appropriate blood pressure control in hypertensive and...

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Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trialRobert W Schrier*, Raymond O Estacio, Philip S Mehler and William R Hiatt

Continuing Medical Education onlineMedscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test.

Learning objectivesUpon completion of this activity, participants should be able to: 1 Describe the prevalence of microvascular and macrovascular complications of type 2 diabetes.2 Describe the prevalence of hypertension in type 2 diabetes.3 Compare the incidence of myocardial infarction between type 2 diabetes patients allocated to an angiotensin-converting enzyme vs a calcium channel blocker.4 Compare all-cause mortality for patients with type 2 diabetes managed with intensive vs moderate blood pressure (BP) lowering.5 Compare the incidence of diabetic retinopathy and stroke in patients with type 2 diabetes managed with intensive vs moderate BP lowering.

IntroduCtIonA worldwide epidemic of diabetes mellitus is emerging. It has been estimated that by 2010 there will be 221 million people in the world with diabetes.1 Of these individuals, 97% will have type 2 insulin-resistant diabetes, which is strongly associated with visceral obesity. These patients with diabetes will experience multiple microvascular and macrovascular complications. Diabetes has become the leading cause of end-stage renal disease and of adult blindness—both are microvascular complications—in industrial-ized countries. Neurological complications, including peripheral neuropathy and autonomic insufficiency, are other microvascular problems that afflict patients with diabetes. Microvascular complications of diabetes are associated with

The hypertensive and normotensive Appropriate Blood Pressure Control in Diabetes (ABCD) studies were prospective, randomized, interventional clinical trials with 5 years of follow-up that examined the role of intensive versus standard blood pressure control in a total of 950 patients with type 2 diabetes mellitus. In the hypertensive ABCD study, a significant decrease in mortality was detected in the intensive blood pressure control group when compared with the standard blood pressure control group. There was also a marked reduction in the incidence of myocardial infarction when patients were randomly assigned to initial antihypertensive therapy with angiotensin-converting-enzyme inhibition rather than calcium channel blockade. The results of the normotensive ABCD study included associations between intensive blood pressure control and significant slowing of the progression of nephropathy (as assessed by urinary albumin excretion) and retinopathy, and fewer strokes. In both the hypertensive and normotensive studies, mean renal function (as assessed by 24 h creatinine clearance) remained stable during 5 years of either intensive or standard blood pressure intervention in patients with normoalbuminuria (<30 mg/24 h) or microalbuminuria (30–300 mg/24 h) at baseline. By contrast, the rate of creatinine clearance in patients with overt diabetic nephropathy (>300 mg/24 h; albuminuria) at baseline decreased by an average of 5 ml/min/year in spite of either intensive or standard blood pressure control. Analysis of the results of 5 years of follow-up revealed a highly significant correlation of all-cause and cardiovascular mortality with left ventricular mass and severity of albuminuria.keywords diabetic nephropathy, left ventricular hypertrophy, plasminogen activator inhibitor, renin–angiotensin system, urinary albumin excretion

RW Schrier is Professor of Medicine , and RO Estacio is Associate Professor of Medicine, at the University of Colorado School of Medicine. RO Estacio is also Director of the Medical Affairs Department at The Colorado Prevention Center. PS Mehler is the Medical Director of the Acute Comprehensive Urgent Treatment for Eating Disorders program in Denver, Chief of Internal Medicine at Denver Health Medical Center, and Professor of Medicine at the University of Colorado Health Center. WR Hiatt is President of the Colorado Prevention Center, Professor of Medicine, and Chief of the Vascular Medicine Section at the University of Colorado Health Sciences Center, CO, USA.

Correspondence*Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado School of Medicine, 4200 East Ninth Avenue B173, Denver, CO 80262, USA [email protected]

received 10 April 2007 Accepted 25 May 2007

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rEvIEw CrItErIAThe PubMed database was searched for all articles related to the ABCD trial.

