Among type 2 diabetic patients, even after correction for other known cardiovascular risk factors, the incidence of myocardial infarction or stroke is increased two- to threefold and the risk of death is increased twofold, suggesting that some feature of diabetes must confer such an excessive propensity toward CVD.⁴

The presence of elevated blood glucose levels, diabetes mellitus, or both contributes to more than 3 million cardiovascular deaths worldwide each year. With the increase in obesity, insulin resistance, and the metabolic syndrome, the worldwide prevalence of diabetes is expected to double by the year 2030. This burgeoning diabetes epidemic will increase the burden of cardiovascular disease attributable to diabetes.⁵

The World Health Organization (WHO) has commented there is ‘an apparent epidemic of diabetes which is strongly related to lifestyle and economic change’. Most will have type-2 diabetes, and all are at risk of the development of complications.⁶

Diabetes causes severe morbidity. Complications of diabetes can be divided into three categories:

- Metabolic complications of low blood glucose levels (hypoglycaemia) and of high blood glucose levels (hyperglycaemia). Diabetic coma is one such metabolic complication of a particularly severe nature;

- Damage to small blood vessels (microvascular complications) leading in turn to damage to the retina (retinopathy) kidney (nephropathy) and nerves (neuropathy);

- Damage to the larger arteries leading to the brain (leading to stroke) or to the heart (leading to coronary heart disease) or to the legs and feet (leading to peripheral vascular disease) (macrovascular complications).⁶

In the United States, one-third of the population born in 2000 will develop diabetes, with an estimated 30% reduction in life expectancy, mostly related to atherosclerosis. Nearly 65% of individuals with diabetes die from cardiovascular disease in the United States, establishing it as the leading cause of death among this growing segment of the population. More than 30 years ago, the Framingham Heart Study followed 239 patients with diabetes and observed a 3-fold increase in age-adjusted cardiovascular mortality. Subsequent studies demonstrated patients with type 2 diabetes without prior myocardial infarction (MI) have a similar risk of death from coronary artery disease as patients without diabetes with prior MI. Diabetes is now considered to be a risk equivalent of coronary artery disease for future MI and cardiovascular death.⁵

From an epidemiological point of view, there is evidence that the risk of cardiovascular mortality increases with the increase of plasma glucose concentrations and A1C levels. Analysis of the U.K. Prospective Diabetes Study (UKPDS) data clearly indicates that for the same degree of A1C, particularly in its low range, the incidence of myocardial infarction is much greater than that of retinopathy. In support for a catalytic effect of diabetic hyperglycemia are the classic results of the Multiple Risk Factor Intervention Trial (MRFIT). In that study, cardiovascular mortality was shown to increase with the number of coexisting cardiovascular risk factors (hypercholesterolemia, hypertension, and smoking). More recently, re-analysis of the UKPDS results have clearly documented a powerful interaction between glycemic and blood pressure control in increasing risk for all cause mortality, myocardial infarction, and stroke.⁴

In addition to being a risk factor for the development of coronary disease, diabetes influences outcomes following ACS. Subgroup analysis of patients with diabetes with ST-segment elevation MI (STEMI) in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial demonstrated significantly higher all-cause mortality at 30 days compared with patients without diabetes. Similarly, the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry of patients with unstable angina/non-STEMI (UA/NSTEMI) observed an increased rate of post-MI complications and mortality among patients with diabetes compared with patients without diabetes during 2 years of follow-up. Moreover, a large, prospective multinational registry, Global Registry of Acute Coronary Events (GRACE), revealed in hospital case fatality rates for patients with diabetes with ACS were almost twice as high as those of patients without diabetes. ⁵

The influence of diabetes on mortality following ACS using a large database spanning the full spectrum of ACS was evaluated in a latest trial where the Mortality at 30 days as well as at 1 year was significantly higher among patients with diabetes than among patients without diabetes at 30days following either UA/NSTEMI or STEMI.

This analysis demonstrates a statistically robust association between diabetes at time of presentation with ACS and all-cause mortality at 30 days and at 1 year, even after adjusting for baseline characteristics as well as features and management of the index event.

