74 HIPPOKRATIA 2008, 12, 2: 74-80

REVIEW ARTICLE

Arterial hypertension in diabetes mellitus: from theory to clinical practice

Sampanis C, Zamboulis C
2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece Abstract Diabetes mellitus and arterial hypertension are two common diseases that often coexist. Patients with diabetes have much higher rate of hypertension than that in general population. The co-existence of these disorders appears to accelerate microvascular and macrovascular complications and greatly increases the cardiovascular risk, risk of stroke and end stage renal disease. Arterial hypertension is clearly related to nephropathy in subjects with type 1 diabetes. In patients with type 2 diabetes insulin resistance seems to play a pivotal role in the pathogenesis of hypertension. Several well designed randomized controlled trials have provided evidence that patients with diabetes will benefit from a more aggressive treatment of hypertension. This benefit is seen at blood pressure level < 130/80 mmHg. Mopreover, most diabetic patients with hypertension require combination therapy to achieve optimal blood pressure goals. Angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, diuretics, -adrenoreceptor blockers and calcium- channel blockers are all effective antihypertensive agents in type 2 diabetes mellitus and no comparative trial showed the superiority of any particular class in either lowering blood pressure or reducing cardiovascular morbidity and mortality. On the basis of experimental arguments and clinical observations that have shown their apparent superiority in slowing diabetic nephropathy, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers are preferred as the first choice alone or in combination with diuretics. Second choice should be long-acting calcium-channel blockers or cardioselective blockers. Clinicians should be aware of the need for aggressive treatment of hypertension and spend more time in order to provide maximal benefit to the treatment of diabetes mellitus and hypertension. Hippokratia 2008; 12 (2): 74-80 Key words: arterial hypertension diabetes mellitus
Corresponding aurhor: Sapmanis C, 49 Konstantinoupouleos St, 546 42, Thessaloniki, Greece, Tel: +30 2310 992 837, +30 2310 892 071, Fax: +30 2310 992834, e-mail: chsambanis.yahoo.gr

Diabetes mellitus and arterial hypertension are common chronic disorders that often coexist. Large epidemiologic studies showed that diabetes is associated with increased cardiovascular mortality and that hypertension accelerates morbidity and mortality markedly in these patients1. Also, cardiovascular events are more than twice as likely in patients with diabetes and hypertension than patients with either disease alone2. The prevalence of hypertension in diabetic patients is approximately twice that of the non diabetic population1. The incidence of diabetes mellitus is rapidly rising and will soon affect 300 million people worldwide while more than half of them will be hypertensives2. Moreover, diabetes mellitus is the most common cause of end stage renal disease in the Western world3. In the past two decades according to the U.S. Renal Data System4, there has been continual increase in the incidence of end-stage renal disease among patients with diabetes, predominantly of those with type 2 diabetes. Recent reports from the United States have shown that almost two thirds of adult diabetic population

use antihypertensive therapy or have blood pressure >130/80 mm Hg5. Many attempts have been made to elucidate the mechanism of the coexistence of diabetes and hypertension. It has been suggested genetic predisposition as possible mechanism even in the presence of insulin resistance, gene alterations, membrane cation transport abnormalities, altered adrenoreceptor responsiveness, increased sodium sensitivity of the vasculature and neurohumoral changes6. Unfortunately, up to now, no hypothesis has been able to elucidate the mechanism of the development of hypertension in patients with diabetes. Among patients with type 1 diabetes mellitus the prevalence of hypertension is similar to that of the general population and becomes more frequent when nephropathy occurs7. Although early hemodynamic changes are similar in both types of diabetes, in type 2 diabetes hypertension seems to antedate these changes8,9. There is convincing evidence that the pathogenesis of hypertension in persons with diabetes mellitus is multifactorial and that