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auGust 2007 vOL 3 NO 8 sCHRIER ET AL. nAtUre clinicAl prActice NEPHROLOGY 429


substantial morbidity, mortality and health-care costs. Nevertheless, it is the macrovascular complications—stroke, heart attack and periph-eral vascular disease—that account for 75–80% of mortality in patients with diabetes. People with diabetes are two to four times more likely than nondiabetic individuals to experience cardiovascular complications. For example, the risk of a diabetic patient having an initial acute myocardial infarction is equivalent to that of a nondiabetic patient having a second myocardial infarction.2 The scale of the diabetes epidemic is increasing, primarily because of the rising occurrence of obesity in the developed, as well as the developing, world. Moreover, the inci-dence of diabetes increases with age, and most populations worldwide are growing older.3

Diagnosis and treatment of patients with diabetes has been focused for decades on the elevation of blood glucose levels. Difficulty controlling blood glucose in the insulin-resistant state of type 2 diabetes has persisted, although recently metformin and thiazolidinediones have been shown to improve insulin responsive-ness. Weight loss and physical activity, however, remain the most effective means of improving insulin sensitivity in patients with type 2 diabetes. In fact, a prospective, randomized trial has shown that diet-related weight loss and physical exercise can each reduce the incidence of diabetes onset in patients with impaired glucose tolerance.4 Unfortunately, these behav-ioral approaches to preventing the onset of diabetes or to improving insulin sensitivity in established diabetes are difficult to implement and sustain. As blood glucose control in patients with diabetes worsens, the risks of cardiovascular sequelae and mortality increase.5

Patients with diabetes mellitus also have an increased likelihood of lipid abnormalities. Intervention to lower plasma LDL cholesterol to less than 2.6 mmol/l (100 mg/dl) has been recommended. In high-risk diabetic patients with cardiovascular disease, an even lower LDL cholesterol goal of 1.8 mmol/l (70 mg/dl) has been proposed.6 In spite of these recommen-dations, a study published in 2003 detected no improvement over a 5-year period in the treat-ment of hyperlipidemia in patients with type 2 diabetes living in a large urban area.7 The high incidence of microvascular and macrovascular complications in patients with diabetes dramati-cally exacerbates the cardiovascular effects of smoking. Unfortunately, smoking cessation

is also a difficult behavioral modification to implement.

Until the results of the UK Prospective Diabetes Study (UKPDS) became available,8 it was not known whether stricter blood glucose control would alter the incidence and complication rate of type 2 diabetes mellitus. The UKPDS enrolled patients at the time of diagnosis of type 2 diabetes and randomly allocated them to dietary intervention or intensive blood glucose control with oral hypo-glycemic agents (metformin or insulin). After 9 years of follow-up, a significant reduction in the incidence of microvascular complica-tions (primarily a decrease in the need for laser treatment of diabetic retinopathy) was observed in the intensive as compared with the moderate blood glucose control group. After 15 years of follow-up, however, there was no difference in diabetes-related death rates between the groups. The UKPDS results indi-cate that factors in addition to blood glucose control must be involved in the development of macrovascular complications in type 2 diabetes, because 75–80% of diabetes-related deaths are due to macrovascular complications. Because 35–40% of patients with type 2 insulin-resistant diabetes are treated with exogenous insulin, it is also worth emphasizing that insulin therapy increases body weight, potentially worsening insulin resistance.

The incidence of hypertension is very high among patients with type 2 diabetes mellitus; the condition is present in approximately 40% of patients at diagnosis, increasing to 80–90% when diabetic nephropathy (urinary albumin excretion >300 mg/24 h) develops. The focus of treatment had previously been on blood glucose control, with the definition of the optimum level of blood pressure control and the preferred antihypertensive agents for patients with type 2 diabetes receiving less attention. The 5-year prospective, randomized Appropriate Blood Pressure Control in Diabetes (ABCD) clinical trial was undertaken to address these issues. The primary hypothesis of the ABCD trial was that intensive (as opposed to moderate) blood pressure control would prevent or slow the progression of diabetic nephropathy, neuro-pathy, retinopathy and cardiovascular events. The secondary hypothesis was that initial therapy with a long-acting dihydropyridine calcium channel blocker, nisoldipine, or an angiotensin-converting-enzyme (ACE) inhibitor,



