Public Institution Nicolae Testemitanu State University of Medicine and Pharmacy of the Republic of Moldova [609611]

Public Institution "Nicolae Testemitanu" State University of Medicine and Pharmacy of the Republic of Moldova
FACULTY OF MEDICINE №2 Department of Internal Medicine Semiology DIPLOMA THESIS HYPERTENSION IN TYPE 2 DIABETES MELLITUS Badear Mohamad Year 6, group_M1432 Scientific advisor: Sasu Diana Assistant Professor

Chisinau, 2020 DECLARATION 
 I Badear Mohamad, hereby declare on my own responsibility that the licentiate thesis entitled " HYPERTENSION IN TYPE 2 DIABETES MELLITUS " is prepared by myself, the materials presented are the results of my own research, are not plagiarized from other scientific papers and have not been presented at another faculty or higher education institution in the country or abroad. I also declare that all sources used, including the Internet, are indicated in the licentia tethesis, in compliance with the plagiarism avoidance rules:
 ü all fragments of text reproduced exactly, even in my own translation from another language, are written with reference to the original source;
 ü rewriting of the texts of other authors in my own words has the reference to the original source; ü summary of other authors' ideas has the exact reference to the original text;
 ü work methods and techniques taken from other sources have exact references to original sources. 
Date _______________________
Graduate Badear Mohamad ___________________
 (Signature)

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CONTENTS INTRODUCTION5I.THE BIBLIOGRAPHIC ANALYSIS OF THE THEME81.1Definition of hypertension in diabetic populations71.2Pathophysiology81.3Risk of high blood pressure in type 2 diabetes81.4 1.5 1.6Arterial hypertension in diabetes mellitus type 2 Nephropathy in diabetes mellitus and hypertension Cardiovascular risk in diabetes mellitus and hypertension9 11 121.7Stroke in diabetes mellitus and hypertension131.8Management of hypertension in diabetes15II.Review of the pharmacological agents in the management of hypertension in diabetes17DISCUSSION 20CONCLUSION30Bibliographic references31
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List of Abbreviations A II – angiotensin AH – arterial hypertension
ACE inhibitor – angiotensin converting enzyme inhibitor ADHD- attention deficit hyperactivity disorder 
BP – blood pressure
CHF – chronic heart failure
CV A / Stroke -Stroke (cerebrovascular accident (CV A))
dBP – diastolic blood pressure
EAH – electrical axis of the heart
ECG – electrocardiogram
essential HTN – essential hypertension
HTN – hypertension
HDL – high density lipoprotein LDL – low density lipoproteins 
VLDL – very low density lipoproteins NIDDM – non-insulin-dependent diabetes mellitus T2DM- type 2 diabetes mellitus
Rx – radiography
RV – right ventricle
WHO – world health organization 4

INTRODUCTION Hypertension is often called the "silent killer" because it rarely causes symptoms. This is a major cause of stroke and other cardiovascular disease (CVD). In England, in 2015, 31% of men and 25% of women received treatment for high blood pressure (defined as blood pressure 140/90 mm Hg. Art. Or higher), but high blood pressure was still the cause of 75,000 deaths. In addition, many with high blood pressure are not treated, and about 5.5 million people in England have undiagnosed high blood pressure. Worldwide, the prevalence of hypertension is expected to increase to 1.56 billion by 2025. Hypertension is an extremely common comorbidity of diabetes, affecting 20–60% of people with diabetes. Hypertension is also a major risk factor for cardiovascular events, such as myocardial infarction and stroke, as well as for microvascular complications, such as retinopathy and nephropathy. Cardiovascular disease is the most costly complication of diabetes and is the cause of 86% of deaths in persons with diabetes [2]. Type 2 diabetes is the most common form of diabetes in the world. This is a chronic disease characterized by the body's inability to use glucose from the bloodstream. This may be the result of 'insulin resistance', in which the tissues do not respond properly to the hormone insulin, or it may be the result of a lack of pancreatic insulin production. As a result, “glucose intolerance” leads to high blood sugar levels. The number of adults with diabetes in the world is estimated at 170 million in 2000, and its prevalence is increasing. It is estimated that only 1.9 million people in the UK have been diagnosed with diabetes (4% of men and 3% of women) and that a large number of cases remain undetected. Type 2 diabetes caused less than 3% of all cases 5

of new diabetes in children and adolescents 20 years ago, but in 2011, up to 45% of new cases of adolescence [1]. An increased cardiovascular risk is observed in those people who have a group of risk factors, as in the case of people with metabolic syndrome. Ower 382 million adults (8·3%) worldwide have diabetes, a figure that could double in the next 20 years. In 2012, diabetes was the direct cause of 1.5 million deaths, and the estimate is projected to rise to more than 592 million by 2035. Diabetes has become a major cause of death in people younger than 60 years [8]. Diabetes is characterized by the development of specific microvascular complications and a high incidence of accelerated atherosclerosis. Microvascular and macrovascular complications are associated with hyperglycemia, its degree and duration. Classically, dysglycemia has two components: chronic hyperglycemia and acute glycemic fluctuations. Both components lead to complications of diabetes, due to two main mechanisms: excessive protection and activation of oxidative stress. A few years ago, these two mechanisms were combined into an elegant theory that suggested that glycemic disorders observed in patients with diabetes lead to the activation of oxidative stress with overproduction of superoxide by the mitohondrial electron transfer chain. The prevalence of hypertension and type 2 diabetes in the population is high and continues to increase. Given that over the last decade it has become clear that there is a close epidemiological relationship between sleep disorders (quality and quantity) and these risk factors for the development of cardiovascular disease, it is extremely important to assess the potential consequences for public and public health. Research is needed to fully understand the mechanism by which diabetes mellitus and hypertension can interact and how to select optimal management for treatment. Due to the aging population in economically developed countries, there has been a significant increase in both cases of hypertension (HA) and non-insulin-dependent diabetes mellitus (NIDDM). According to a number of researchers, 35-75% of complications of diabetes in the cardiovascular system or kidneys may be associated with high blood pressure. AH is seen in people with diabetes, 2 times more often than other groups of people. Important in the development of both diseases are lifestyle and heredity. AH also contributes to the development of diabetic retinopathy, the leading cause of blindness in the United States [3]. Based on these considerations, hypertension and diabetes should be actively diagnosed and treated as soon as possible. 6