HIPPOKRATIA 2008, 12, 2

75

this pathogenesis could not be explained by one simple hypothesis. Arterial hypertension and type 1 diabetes mellitus In patients with type 1 diabetes mellitus the development of arterial hypertension is clearly related to microalbuminuria10. Recent studies, using ambulatory blood pressure monitoring, have shown that subjects with type 1 diabetes mellitus and microalbuminuria have higher nocturnal blood pressure than either subjects with type 1 diabetes and normal urinary albumin excretion or agematched controls10,11. Lurbe et al12 studied 75 adolescents and young adults who had type 1 diabetes with normal urinary albumin excretion and blood pressure for more than five years and concluded that in patients with type 1 diabetes an increase in systolic blood pressure during sleep precedes the development of microalbuminuria. In those whose blood pressure during sleep decreased normally, the progression from normoalbuminuria to microalbuminuria was less likely. They suggested that an evaluation of the risk of nephropathy at an early stage of type 1 diabetes would provide the best basis for choosing therapies designed to prevent the progression to microalbuminuria e.g. angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensin II-receptor blockers (ARBs). On the other hand documentation of normal nocturnal blood pressure might suggest that there is no need for early therapeutic interventions other than those designed to provide optimal glycemic control. The results of recent studies have shown that a predisposition to essential hypertension increases the risk of diabetic nephropathy. This concept has been based on studies showing that parents of patients with type 1 diabetes have a higher prevalence of hypertension than that of general population13. In type 1 diabetes the onset of hypertension seems to be associated with microalbuminuria and appears to be a consequence rather than a cause of renal disease. Moreover it has been shown that there is an increased activity of sodium-lithium exchanger14 and of sodiumhydrogen exchanger15 in both subjects with essential hypertension and those with type 1 diabetes mellitus and nephropathy16. In type 1 diabetes mellitus hypertension is often secondary to overt nephropathy17. Elevated blood pressure in turn exacerbates nephropathy; thus these comorbid states reinforce each other18. Arterial hypertension and 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 atherosclerosis19,20. This syndrome has been described as insulin resistance syndrome27, metabolic syndrome20 or syndrome X21. Although underlying explanation for this constellation of clinical features remains unexplained, insulin resistance

seems to play a pivotal role20. Insulin resistance is a metabolic disorder, manifested by a reduction of glucose utilization in peripheral skeletal muscle22. 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 level23. A genetic predisposition to insulin resistance and hypertension is present in patients with type 2 diabetes mellitus24. 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 derangements17,24,25. These would include cell membrane ion exchange, enhanced sympathetic and renin-angiotensin-aldosterone system activity (RAAS) as well as suppressed atrial natriuretic peptide activity, sodium retention with consequent volume expansion, progressive renal disease, cardiac hyperactivity, left ventricular hypertrophy, dyslipidemia, chronic hyperglycemia and increased oxidative stress26 (Figure 1). 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 pressure27. In the insulin-resistant state, there is inhibition of several insulin signalling pathways, thus contributing to vasoconstriction25. Insulin resistance is often present in persons with impaired fasting glucose levels and represents a risk factor for cardiovascular disease even in the absence of significant hyperglycemia20. Hyperinsulinemia may contribute to the genesis of hypertension through its effect on sodium homeostasis

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.

76

SAMPANIS C

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 expansion28. Obesity is a well established risk factor for development of type 2 diabetes mellitus and hypertension29. 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. Nephropathy in patients with diabetes mellitus and arterial 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 diagnosis30. 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 controls31 and the risk of nephropathy with progression to end-stage renal disease is similar in both types of diabetes32. Both the prevalence and the incidence of end-stage renal disease are approximately twice than that 10 years ago33. Unfortunately hypertension is controlled in less than 25% of the hypertensive population34 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 diabetes35. Therefore more aggressive treatment of hypertension in patients with type 2 diabetes is mandatory. The issue is if the progress in understanding the mechanisms involved in the genesis of nephropathy in patients with diabetes and hypertension could be translated adequately into clinical practice. The Captopril Collaborative Study Group36 demonstrated a significant risk reduction nephropathy progression in patients with type 1 diabetes treated with captopril. A meta analysis of 12 trials in 698 type 1 diabetic patients with microalbuminuria37 revealed that the treatment with ACE inhibitor for two years was associated with a 60% reduction in progression to macroalbumin-