Diabetes had an even greater adverse impact on long-term mortality following UA/NSTEMI than STEMI. The burden of cardiovascular risk inherent among the patients presenting with UA/NSTEMI marked the index ACS presentation as a sentinel event in a chronic, progressive course that was more accelerated among patients with diabetes.⁵

It is estimated that there are 66.58 million diabetics in India in 2004; 37.73 million in urban areas and 28.85 million in rural areas. Diabetes accounts for 1.09 lakh deaths in a year. Diabetes mellitus is responsible for 11.57 lakh years of life lost due to the disease, and for 22.63 lakh DALYs (disability-adjusted life year) during 2004. It is seen that diabetes is directly responsible for 9% of AMI cases 4% of stroke cases, 2% of neuropathy, and 32% of cataract cases.

These figures reflect independent contribution of diabetes to various noncommunicable diseases. Since the risk factors occur in clusters more often rather than individually, the contribution of diabetes in combination with other risk factors would have more serious dimensions.⁶

4. The Pathophysiology of Cardiovascular Disease and Diabetes⁷

Diabetes is a prime risk factor for cardiovascular disease (CVD). Vascular disorders include retinopathy and nephropathy, peripheral vascular disease (PVD), stroke, and coronary artery disease (CAD). Diabetes also affects the heart muscle, causing both systolic and diastolic heart failure. The etiology of this excess cardiovascular morbidity and mortality is not completely clear. Evidence suggests that although hyperglycemia, the hallmark of diabetes, contributes to myocardial damage after ischemic events, it is clearly not the only factor, because both pre-diabetes and the presence of the metabolic syndrome, even in normoglycemic patients, increase the risk of most types of CVD.

However, managing cardiovascular risk factors in patients with diabetes does not eradicate these complications. The complex and multifactorial etiology is from defects in the large blood vessels (macrovasculature) and the small blood vessels (microvasculature) to the less well-understood cellular and molecular mechanisms of CVD in patients with diabetes.

Macrovasculature-

Atherosclerosis is the major threat to the macrovasculature for patients with and without diabetes. Clinically, dyslipidemia is highly correlated with atherosclerosis, and up to 97% of patients with diabetes are dyslipidemic. In addition to the characteristic pattern of increased triglycerides and decreased HDL cholesterol found in the plasma of patients with diabetes, abnormalities are seen in the structure of the lipoprotein particles. In diabetes, the predominant form of LDL cholesterol is the small, dense form. Small LDL particles are more atherogenic than large LDL particles because they can more easily penetrate and form stronger attachments to the arterial wall, and they are more susceptible to oxidation. Because less cholesterol is carried in the core of small LDL particles than in the core of large particles, subjects with predominantly small LDL particles have higher numbers of particles at comparable LDL cholesterol levels.

Oxidized LDL is pro-atherogenic because once the particles become oxidized they acquire new properties that are recognized by the immune system as “foreign.” Thus, oxidized LDL produces several abnormal biological responses, such as attracting leukocytes to the intima of the vessel, improving the ability of the leukocytes to ingest lipids and differentiate into foam cells, and stimulating the proliferation of leukocytes, endothelial cells, and smooth muscle cells, all of which are steps in the formation of atherosclerotic plaque. In patients with diabetes, LDL particles can also become glycated, in a process similar to the glycation of the protein hemoglobin (measured in the hemoglobin A1c [A1C] assay). Glycation of LDL lengthens its half-life and therefore increases the ability of the LDL to promote atherogenesis. Paradoxically, however, glycation of HDL shortens its half-life and renders it less protective against atherosclerosis.

Moreover, diabetic blood is more likely to be high in triglycerides. Hypertriglyceridemia in diabetes occurs, in part, because insulin action regulates lipid flux. Insulin promotes the activity of the enzyme lipoprotein lipase, which mediates free fatty acid uptake into adipose tissue (storage) and also suppresses the activity of the enzyme hormone-sensitive lipase, resulting in decreased release of free fatty acids into the circulation. Hypertriglyceridemia can lead to increased production of the small, dense form of LDL and to decreased HDL transport of cholesterol back to the liver.

Dyslipidemia is only one mechanism by which diabetes promotes atherosclerosis; endothelial dysfunction often contributes. Healthy endothelium regulates blood vessel tone, platelet activation, leukocyte adhesion, thrombogenesis, and inflammation. The net effect of healthy endothelium is vasodilatory, anti-atherogenic, and anti-inflammatory. When these mechanisms are defective, the process of atherosclerosis is accelerated. Therefore, both insulin deficiency and insulin resistance promote dyslipidemia accompanied by increased oxidation, glycosylation, and triglyceride enrichment of lipoproteins. In addition, endothelial dysfunction is present, and all of these factors contribute to the increase in atherogenicity, and thus macrovascular disease, found in patients with diabetes.