The aim of this thesis: to provide an actualized overview of arterial hypertension in patients with type 2 diabetes mellitus. The objectives of the thesis: 1. To collect the material in order to make a good analysis of the topic; 2. To establish the general approach of arterial hypertension in patients with type 2 diabetes mellitus; 3. To estimate the cardiovascular risk at the patients with type 2 diabetes mellitus; 4. To study based on the literature review the optimal blood pressure goals and management of the hypertension in type 2 diabetes
I.THE BIBLIOGRAPHIC ANALYSIS OF THE THEME In the past several decades, type 2 diabetes mellitus as rapidly emerged as a worldwide health challenge, and especially in developing countries. Two studies on Asian Indians reported one of the highest global rates of prediabetes progression to T2DM. In terms of annual incidence rates, these translate to 15%–19% annual risk of progression to T2DM, much higher than the 2.5% prevalence rate reported in the Diabetes Prevention Program study Type 2 diabetes mellitus is a common disease with subadverse diabetes outcomes are a result of vascular complications, both at a macrovascular level (coronary artery disease, cerebrovascular disease, or peripheral vascular disease) and a microvascular level (retinopathy, nephropathy, or
neuropathy) (3). Macrovascular complications are more common; up to 80% of patients with type 2 diabetes will develop or die of macrovascular disease (4), and the costs associated with macrovascular disease are an order of magnitude greater than those associated with microvascular disease (13). Because diabetes is defined by blood glucose levels, much of the attention in diabetes care focuses on the management of hyperglycemia. This has been magnified by the causal link between hyperglycemia and microvascular outcomes (3). However, while some observational evidence suggests that level of glycemia is a risk factor for
macrovascular disease (15), experimental studies to date have not clearly shown a causal 7

relationship between improved glycemic control and reductions in serious cardiovascular outcomes. Given these results and the epidemiologic characteristics of diabetes complications, it would seem more logical to focus diabetes care on prevention of macrovascular complications rather than on glucose control and microvascular complications. Indeed, the importance of preventing the macrovascular complications of type 2 diabetes has started to receive greater attention. In particular, several trials have examined the benefit of management of highly prevalent risk factors, such as hypertension. Hypertension is extremely common in patients with type 2 diabetes, affecting up to 60% (2), and there are a growing number of pharmacologic treatment options. 1.1 Definition of hypertension in diabetic populations Epidemiological studies and therapeutic trials have often used different criteria to define hypertension in diabetic patients. Studies in the general population indicate an increased risk of cardiovascular disease with an increase in the level of blood pressure. Thus, an increase in diastolic or systolic blood pressure of 5 mmHg is associated with a concomitant increase in cardiovascular disease of 20–30% (14). Studies in diabetic populations have shown a markedly higher frequency of the progression of diabetic retinopathy when diastolic blood pressure is in excess of 70 mmHg (15). The standard definition of hypertension is a blood pressure ≥140/90 mmHg (16). Evidence obtained from clinical trials in diabetic patients suggests a continuum of risk and clinically significant benefit in outcomes with reductions of blood pressure below 140 mmHg systolic and 80 mmHg diastolic blood pressure. In type 2 diabetes, hypertension may be present at the time of diagnosis or even before the development of hyperglycemia. 1.2. Pathophysiology In the presence of nephropathy, extracellular fluid volume and total body sodium levels are increased. The activity of the renin-angiotensin-aldosterone system (RAAS) is reduced in these patients, and the hypertension is volume-dependent, similar to other nephropathies (17). In the absence of diabetic nephropathy, other factors must play a role in the development of hypertension. These factors are both genetic and acquired. Elevated total body sodium with low or normal activity of the RAAS has been reported. Studies in humans with hypertension have found hyperinsulinemia secondary to insulin resistance and decreased insulin clearance. 8

Hyperinsulinemia may possibly be associated with increased renal sodium resorption and sympathetic nervous system overactivity, leading to hypertension in obese individuals and other insulin-resistant states, such as type 2 diabetes. Insulin resistance is also associated with a decreased vasodilatory response to insulin in skeletal muscle and an increased vasoconstrictor response to various vasopressors. However, the role of insulin resistance in the etiology and pathogenesis of hypertension is not fully understood (11). 1.3 Risks of high blood pressure in type 2 diabetes High blood pressure is an important risk factor for the major forms of cardiovascular disease (CVD), including coronary heart disease, heart failure, stroke, and peripheral arterial disease (11). CVD is the leading cause of death and a major cause of morbidity in the US, regardless of diabetes status. The adverse effect of high blood pressure on risk of coronary heart disease and stroke has been recognized for several decades (12), and for over a decade in persons with diabetes. The risk of major CVD events increases in a continuous manner across the distribution of blood pressure. In patients with type 2 diabetes, there is also a graded increase in risk for CVD and microvascular complications across the entire range of blood pressure levels, including blood pressure levels below current treatment thresholds. Among 347,978 middle-aged men screened for participation in the Multiple Risk Factor Intervention Trial (MRFIT), the absolute risk of CVD mortality increased more steeply across progressively higher systolic blood pressure (SBP) categories among men with diabetes than among men without diabetes. In the observational component of the United Kingdom Prospective Diabetes Study (UKPDS), higher baseline and subsequent SBP levels were associated with greater relative and absolute risk of total mortality, deaths, and complications related to diabetes, including CVD events and microvascular complications (13). 1.4. Arterial hypertension in type 2 diabetes mellitus Many large, well designed multicentre, studies have shown that arterial hypertension and type 2 diabetes appear to be associated clinically as a syndrome involving also other conditions such as dyslipidemia, central obesity, hyperuricemia and accelerated atherosclerosis. This syndrome has been described as insulin resistance syndrome, metabolic syndrome or "syndrome X". Although underlying explanation for this constellation of clinical features remains unexplained, insulin resistance seems to play a pivotal role. 9