Figure 2. Target levels for the modifiable risk factors in patients with diabetes mellitus

uria 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 shown to prevent progression from normoalbuminuria to overt nephropathy and that these drugs have long lasting (eight years) beneficial renoprotective effect38. A number of meta-analyses have suggested that for the same reduction in blood pressure ACE inhibitors are more effective in decreasing albuminuria than other antihypertensive drugs39. This has been supported by the findings of the Microalbuminuria, Cardiovascular and Renal Outcomes Heart Outcomes Prevention Evaluation (MICRO-HOPE) study40 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. Three multicentre randomized double-blind placebo controlled studies with ABRs have provided recently convincing evidence that these drugs have renoprotective effect in patients with type 2 diabetes mellitus and nephropathy41-43. Parving et al41 administered irbesartan to 590 hypertensive patients with type 2 diabetes and microalbuminuria at a dose of 150 mg daily or 300 mg daily and followed them for 2 years. They concluded that irbesartan had a renoprotective effect that was independent of its blood pressure lowering effect. Furthermore in this study (IRMA II) the restoration of normoalbuminuria was more evident in the group receiving irbesartan at a dose of 300 mg daily. Two other studies, IDNT42 and RENAAL43 also used ARBs, but they enrolled patients with higher grade of proteinuria and established renal insufficiency. In patients whose disease was at this more advanced phase, the use of ARBs led to lower levels of proteinuria, lower rates of decline in the glomerular filtration rate and later onset of end-stage renal disease than the use of control medications. Patients with diabetes often require combination therapy to achieve blood pressure target detailed in various international guidelines. The Candesartan and Lisinopril Microalbuminuria (CALM) study44 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 study73 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 20 mg in combination with 16 mg candesartan once daily in reducing systolic blood pressure in hypertensive patients with diabetes. However, in two recently published stud-

HIPPOKRATIA 2008, 12, 2

77

ies46,47 where dual blockade was added to maximal recommended dose of ACE inhibitor, significant additional effects on blood pressure and proteinuria were obtained in both patients with type 1 and type 2 diabetes mellitus. The DETAIL Study48 a prospective, multicenter, double blind, five-year study compared angiotensin IIreceptor blocker telmisartan 80 mg once daily with ACE inhibitor enalapril 20 mg once daily in 250 subjects 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 in patients that place them at high risk for cardiovascular events. The combination of an ACE inhibitor and a calcium channel blocker seems to be also effective in reducing blood pressure and proteinuria. In the BENEDICT Study49, a multicenter, double-blind, randomized study 1204 subjects with type 2 diabetes and hypertension but with normoalbuminuria were randomly assigned to the treatment with trandolapril at a dose 2 mg daily plus verapamil at a dose 180 mg daily or trandolapril alone 2 mg daily, verapamil alone at a dose 240 mg daily or placebo for at least three years. The target blood pressure was 120/80 mm Hg. The primary end-point was the development of persistent microalbuminuria. This study showed that the combination of trandolapril with verapamil, was no superior than trandolapril in reducing of the incidence of microalbuminuria and that the effect of verapamil was similar to that of placebo. Diabetes mellitus, arterial hypertension and cardiovascular risk Cardiovascular disease is the leading cause of death in patients with both types of diabetes and the mortality in these patients is two or three times increased compared to nondiabetic population2. In a population-based study in Finland, Haffner et al50 have shown, that the incidence of fatal myocardial infarction was 18.8% for nondiabetic individuals with a history of myocardial infarction and 3.5% for those without prior infarction. In patients with diabetes mellitus, the incidence of myocardial infarction was 45% for those with prior myocardial infarction and 20.2% for those without. Randomized controlled trials provided conclusive evidence for the benefits of blood pressure reduction below 130/80 mm Hg. In the United Kingdom Prospective Diabetes Study (UKPDS)51 patients assigned to a tight blood pressure control had a 37% reduction in the risk of developing microvascular end points compared with those assigned to less tight blood pressure control. Moreover this tight blood pressure control resulted in a significant 32% reduction of diabetes related mortality, 44% strokes and 24% of all diabetes-related endpoints. This study showed that the relative benefit of cardiovascular disease reduction conferred far more potently by intensive blood pressure reduction than by intensive blood glucose control51,52.

