Endothelial dysfunction and hypertension in diabetes mellitus

Endothelial dysfunction and hypertension in diabetes mellitus

Med Clin N Am 88 (2004) 911–931 Endothelial dysfunction and hypertension in diabetes mellitus Paresh Dandona, MD, DPhil, FRCP, FACP, FACC*, Ajay Chau...

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Med Clin N Am 88 (2004) 911–931

Endothelial dysfunction and hypertension in diabetes mellitus Paresh Dandona, MD, DPhil, FRCP, FACP, FACC*, Ajay Chaudhuri, MBBS, MRCP, Ahmad Aljada, PhD Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, 3 Gates Circle, Buffalo, NY 14209, USA

The maintenance of the vascular tone and luminal diameter of a blood vessel is dependent on the net balance between vasoconstrictor and vasodilator forces. This is relevant both to the basal state and to states following a challenge or stress. The major endothelial vasodilatory factors acting on the vascular smooth muscle are nitric oxide (NO), prostacyclin (PGI2), and hyperpolarizing factor, whereas the major vasoconstrictor forces are endothelin-1, angiotensin II, norepinephrine, serotonin (5-HT), and thromboxane (TX)A2 [1–7]. Although the net balance between vasoconstriction and vasodilation determines the tone of the blood vessel, the vasodilatory–vasoconstrictive response following a challenge may also be determined by the intrinsic mechanical and biological properties of the vascular smooth muscle. In both diabetes mellitus and obesity, vascular reactivity, defined as the response to a challenge, is known to be abnormal, whereas the basal vascular tone and blood flow is usually normal; however, in some cases the blood flow may even be supranormal [8–12]. Following ischemia, CO2 challenge, thermal challenge, or exercise, the diabetic or the obese subject is unable to increase blood flow or to vasodilate in a manner similar to that in normal subjects [8,13–20]. Subnormal vasodilation has been shown to occur following CO2 challenge in cerebral blood flow [16], after exercise in muscle blood flow [17], thermal challenge in skin blood flow and transcutaneous pO2 [18], and following exercise in the myocardium [19,20]. The mechanisms involved in abnormal reactivity may involve both the endothelium and the vascular smooth muscle. Consistent with the endothelial damage known to occur in diabetics, the level of secretion and * Corresponding author. E-mail address: [email protected] (P. Dandona). 0025-7125/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.04.006

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the bioavailability of NO and PGI2, the two major vasodilators, is diminished [8,14,21–24]. This appears to be particularly relevant to their secretion/release following a challenge, for example, from acetylcholine, CO2, ischemia, thermal stress, or exercise. There is a simultaneous increase in the synthesis, secretion, and action of the vasoconstrictors, endothelin-1, TXA2, and sensitivity to angiotensin II [25–27]. Plasma concentrations of 5HT are increased whereas intra-platelet 5-HT content is depleted [6,28,29]; thus, there is an increase in vasoconstrictors whereas there is a decrease in vasodilators. In diabetes, TXA2 may be derived both from hyperaggregable platelets and from the arterial wall [30–33]. It is of interest that the basal vascular tone and flow in diabetics is often not subnormal. In fact, the basal blood flow, as measured in the diabetic foot, may be increased; however, the ability of the flow and the arterial diameter to be increased following challenge is markedly reduced [8,34].

Action of nitric oxide, acetylcholine, and insulin NO is a vasodilator, and its vasodilatory action is mediated by a sequence of steps. NO activates guanylate cyclase, which converts guanosine triphosphate into c-GMP in vascular smooth muscle cells (VSMC), which in turn causes the VSMC to relax. This sequence results in vasodilation [35,36]. Acetylcholine (ACh), acting through a muscarinic receptor, stimulates NO release. Insulin causes vasodilation through the sequential phosphorylation of its receptor, the activation of phosphatidylinositol (PI) 3-kinase, Akt kinase, NO synthase (NOS) activation, and NO generation [37–39]. Insulin also causes an increase in NOS expression [40]. Thus, both ACh and insulin cause endothelium-dependent NO-mediated vasodilation. Post-ischemic vasodilation is also endothelium dependent and is mediated by NO. Endothelial function as mediated by NO can be tested by any of the three modalities ACh, insulin, and ischemia. PGI2, a potent vasodilator and an inhibitor of platelet aggregation, exerts these effects through the activation of adenyl cyclase and the formation of c-AMP, which causes the relaxation of VSMC and the inhibition of platelet aggregation [41,42].