Insulin resistance is a metabolic disorder, manifested by a reduction of glucose utilization in peripheral skeletal muscle. The result of this disorder is that larger amounts of insulin are needed to achieve normoglycemia. In untreated patients with essential hypertension, fasting and postprandial insulin levels are higher than in normotensive controls, regardless of the body mass index, with a direct correlation between plasma insulin concentrations and blood pressure level. A genetic predisposition to insulin resistance and hypertension is present in patients with type 2 diabetes mellitus. In addition to the genetic predisposition, insulin resistance / hyperinsulinemia is incriminated in the development of hypertension through abnormalities in insulin signalling and associated cardiovascular and metabolic derangements (figure 1.) (7,10).
" Figure 1. Insulin resistance/hyperinsulinemia seems to play a pivotal role in the pathogenesis of hypertension in genetically predisposed people. Chronic hyperglycemia contributes to progressive renal damage via glycosylation of glomerular proteins. Reduced atrial natriuretic peptide activity, enhanced RAAS activity and sympathic nerve activity as a consequence of insulin resistance/hyperinsulinemia are also involved in the pathogenesis of hypertension. Hypertension exacerbates renal damage and these comorbid states reinforce each other. The role of hyperinsulinemia in the pathogenesis of arterial hypertension is still debated. For example, patients with insulinoma do not appear to have increased arterial blood pressure. In the insulin-resistant state, there is inhibition of several insulin signalling pathways, thus contributing to vasoconstriction. Insulin resistance is often present in persons with impaired
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fasting glucose levels and represents a risk factor for cardiovascular disease even in the absence of significant hyperglycemia (10). Hyperinsulinemia may contribute to the genesis of hypertension through its effect on sodium homeostasis and enhanced responsiveness of the sympathetic nervous system. Both experimental and clinical studies suggest that increased sympathetic nervous system activity is an important mediator of insulin resistance via stimulating renal sodium reabsorption and subsequent volume expansion. Obesity is a well established risk factor for development of type 2 diabetes mellitus and hypertension. Almost ninety percent of the patients with type 2 diabetes are obese. Although the obese individuals uniformly develop insulin resistance, not all of them develop type 2 diabetes mellitus or arterial hypertension (11). 1.5 Nephropathy in diabetes mellitus and hypertension Hypertension plays a major role in the development and progression of nephropathy in both type 1 and type 2 diabetes mellitus. Although hypertension often develops after the onset of nephropathy, up to 50% of patients with type 2 diabetes have hypertension at the time of diagnosis. The prevalence of hypertension in type 2 diabetes is high. The rate of hypertension is already twice as high in patients with impaired glucose tolerance as compared to normal controls and the risk of nephropathy with progression to end-stage renal disease is similar in both types of diabetes (11). Unfortunately hypertension is controlled in less than 25% of the hypertensive population and a target blood pressure of less than 130/80 mmHg is achieved only in a minority of type 2 diabetes patients. The risk of end-stage renal disease is particularly high in patients with hypertension and diabetes, almost five to six times higher than in patients with hypertension without diabetes. Therefore more aggressive treatment of hypertension in patients with type 2 diabetes is mandatory (4). The Captopril Collaborative Study Group demonstrated a significant risk reduction nephropathy progression in patients with type 1 diabetes treated with captopril. A meta analysis of 12 trials in type 1 diabetic patients with microalbuminuria revealed that the treatment with ACE inhibitor for two years was associated with a 60% reduction in progression to macroalbuminuria and in threefold increase in regression to normoalbuminuria in comparison with placebo. In addition the 2-year urinary albumin excretion was 50% lower in the ACE inhibitor than in placebo group. Recently in a randomized controlled trial ACE inhibitor has been 11

shown to prevent progression from normoalbuminuria to overt nephropathy and that these drugs have long lasting (eight years) beneficial renoprotective effect (13). A number of studies have suggested that for the same reduction in blood pressure ACE inhibitors are more effective in decreasing albuminuria than other antihypertensive drugs. This has been supported by the findings of the Microalbuminuria, Cardiovascular and Renal Outcomes – Heart Outcomes Prevention Evaluation (MICRO–HOPE) study showing that overt nephropathy was reduced by 24% in the ramipril treated group resulting in significant protection against cardiovascular events. Therefore this study provides a rationale for using ACE inhibitors in patients with type 2 diabetes, nephropathy and other cardiovascular risk factors (8). Patients with diabetes often require combination therapy to achieve blood pressure target detailed in various international guidelines. The Candesartan and Lisinopril Microalbuminuria (CALM) study has investigated the role of the combination of the ACE-I lisinopril and the ARB candesartan in hypertensive type 2 diabetic subjects with microalbuminuria. This combination showed that candesartan was as effective as lisinopril in reducing blood pressure and microalbuminuria and that combination therapy was well tolerated and was more effective in reducing blood pressure. Recently the CALM II study has been published with the longest follow-up regarding dual blockade in diabetic patients. The conclusion of this study was that there was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20mg in combination with 16 mg candesartan once daily in reducing systolic blood pressure in hypertensive patients with diabetes (14, 15). The DETAIL Study compared angiotensin II receptor blocker telmisartan 80 mg once daily with ACE inhibitor enalapril 20 mg once daily in patients with type 2 diabetes and early nephropathy. This study showed that telmisartan was not inferior to enalapril in providing long-term renoprotection in patients with type 2 diabetes and supported that ABRs and ACE inhibitors are clinically equivalent (7). 1.6 Cardiovascular risk in diabetes mellitus and hypertension Cardiovascular disease is the leading cause of death in patients with both types of diabetes, and mortality in these patients is two to three times higher than in a non-diabetic population. In patients with diabetes, the incidence of myocardial infarction was 45% for those who had a previous myocardial infarction, and 20.2% for those who did not. 12

More provided compelling evidence of the benefits of lowering blood pressure below 130/80 mmHg. In the Optimal Hypertension Study (HOT), studies of diabetic patients with arterial hypertension were randomly assigned to achieve diastolic blood pressures of less than 90, 85, or 80 mmHg. often with the addition of one or two other drugs. Based on this study, it was concluded that the risk of serious cardiovascular events was 50% lower in patients with type 2 diabetes, in whom the target diastolic blood pressure was set at 80 mm Hg. The importance of controlling systolic blood pressure has been noted in many studies. These studies have provided strong evidence that after 50 years, systolic blood pressure is a more reliable measure of cardiovascular risk, and even pulse pressure is becoming increasingly important with higher systolic pressure in correlation with cardiovascular morbidity and mortality (7,8). Consequently, many clinical trials have focused on determining the optimal levels of blood pressure, as well as the class and dose of the drug needed to achieve this goal. Grossman et all compared the efficacy of different classes of antihypertensive drugs and argued that intensive blood pressure control reduced cardiovascular morbidity and mortality in patients with diabetes, regardless of whether there are low doses of diuretics, β-blockers, angiotensin-converting enzyme inhibitors or calcium antagonists have been used as a first-line treatment (8). The metabolic effects of antihypertensive drugs have been of great concern, as in the United States alone, more than 20 million adults use these drugs. Initially, short-term studies of the metabolism of thiazide diuretics have raised concerns about the diabetic potential of these drugs. Subsequently, the results of epidemiological and clinical studies suggest a causal relationship between the use of β-blockers or thiazide diuretics and the further development of type 2 diabetes (10). Traditionally, the use of β-blockers is not recommended in patients with diabetes, as they are associated with side effects such as weight gain, decreased peripheral blood flow, severe hypoglycemia and nightmares. Non-cardioselective blockers are preferred for the non-selective type because they are associated with less awareness of hypoglycemia and a lower increase in lipid and glucose levels. On the other hand, drugs that disrupt the renin-angiotensin system have a beneficial effect on glucose metabolism(table 1) (11,12). Table1. Reducing the risk of new diabetes 13