In the Hypertension Optimal Treatment (HOT)53 study 1051 diabetic patients with hypertension were randomly assigned to achieve diastolic blood pressure of less than 90, 85 or 80 mm Hg while taking the dihydropyridine calcium-channel blocker felodipine, often with the addition of one or two other drugs. The conclusion based on this study was that the risk of major cardiovascular events was 50% lower among patients with type 2 diabetes whose target diastolic blood pressure was set at 80 mm Hg than among patients whose target diastolic blood pressure was set at 90 mm Hg53,54. The significance of systolic blood pressure control has been noted in many studies. These studies have provided convincing evidence that after the age of 50 years systolic blood pressure is more valid measure of cardiovascular risk and even the pulse pressure assumes increasing importance with higher systolic blood pressure in correlating with cardiovascular morbidity and mortality55. Consequently, many clinical studies have focused on defining optimal levels of blood pressure as well as the class and the dose of drug needed to achieve this goal. Grossman et al 58 compared the effectiveness of the different classes of antihypertensive drugs and supported that intensive blood pressure control reduced cardiovascular morbidity and mortality in patients with diabetes regardless of whether low-dose diuretics, -blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists were used as the first-line treatment. The metabolic effects of antihypertensive medications aroused a great concern because these drugs are used by more than 20 million adults in the United States alone59. Initially, short-term metabolic studies of thiazide diuretics aroused concern about the diabetogenic potential of these drugs60. Subsequently, the results of some epidemiologic studies and clinical trials suggested a causal link between the use of -blockers or thiazide diuretics and subsequent development of type 2 diabetes61. Traditionally the use of -blockers has been discouraged in patients with diabetes because they were associated with adverse effect such as weight gain, reduced peripheral blood flow, pronounced hypoglycemia and nightmares. Cardioselective -blockers are preferred to the nonselective type because they are associated with less blunting of hypoglycemia awareness and less elevation of lipid and glucose levels. On the other hand drugs that interrupt the renin-angiotensin system have beneficial effect on glucose metabolism40,62 (Table 1).
Table 1. Risk reduction of new onset diabetes mellitus

78

SAMPANIS C

Arterial hypertension, diabetes mellitus and stroke Stroke is a major public health problem and an important cause of morbidity and mortality. Epidemiological data from the United States showed that stroke is the third leading cause of death and the leading cause of disability63,64. Both arterial hypertension and diabetes mellitus are independent risk factors for stroke and when these disorders coexist the risk of stroke is further increased. Silent cerebral infarcts are often incidentally detected on imaging techniques in the elderly population with hypertension and diabetes and occur without localized neurological symptoms. Recently Eguchi et al65 studied the impact of hypertension and diabetes on silent cerebral infarcts in 360 asymptomatic hypertensive patients with or without diabetes. This study showed that the presence of diabetes mellitus was the most powerful determinant of silent cerebral infarcts in patients with hypertension. Large randomized clinical trials with diabetic population have clearly demonstrated that adequate blood pressure control improves the cardiovascular disease risk, particularly for stroke40,51,56,66-68. There are nonmodifiable, and modifiable risk factors for stroke. In the diabetic hypertensive population, among the most important modifiable risk factors is elevated blood pressure. Lowering blood pressure to <130/80 mm Hg is strongly recommended for the primary and secondary stroke prevention69. Arterial hypertension in diabetic patients: from guidelines to clinical practice The Seventh Report of the Joint National Committee on Prevention, Detection Evaluation and Treatment of High Blood Pressure (JNC 7)70 and American Diabetes Association71 have recognized the patients with diabetes as a population at particular high risk and have recommended that blood pressure should be decreased to less than 130/80 mm Hg in these patients (Table 2) and in
Table 2. Blood pressure control in patients with diabetes mellitus Current recommendations

*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

the presence of renal impairment or of significant proteinuria > 1 gr/24 hours the recommended treatment target is <125/75 mm Hg72. There is evidence that intensive reduction in blood pressure to this level will reduce microvascular and macrovascular complications in patients with diabetes. Lifestyle modification is a part of therapy in patients with diabetes and hypertension. In obese patients with diabetes and mild hypertension, body weight reduction, increased physical activity, decrease in dietary sodium intake and avoidance of alcohol ingestion should be encouraged73.