Effect of hyperglycemia, increase in free fatty acids, diabetes, and obesity High glucose concentrations cause a reduction in NOS expression in endothelial cells [43,44]. In humans, acute hyperglycemia causes a reduction in postischemic and ACh-induced vasodilation [45]. Intake of glucose (75 g) also results in an increase in the generation of reactive oxygen species (ROS), an increase in intranuclear nuclear factor kappa B (NF-jB), and a decrease in total cellular inhibitor of kappa B (IjB) in mononuclear cells (MNC), reflecting inflammation at the cellular level [46,47]. Increased ROS generation may decrease NO bioavailability and thus alter the vascular

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responses. An acute increase in free fatty acids (FFAs) also causes an inflammatory response, as reflected in an increase in ROS generation by MNC and an increased intranuclear NF-jB binding and NF-jB expression by MNC [48]. There is also an increase in macrophage migration inhibitory factor and C-reactive protein, along with a decrease in postischemic vasodilation by the brachial artery. An increase in FFAs also causes a fall in insulin-induced increase in femoral artery blood flow [49], in addition to causing an induction of a state of insulin resistance (reduction of insulin induced glucose uptake) [50]. In the plasma of insulin-resistant states of obesity and type 2 diabetes, FFA concentration is increased. This may also contribute to abnormal vascular reactivity because FFAs induce a state of insulin resistance and inflammation in addition to reducing NO release by the endothelium. FFAs also reduce vascular PGI2 secretion as well as rendering it unstable [24,51,52]. Similarly, hyperglycemia of diabetes may contribute to altered vascular responses in that condition. Diabetes is associated with reduced postischemic, ACh-, and insulininduced vasodilation in both arterial and venous systems [14,53–55]. Obesity is also associated with diminished vasodilation following ischemia and insulin [56]. Both obesity and diabetes cause marked increases in oxidative stress and have underlying inflammation. ROS, superoxide (O2) in particular, combine with NO and thus reduce its bioavailability [35,36]. The insulin-resistant obese person probably also has a reduced action of insulin on NO release and e-NOS suppression. A part of this effect may be caused in part by the inhibitory effect of the proinflammatory cytokine, tumor necrosis factor (TNF)a, on e-NOS expression, and in part because of the suppression by TNFa of insulin receptor expression and insulin receptor phosphorylation [57–59]. Plasma TNFa is known to be increased in obesity and diabetes type 2 [58,60,61]. It is possible that other proinflammatory cytokines such as interleukin-6, known to be increased in obesity and type 2 diabetes, may exert a similar inhibitory effect on e-NOS and NO release [62,63]. Hyperactive, hyperaggregable platelets may also contribute to a vasoconstrictor and proinflammatory state because the platelets contain norepinephrine, 5-HT, and histamine, all of which are potentially proinflammatory. In addition, platelets have arachidonic acid, which is liberated from phospholipids by phospholipase A2 on platelet activation. Arachidonic acid is converted to proinflammatory prostaglandins, including TXA2, and leukotrienes [64–66]. Platelets are also abundant in CD40, which with its ligand CD40L in leucocytes and the endothelium activates inflammatory cascades [67–71]. This too may affect NO release and vascular reactivity. The platelets are known to be hyperaggregable in diabetes and obesity and may therefore contribute to abnormalities of vascular reactivity in these conditions. Thus, the state of diabetes with associated hyperglycemia, increase in FFA concentrations, relative or absolute lack of insulin, and insulin resistance is a proconstrictor state that would support hypertension. It is

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still not totally clear, however, what the specific mediator of hypertension in diabetes is.

Treatment of hypertension in diabetes mellitus Diabetes mellitus and hypertension coexist in approximately 30% of type 1 and 20% to 60% of type 2 diabetics [72,73]. In type 1 diabetes, hypertension usually occurs in association with nephropathy whereas in type 2 diabetes, it may be present at diagnosis or even before hyperglycemia, as a part of the metabolic syndrome. Hypertension is twice as common in the type 2 diabetic, compared with the nondiabetic [74]; it is present in 85% of subjects with nephropathy [75], and the coexistence of these two conditions is associated with an increase in the risk of retinopathy, renal failure, and cardiovascular disease (CVD) [74]. An increase of 5 mm Hg in systolic or diastolic blood pressure increases the risk of CVD by 20% to 30%; a diastolic blood pressure above 70 mm Hg increases the risk of retinopathy; and end-stage renal disease is 5 to 6 times more common in the hypertensive diabetic [75–77]. In contrast to type 1 diabetes, in which microvascular complications are the major cause of mortality and morbidity, ischemic heart disease and stroke account for approximately 70% of the morbidity and mortality associated with type 2 diabetes [74]. Treatment of hypertension decreases the risk of CV and microvascular complications largely in the diabetic, compared with the nondiabetic, and, although the benefit of lowering blood pressure is clear, the effect of individual agents beyond their antihypertensive effect is debatable.