1.7. Stroke in diabetes mellitus and hypertension Stroke is a serious public health problem and a major cause of morbidity and mortality. Epidemiological data in the United States has shown that stroke is the third leading cause of death and the leading cause of disability. Both hypertension and diabetes are independent risk factors for stroke, and when these disorders co-exist, the risk of stroke increases further. Accidents are often detected by accident using imaging techniques in older people with high blood pressure and diabetes and occur without localized neurological symptoms. Recently, Eguchi et al. studied the effect of hypertension and diabetes on silent brain infarction in 360 asymptomatic patients with hypertension with or without diabetes. This study found that diabetes is the most powerful determinant of strokes in patients with hypertension. Randomized clinical trials conducted with a diabetic population have clearly shown that adequate blood pressure control increases the risk of heart disease, especially stroke (2). There are constant and variable risk factors for stroke. In the group of diabetics with hypertension, one of the most important modifiable risk factors is high blood pressure. Lowering blood pressure to <130/80 mmHg is strongly recommended to prevent primary and secondary stroke. Stroke is the third leading cause of death and a major cause of morbidity in persons with and without diabetes (11). At the population level, high blood pressure is probably the most important risk factor for stroke; nevertheless, diabetes and high blood pressure each independently increase the risk of stroke (12). Little evidence exists regarding the precise nature of the association between blood pressure and the risk of stroke in patients with diabetes; however, Hu et al reported that the effect of high blood pressure on risk of stroke was similar among persons with and without diabetes. It
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seems prudent to presume that the continuous relationship observed between blood pressure and risk of stroke in persons without diabetes exists in persons with diabetes. Consequently, given the greater absolute risk of stroke in patients with diabetes versus those without, the excess risk of stroke related to high blood pressure is likely to be much greater in people with diabetes than in those without diabetes (12,13). Heart failure is a major public health problem in people with diabetes. Bertoni, et al. reported a prevalence of heart failure of 22% in Medicare beneficiaries with diabetes; in addition, the incidence of heart failure was 12.6 per 100 person-years. In the general population of people ≥ 65 yr. old, the prevalence of heart failure is less. High blood pressure is a common medical problem in patients with type 2 diabetes. According to results from the National Health and Nutrition Examination Survey (NHANES) 1999–2000, 31% of men and 43% of women with diabetes in the United States had high blood pressure. In addition, diabetes has been shown to increase the incidence of high blood pressure by approx 50% (3). This increased risk may be caused by mechanisms related to insulin resistance and hyperinsulinemia, including effects on salt sensitivity, the nocturnal fall in blood pressure, the response of blood pressure to exercise , and left ventricular mass and structure. High blood pressure is an important risk factor for the major forms of cardiovascular disease (CVD), including coronary heart disease, heart failure, stroke, and peripheral arterial disease. Stroke is the 3 leading cause of death and a major cause of morbidity in the US in persons with and without diabetes. At the population level, high blood pressure is probably the most important risk factor for stroke; nevertheless, diabetes and high blood pressure each independently increase the risk of stroke (8). 1.8 Management of hypertension in diabetes Screening and initial evaluation All patients with diabetes should have blood pressure measured at the time of diagnosis or initial office evaluation and at each scheduled diabetes visit. Because of the high cardiovascular risk associated with blood pressure ≥130/80 mmHg in patients with diabetes, 130/80 mmHg is considered to be the cut point for defining hypertension, rather than 140/90 mmHg, as in the general population. Initial assessment of a hypertensive diabetic patient should include a complete medical history with special emphasis on cardiovascular risk factors and the presence of diabetes complications and other cardiovascular complications (3,14). 15

The measurement of blood pressure should ideally be performed in the supine and standing position. Two or more determinations in each position should be obtained using an appropriately sized cuff; obese patients generally require a large arm cuff and sometimes a thigh cuff to ensure accuracy. Cardiovascular autonomic neuropathy with significant orthostatic changes in blood pressure is common in diabetic subjects; can cause falsely low or high readings, depending on the position of the patient when the blood pressure is taken. The diagnosis of hypertension in patients with diabetes should be reserved for those individuals whose blood pressure levels exceed 130/80 mmHg on at least two separate occasions separated by at least 1 week. The physical exam should include height, weight, funduscopic examination, and careful evaluation of arterial circulation. Initial laboratory examination should include serum creatinine, electrolytes, A1C test, fasting lipid profile, and urinary albumin excretion (8). Behavioral treatments of hypertension Dietary management with moderate sodium restriction has been effective in reducing blood pressure in individuals with essential hypertension. Several controlled studies have looked at the relationship between weight loss and blood pressure reduction. Weight reduction can reduce blood pressure independent of sodium intake and can also improve blood glucose and lipid levels. The loss of 1 kg body wt has resulted in decreases in mean arterial blood pressure of ∼1 mmHg. Moderately intense physical activity, such as 30–45 min of brisk walking most days of the week, has been shown to lower blood pressure and is recommended in JNC. Smoking cessation and moderation of alcohol intake are also recommended by JNC VI to reduce blood pressure (15). Drug therapy The purpose of antihypertensive treatment is to reduce the morbidity and mortality from cardiovascular complications (congestive heart failure, coronary artery disease, and stroke) and microvascular complications (nephropathy, neuropathy, and retinopathy) (17). Effects of antihypertensive drugs on microvascular complications Nephropathy. Approximately 20–30% of patients with type 1 diabetes and 10–20% with type 2 diabetes wild develop end-stage renal disease (ESRD). Diabetes now accounts for ∼50% of all new patients with ESRD and is the most common cause of this condition in adults. 16