All patients with diabetes and hypertension should be treated with a regimen that includes an ACE inhibitor or an angiotensin receptor blocker as a first-line therapy. To achieve the desired reduction in blood pressure (<130/80 mm Hg) most diabetic patients will require therapy with three to five antihypertensive drugs74. Patients with diabetes retain sodium and their hypertension is volume-sensitive. Therefore diuretic therapy with thiazide diuretic or loop diuretic if renal failure is present (creatinine >1.8 mg/dl) is often required75 in combination with ACE inhibitors or ARBs. If additional therapy is required a calcium channel blocker, selective - blocker or -blocker may be used76. The elderly patients with diabetes have often vascular disease. Therefore these patients should be examined carefully to rule out the presence of stenotic lesions. The blood pressure should be lowered slowly in these patients because their ability of the cerebral and renal autoregulation is reduced77. Moreover renal function and potassium levels should be monitored in patients with diabetes treated with ACE inhibitors or ARBs because of potential risk of hyperkalemia or unrecognised renal-artery stenosis. In addition, the possibility of orthostatic hypotension that is often seen in patients with longstanding diabetes as a consequence of autonomic neuropathy should be examined. Comparative trials have failed to show definite superiority of any particular class in either lowering blood pressure or reducing cardiovascular morbidity and mortality up to now78. The control of blood pressure to level <130/80 mm Hg is strongly recommended, but only a small proportion of the patients with diabetes achieves this target. The reasons for poor rates of control of hypertension have been discussed extensively and they have been attributed to patients-related factors, such as lack of awareness and knowledge of hypertension, lack of access to health care, low literacy rates, poor adherence to prescribed treatment and clinical visits, and the cost of drugs79,80. Other factors include decreased time for interaction between patients and health care practitioners and the environment or setting where interaction occurs. Guidelines can be effectively translated into clinical practice only if clinicians have the will to implement what is already known81. However, multifactorial intervention82 directed towards modifiable risk factors that include blood pressure control, glycemic control, lipid control and lifestyle modification is the most appropriate strategy that would provide maximal benefit to patients with diabetes mellitus. References
1. Ebstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992; 19: 403-418 2. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in The Multiple Risk Intervention Trial. Diabetes Care 1993; 16:434-444 3. Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998; 352:213-219

HIPPOKRATIA 2008, 12, 2

4. Renal Data System. USRDS 1998 annual data report. Bethesda, Md: National Institute of Diabetes and Digestive and Kidney Disease, April 1998 (NIH publication no. 98-3176) 5. National Diabetes Information Clearinghouse. Diabetes Statistics. Bethesda, MD: National Institutes of Health, 2000. NIH publication 02-3892 6. Bakris G. Pathogenesis of hypertension in diabetes. Diabetes Reviews 1995; 3: 460-474 7. Parving HH, Andersen AR, Smidt UM. Diabetic nephropathy and arterial hypertension. Diabetologia 1983; 24:10-12 8. Vora J, Dolben J, Dean JD, et al. Renal hemodymanics in newly presenting non-insulin-dependent diabetes. Kidney Int 1992; 41:829-835 9. Mykkanen L, Haffner SM, Kuusisto J, et al. Microalbuminuria precedes the development of NIDDM. Diabetes 1994; 43: 552557 10. Lafferty AR, Werther GA, Clarke CF. Ambulatory blood pressure, microalbuminuria, and autonomic nephropathy in adolescents with type 1 diabetes. Diabetes Care 2000; 23: 533-538 11. Pecis M, Azevedo MJ, Moraes RS, et al. Autonomic dysfunction and urinary albumin excretion rate are associated with an abnormal blood pressure pattern in normotensive normoalbuminuric type 1 diabetic patients. Diabetes Care 2000; 23: 989-993 12. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002; 347:797-805 13. Earle K, Viberti GC. Familial, hemodynamic and metabolic factors in the predisposition to diabetic kidney disease. Kidney Int 1994; 45: 434-437 14. Mangili R, Bending JJ, Scott G, et al. Increased sodium-lithium countertransport activity in red cells of patients with insulindependent diabetes and nephropathy. N Engl J Med 1988; 318:146-150 15. Rosskopf D, Fromter E, Siffert W. Hypertensive sodium-proton exchanger phenotype persists in immortalized lymphoblasts from essential hypertensive patients: a cell culture model for human hypertension. J Clin Invest 1993; 92: 2553-2559 16. Lurbe A, Fioretto P, Mauer M, et al. Growth phenotype of cultured skin fibroblasts from IDDM patients with and without nephropathy and overactivity of the Na+/H+ antiporter. Kidney Int 1996; 50: 1684-1693 17. Sowers JR, Epstein M, Frolich ED. Diabetes, hypertension and cardiovascular disease: an update. Hypertension 2001; 37: 1053-1059 18. McFarlane SL, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001; 86: 713718 19. Williams B. Insulin resistance: the shape of things to come. Lancet 1994; 344:521-524 20. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683-689 21. Stern S, Grosskopf I, Shapira I, et al. Risk factor clustering in hypertensive patients: impact of the reports of NCEP-II and second joint task force on coronary preventionon JNC-6 guidelines. J Intern Med 2000; 248: 203-210 22. De Fronzo RA, Bonnadonna RC, Ferrannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 1992; 15: 318368 23. El-Atat F, Aneja A, Mcfarlane S, Sowers JR. Obesity and Hypertension. Endocrinol Metab Clin North Am 2003; 32: 823-854 24. Grunfeld B, Balzareti M, Romo M, et al. Hyperinsulinemia in normotensive offspring of hypertensive patients. Hypertension1994; 23 (Suppl 1): 112-115 25. Sowers JR. Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 2004; 286: H1597-H1602 26. El-Atat FA, Sameer NS, Mcfarlane SI, Sowers JR. Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease. J Am Soc Nephrol 2004; 15:2816-2827