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enalapril, would have equivalent effects on the prevention or delay of progression of these complications in patients with type 2 diabetes.9

BAsELInE ChArACtErIstICs of ABCd trIAL EnroLLEEsBaseline data from the ABCD trial yielded a number of interesting findings that have improved our understanding of the relation-ships between various patient characteristics and diabetic complications. At enrollment, nephropathy, retinopathy, cardiovascular disease and neuropathy were significantly more preva-lent among hypertensive patients with type 2 diabetes (diastolic blood pressure >90 mmHg) than among those with normotensive diastolic blood pressure (80–90 mmHg; Figure 1).10 The results of the 5-year interventional phase of the ABCD trial were, therefore, analyzed separa-tely for the hypertensive and normotensive cohorts. There were no significant differ-ences in age, duration of diabetes, glycosylated hemoglobin level or BMI between the patients randomly allocated to intensive or moderate anti-hypertensive therapy in either the hypertensive or the normotensive substudies.

Among the 950 patients with type 2 diabetes enrolled in the ABCD trial, there was a highly significant relationship between the rate of urinary albumin excretion and the presence

of retinopathy (P <0.001), neuropathy (P <0.001) and cardiovascular disease (P <0.001), accor-ding to χ2 analysis.11 Furthermore, Cohen et al. detected a relationship in the ABCD trial between diabetic autonomic insufficiency and peripheral neuropathy, with the duration of diabetes and the presence of retinopathy.12 Deletion polymorphism of the ACE gene was associated with nephropathy13 and increased left ventricular mass (LVM) in patients with diabetes enrolled in the ABCD trial.14 Smoking was also shown to be a risk factor for nephro-pathy in these individuals.15 Blood homo-cysteine levels were highly correlated with diabetic nephropathy16 and autonomic neuro-pathy;17 the cause and effect of this relation-ship is, however, unclear. Diminished exercise capacity, as assessed by peak oxygen consump-tion (peak VO2), was independently asso-ciated with an increased incidence of diabetic nephropathy and retinopathy in patients with diabetes without a history of coronary artery disease.18 A provocative observation was that patients treated with insulin were significantly more likely to have retinopathy, neuropathy or nephropathy than those treated with oral hypo-glycemic agents.19 This difference persisted when patients who had had diabetes for the same amount of time were compared. The effect on vascular permeability of insulin, as well as its mitogenic, atherogenic and thrombogenic actions, were proposed as potential explanations for these findings.

The ABCD trial also revealed that the pres-ence of certain diabetic complications at base-line—namely, overt albuminuria and autonomic neuropathy—was a strong predictor of future cardiovascular events over 5 years of follow-up. Overt albuminuria (>300 mg/24 h) in patients with type 2 diabetes was a highly significant predictor of future heart failure,20 and auto-nomic neuropathy was associated with an increased incidence of stroke.21

IntErvEntIon phAsE of thE ABCd trIAL: hypErtEnsIvE CohortThe randomization protocol for the hypertensive ABCD study is shown in Figure 2. The following baseline demographics of the intensive (n = 237) and moderate (n = 233) blood pressure therapy groups were comparable: age (58 years for both groups); gender (58% male for both groups); duration of diabetes (11.9 vs 11.5 years); glycosylated hemoglobin (11.6 vs 11.5%); BMI

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49P = 0.05a

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figure 1 Complications at baseline in patients enrolled in the ABCD randomized clinical trial. There were significantly more complications in hypertensive than in normotensive patients with type 2 diabetes. aFor systolic hypertension only. Abbreviation: CVD, cardiovascular disease. Permission obtained from Elsevier © Mehler PS et al. (1997) Am J Hypertens 10: 152–161.