Benefits of blood pressure lowering Numerous trials have compared the effect of blood pressure (BP) control on CV outcomes. In these trials, diabetics have been a part of subgroup analysis or were the primary group studied, and control of blood pressure with an active agent was compared with a placebo (Table 1). In the Systolic Hypertension in The Elderly Program (SHEP) study [78], a difference of 9.8 mm Hg in systolic and 2.2 mm Hg in diastolic blood pressure in a diabetic subgroup (583 subjects) treated with chlorthalidone and atenolol or reserpine, compared with placebo, resulted in a relative reduction of 34% in CV events and a trend toward lower total mortality. The Systolic Hypertension in Europe (Syst-Eur) study [79], which compared patients treated with nitrendipine or placebo showed a benefit on CV outcomes with a decrease in systolic BP of 8.6mm Hg and diastolic BP of 3.9 mm Hg in a diabetic subgroup of 492 subjects. Cardiovascular mortality was reduced by 70%, CV events by 62%, and strokes by 69%. The incidence of CV events in the placebo-treated diabetics was twice that of the nondiabetics. These trials demonstrated that diuretics and calcium

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Table 1 Benefits of blood pressure control; placebo-controlled trials

Trial SHEP

Step therapy vs placeboa

Eligibility (BP at entry mm Hg)

1. Chlorthalidone 2. Atenolol HTN (170/77) 3. Reserpine

BP difference (mm Hg) Duration (yrs) CVDb Sy Di

Microb

5

9.8

2.2

# 34%

N/A

Syst-Eur

1. Nitrendipine 2. Enalapril 3. Hctz

HTN (175/85)

2

8.6

3.9

# 69%

N/A

HOPE

Ramipril

CVD/CVDRF (142/80)

4.5

2.4

1

# 25%

#16%c

RENAAL Losartan

DM, nephro (152/82)

3.4

2

0

# 10% (NS) # 21%d

IPDM

HTN, DM, 2 microalbumin (153/91)

3

0

N/A

Irbesartan

# 70%e

Abbreviations: BP difference, difference in BP between the treated and placebo groups; Di, diastolic; DM, diabetes mellitus; HOPE, Heart Outcomes and Prevention Evaluation; HTN, hypertension; IPDM, Irbesartan in Patients with type 2 Diabetes and Microalbuminuria; nephro, nephropathy; NS, nonsignificant; N/A, not available; RENAAL, Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan; RF, risk factor; SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe; Sy, systolic. a Agents added sequentially if BP goal was not achieved. b Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in the treated group compared with placebo. c Reduction in overt nephropathy albumin/creatinine >36 mg/mmol, laser therapy, dialysis. d Nephropathy, albumin/creatinine >300 mg/g, creatinine 1.3–3 mg/dl, 21% decrease in doubling of serum creatinine and end-stage renal disease. e 70% reduction in the risk of overt nephropathy for irbesartan 300 mg.

channel blocker (CCB) agents were safe and effective in reducing blood pressure and in reducing CV complications. In a subgroup analysis of the Heart Outcomes and Prevention Evaluation (HOPE) study [80], subjects with diabetes and an additional risk factor for atherosclerosis or a history of CV disease were randomized to ramipril, 10 mg or placebo. Subjects had a baseline BP of 142/80 mm Hg, the ramipril treated group had a BP fall of 2.4/1 mm Hg at the end of the study compared with the placebo-treated group. Ramipril-treated patients had a 25% reduction in CV outcomes, 24% reduction in total mortality, and a 16% reduction in microvascular endpoints. This effect of ramipril was significant even after adjusting for the blood pressure differences. Another arm of this study demonstrated a significant ramipril-induced decrease in progression of carotid intimal-media thickness [81]. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study [82], 1500 subjects with type 2

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diabetes and nephropathy received losartan or a placebo. The blood pressure differences were minimal, but there was a 21% reduction in the risk of renal outcomes (doubling of serum creatinine or end-stage renal disease) in subjects treated with losartan. There was also a reduction of 32% in hospitalization for heart failure. In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IPDM) study [83], 590 type 2 diabetic and hypertensive subjects were randomized to irbesartan, 300 or 150 mg or placebo, with the primary aim to assess the effect on progression to macroalbuminuria. Systolic blood pressure was 3 and 2mm Hg lower in the irbesartan 300 mg and 150 mg groups, respectively, compared with placebo. This resulted in a 70% reduction in the progression to nephropathy in the group treated with irbesartan 300 mg. Benefits persisted even after adjustment for blood pressure differences. These trials were not powered to detect improvements in CV outcomes. On the basis of these trials, we can conclude that CV outcomes are improved in the diabetic with the lowering of blood pressure from baseline. They also show that angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II receptor antagonist (ARB) agents reduce CV and microvascular complications with minimal changes in blood pressure.