Microvascular Disease –

Typically, the term “microvascular disease” associated with diabetes, means retinopathy, nephropathy, and neuropathy. In addition, however, small vessels throughout the body are affected by diabetes, including those in the brain, heart, and peripheral vasculature. This small vessel damage is typically not related to atherosclerosis and is not predicted by lipid levels. Whereas atherosclerosis is the major threat to the macrovasculature, a variety of cellular and molecular mechanisms contribute to microvascular disease in diabetes.

The microcirculation is regulated by central and local regulatory mechanisms. The central regulation is via autonomic sympathetic and parasympathetic nerves that reach the vascular smooth muscle. Local regulation is carried out by substances produced by the endothelial cells and by local products of metabolism. The endothelium produces both vasodilators and vasoconstrictors. Normally, the vascular smooth muscle receives continuous regulatory nerve signals and a continual supply of vasodilating nitric oxide (NO) from the endothelium, as well as a continuous flow of metabolic products. These regulatory mechanisms adjust microvascular flow instantaneously to meet the metabolic needs of the tissue.

Diabetes contributes to defects in the autonomic nervous system, the endothelium, and local metabolism, all of which can result in microvascular disease. Diabetic autonomic neuropathy (DAN) is one factor associated with impaired autoregulation of blood flow in a variety of vascular beds, including the skin and the heart. Patients with DAN have increased rates of sudden cardiac death as well as a higher overall cardiovascular mortality rate. These patients have been found to lack the normal cardiac flow reserve that is activated under conditions of increased demand for myocardial perfusion, which may partially explain the high mortality rate in this population.

In addition to the dysregulation of vascular tone caused by DAN, subjects with diabetes have been found to have decreased bioavailability of NO, a potent vasodilator, as well as increased secretion of the vasoconstrictor endothelin-1. This resulting state of vasoconstriction has been found in subjects with the metabolic syndrome as well as those with diabetes. In this situation, the vasculature is in a hyper-constricted state. Not only do hypertension and its concomitant complications result from vasoconstriction, but blood flow is limited to respective tissues. Diabetes decreases NO bioavailability because of either insulin deficiency or defective insulin signaling (insulin resistance) in endothelial cells. Hyperglycemia also acutely inhibits the production of NO in arterial endothelial cells.

In a sense, the ultimate outcome of blood flow to tissues is the transport and exchange of substances between blood and tissue fluid. Thus, despite an appropriate amount of blood flow, any process that inhibits product exchange will impair the homeostasis of the tissue containing the vascular bed. Capillary basement membrane thickening associated with prolonged hyperglycemia is a structural hallmark of diabetic microvascular disease. Thickening of the basement membrane impairs the amount and selectivity of transport of metabolic products and nutrients between the circulation and the tissue. In fact, in skeletal muscle of patients with type 2 diabetes, exercise-stimulated oxygen delivery from the capillaries is delayed, which may account in part for the poor exercise tolerance found in people with type 2 diabetes.

Transport of substances from the circulation, across the microvessel wall, and into tissue interstitium is regulated by a variety of interdependent mechanisms, including pressure, flow, and size and charge specificity. Paradoxically, basement membrane thickening increases microvascular permeability because of alterations in the physical dimensions of the meshwork and changes in the normal electrical charge surrounding the pores between endothelial cells. These abnormalities allow for the transport of large molecules normally excluded from passage across the microvasculature. In clinical terms, transcapillary leak of albumin in the kidney provides an important indicator of microvascular disease. The urine microalbumin test, initially indicated for the detection of early diabetic nephropathy, actually reflects the health of the entire microvasculature. Thus, a patient with a microalbuminuria not only has nephropathy, but also can be assumed to have widespread microvascular disease.

Inflammation –

Inflammation is a normal response to tissue injury or pathogen exposure and is a critical factor in the body’s ability to heal itself or to fight off infection. The inflammatory response involves the activation of leukocytes (white blood cells) and is mediated, in part, by a family of cytokines and chemokines. Although inflammation is beneficial, if this response is chronically activated it can have a detrimental effect. Diabetes has long been considered a state of chronic, low-level inflammation, and there is some evidence to suggest that this immune activation may precede insulin resistance in diabetic and pre-diabetic states and ultimately may be the factor that initially increases cardiovascular risk in these disease processes.