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(31.8 vs 31.7 kg/m2); total cholesterol (5.6 [215] vs 5.7 mmol/l [221 mg/dl]); blood pressure (156/98 vs 154/98 mmHg); and duration of hypertension (11.9 vs 11.5 years). After 4 years of follow-up, the ABCD Data and Safety Monitoring Committee halted the comparison between nisoldipine and enalapril in the hypertensive cohort because fewer myocardial infarctions occurred in the patients with diabetes randomly allocated to initial therapy with enalapril (Figure 3).22

The lower incidence of myocardial infarction in the enalapril group than in the nisoldipine group was associated with a greater decrease in LVM over the 4-year follow-up period.23 ACE inhibitors have also been shown to more effectively reduce LVM than calcium channel blockers in patients with polycystic kidney disease.24 Results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET)25 and the Captopril Prevention Project (CAPPP)26 also showed fewer cardio-vascular complications associated with the use of ACE inhibitors (compared with calcium channel blockers and beta-blockers, respectively) in patients with type 2 diabetes.

The Heart Outcomes Prevention Evaluation (HOPE) study compared the effects of the ACE inhibitor ramipril versus placebo on cardio-vascular complications.27 There were 3,577 patients in the HOPE study who had diabetes and at least one cardiovascular risk factor (e.g. smoking, hypertension or lipid abnormali-ties). The results for the patients with diabetes were published as the MICRO-HOPE study.28

The Kaplan–Meier curves from the MICRO-HOPE study demonstrated the beneficial effects of ramipril on cardiovascular and all-cause mortality in patients with diabetes. These beneficial effects persisted even when data were adjusted to account for the slightly lower blood pressure (mean 3/2 mmHg lower) in the ramipril group than in the placebo group. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), no advantage of lisinopril over chlortalidone was detected with regard to the primary end point of heart attack.29 A third of the study population were black and, in this subgroup, those randomly assigned to lisinopril had a higher rate of cardiovascular complica-tions.30 It should be noted, however, that lisino-pril lowered blood pressure less effectively than chlortalidone did in this subgroup. The ALLHAT findings might, therefore, be a result of ineffective blood pressure control with the ACE inhibitor, particularly in the black population.

After the decision of the Data and Safety Monitoring Committee to halt the compar-ison between enalapril and nisoldipine in the hypertensive ABCD study, the remainder of the 5-year follow-up period was conducted as an open-label trial with enalapril administered in both the moderate and intensive blood pressure


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figure 3 Cardiovascular complications in patients receiving enalapril or nisoldipine. After 4 years of follow-up, hypertensive patients with diabetes randomly assigned to the angiotensin-converting-enzyme inhibitor enalapril had significantly fewer cardiovascular complications than those randomly assigned to the calcium channel blocker nisoldipine. Abbreviations: CV, cardiovascular; MI, myocardial infarction.


Hypertensive patients(DBP >89 mmHg)

n = 470

Intensiveblood pressure control

DBP 75 mmHgn = 237

Moderateblood pressure control

DBP 80–90 mmHgn = 233

Nisoldipinen = 119

Enalapriln = 121

Nisoldipinen = 116

Enalapriln = 114

figure 2 Randomization protocol for the hypertensive ABCD study. Abbreviation: DBP, diastolic blood pressure.



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control groups. Although these patients with diabetes were in their 60s, their mean renal function after 5 years (as assessed by 24 h creati-nine clearance) remained stable for those with either normoalbuminuria (<30 mg/24 h) or microalbuminuria (30–300 mg/24 h) at base-line.31 This effect occurred in both the moderate and intensive blood pressure control groups, and was independent of initial therapy (i.e. either nisoldipine or enalapril). This finding indicates that reported declines in renal function with increasing age might be due to inadequate blood pressure control in elderly patients. In patients with overt diabetic nephropathy

(>300 mg/24 h; albuminuria) at baseline, neither moderate nor intensive blood pressure control stabilized renal function, regardless of the initial antihypertensive agent used (Table 1). Hypertensive patients with diabetes with overt nephropathy lost kidney function at a rate of approximately 5 ml/min/year of creatinine clearance.31 Although this rate of loss is clearly better than the loss of kidney function of 10–12 ml/min/year in patients with type 2 diabetes whose hypertension is untreated,32 it indicates that prevention of diabetic nephropathy—in contrast to slowing its progression—requires early intervention at the normoalbuminuric or microalbuminuric stage.