79

27. Vettor R, Mazzonetto P, Macor P, et al. Effect of endogenous organic hyperinsulinemia on blood pressure and serum triglycerides. Eur J Clin Invest 1994; 24: 350-354 28. Castro JP, El-Atat FA, McFarlane SI, et al. Cardiometabolic syndrome: Pathophysiology and treatment. Curr Hypertens Rep 2003; 5: 393-401 29. Huang Z, Willett WC, Manson JE, et al. Body weight, weight change, and risk of hypertension in women. Ann Intern Med 1998;128: 81-88 30. Pell S, D`Allonzo CA. Some aspects of hypertension in diabetes mellitus. JAMA 1967; 202: 104-110 31. Harris MI. Impaired glucose tolerance in the U.S. population. Diabetes Care 1989; 12: 464-447 32. Hasslacher C, Ritz E, Wahl P. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 1989; 4: 859-863 33. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada and the United States. JAMA 2003; 289: 2363-2369 34. U.S. Renal Data System. USRDS 2001 Annual Data Report: atlas of end-stage renal disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Disease, 2001 35. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000; 36: 646-661 36. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456-1462 37. The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensine-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001; 34: 370-379 38. Mathiesen R, Hommel E, Hansen HP, et al. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 1999; 319: 24-25 39. Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-analysis. Ann Intern Med 1993; 118: 129-138 40. Gerstein HC, Yusuf S, Mann JFE, et al. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICR-HOPE substudy. Lancet 2000; 355: 253-259 41. Parving HH, Lehnert H, Mortensen JB, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870-876 42. Lewis EJ, Hunsicker LG, Clarke WR. The Collaborative Study Group: Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-860 43. Brenner BM, Cooper ME, Zeeuw D, et al. The RENAAL Study Investigators: Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869 44. Mogensen CE, Neldam S, Tikkanen L, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes : the Candesartan and Lisinopril microalbuminuria (CALM) study. Brit Med J 2000; 321: 1440-1444 45. Andersen NH, Poulsen PL, Knudsen ST, et al. Long-Term Dual Blockade With Candesartan and Lisinopril in Hypertensive Patients With Diabetes (The CALM II study). Diabetes Care 2005; 28: 273-277 46. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int 2003; 63: 1874-1880