Intensity of blood pressure control Three trials have assessed the effects of targeting different blood pressure levels on macro- and microvascular complications in diabetics (Table 2). In the Hypertension Optimal treatment (HOT) trial [84], 19,000 patients were randomized to three groups aimed at a diastolic blood pressure of 80, 85, or 90 mm Hg. There was a substantial decrease in diastolic blood pressure in all three groups (24.3, 22.3, and 20.3 mm Hg, respectively), with a mean diastolic blood pressure of 81.1, 83.2, and 85.2 mm Hg that was achieved by a five-step titration with felodipine followed by an ACE inhibitor or b-blocker. There was no difference in CV outcomes among the three groups in the nondiabetic population; however, in the 1500 diabetics in this trial, there was a 51% reduction in CV events in the group who achieved a diastolic blood pressure of 81 mm Hg compared with 85 mm Hg (a 4-mm Hg difference). Significant reductions were seen even between the groups (with a 2-mm Hg difference). More than three antihypertensive agents were required to reach a diastolic blood pressure of less than 80 mm Hg. In the United Kingdom Prospective Diabetes Study (UKPDS) [85], 1148 subjects with a mean blood pressure of 160/94 mm Hg were randomized into a target blood pressure group of 180/105 or 150/85 mm Hg. The first group achieved a blood pressure of 154/87 mm Hg whereas the second group achieved 144/82 mm Hg. This respective difference of 10 mm Hg systolic and 5 mm Hg diastolic was associated with a 34% reduction in macrovascular complications, including a significant reduction in any diabetes related

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P. Dandona et al / Med Clin N Am 88 (2004) 911–931 Table 2 Trials targeting different levels of BP control Target BP (mm Hg) control

Achieved BP (mm Hg)

Trial

Step therapya

HOT

1. Felodipine 5 mg 2. b-Blocker or Diastolic BP Diastolic BP 144/85 ACE inhibitor 3. " Felodipine to 10 mg 4. " step2 drug \90 \80 5. Diuretic

UKPDS 1. Captopril or atenolol 2. Furosemide 3. Nifedipine SR 4. Methyldopa 5. Prazosin ABCD

1. Nisolodipine or enalapril 2. Metoprolol 3. Hctz

\180/105

Active

\150/85

Control Active CVDb

154/87

Diastolic BP Diastolic BP 138/86

\75

140/81 # 51%

Microb N/A

144/82 # 34%c # 37%d

132/78 NSe

NS

80–90

Abbreviations: ABCD, Apropriate Blood Pressure Control in Diabetes; HOT, Hypertension Optimal treatment; UKPDS, United Kingdom Prospective Diabetes Study. a Agents added sequentially if BP goal was not achieved. b Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in the active group compared with the control group. c Included a # diabetes related death by 32%, stroke by 44%, heart failure by 56%. d Included a 47% reduction in deterioration of visual acuity. e Reduction in mortality by 49%.

endpoint, deaths related to diabetes, stroke, and heart failure. There was also a 37% decrease in microvascular complications, primarily because of a decrease in retinal photocoagulation, and an improvement in visual acuity. It was estimated that for every 10 mm Hg of decrease in systolic blood pressure, there is a 12% reduction in a diabetes related endpoint, a 15% reduction in death because of diabetes, an 11% reduction in myocardial infarction, and a 13% decrease in microvascular complications [86]. There was no threshold of risk, and the best outcomes were seen in subjects with a systolic BP of less than 120 mm Hg. The benefits of better blood pressure control were greater than that of improvement in glycemic control (glycosylated hemoglobin 7.9% versus 7.0%), with a 2- to 5-fold greater absolute risk reduction and much lower numbers needed to treat [87]. The benefits of blood pressure lowering, however, were seen in both the conventional and intensively treated groups, and the benefits of glycemic control were seen in the aggressively and conservatively targeted blood pressure groups [85]. Thus, treatment of a single risk factor does not eliminate the risk of complications, and all risk factors need to be