Recent evidence suggests cross-talk between the molecular pathways involved in both inflammation and insulin signaling, and this cross-talk may provide clues to the strong relationship between insulin-resistant states (such as the metabolic syndrome and type 2 diabetes), inflammation, and CVD. As previously discussed, researchers have found a reduced production of the potent vasodilator NO and an increased secretion of the vasoconstrictor and growth factor endothelin-1 in subjects with the metabolic syndrome, and these abnormalities not only enhance vasoconstriction, but are associated with the release of pro-inflammatory cytokines. Proinflammatory cytokines cause or exacerbate injury by a variety of mechanisms including enhanced vascular permeability, programmed cell death (apoptosis), recruitment of invasive leukocytes, and the promotion of reactive oxygen species (ROS) production.

Recently, it is found that serum sialic acid, a marker of low-grade inflammation, to be strongly predictive of type 2 diabetes in 128 patients from the United Kingdom who were followed for a mean of 12.8 years. In addition to predicting type 2 diabetes, this marker also predicted cardiovascular mortality independent of other known risk factors for CVD, including pre-existing CVD. These observations have led investigators to suspect a common, unknown antecedent and to consider chronic inflammation as one candidate for this precursor.

In addition to diabetes, obesity is associated with increased levels of a number of adipokines (cytokines released from adipose tissue), including tumor necrosis factor-α, interleukin 1β, interleukin 6, and plasminogen activator inhibitor 1 (PAI-1), all linked to the inflammatory response. The levels of these pro-inflammatory cytokines typically increase as fat mass increases; however, one exception is the adipokine adiponectin, which has anti-inflammatory properties and is decreased in obese subjects, exacerbating the chronic inflammatory nature of obesity. In addition to their endocrine properties, these locally produced cytokines have been found to possess autocrine and paracrine properties that can influence neighbouring tissues as well as the entire organism.

Oxidative Stress –

As discussed earlier, pro-inflammatory cytokines can enhance the production of ROS. The term ROS refers to a subset of molecules called “free radicals.” This term refers to any molecule that contains an unpaired electron in the outer orbital. This unpaired electron makes the molecule highly reactive, seeking to either donate an electron to another compound or take up protons from another compound to obtain a stable electron pair. This high reactivity leads to the formation of bonds between the ROS and other compounds, altering the structure and function of the tissue. Because of the reactive propensity of these molecules, ROS can directly damage a number of cell components, such as plasma membranes and organelles.

ROS are produced by the immune system as a way to injure and destroy pathogens, but they are also generated as a result of daily living. Normal metabolism results in the production of ROS, which act as signalling molecules for both physiological and pathophysiological properties. Oxidative stress occurs when the cellular production of ROS exceeds the capacity of anti-oxidant defences within cells. Numerous studies have demonstrated chronic oxidative stress in diabetic humans and animals, purportedly related to the metabolism of excess substrates (glucose and fatty acids) present in the hyperglycemic state, as well as to the mitochondrial dysfunction associated with insulin resistance. For example, plasma levels of hydroperoxides (one ROS) are higher in subjects with type 2 diabetes compared to nondiabetic subjects, and these levels are inversely correlated with the degree of metabolic control.

The mitochondria are the major source of ROS. At the subcellular level, the etiologies of insulin resistance and diabetes, as well as their complications, are deeply related to defects in mitochondrial function. The mitochondria produce most of the body’s required adenosine triphosphate through the process of oxidative phosphorylation (via the electron transport chain). Oxidative phosphorylation is the major source of ROS under normal physiological conditions. There are two sites in the mitochondrial electron transport chain that generate ROS, and the increased flux of glucose in diabetes has been found to increase ROS production.

Oxidative stress is currently the unifying factor in the development of diabetes complications. In 1994, the Banting Medal for Scientific Achievement, the most prestigious award of the ADA, was given to Michael Brownlee, MD, for his pivotal work in the etiology of diabetes complications. According to Brownlee, there are four mechanisms by which chronic hyperglycemia causes diabetes complications: activation of the polyol pathway; increased formation of advanced glycosylation end products; activation of protein kinase C, an enzyme involved in numerous molecular signalling pathways; and activation of the hexsosamine pathway. Through decades of research, Brownlee and his colleagues found that hyperglycemia-induced mitochondrial ROS production activates each of the four major pathways of hyperglycemic damage. Moreover, blocking ROS production or interfering with ROS signaling attenuated the activity of all four pathways. Thus, oxidative stress is a crucially important concept in the complications in diabetes.