All-cause mortality over the 5 years of the hypertensive ABCD study was significantly lower in the intensive than in the moderate blood pressure control group (5.5% vs 10.7%; P <0.037).31 It is important to emphasize that this beneficial effect on mortality of intensive (mean 133/78 mmHg) versus moderate (mean 139/86 mmHg) blood pressure control was noted in the absence of any differences between treatment groups in blood glucose concentra-tion, lipid levels or smoking prevalence. During the ABCD study, blood pressure control was managed by nurse practitioners under physician supervision, whereas blood glucose and treat-ment of lipid abnormalities remained under the management of the patients’ primary care physician. The potential mechanisms by which obesity and insulin resistance might increase blood pressure in patients with type 2 diabetes are illustrated in Figure 4.

IntErvEntIon phAsE of thE ABCd trIAL: norMotEnsIvE Cohort The randomization protocol for the normo-tensive ABCD study is shown in Figure 5. The following baseline demographics of the inten-sive (n = 237) and moderate (n = 243) blood pressure therapy groups were comparable: age (58.5 vs 59.6 years); gender (53 vs 56% male); duration of diabetes (8.8 vs 9.2 years); glycosyl-ated hemoglobin (11.5 vs 11.6%); BMI (11.5 vs 11.6 kg/m2); total cholesterol (5.6 [216] vs 5.5 mmol/l [214 mg/dl]); blood pressure (136/84 vs 137/84 mmHg); and creatinine clearance (84 [1.4] vs 83 ml/min [1.4 ml/s]). The goal of inten-sive intervention was to reduce diastolic blood pressure by 10 mmHg using either nisoldipine or enalapril; the moderate blood pressure control group received placebo.


Obesity

HeartVessels

Cardiac outputVasoconstriction

Insulin resistance

HyperinsulinemiaSmooth musclecell proliferation

?

Kidney

SNS activity Na+

reabsorption

Blood pressure

figure 4 Interactions by which obesity and insulin resistance might lead to hypertension in patients with type 2 diabetes. Abbreviations: Na+, sodium; SNS, sympathetic nervous system.

table 1 Effect of intensive versus moderate blood pressure control on the renal function of hypertensive and normotensive patients with overt diabetic nephropathy in the ABCD trial.30

degree of blood pressure control

Mean creatinine clearance (ml/min/1.73 m2 ± se)

P value

Baseline 5 years

Hypertensive patients

Intensive 75.0 ± 4.4 56.9 ± 5.8 0.035

Moderate 77.5 ± 5.5 52.6 ± 5.8 0.006

Normotensive patients

Intensive 84.5 ± 7.2 57.7 ± 9.2 0.032

Moderate 76.0 ± 6.3 52.9 ± 9.7 0.042



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Over the course of the 5-year follow-up period, the rate of urinary albumin excre-tion (as an index of the progression of renal dysfunction) rose significantly in the moderate blood pressure control group, but was stable in the intensive control group.33 As in the hyper-tensive ABCD study, the mean renal func-tion (assessed as 24 h creatinine clearance) of patients with either normoalbuminuria or microalbuminuria at enrollment remained stable for the 5 years of follow-up in both the intensive and the moderate blood pres-sure control groups. By contrast, the rate of creatinine clearance in patients with overt albuminuria, and hence diabetic nephropathy, dropped by an average of 5 ml/min/year in both groups (Table 1). The progression from normoalbuminuria to microalbuminuria (i.e. incipient diabetic nephropathy) and from microalbuminuria to overt diabetic nephro-pathy (macroalbuminuria; >300 mg/24 h) was markedly slower in the intensive than in the moderate blood pressure control group (Table 2). Exacerbation of albuminuria is the best-established surrogate for the progression of renal dysfunction as well as an important prog-nostic index for mortality in patients with type 2 diabetes (Figure 6). Compared with moderate blood pressure control, intensive treatment was associated with a slower progression of diabetic retinopathy and a lower incidence of stroke (Table 2).33