The purpose of clinical interventions is to reduce the morbidity and mortality from this complication. Normotensive patients with advanced diabetic nephropathy show slower progression compared with hypertensive patients (19). Type 2 diabetic patients There is little evidence that the use of ACE-inhibitors as prophylactic treatment in type 1 or type 2 patients without microalbuminuria can prevent the development of diabetic nephropathy, although there was a nonsignificant decrease in the development of microalbuminuria in type 2 patients in the MICRO-Heart Outcomes Prevention Evaluation (HOPE) study. Angiotensin receptor blockers (ARBs) have been shown to retard the progression of albuminuria and the development and progression of nephropathy. Losartan, irbesartan, telmisartan, candesartan, eprosartan, and valsartan are effective antihypertensive agents. They are not associated with cough, like ACE inhibitors. Angiotensin II receptor blockers have been shown to decrease proteinuria (8,14). Effects of antihypertensive drugs on cardiovascular disease in diabetic patients In several recent studies using various antihypertensive drug regimens, indications are that the incidence of cardiovascular events can be effectively reduced in patients with diabetes and hypertension. Two studies have compared the efficacy of dihydropyridine calcium channel blockers (DCCBs) and ACE inhibitors on cardiovascular events in diabetic patients with hypertension. A similar reduction in blood pressure was observed with both drugs. The results of this study suggest either that enalapril had a marked protective effect beyond its antihypertensive properties or that nisoldipine has a deleterious effect (6). The Hypertension Optimal Treatment (HOT) trial was a large-scale multinational study that included patients, whom had diabetes (16,17). The baseline diastolic blood pressure was 105 mmHg. Diabetic patients had a rate of cardiovascular events two to three times higher than the group as a whole for the ≤90 and ≤85 mmHg groups. In the ≤80 mmHg group, the rate of cardiovascular disease events in the diabetic group was lower than in the ≤90 mmHg group.
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II.REVIEW OF PHARMACOLOGICAL AGENTS IN THE MANAGEMENT OF HYPERTENSION IN DIABETES The most commonly prescribed antihypertensive agents available in the U.S. and their classification are presented in Table 2. At the doses available for clinical use, most antihypertensives will produce a reduction in systolic or diastolic blood pressure of 5–10% in patients with mild or moderate hypertension (8). Table 2.Antihypertensive agents and their effects on adult hypertensive diabetic patients
Thiazide diuretics Diuretics reduce total body sodium through their natriuretic action and have been shown to have vasodilatory effects as well. Treatment with thiazide diuretics at doses equivalent to 25–50 mg of hydrochlorothiazide has been associated with hypokalemia, hyponatremia, volume depletion, hypercalcemia, and hyperuricemia. Potassium supplementation should be used as clinically indicated. Their efficacy in reducing the risk of stroke and congestive failure in large randomized clinical trials including subjects with mild-to-severe hypertension has been demonstrated. In elderly populations with isolated systolic hypertension, thiazides have resulted ClassEffects on coronary events ratesEffects on progression of renal diseaseEffects on strokeThiazide diureticsBeneficial UnknownBeneficialLoop diureticsUnknownUnknownUnknownC e n t r a l l y a c t i n g adrenergic agentsUnknownUnknownUnknownβ-BlockersBeneficial Beneficial Beneficialα-BlockersControversialUnknownUnknownDCCBsControversialControversialBeneficialNDCCBsUnknownBeneficial UnknownACE inhibitorsBeneficial Beneficial Beneficial A n g i o t e n s i n – 2 antagonistsUnknownBeneficial Unknown
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in decreased cardiovascular morbidity. Hydrochlorothiazide at a daily dose of 25 mg or bendrofluazide at 1.25 mg daily does not significantly decrease insulin sensitivity (5,6). Loop diuretics The antihypertensive mechanism of loop diuretics is related to a significant decrease in total body sodium; although acutely, these agents also act as vasodilators. Treatment with loop diuretics can be associated with hypokalemia, hyponatremia, and volume depletion. Their use is recommended for patients with decreased renal, usually in combination with other agents (8). Adrenergic blockers β-Blockers. β-Blockers are competitive inhibitors of the β-adrenergic receptors. Nonselective β-blockers markedly inhibit both the B1- and B2-receptors. In few studies in diabetic hypertensive patients in which proteinuria was examined atenolol (a selective β-blocker) produced similar reductions in proteinuria compared with an ACE inhibitor. Atenolol and lisinopril produced similar reductions in the decline of the GFR in patients with type 2 diabetes and nephropathy (17). Calcium channel blockers Calcium channel blockers inhibit calcium influx through membrane-bound voltage-dependent calcium channels, resulting in decreased intracellular calcium levels and vasodilation. The dihydropyridine group (DCCBs) has mainly vasodilatory effects and relatively small effects on cardiac inotropism or atrio-ventricular conduction. The second group, the benzothiazepines have moderate vasodilatory effects and moderate negative inotropic and chronotropic effects. Diltiazem is the only agent available in this group (15). ACE inhibitors These drugs are useful in the management of hypertension in diabetic patients with or without diabetic nephropathy. More studies show similar beneficial effects of the ACE inhibitor captopril and the β-blocker atenolol on diabetes-related mortality and microvascular and cardiovascular complications in patients with type 2 diabetes. The most common side effects of ACE inhibitors include cough and, occasionally, acute decreases in renal function (16). 19

ARBs As has been previously discussed, ARBs have been shown to retard the progression of albuminuria and the development and progression of nephropathy (18). Combinations of antihypertensive agents Many studies of combinations of antihypertensive agents have been published. Diuretic agents in combination with adrenergic blockers have been used in several nephropathy studies. ACE inhibitors have been used in combination with diuretics and calcium channel blockers. Calcium channel blockers in combination with diuretics or ACE inhibitors have been reported. In general, combination therapy may help to improve compliance, as one drug may antagonize the adverse effects of another. Fixed-dose combinations of many drugs are available and may be appropriate when the patient requires more than one drug, the dosages in the product are appropriate for the patient, and the costs are not greatly increased. However, it is clear that intensive treatment of hypertension, with goals similar to those recommended by the American Diabetes Association’s new target of <130/80 mmHg, will require more than one drug in most patients and three or more in many (17,8). Blood pressure goals in diabetic patients The UKPDS and the HOT study demonstrate improved outcomes, especially in preventing stroke, in patients assigned to tighter control (HOT, diastolic blood pressure ≤80 mmHg, achieved 81 mmHg; UKPDS, <150/85 mmHg, achieved 144/82 mmHg) and less tight control (HOT, ≤90 mmHg; UKPDS, <180/105 mmHg). Optimal outcomes in the HOT study were achieved at a mean diastolic blood pressure of 82.6 mmHg. Although patients with diabetes had the best results in the group assigned to a target blood pressure <80 mmHg, the mean result was somewhat higher than this. The ABCD trial, showed a decrease in all-cause mortality in the group treated to a goal diastolic blood pressure of 75 mmHg (achieved 132/78) vs. 80–89 (achieved 138/86). However, this was a secondary outcome, and the study was not powered to detect a decrease in cardiac versus all-cause mortality. There is support from these clinical trials for reducing systolic blood pressure to ≤140 mmHg and for reducing diastolic blood pressure to ≤80 mmHg (18). Epidemiological evidence demonstrates that blood pressures≥120/80 mmHg are associated with increased cardiovascular event rates and mortality in persons with diabetes. Therefore, a target blood pressure goal of ≤130/80 mmHg is reasonable, if it can be safely achieved. A similar target has recently been advocated by the National Kidney Foundation. Even more aggressive treatment would reduce the risk still further is an unanswered question. There is 20