Activated Leukocytes –

As previously discussed, the inflammatory response appears to be over-activated in insulin resistance and in diabetes. Leukocytes are major mediators of inflammation. They also contribute to the oxidative stress associated with diabetes. ROS are generated not only from the mitochondria, but also from activated leukocytes. Hokama et al. found that the expression of adhesion proteins on the surface of neutrophils, which suggests activation and ROS production, was significantly increased in diabetes. Freedman and Hatchell found that stimulated neutrophils from diabetic animals generated superoxide radical (a type of ROS) at significantly higher rates than did those from normal animals. Under ischemic conditions, Hokama et al. found that leukocyte accumulation during reperfusion was enhanced in the diabetic coronary microcirculation, suggesting an increased ability of leukocyte-generated ROS to exacerbate tissue damage after experimental myocardial infarction (MI). The excess chronic oxidative stress produced in the hyperglycemic state by the mitochondria, as well as the additional acute stress mediated by accumulated leukocytes, may largely explain the mechanism of increased oxidative injury associated with ischemic heart disease in diabetes. This explanation, in turn, aids our understanding of the excessive morbidity and mortality in patients with diabetes after heart attacks when compared to patients without diabetes.

Hypercoagulability-

In addition to affecting the leukocytes in the blood, diabetes is also related to a hypercoagulable state. The coagulability of the blood is crucially important in ischemic cardiovascular events because the majority of MI and stroke events are caused by the rupture of atherosclerotic plaque and the resulting occlusion of a major artery by a blood clot (thrombus).

Up to 80% of patients with diabetes die a thrombotic death. Seventy-five percent of these deaths are the result of an MI, and the remainder are the result of cerebrovascular events and complications related to PVD. The first defence against a thrombotic event is the vascular endothelium. As previously discussed, diabetes contributes to widespread endothelial dysfunction. The endothelium and the components of the blood are intricately linked, such that clotting signals initiated in the endothelial cell can activate platelets and other blood components, and vice versa.46 Patients with diabetes exhibit enhanced activation of platelets and clotting factors in the blood. Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, and the presence of higher plasma levels of platelet coagulation products, such as beta-thromboglobulin, platelet factor 4, and thromboxane B2, demonstrate platelet hyperactivity in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1+2 and thrombin–anti-thrombin complexes are also elevated in diabetes. In addition, patients with diabetes have elevated levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein, and von Willebrand factor. Conversely, anticoagulant mechanisms are diminished in diabetes. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes because of abnormal clot structures that are more resistant to degradation, and also because of an increase in PAI-1.

Clinicians attempt to reverse this hypercoagulable state with aspirin therapy, widely recommended for use as primary prevention against thrombotic events in patients with diabetes. However, numerous studies have suggested that aspirin in recommended doses does not adequately inhibit platelet activity in patients with diabetes. This concept of “aspirin resistance” is controversial and has not been found consistently in all diabetic patient populations, but it may provide insight into the high rates of thrombotic events in diabetes even among those appropriately treated.

In summary, the increase in cardiovascular morbidity and mortality is complex and multifactorial and is usually related to a combination of both macrovascular and microvascular dysfunction.

5. Management of Cardiovascular risk factors in Diabetes Mellitus⁸

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with type 2 diabetes, and managing cardiovascular risk factors is at least as important as managing blood glucose in these patients. There is a controversy that patients with type 2 diabetes should be treated just as aggressively for cardiovascular risk factors as patients with a history of CVD (i.e. as secondary prevention), as they have a similar risk of future events. However, it is likely that this will become increasingly common if more studies lend support to it.

Current guidelines recommend that cardiovascular drug treatment for people with type 2 diabetes is based on their absolute risk of a coronary event. They define patients as being at higher or lower risk as follows:

A person at higher risk is someone - Who has manifest CVD (history of CHD, stroke or PVD) or whose 10-year coronary event risk is >15%. A person at lower risk is someone - Who does not have manifest CVD and whose 10-year coronary event risk is <15%.

Drug management of blood pressure-

The guidelines for people with type 2 diabetes recommend a target BP of <140/80mmHg or <135/75mmHg if they also have microalbuminuria or proteinuria.