To summarize, in the normotensive ABCD study, both intensive (mean blood pressure 128/75 mmHg) and moderate (mean blood pressure 137/81 mmHg) control of blood pres-sure stabilized creatinine clearance over 5 years in normoalbuminuric and microalbuminuric patients, but not in those with overt macro-albuminuria.34 As such, early intervention to prevent the occurrence and progression of diabetic kidney disease is important in both hypertensive and normotensive individuals with type 2 diabetes. Intensive blood pressure control also considerably slows the progression of microvascular retinopathy and reduces the


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figure 6 Progressive increases in urinary albumin excretion rate are associated with decreased survival in patients with type 2 diabetes. aP <0.05 for macroalbuminuria versus microalbuminuria and normoalbuminuria.

table 2 Effect of intensive versus moderate blood pressure control on the progression of complications in patients with type 2 diabetes in the normotensive ABCD study.

disease state Blood pressure control (% of patients who progressed)

P value

Intensive Moderate

Normoalbuminuria to microalbuminuria

17 28 0.02

Incipient to overt diabetic nephropathy

18 37 0.02

Retinopathy 35 46.5 0.02

Stroke 1.75 5.5 0.03


Normotensive patientsDBP 80–89 mmHg

n = 480

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PlaceboEnalapriln = 119

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figure 5 Randomization protocol for the normotensive ABCD study. Abbreviation: DBP, diastolic blood pressure. Permission obtained from Nature Publishing Group © Schrier RW et al. (2002) Kidney Int 61: 1086–1097.



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incidence of the macrovascular complica-tion of stroke in normotensive patients. These beneficial effects were observed during the normotensive ABCD study in the absence of any differences between study groups in blood glucose concentration, lipid levels, smoking prevalence or antihypertensive medications.

The UKPDS also compared the effects of strict (mean blood pressure 144/82 mmHg) and less-strict (mean blood pressure 154/87 mmHg) blood pressure control in a randomized cohort of 1,148 patients with type 2 diabetes. The inci-dences of diabetes-related death and of stroke were lower in patients with strictly controlled blood pressure than in those with less-strict blood pressure control (Figure 7).35 The main effect of strict glucose control was to decrease the need for laser therapy for diabetic retino-pathy.8 Thus, in the UKPDS study of type 2 diabetes, strict control of blood glucose level decreased the rate of microvascular, but not of macrovascular, complications. By contrast, more-intensive blood pressure control reduced the incidence of macrovascular complications, the main cause of death in patients with type 2 diabetes. In a subgroup analysis of 1,501 patients with diabetes in the Hypertension

Optimal Treatment (HOT) randomized trial (total n = 18,790), a substantial decrease in cardiovascular mortality (by 51%; P = 0.016) was detected when a diastolic blood pressure goal of 80 mmHg, as opposed to 90 mmHg, was set.36 There was, however, no significant difference in cardiovascular mortality in the total population when the results from diastolic blood pressure goals of 80, 85 and 90 mmHg were compared. Also worthy of mention are the results of the ABCD study that showed that intensive, as compared to moderate, blood pres-sure control reduced the risk of cardiovascular events in patients with type 2 diabetes with peripheral vascular disease.37

The Joint National Commission on Hypertension in the US (JNC-VII) has estab-lished a blood pressure goal of less than 130/80 mmHg for patients with diabetes. As shown in Figure 8, the results of intensive treat-ment during the hypertensive and normotensive ABCD studies support this recommendation. It should also be stated that, whether analyzed on the basis of diastolic or systolic blood pressure, the ABCD results are comparable. This fact is important, because recent studies indicate that elevation of systolic blood pressure might be a more important cardiovascular risk factor in elderly individuals than is an increase in diastolic blood pressure.