no threshold value for blood pressure, and risk continues to decrease well into the normal range. Achieving lower levels, however, would increase the cost of care as well as drug side effects and is difficult in practice (8). Blood pressure goals are outlined in Table 3. Table 3 Indications for initial treatment and goals for adult hypertensive diabetic patients
III.DISCUSSION High blood pressure is a common coexisting condition in patients with type 2 diabetes mellitus, affecting over a third of adults with diabetes. The presence of high blood pressure increases the risk of numerous macro- and micro-vascular complications of diabetes, including cardiovascular disease, nephropathy, retinopathy, and possibly, neuropathy, and the association of blood pressure with complications extends into the blood pressure range usually considered normal in persons without diabetes. The relative increase in risk attributable to high blood pressure is comparable in persons with and without diabetes, but the combination of high baseline risk of complications in patients with diabetes and this relative risk generate a much larger absolute excess risk of high-blood-pressure-related complications in persons with diabetes than in those without (11,17). The mechanism of diabetes mellitus and endothelial disfunction relationship which are leading to vascular changes and and forming base for arterial hypertension is reflected in fig.2. SystolicDiastolicGoal (mmHg)<130<80Behavioral therapy alone (maximum 3 months) then add pharmacologic treatment130–13980–89Behavioral therapy and pharmacological treatment≥140≥90Blood pressure "
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Figure 2. Hyperglycemia, oxidadive stress and endothelial dysfunction. The clinical trial evidence clearly supports systolic blood pressure levels less than 150 mm Hg and diastolic blood pressure levels less than 80 mm Hg. Lower systolic blood pressure goals are supported by observational data. The relative benefits of various blood pressure lowering medications has received much attention and generated much controversy. Because most patients with diabetes will require triple drug therapy with a diuretic, ACE inhibitor (or angiotensin receptor blocker), and calcium channel blocker to achieve blood pressure control, this debate is largely academic. In patients with high blood pressure but not diabetes, the risk of developing diabetes may be reduced by ACE inhibitors, angiotensin receptor blockers and calcium channel blockers relative to diuretics and beta-blockers. Prevention of diabetes and high blood pressure remain important long-term public health goals; however, given the frequency and complications of high blood pressure in patients with diabetes, and the proven benefits of blood pressure control, attention to improving the quality of care for high blood pressure in patients with diabetes is of major importance (17,18). Most patients with NIDDM, who make up about 90% of people with diabetes and high blood pressure, have essential high blood pressure. Diabetic nephropathy occurs in one-third of patients with insulin-dependent diabetes mellitus (IDDM) and in 20% with IDDM, which is an
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important pathogenetic factor in the development of hypertension. AH, combined with diabetic nephropathy, is characterized by fluid and sodium retention, an increase in total peripheral resistance. For patients with diabetes, systolic hypertension is characteristic, and the addition of autonomic neuropathy causes a rare occurrence of orthostatic hypotension in them (13). The mechanisms of pathogenesis of vascular disease in patients with diabetes mellitus with hypertension can be represented as follows: 1. Increased platelet adhesion and aggregation; 2. Anomalies of the coagulation system; 3. Lipoprotein pathology; 4. Endothelial dysfunction; 5. Insulin-like growth factor-1 and vascular contractility; 6. The effect of hyperglycemia on vascular abnormalities in diabetes and hypertension In patients with diabetes, the hemodynamic disorders of the kidney vessels and the systemic circulation are very similar (14). The community of functional and morphological changes of the microcirculation of the retina and the glomeruli of the kidneys is presented. The appearance of albuminuria in patients with diabetes indicates not only the development of nephropathy, but also proliferative retinopathy (17). Based on these data, generalized hyperperfusion theory is considered to be the basis for the pathogenesis of diabetes complications in the form of microangiopathies of the retina, renal glomeruli and peripheral vascular bed. A long-term consequence of severe hyperglycemia is an increase in the volume of extracellular fluid, which leads to a decrease in the renin content and an increase in the content of sodium-uretic peptide in the blood plasma, which in combination with an altered level of other vasoactive hormones leads to generalization of the observed vasodilation. Generalized vasodilation causes a thickening of the basement membrane in all capillaries and an increase in capillary pressure in the kidneys and retina (10). Platelet adhesion and their aggregation are significantly increased in both patients with diabetes and hypertension. Mechanisms responsible for aggregation the platelet count for both diseases is sufficient interdependent. Apparently, in these diseases, a certain role is played by the intracellular metabolism of divalent cations. In the early stages of activation platelets attach special importance to intracellular calcium and magnesium ions (6, 14) Platelet aggregation is associated with an increase in the intracellular calcium content required to initiate this process. 23

An increase in intracellular magnesium in vitro has an inhibitory effect on platelet aggregation. Platelet abnormalities in patients with diabetes and hypertension may be represented as follows (4) : 1. Increased platelet adhesion; 2. Increased platelet aggregation; 3. Decreased platelet life; 4. Increased tendency for blood clots to form in vitro; 5. Increased platelet production of thromboxane and other vasoconstrictive prostanoids; 6. Decreased platelet production of prostacyclin and other vasodilating prostanoids; 7. Violation of homeostasis of divalent cations in platelets; 8. Increased non-enzymatic glycolysis of platelet proteins. Lipoprotein disorders and pathology of the coagulation system, which determine insulin resistance and hypertension in patients with ADHD, can be represented as follows (2,3): 1. Increased plasma levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL) and lipoprotein (a); 2. Decreased high density lipoprotein (HDL) content; 3. Increased triglyceride content in the blood plasma; 4. Increased oxidation of lipoproteins; 5. Increased glycolysis of lipoproteins; 6. Increasing the content of LDL products; 7. Decreased lipoprotein lipase activity; 8. Increased inhibitor of 1 fibrinogen and plasminogen; 9. Reduction of plasminogen activator content and fibrinolytic activity; A whole a number of anatomical and functional disorders of the vascular endothelium can be detected in diabetes and hypertension (2).: 1. Increasing the content of von Willebrand factor in blood plasma; 2. Increased expression, synthesis and plasma content of endothelin-1; 3. Limitation of prostacyclin production; 4. Reduction of the production of endothelium-dependent relaxation factor (NO) and a decrease in sensitivity to it; 5. Deterioration of fibrinolytic activity; 6. Violation of plasmin degradation by glycated fibrin; 24