All people with type 2 diabetes and BP >160/100mmHg, or those with BP >140/80mmHg who are at higher risk or have concomitant microalbuminuria or proteinuria, should receive drug treatment to lower their BP to these targets. However, for lower risk people with diabetes and a BP of between 140/80mmHg and 160/100mmHg, routine antihypertensive drug treatment is not recommended initially.

In UKPDS, tight control of BP significantly reduced both microvascular and macrovascular complications compared with less tight control. The incidence of any diabetes related endpoint, diabetes-related death; stroke and microvascular disease (a composite of retinopathy, vitreous haemorrhage or renal failure) was reduced. The main factor in reducing cardiovascular risk in all patients, including those with diabetes, is BP reduction itself. In the large hypertension study, ALLHAT, thiazide diuretics were unsurpassed as first-line treatment in all patients, including those with type 2 diabetes. Thiazides are, therefore, the first-line antihypertensives of choice in people with type 2 diabetes. If thiazides are contraindicated, not tolerated or ineffective, ACE inhibitors are a reasonable alternative, as they have been widely studied in people with type 2 diabetes.

It is widely reported that, to meet BP targets, the majority of people with type 2 diabetes will require more than one antihypertensive. However, there is very little trial evidence on which to base this choice of combination treatment, especially in patients with diabetes. The hypertension guidelines recommend that if further BP lowering is required in addition to a thiazide, a Beta - blocker or an ACE inhibitor should be added. A third-line addition would be a dihydropyridine calcium-channel blocker. The place in therapy of Alpha - blockers is limited because, in ALLHAT, the doxazosin arm was discontinued early due to a higher risk of stroke and combined CVD (particularly heart failure). Concerns have been raised about an increased risk of new-onset diabetes in patients taking a thiazide and a Beta-blocker together. Therefore, this combination is not recommended initially if patients are at raised risk of developing diabetes. For these patients a thiazide plus an ACE inhibitor is preferred. For people with type 2 diabetes and microalbuminuria or proteinuria, guidelines recommend ACE inhibitors first-line. Where these are contraindicated or not tolerated (especially if because of cough), angiotensin II receptor antagonists are an alternative.

Drug management of blood lipids –

International guidelines recommend lipid-lowering drugs for people with type 2 diabetes based on their absolute risk of a coronary event and whether or not they have adverse lipid profiles. Adverse lipid profiles are defined as total cholesterol (TC) >5.0mmol/l, or low-density lipoprotein cholesterol (LDL-C) >3.0mmol/l, or triglyceride (TG) >2.3mmol/l.

For patients with an adverse lipid profile, statins are recommended if they are at higher risk. If patients have an adverse lipid profile but are at lower risk, drug treatment could be considered if cholesterol or TG levels are high. As a minimum, the target threshold for cholesterol should be reduction in TC to <5.0mmol/l or by 20–25%, whichever is the greater reduction, or reduction in LDL-C to <3.0mmol/l or by 30%, whichever is the greater reduction.

Based on studies published the British Hypertension Society have lowered the treatment threshold in their new hypertension guidelines to TC >3.5mmol/l and have set more stringent targets (TC <4.0mmol/l or a 25% reduction, or LDL-C <2.0mmol/l or a 30% reduction).17 They consider people with type 2 diabetes who are aged 50 years or over (or who have been diagnosed for at least 10 years) as having the same cardiovascular risk as those with manifest CVD. Therefore, they recommend statins in all these diabetic patients if they have TC >3.5mmol/l.17 such targets may be difficult to achieve in many patients and this increased use of statins would have a huge financial impact. Overall, results from the newer studies, such as the Heart Protection Study and CARDS, support statin use in people with type 2 diabetes. However, it is still unclear whether statin use should be extended to all patients with type 2diabetes regardless of their cholesterol levels, or whether all people with diabetes are at great enough absolute risk of a cardiovascular event to benefit from treatment.

Antiplatelet treatment-

The international diabetes guidelines recommend that aspirin 75mg should be given to people with type 2 diabetes if they have manifest CVD (i.e. secondary prevention), or no overt CVD but a 10-year coronary event risk >15% (i.e. primary prevention), providing systolic BP is reduced and maintained to 145mmHg or below. However, trials of antiplatelet treatment specifically in people with diabetes are limited, and results are disappointing. Clopidogrel should not be used routinely in patients with treatment. It is significantly more expensive than aspirin, and there is no evidence to suggest that it has any advantages over aspirin in a diabetic population.

