the incidence and prevalence of T2DM and CVD, and improve the quality of life and well-being of patients.