othEr rEsuLts of thE ABCd trIALEffect of increased LvM on cardiovascular mortalityProspective 5-year follow-up of 880 patients with diabetes in the ABCD trial showed that those who did not survive, analyzed on the basis of either all-cause mortality (P = 0.01) or cardiac death (P = 0.004), had markedly greater LVM, as assessed by adjusted Cornell voltage, than did survivors.38 Moreover, there was a highly significant relationship between increased LVM and the three stages of albumin-uria, (P <0.0001 for all) independent of blood pressure (Figure 9). These results indicate that the relationship between urinary albumin excretion and cardiovascular mortality might be related to increased LVM. Albuminuria in diabetes is associated with damage to the endo-thelium, which presumably occurs not only in the kidney but also in other organs including the heart. An increase in LVM is associated with decreased capillary-to-cardiac-myocyte density, and confers predisposition to ischemic


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figure 7 Results of the randomized UKPDS trial show that strict control of blood pressure is more effective than strict control of blood glucose level in decreasing the incidence of both microvascular and macrovascular complications in patients with type 2 diabetes.



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heart disease, systolic and diastolic heart failure, arrhythmias and sudden death.

Effect of decreased exercise peak oxygen consumption on rate of cardiovascular eventsA cohort of 468 patients with type 2 diabetes in the ABCD trial underwent graded exercise testing at baseline to measure peak VO2.39 These patients were then followed up for 5 years. Those with the lowest peak VO2 experienced significantly more cardiovascular disease events than those with a higher peak VO2. Multiple Cox regression analysis showed that low peak VO2 was an independent risk factor for cardiovascular events.

Cardiovascular and renal implications of impaired fibrinolysisThe increased levels of plasminogen activator inhibitor and the associated impairment of fibrinolytic activity that occurs in type 2 diabetes mellitus40 might be related to insulin resistance. A correlation between impaired fibrinolysis and urinary albumin excretion, as well as progres-sion of renal disease, was observed in patients with type 2 diabetes. As proposed in Figure 10, the observed increase in levels of plasminogen

activator inhibitor in type 2 diabetes could be a crucial factor in the thrombosis and fibrosis that occur in diabetic cardiovascular and renal disease.

ABCd-2 valsartan trialData from the normotensive ABCD study support a blood pressure goal of less than


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figure 9 Left ventricular mass (as adjusted Cornell voltage) across the three stages of albuminuria (P <0.0001) in patients from the ABCD trial with type 2 diabetes. Permission obtained from Lippincott, Williams and Wilkins © Nobakhthaghighi N et al. (2006) Clin J Am Soc Nephrol 1: 1187–1190.


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figure 8 Mean blood pressure achieved in diabetic patients in the UKPDS, HOT and ABCD trials. Only the intensive blood pressure control groups in the hypertensive and normotensive ABCD studies reached the consensus JNC goal of <130/80 mmHg. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.



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130/80 mmHg in type 2 diabetes. Results of a more-recent investigation, the ABCD-2 Valsartan trial, provide some support for a blood pressure goal of 120/80 mmHg.41 During this study, 129 normotensive patients with type 2 diabetes with a mean baseline blood pressure of 128 mmHg were randomly assigned to receive either placebo or the angiotensin-receptor blocker valsartan. The blood pres-sure goals were less than 120/80 mmHg in the valsartan group and less than 140/90 mmHg in the placebo group. After a mean of approxi-mately 2 years, those who had received placebo had a mean (± SE) blood pressure of 124 ± 11/80 ± 6.5 mmHg. The blood pressure of patients in the valsartan group was signifi-cantly lower, at 118 ± 11/75 ± 6 (P <0.001). During follow-up, no difference in creatinine

clearance between the groups was detected. There was, however, a significant decrease in urinary albumin excretion rate, a harbinger of renal and cardiovascular complications, in the valsartan group (P <0.007).