7. An increase in the surface area of the thrombomodel by an endothelial cell; 8. Increased procoagulant activity of endothelial cells; 9. Increasing the level of end products of glycosylation. A number of metabolic and hemodynamic factors can affect endothelial dysfunction in patients with diabetes and hypertension. Hypercholesterolemia and possibly hypertriglyceridemia violate endothelium-dependent relaxation. Like insulin and insulin-like growth factor. Permanent hyperglycemia amplify vascular diseases associated with diabetes and hypertension. In high concentrations, glucose has a direct toxic effect (independent of osmolarity) on vascular endothelial cells. It is the toxic effect may lead to a decrease in endothelium-dependent relaxation of blood vessels, an increase in vasoconstriction, stimulation of smooth muscle cell hyperplasia, vascular remodeling and development of atherosclerosis (7). Considering the relationship of diabetes and AH by all authors is performed with emphasis on kidney damage. Diabetic nephropathy is the leading cause of advanced kidney disease in the United States. AH is a significant risk factor for the progression of kidney damage in diabetes. Finally, an assessment of the relationship of diabetes, hypertension and diabetic nephropathy may play a significant role in the selection of rational drug therapy (7,8). The pathogenesis of diabetic nephropathy has been previously studied. Patients with a genetic predisposition to diabetes, high blood pressure, or both are more vulnerable to vascular lesions with significant hyperglycemia than patients with the same degree of hyperglycemia but no genetic predisposition. The subclinical stage of nephropathy, characterized by microalbuminuria, is either preceded by hypertension, or its development occurs together with an increase in blood pressure (18). Benefits of Blood Pressure Control 
 The Systolic Hypertension in the Elderly Program (SHEP) enrolled a diabetes subgroup of patients and randomly assigned these patients to chlorthalidone plus atenolol or reserpine versus placebo and usual care. The intensive group had a 9.8 mm Hg decrease in systolic blood pressure and a 2.2 mm Hg decrease in diastolic blood pressure, as well as a significant decline in total cardiovascular events and a nonsignificant trend for lower all-cause mortality (7). The Systolic Hypertension in Europe (Syst-Eur) study randomly assigned elderly patients (60 years of age) with systolic hypertension to nitrendipine or placebo. The mean decreases in systolic blood pressure and diastolic blood pressure were 8.6 and 3.9 mm Hg in the intervention group compared with the placebo group. In the subgroup of patients with diabetes, this led to an 25

improvement in the risk for cardiovascular death, all cardiovascular events, and stroke. There was no significant difference in overall mortality in unadjusted analyses; however, after adjustment for baseline differences between groups, there was a 55% reduction in overall mortality in the active treatment group (9).
Figure 3. Target levels for the modifiable risk factors in patients with diabetes mellitus The seventh report of the National Joint Committee for the Prevention, Evaluation, Detection, and Treatment of High Blood Pressure (JNC 7) and the American Diabetes Association recognized patients with diabetes as a high-risk group and recommended lowering blood pressure below 130/80 mmHg. In these patients and in the presence of renal failure or significant proteinuria > 1 g / 24 hours, the recommended treatment goal is <125/75 mm Hg (13,14). There is evidence that an intense decrease in blood pressure at this level will reduce microvascular and macrovascular complications in patients with diabetes. Lifestyle changes are part of the therapy in patients with diabetes and hypertension. In obese patients with diabetes and mild hypertension, weight loss, increased physical activity, decreased sodium intake with food, and refusal to drink alcohol should be encouraged. Table 4. Blood pressure control in patients with diabetes mellitus. Current recommendations &
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*The 7th report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC report, JAMA 2003;289:2560-2572 ** ADA Standards of medical care for pts with diabetes mellitus, Diabetes Care 2003; 26(suppl1)539-550 All patients with diabetes and high blood pressure should be treated with an ACE inhibitor or angiotensin receptor blocker as first-line therapy. To achieve the desired reduction in blood pressure (<130/80 mm Hg), most patients with diabetes will require therapy with three to five antihypertensive drugs. Diabetic patients retain sodium, and their hypertension is volume sensitive. Therefore, in the presence of renal failure (creatinine> 1.8 mg / dL), thiazide diuretic or diuretic cyclic therapy is often required in combination with ACE inhibitors or ARB. If additional therapy, a calcium channel blocker, is required, a β-blocker or selective α-blocker can be used (7). Elderly patients with diabetes often have vascular disease. Therefore, such patients should be carefully examined to exclude the presence of stenotic lesions. In these patients, blood pressure should be slowly reduced, since their ability to self-regulate the brain and kidneys is reduced. In addition, renal function and potassium levels should be monitored in patients with diabetes receiving ACE or ARB inhibitors because of the potential risk of unrecognized hyperkalemia or renal artery stenosis. In addition, the possibility of orthostatic hypotension, which is often observed in patients with long-term diabetes due to autonomic neuropathy, should be examed. It is highly recommended that control of blood pressure up to <130/80 mmHg, but only a small proportion of patients with diabetes achieve this goal (14). The reasons for the low level of blood pressure control were widely discussed and explained by factors related to the patient, such as lack of awareness and knowledge of high blood pressure, lack of access to medical care, low literacy rate, poor adherence to prescribed treatment and clinical visits, as well as the cost of drugs. Other factors include reducing the interaction time between patients and healthcare providers, as well as the environment or environment in which the interaction occurs. However, multifactorial intervention aimed at modifiable risk factors, including blood pressure control, glycemic control, lipid control and lifestyle changes, is the most appropriate strategy that will maximize the benefits for patients with diabetes (13,14). Choice of antihypertensive drug for diabetes 27

The choice of antihypertensive therapy in patients with diabetes is not easy, because this disease imposes a number of restrictions on the use of a particular drug, given the spectrum of side effects and, especially, the effect on carbohydrate and lipid metabolism. When choosing the optimal antihypertensive drug for diabetes, it is necessary to take into account the concomitant vascular complications. High blood pressure is a common coexisting condition in patients with type 2 diabetes mellitus, affecting over a third of adults with diabetes. The presence of high blood pressure increases the risk of numerous macro- and micro-vascular complications of diabetes, including cardiovascular disease, nephropathy, retinopathy, and possibly, neuropathy, and the association of blood pressure with complications extends into the blood pressure range usually considered normal in persons without diabetes (8). The relative increase in risk attributable to high blood pressure is comparable in persons with and without diabetes, but the combination of high baseline risk of complications in patients with diabetes and this relative risk generate a much larger absolute excess risk of high-blood-pressure-related complications in persons with diabetes than in those without (7). Clinical trial data have proven the benefits of blood pressure lowering therapy in patients with diabetes. Studies of hypertension control in diabetes show a clear and consistent effect: improved control of blood pressure leads to substantially reduced risks for cardiovascular events and death. In addition, findings suggest that in patients with diabetes, aggressive hypertension control also reduces the risk for microvascular events, including end-stage of functional impairment (such as decreased visual acuity and end-stage renal disease) (14,15). Choice of initial blood pressure agent in patients with diabetes is difficult to define precisely. It could be given the conflicting available evidence, that there are no obviously superior agents. It is clear, however, that most patients will require more than one blood pressure agent. The weight of current evidence suggests that thiazide diuretics and angiotensin II receptor blockers, and perhaps ACE inhibitors, are reasonable first-choic agents, although angiotensin II receptor blockers and ACE inhibitors are considerably more expensive than diuretics(some ACE inhibitors are now off patent). However, high doses of thiazide diuretics can worsen important metabolic variables, including glucose and lipid levels. Available data suggest that angiotensin II receptor blockers have impressive benefits (8). ACE inhibitors were superior to b-blockers and diuretics. The UKPDS and STOP-2 found that ACE inhibitors were equivalent to b-blockers and diuretics (9). 28