80

SAMPANIS C
the stroke council of the American Heart Association. Circulation 2001; 103: 163-182 64. Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention. JAMA 2002; 288: 1388-1395 65. Eguchi K, Kario K, Shimada K. Greater impact of coexistence of hypertension and diabetes on silent cerebral infarcts. Stroke 2003; 34: 2471-2474 66. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981-2997 67. Bakris GL, Gaxiola E, Messerli FH, et al. Clinical outcomes in the diabetes cohort of the International Verapamil SR Trandolapril study. Hypertension 2004; 44: 637-642 68. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004; 363: 2022-2231 69. McFarlane SI, Sica DA, Sowers JR. Stroke in Patients With Diabetes and Hypertension. J Clin Hypertens 2005; 7: 286-292 70. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC 7 report. JAMA 2003; 289: 2560-2572 71. Position Statement. Hypertension management in adults with diabetes. Diabetes Care 2004; 27: S65-S67 72. Compendium of ESC Guidelines 2007, Section III: Diabetic Heart Disease, Eds. Lippincott Williams and Wilkins, 2007; 33-52 73. Zanella MT, Kohlmann O, Ribeiro AB. Treatment of Obesity Hypertension and Diabetes Syndrome. Hypertension 2001; 38 [part 2]: 705-708 74. Weir MR. Diabetes and Hypertension: How Low Should You Go and With Which Drugs? Am J Hypertens 2001; 14: S17S26 75. Bakris GL. The Importance of Blood Pressure Control in the Patients with Diabetes. Am J Med 2004; 116(5A): S30-S38 76. Kaplan NM. Management of Hypertension in Patients with Type 2 Diabetes Mellitus: Guidelines Based on Current Evidence. Ann Intern Med 2001; 135: 1079-1083 77. Christensen PK, Hansen HP, Parving HH. Impaired autoregulation of GFR in hypertensive non-insulin dependent diabetic patients. Kidney Int 1997; 52: 1369-1374 78. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of ACE inhibitors, calcium antagonists, and other bloodpressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000; 355: 1955-1964 79. Knight EL, Bohn RL, Wang PS, et al. Predictors of uncontrolled hypertension in ambulatory patients. Hypertension 2001; 38: 809-814 80. Douglas JG, Ferdinand KC, Bakris GL, Sowers JR. Barriers to blood pressure control in African Americans. Overcoming obstacles is challenging, but target goals can be attained. Postgrad Med 2002; 112: 51-62 81. Hart PD, Bakris GL. Hypertension Control Rates: Time for Translation of Guidelines into Clinical Practice. Am J Med 2004; 117: 62-64 82. Gaede P, Vedel P, Larsen N, et al. Multifactorial Intervention and Cardiovascular disease in Patients with Type 2 Diabetes. N Engl J Med 2003; 348: 383-393

47. Rossing K, Jacobsen P, Pietraszek L, Parving HH. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial. Diabetes Care 2003; 26: 2268-2274 48. Barnett AH, Bain SC, Bouter P, et al. The Diabetics Exposed to Telmisartan and Enalapril Study Group. N Engl J Med 2004; 351: 1952-1961 49. Ruggeneti P, Fassi A, Parvanova Ilieva A, et al. The Bergamo Nephrologic Complications Trial (BENEDICT) Investigators: Preventing Microalbuminuria in Type 2 Diabetes. N Engl J Med 2004; 351: 1941-1951 50. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229-234 51. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703-713 52. Mogensen CE. Combined high blood pressure and glucose in type 2 diabetes: double jeopardy: British trial shows clear effects of treatment, especially blood pressure reduction. BMJ 1998; 317 :693-694 53. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351: 1755-1762 54. Ruilope LM, Garcia-Robles R. How far should blood pressure be reduced in diabetic patients? J Hypertens Suppl 1997; 15: S63-S65 55. Franklin SS, Gustin W, Wong ND, et al.. Hemodynamic patterns of age-related changes in blood pressure: the Framingham Heart Study. Circulation 1997; 96: 308-315 56. Staessen JA, Fagard R, Thijs L, et al. Sub-group and per-protocol analysis of the randomized European Trial of Isolated Systolic Hypertension in the Elderly. Arch Intern Med 1998; 158: 1681-1691 57. Lindholm LH, Hansson H, Ekbom T, et al. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2. STOP Hypertension-2 Study Group. J Hypertens 2000; 18: 1871-1875 58. Grossman E, Messerli FH, Goldbourt U. High blood pressure and diabetes mellitus: are all antihypertensive drugs created equal? Arch Intern Med 2000; 160: 2447-2452 59. Burt V, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25: 305-313 60. Kohner EM. Effect of diuretic therapy on glucose tolerance in hypertensive patients. Lancet 1971; 1: 986-990 61. Gurwitz HJ, Bohn RL, Glynn RJ, et al. Antihypertensive drug therapy and the initiation of treatment for diabetes mellitus. Ann Intern Med1993; 118: 273-278 62. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension Study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 995-1003 63. Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from