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aggressively treated in diabetes to reduce the risk of micro- and macrovascular complications. As in the HOT trial, more than two antihypertensive agents were required to reach the lower BP, and 29% of the subjects required three agents. In the Appropriate Blood Pressure Control in Diabetes (ABCD) [88], 470 patients with diabetes were randomized to an intensive (diastolic blood pressure 75 mm Hg) or a moderate control (diastolic blood pressure of 80– 89 mm Hg) group. The primary aim was to assess the effect of blood pressure control on nephropathy. The intensive group achieved a blood pressure of 132/78 mm Hg whereas the moderate control group achieved a blood pressure of 138/86 mm Hg. There was a 50% reduction in total mortality between the groups that could not be explained on the basis of CV outcomes. No difference was seen in microvascular endpoints. Mean glycosylated hemoglobin was greater than 11% during the 5 years of this trial, and there was only a 45% adherence to the assigned study medication. These factors may have contributed to the lack of benefit on micro- and macrovascular outcomes with more intensive blood pressure control in this trial. Analysis of other clinical trials over the past decade, including the Modification of Diet in Renal Disease (MDRD) trial [89], has shown that the lower the blood pressure, the greater is the preservation of renal function in subjects with kidney disease, irrespective of diabetes. In subjects with proteinuria greater than 1 g/d and renal insufficiency, a blood pressure lower than 125/75 mm Hg is associated with a slower rate of decline in kidney function. There is evidence to suggest an increase in CV and renal disease risk with systolic BP greater than 127 mm Hg and diastolic BP greater than 83 mm Hg [90,91]. In the RENAAL study, a baseline systolic BP of 140 to 159 mm Hg was associated with an increased risk of end-stage renal disease or death by 38% compared with subjects with a systolic BP of 130 mm Hg [92]. Moreover, in the trials of intensive blood pressure control in diabetics, there is no indication of an adverse effect on CV or renal events with a lower BP [85]. This is in contrast to a recent meta-analysis of trials in non-diabetic kidney disease, in which a systolic BP less than 110 mm Hg in subjects with a daily protein excretion of greater than 1 g/d was associated with an increase in the risk of disease progression [93]. On the basis of these observations, the American Diabetes Association, National Kidney Foundation, and the Joint National Committee VII recommend a blood pressure target of 130/80 mm Hg in diabetics [94–96].

Comparison of specific antihypertensive therapies on cardiovascular outcomes Numerous trials have compared newer antihypertensive agents of ACE I, CCB, and ARB classes with each other or against diuretics and b-blockers (Table 3). In a substudy of the ABCD trial, nisoldipine was compared with

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Table 3 Trials comparing specific anti-hypertensive therapies on cardiovascular outcomes Active

CVDa

Microa

ACE I vs calcium channel blockers FACET Amlodipine ABCD Nisolidipine STOP-2 Isradipine/felodipine

Fosinopril Enalapril Enalapril/lisinopril

# 51% # 57% NSb

N/A N/A N/A

ACE I vs b-blocker/diuretic STOP-2 b-Blocker  diuretic CAPP b-Blocker  diuretic UKPDS Atenolol ALLHAT Chlortahlidone

Enalapril/lisinopril Captopril Captopril Lisinopril

NS # 41%c NS NSd

N/A N/A NS NS

Diltiazem Nifedipine GITS Amlodipine Enalapril/lisinopril

NSe NS NSf NS

N/A N/A N/A N/A

ARB vs b-blocker LIFE Atenolol

Losartan

# 24%

N/A

ARB vs calcium channel blocker IDNT Amlodipine

Irbesartan

NS

# 23%

Trial

Calcium channel NORDIL INSIGHT ALLHAT STOP-2

Reference

blocker vs b-blocker/diuretic b-Blocker  diuretic Coamilozide Chlorthalidone b-Blocker  diuretic

Abbreviations: ABCD, Appropriate Blood pressure Control in Diabetes; ALLHAT, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; CAPP, Captopril Prevention Project; FACET, Fosinopril versus Amlodipine Cardiovascular Events Trial; IDNT, Irbesartan Diabetic Nephropathy trial; INSIGHT, International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention for Endpoint reduction; NORDIL, Nordic Diltiazem; NS, non significant; N/A, not available; STOP-2, Swedish Trial in Old Patients with Hypertension-2; UKPDS, United Kingdom Prospective Diabetes Study. a Reduction in CVD (cardiovascular disease) and Micro (microvascular complications) in the active group compared to the reference group. b Reduction in myocardial infarction by 49% in ACE I group. c Reduction in myocardial infarction by 66%. d 22% increase in heart failure in lisinopril group. e 20% reduction in stroke with diltiazem. f 42% increase in heart failure with amlodipine.