Some have argued for the use of ACE inhibitors as first-line agents based on the HOPE study, which showed a hypertension-independent benefit on mortality. However, these
benefits were not apparent in ALLHAT, which suggests that the HOPE study may have been little more than a trial of blood pressure treatment versus placebo in high-risk patients (7). Some limited evidence shows that ACE inhibitors may have hypertension-independent renoprotective effects in patients with diabetes, although this is tempered by the at best inconsistent data comparing ACE inhibitors with other drugs for preventing progression of renal disease. There are as yet no long-term trials comparing angiotensin II receptor blockers with ACE inhibitors in patients with diabetes. Early data on renal outcomes appear to be equivalent and effects on intermediate end points such as blood pressure control seem to be similar, although angiotensin II receptor blockers may be slightly better tolerated (9). Beta blockers and calcium-channel blockers have proven efficacy compared with placebo, and the evidence suggests that they are similarly efficacious (11,12). There is evidence that diuretics, angiotensin-receptor blockers, and ACE inhibitors may be superior to these agents; thus, b-blockers and calcium-channel blockers are probably best used as second- or third-line treatments for hypertension in diabetes. Beta blockers are safe, effective, and inexpensive and at moderate doses have relatively few side effects. However, in the UKPDS, patients taking b-blockers gained more weight than those taking ACE inhibitors, and b-blocker therapy was more frequently discontinued. In addition, patients taking b -blockers required the addition of new glucose lowering agents more frequently than those taking ACE inhibitors. However, there is little evidence to support the common concern that b-blockers increase risks for hypoglycemia or hypoglycemia unawareness (16). Some data suggest that, in the general population, calcium-channel blockers may be more effective in reducing stroke than other agents, but this has not been definitively
shown in patients with diabetes. Given the lack of clear difference in effectiveness between calcium-channel blockers and b-blockers, cost and side effect profiles should be key considerations in choosing between these agents. There is also no obvious choice of which class of calcium-channel blocker to use in patients with diabetes. The large-scale studies show no consistent distinction among classes. The NORDIL trial, which used diltiazem, and INSIGHT and STOP-2, which used dihydropyridine agents, had similar overall results. There has been some concern about the use of dihydropyridine agents in patients with type 2 diabetes and albuminuria; however, only limited and inconsistent data suggest that these agents are substantially worse than other classes of drugs (17,18). 29

Other agents may have a role in achieving desired blood pressure targets in patients with type 2 diabetes. However, there is little information on the effectiveness of these drugs in reducing microvascular and macrovascular outcomes. In view of the proven efficacy of other agents, b-blockers should be reserved for hypertension that is refractory to other agents in patients with type 2 diabetes (19). One of the limitations of the current literature is a lack of strong evidence comparing the effects of blood pressure treatment according to demographic factors, such as ethnicity and age. These factors are important because ethnicity may be a strong predictor of adverse events in patients with diabetes, and age may change relative or absolute benefits of hypertension treatment, in part because of competing risks for death. Also, the effectiveness of different antihypertensive agents in blood pressure lowering may vary by ethnicity and age (18). Pharmacologic Class Effects in Hypertension and Diabetes Several studies have also evaluated the effectiveness of angiotensin II receptor blockers on outcomes in patients with type 2 diabetes. Several studies have specifically compared the effects of different blood pressure targets on diabetes outcomes. The Hypertension Optimal Treatment (HOT). There were substantial improvements in diastolic blood pressure in these groups. In patients with diabetes, the group randomly assigned to a diastolic blood pressure target of 80 mm Hg had a significantly reduced risk for cardiovascular death and major cardiovascular events and a nonsignificant trend toward improved overall mortality compared with those who had a target diastolic blood pressure of 90 mm Hg (12,14). Several studies have compared ACE inhibitors with calcium-channel blockers. In a substudy of the ABCD trial, hypertensive patients with diabetes were assigned to treatment with nisoldipine or enalapril; the achieved blood pressure was equivalent. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study compared treatment with long-acting nifedipine with coamilozide. Blood pressure reduction was in both groups (14). Treatment of hypertension in type 2 diabetes provides serious benefit. Target diastolic blood pressures of less than 80 mm Hg appear optimal; systolic targets have not been as
rigorously evaluated, but targets of 135 mm Hg or less are reasonable. Studies that compare drug classes do not suggest obviously superior agents. However, it is reasonable to conclude that 30

thiazide diuretics, angiotensin-II receptor blockers, and perhaps angiotensin-converting enzyme (ACE) inhibitors may be the preferred first-line agents for treatment of hypertension in diabetes. β-Blockers and calcium-channel blockers are more effective than placebo, but they may not be as effective as diuretics, angiotensin-II receptor blockers, or ACE inhibitors; however, study results are inconsistent in this regard (18). Treatment of high blood pressure in type 2 diabetes this is very useful. Target diastolic blood pressure is lower 80 mmHg seems optimal; systolic goals were not strictly rated, but targets of 135 mmHg or less are reasonable. Studies comparing drug classes do not suggest that the agents are clearly superior. It is important to conclude that thiazide diuretics, angiotensin II receptor blockers and angiotensin converting enzyme (ACE) inhibitors may be the preferred first-line medications for the treatment of high blood pressure in diabetes. Beta blockers and calcium channel blockers are more effective than placebo, but they may not be as effective as diuretics, angiotensin II receptor blockers, or ACE inhibitors; however, research results are inconsistent in this regard. CONCLUSIONS 1.High blood pressure is a common medical problem in patients with type 2 diabetes. 2.Treatment of hypertension in type 2 diabetes, with blood pressure goals of 130/80 mm Hg, provides great benefits. Target diastolic blood pressures of less than 80 mm Hg appear optimal; systolic targets have not been as rigorously evaluated, but targets of 135 mm Hg or less are reasonable. 3.Thiazide diuretics, angiotensin II receptor blockers, and ACE inhibitors may be the best first-line treatments, although other agents are usually necessary and goals may not be achieved even with three or four agents. 4. Aggressive blood pressure control may be the most important factor in preventing adverse outcomes in patients with type 2 diabetes. 5.Early evaluation for hypertension and periodic evaluation the patient with type 2 diabetes, applying life style modifications and prompt treatment of hypertension will favours the good outcome.
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