Future Directions

The magnitude of risk conferred by diabetes demands a major research effort to reduce the influence of diabetes on coronary artery disease. Reducing coronary risk from diabetes requires a multifactorial approach to manage all atherogenic influences. Long-term, targeted, intensive use of proven therapies for the traditional coronary risk factors must be widely promoted for patients with diabetes. As with lipids levels, more stringent targets for patients with diabetes may be better all around. Many patients may well be eligible for treatment with one or two oral hypoglycaemic drugs, two antihypertensives, a statin and aspirin, not to mention lifestyle changes. Management needs to be evidence-based and equitable nationwide, in line with national targets for blood glucose and cardiovascular risk factors. However, patients with diabetes have specific needs, priorities and preferences, which are important to consider when individual management decisions are made.

6. REFERENCES:

1. WHO report – The global burden of disease 2004 update.

2. CVD Atlas - risk factors, 2003.

3. Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of Diabetes Mellitus With Total Life Expectancy and Life Expectancy With and Without Cardiovascular Disease. Arch Intern Med 2007;167(11):1145-51.

4. Bianchi C, Miccoli R, Penno G, Prato SD. Primary Prevention of Cardiovascular Disease in People With Dysglycemia. Diabetes Care. 2008;31(2):S208-14.

5. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and Mortality Following Acute Coronary Syndromes. JAMA. 2007;298(7):765-775.

6. An update on Diabetes - www.whoindia.org/SCN/AssBOD/06-Diabetes.

7. Dokken BB. The Pathophysiology of Cardiovascular Disease and Diabetes: Beyond Blood Pressure and Lipids. Diabetes Spectrum 2008;21(3):160-5.

8. The National Prescribing Centre, MeReC Bulletin Volume 15, Number 1.

Received on 25.04.2013

Modified on 30.05.2013

Accepted on 12.06.2013

Research J. Pharmacology and Pharmacodynamics. 5(4): July–August 2013, 249-256

High blood pressure	Major risk for heart attack and the most important risk factor for stroke
Abnormal blood lipids	High total cholesterol, LDL-cholesterol and triglyceride levels, and low levels of HDL cholesterol increase risk of coronary heart disease and ischaemic stroke.
Tobacco use	Increases risks of cardiovascular disease, especially in people who started young and heavy smokers. Passive smoking an additional risk.
Physical inactivity	Increases risk of heart disease and stroke by 50%.
Obesity	Major risk for coronary heart disease and diabetes.
Unhealthy diets	Low fruit and vegetable intake is estimated to cause about 31% of coronary heart disease and 11% of stroke worldwide; high saturated fat intake increases the risk of heart disease and stroke through its effect on blood lipids and thrombosis.
Diabetes mellitus	Major risk for coronary heart disease and stroke

Low socioeconomic status (SES)	Consistent inverse relationship with risk of heart disease and stroke
Mental ill-health	Depression is associated with an increased risk of coronary heart disease.
Psychosocial stress	Chronic life stress, social isolation and anxiety increase the risk of heart disease and stroke.
Alcohol use	One to two drinks per day may lead to a 30% reduction in heart disease, but heavy drinking damages the heart muscle.
Use of certain medication	Some oral contraceptives and hormone replacement therapy increase risk of heart disease.
Lipoprotein(a)	Increases risk of heart attacks especially in presence of high LDL-cholesterol.
Left ventricular hypertrophy (LVH)	A powerful marker of cardiovascular death.

Advancing age	Most powerful independent risk factor for cardiovascular disease; risk of stroke doubles every decade after age 55.
Heredity or family history	Increased risk if a first-degree blood relative has had coronary heart disease or stroke before the age of 55 years (for a male relative) or 65 years (for a female relative).
Gender	Higher rates of coronary heart disease among men compared with women (premenopausal age); risk of stroke is similar for men and women.
Ethnicity or race	Increased stroke noted for Blacks, some Hispanic Americans, Chinese, and Japanese populations. Increased cardiovascular disease deaths noted for South Asians and American Blacks in comparison with Whites.

Excess homocysteine in blood	High levels may be associated with an increase in cardiovascular risk.
Inflammation	Several inflammatory markers are associated with increased cardiovascular risk, e.g. elevated C-reactive protein (CRP).
Abnormal blood coagulation	Elevated blood levels of fibrinogen and other markers of blood clotting increase the risk of cardiovascular complications.