enalapril [88]. Blood pressure reduction was similar in both arms, but by the end of the trial, half the subjects were not taking the initially assigned treatment. In an intention-to-treat analysis, the subjects in the nisoldipine group had a 5 times higher risk of myocardial infarction (a secondary endpoint) that was attributed to a beneficial effect of ACE inhibition rather than an adverse effect of nisoldipine. In the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) [97], 380 diabetic subjects were randomly assigned to Fosinopril or Amlodipine. Although the Amlodipine group had a lower systolic blood pressure than the Fosinopril group, combined CV events were significantly lower in the fosinopril group primarily because of a difference in the number

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of subjects with hospitalized angina (0 versus 4). The trial was designed to study treatment-related differences in serum lipids and diabetes control, with CV endpoints as secondary outcomes. This was also an open-label study, and if the blood pressure goal was not attained on the assigned study drug, the other study drug was added. The best outcomes were seen in the subjects receiving both drugs (108 subjects). In the Swedish Trial in Old Patients with Hypertension (STOP)-2 [98], CCB, ACE I, and diuretics plus b-blockers were compared with each other. Blood pressure lowering was similar between the groups with no difference in combined CV events or total mortality. However, myocardial infarction was significantly lower and strokes non-significantly higher in patients treated with ACE I compared with CCB. The largest hypertension trial to date, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [99], compared the effectiveness of a thiazide diuretic (chlorthalidone), an ACE I (lisinopril), a CCB (Amlodipine), and an a1-blocker (Doxazosin) as an initial treatment for hypertension in patients at high risk for a CV event. The doxazosin arm was suspended early because of an increase in the incidence of heart failure. The primary outcome was combined nonfatal and fatal myocardial infarction. Secondary outcomes were all-cause mortality, stroke, combined coronary heart disease (primary outcome, coronary revascularization or angina with hospitalization), and combined CVD (combined coronary heart disease, stroke, angina without hospitalization, heart failure, and peripheral arterial disease). Systolic blood pressure was the lowest in the diuretic group whereas diastolic blood pressure was the lowest in the Amlodipine group. In a pre-specified subgroup analysis of 12,063 type 2 diabetics, the incidence of heart failure was the lowest in the diuretic group compared with lisinopril (RR 1.22 [confidence interval {CI}, 1.05–1.42]) and Amlodipine (RR 1.42 [CI, 1.23–1.64]). Combined CVD was higher in the ACE I group compared with the diuretic group (RR 1.08 [CI, 1.00–1.17]) primarily because of a higher risk of heart failure and stroke in the black population; systolic blood pressure was 4 mm Hg higher than the diuretic group in this population. There was no difference between the groups with regard to other outcomes in the diabetic population. Forty percent of the patients required two medications and one third did not reach the BP goal of 140/90 mm Hg. Microvascular endpoints are also being evaluated, but they have not yet been reported. There have been numerous explanations of the results of the ALLHAT. One explanation is the withdrawal of diuretics in patients receiving this treatment in the ACE inhibitor and Amlodipine arm at the beginning of the study, which may have unmasked heart failure in these patients and therefore resulted in the higher incidence of this complication in these groups. The other explanation is the inability to use diuretics in the ACE inhibitor arm, a combination that is commonly used in clinical practice to enhance the BP-lowering effects of ACE I in blacks. On the basis of these arguments, it has been suggested that ALLHAT should be

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viewed as a trial that showed diuretics, CCB, and ACE I to be equally efficacious as initial hypertensive agents. In contrast to ALLHAT, a recent Australian trial, the Second Australian National Blood Pressure study (ANBP)-2 [100] has shown a superiority of ACE inhibition over diuretics in an elderly white population (RR 0.89 [CI, 0.79–1.00]), with benefits seen primarily in the male subgroup. Overall, there was an 11% reduction in the first CV event or death from any cause, with a 32% reduction in the incidence of myocardial infarction in the ACE I group; however, it should be noted that the population studied in ANBP-2 was different from that of ALLHAT. Also, ANBP-2 was an open-label study, and the number of events in this study was much lower. The UKPDS study compared ACE I with b-blockers [101]. In this study, there was no difference in microvascular or macrovascular outcomes in subjects randomized to either captopril or atenolol. Blood pressure lowering was similar between the two groups (143/81 mm Hg in atenolol versus 144/ 83 mm Hg in captopril). Smaller studies in type 2 diabetics have also not shown a consistent superiority of ACE inhibition over b-blockers with respect to renal outcomes [102]. Studies comparing calcium channel blockers to b-blockers and diuretics include the Nordic Diltiazem Trial (NORDIL) and The International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) [84,103]. In both the NORDIL (diltiazem versus b-blocker with and without diuretic) and INSIGHT (long-acting nifedipine versus coamilozide) trials, there were no differences in CV outcomes between the groups studied. NORDIL randomized 727 patients, whereas INSIGHT included 1302 patients with type 2 diabetes. Three trials have assessed the effect of ARBs in diabetic patients with nephropathy, assessing CV endpoints as secondary outcomes. The Irbesartan Diabetic Nephropathy trial showed the superiority of irbesartan over amlodipine or placebo in terms of renal outcomes but did not show any difference in CV outcomes between the agents [104]. There was a 23% reduction in heart failure requiring hospitalizations. In the Losartan Intervention for Endpoint Reduction (LIFE) study, there was 24% reduction in CV endpoints, 37% reduction in CV-related deaths, and 39% reduction in all-cause mortality in 1195 hypertensive diabetic subjects with left ventricular hypertrophy treated with losartan, compared with those treated with atenolol [105]. Albuminuria was less frequent in the losartan group. Although systolic blood pressure was 2 mm Hg lower in the Losartan group, benefits were independent of this effect.

Effect of antihypertensive therapy on microvascular complications A large placebo-controlled clinical trial in type 1 diabetics with overt nephropathy (urinary protein 500 mg/24 h) has shown a beneficial effect of

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captopril on slowing the progression of renal disease [106]. There was a 50% reduction in the endpoints of death, dialysis, transplantation, and doubling of serum creatinine with captopril, compared with placebo. Although mean arterial blood pressure was lower by 2 mm Hg in the captopril group, this effect was shown to be independent of the BP lowering. Studies in type 1 diabetics with microalbuminuria in both hypertensive and normotensive populations have also shown a reduction in progression to macroalbuminuria and in regression to normoalbuminuria [107]. A recent trial [108] has also shown an improvement in microalbuminuria unrelated to ACE inhibition in type 1 diabetics. In this trial, one of the factors associated with regression of microalbuminuria was a systolic BP less than 115 mm Hg. ACE I has also been shown to reduce the risk of retinopathy and neuropathy in type 1 diabetes [109,110]. In type 2 diabetes, ACE I, ARB, b-blockers and nondihydropyridine CCBs have been shown to reduce the progression to nephropathy and decline in renal function in micro- and macroalbuminuric normotensive and hypertensive subjects [82,83,102,106,107,111]. Data regarding a renoprotective effect in overt nephropathy, however, are most convincing for ARBs because they have been tested in large placebo-controlled clinical trials in which the benefit has been shown to be independent of their BP-lowering effect. Small trials [112–114] have also shown a beneficial effect of combining ACE I and ARB, and thiazolidinediones and spironolactone on proteinuria. Although there is little evidence regarding the prophylactic use of ACE I or ARBs to prevent microalbuminuria, there was a nonsignificant decrease in the development of albuminuria in the type 2 diabetics in the HOPE and LIFE studies [80,98]. Choice of antihypertensive regimen Clinical trial data have shown that to reach the recommended blood pressure goals in type 2 diabetics, usually two and frequently three agents are required. Treatment choices depend on coexistent conditions, side effects, and contraindications. On the basis of the evidence, in the absence of any complications of diabetes, a thiazide diuretic along with an ACE I or ARB is recommended for initial therapy in a type 2 diabetic with hypertension. Thiazide diuretics are as efficacious as any other antihypertensive, are cost effective, and they work synergistically with ACE I, ARBs, b-blockers, and CCBs. Potassiumsparing diuretics such as spironolactone can also be used because they have been shown to improve prognosis in heart failure and after myocardial infarction, a benefit attributed to the antagonism of aldosterone [115]. There is strong evidence of a CV protective effect of ACE I and ARB, independent of their BP-lowering effect. These agents are also effective in reducing the progression of nephropathy in micro- and macroalbuminuric subjects; they improve the prognosis following myocardial infarction and in

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heart failure, the risks of which are high in a diabetic; and they limit the side effects of diuretics (hypokalemia) and CCBs (edema). Moreover, therapy with ACE I or ARB is well tolerated. Presently the only indication for choosing an ARB over an ACE I is in patients with overt nephropathy and those with left ventricular hypertrophy in view of the observations in RENAAL, IDNT, and LIFE studies. Therapies with the two agents are interchangeable if there are side effects, most commonly a cough with ACE I. In blacks, there is also a higher incidence of angioedema with these agents. With the initiation of ACE I therapy, a noncontinuous increase in creatinine of up to 30% from baseline can be expected, and this should not prompt discontinuation of this therapy [116]. Although it is associated with an increase in the incidence of hyperkalemia, ACE I therapy in subjects with creatinine levels greater than 3 mg/dL can delay the time to dialysis and confer CV protection in these high-risk patients [116,117]. Combination therapy with a diuretic and ACE I or ARB should be considered if blood pressure lowering of greater than 15 mm Hg systolic or 10 mm Hg diastolic is required; however, it should be initiated carefully in subjects at a risk for orthostatic hypotension. In subjects with coronary artery disease (CAD) and heart failure, b-blockers should be instituted along with ACE I or ARB because they are known to improve prognosis in these conditions [118]. If BP is inadequately controlled with a combination of ACE I or ARB and diuretic, the present authors still favor the use of bblockers as the third-line agent, even in the absence of CAD or heart failure. This recommendation is based on the increased prevalence of asymptomatic heart disease and autonomic neuropathy in diabetics, the increased risk of CAD and heart failure in this population, and the evidence of equal efficacy to ACE inhibition in the UKPDS. b-blockers, however, have been shown to be less efficacious in the elderly, less tolerated in clinical studies, and associated with mild weight gain in the UKPDS trial. In subjects with proteinuria, there is evidence that suggests a beneficial effect of nondihydropidine CCB, and in the National Kidney Foundation guidelines, these agents are the preferred third-line agents in the treatment of hypertension. There is also evidence regarding a synergistic effect of CCBs when combined with ACE I. In both the HOT and HOPE trials, approximately 45% of the subjects were taking this combination therapy, and the best outcomes in FACET were seen in the group taking this combination. CCBs are also more effective than b-blockers and ACE I in lowering BP in the elderly. CCBs have a neutral effect on metabolic parameters, and there are no contraindications to dihydropyridine CCBs; however, dihydropyridine CCBs should be used in combination with ACE I in the presence of nephropathy, and nondihydropyridine CCB should be combined cautiously with b-blockers in the elderly because b-blockers might lead to bradyarrhythmias. If further BP lowering is required, any other agent can be used; however, clonidine should not be used with b-blockers for numerous reasons including an increased likelihood of bradycardia.

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Apart from blood pressure control, it is also important to aggressively improve glycemic control and target hyperlipidemia. Aspirin therapy should be prescribed in any diabetic with CVD or a diabetic over 30 years of age with an additional CVD risk factor. Such a comprehensive approach has resulted in a 53% reduction in macrovascular complications, 61% reduction in nephropathy, 58% reduction in retinopathy and 63% reduction in autonomic neuropathy in a small study [119]. In conclusion, lowering blood pressure to a target of 130/80 mm Hg reduces CV and microvascular complications in diabetes. Therapy with more than one agent is required to reach these goals in this population. In the absence of any complications or contraindications, treatment should be initiated with a diuretic combined with an ACE I or an ARB. The choice of a third-line agent depends on coexistent factors. b-blockers are preferred in the young and for their cardioprotective effects, whereas CCBs are preferred in the elderly and for their renoprotective effect. Antioxidant and anti-inflammatory effects of antihypertensive drugs Recent observations on the actions of b-blockers and ARBs are worth noting. Carvedilol and nadolol have been shown to suppress ROS generation by leucocytes. This may contribute to their antihypertensive effect through a reduction in O2 formation and an increase in NO bioavailability. The angiotensin II receptor blocker, valsartan, has been shown to suppress not only ROS generation by leucocytes but also to exert a potent anti-inflammatory effect at the cellular and molecular level [120]. It is possible that ACE inhibitors will exert similar effects. Because oxidative stress and inflammation are cardinal to atherogenesis, it is possible that the novel effects of b-blockers and ARBs contribute to their beneficial action on CV outcomes. The potential role of antidiabetic drugs in the treatment of hypertension In this discussion of antihypertensive drugs and their effect on CV and renal outcomes, it is important to mention that, in the UKPDS study [121], metformin has been shown to significantly improve CV outcomes, and more recently, it has been shown to exert an anti-inflammatory action. Thiazolidinediones have been shown to have an anti-inflammatory effect [122,123], and thus in the long term they may be antiatherogenic. They also reverse abnormalities in vascular reactivity in both the obese and type 2 diabetics while improving microalbuminuria. Insulin has been shown to be a vasodilator with antiplatelet activity as well as exerting a potent anti-inflammatory effect [124–126]. Its usage improves vascular reactivity in the long term [127]. Thus, the use of these drugs may facilitate the action of other antihypertensive drugs. This, however, has yet to be proved.

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