ConCLusIonsA diabetes epidemic has emerged during the latter part of the 20th century and continues unchecked in the 21st century. Efforts to prevent the formidable microvascular and macrovascular complications of diabetes are urgently needed. Data from the ABCD studies give credence to the importance of aggressive blood pressure control, in both hypertensive and normotensive patients, as one effective means of lessening the burden of complications caused by type 2 diabetes mellitus.


InsulinLDL and VLDL Adipocytes

Type 2 diabetes

PAI-1

Glucose Angiotensin II

Fibrinolysis Proteolysis

Thrombosis Fibrosis

tPA and uPA

Plasmin

APC TGF-β

Extracellular matrixsynthesis

Extracellular matrix degradation

Cardiovascular and renal mortality

Myocardial infarction, stroke,peripheral vascular disease

Cardiomyopathy and nephropathy

figure 10 Potential effects of increased levels of plasminogen activator inhibitor in type 2 diabetes on cardiovascular and renal mortality. In individuals with type 2 diabetes, insulin, glucose, angiotensin II, obesity, and hyperlipidemia all increase levels of plasminogen activator inhibitor. Abbreviations: APC, activated protein C; PAI-1, plasminogen activator inhibitor-1; TGF-β, transforming growth factor β; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; VLDL, very LDL. Permission obtained from Nature Publishing Group © Kamgar M et al. (2006) Kidney Int 69: 1899–1903.



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references1 Amos AF et al. (1997) The rising global burden of

diabetes and its complications: estimates and projections to the year 2010. Diabet Med 14 (suppl 5): S1–S15

2 Haffner SM et al. (1998) 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 339: 229–234

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KEy poInts■ The primary hypothesis of the 5-year

prospective Appropriate Blood Pressure Control in Diabetes (ABCD) trial was that intensive (as opposed to moderate) control of blood pressure, via randomization to either nisoldipine or enalapril treatment, would prevent or slow the progression of diabetic complications and cardiovascular events in individuals with type 2 diabetes mellitus

■ The prevalences of diabetic complications and cardiovascular disease at baseline were significantly greater among enrollees whose diastolic blood pressure exceeded 90 mmHg; trial data for the hypertensive and normotensive cohorts were, therefore, analyzed separately

■ Comparison of the angiotensin-converting-enzyme inhibitor enalapril and the calcium channel blocker nisoldipine was halted after 4 years in the hypertensive cohort because treatment with the former was associated with significantly fewer myocardial infarctions than was treatment with the latter

■ In the hypertensive cohort, open-label treatment with enalapril for a further year was associated with preservation of renal function in patients with normoalbuminuria or microalbuminuria in both the moderate and intensive blood pressure control groups; this finding was replicated in the normotensive cohort

■ All-cause mortality in the hypertensive cohort after 5 years was markedly lower in the intensive than in the moderate blood pressure control group

■ The progression of microvascular retinopathy and the incidence of stroke were decreased by intensive blood pressure control in the normotensive cohort



review



AcknowledgmentsThe ABCD trial was supported by Bayer and the National Institute of Diabetes, Digestive, and Kidney Diseases (DK50298-02). The valsartan study was supported by Novartis Pharmaceutical Company. We sincerely thank Jan Darling for her excellent support in the preparation of the manuscript. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Competing interests RW Schrier has declared associations with the following companies: Amgen, Astellas Pharma and Otsuka America Pharmaceuticals. See the article online for full details of the relationship. The other authors declared no competing interests.

24 Schrier RW et al. (2002) Cardiac and renal effects of standard versus rigorous blood pressure control in autosomal-dominant polycystic kidney disease: results of a seven-year prospective randomized study. J Am Soc Nephrol 13: 1733–1739

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26 Hansson L et al. (1999) Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 353: 611–616

27 The Heart Outcomes Prevention Evaluation Study Investigators (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 342: 145–153

28 Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355: 253–259

29 ALLHAT Collaborative Research Group (2002) 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 288: 2981–2997

30 Wright JT Jr et al. (2005) Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA 293: 1595–1608

31 Estacio RO et al. (2000) Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23 (suppl 2): SB54–SB64

32 Parving HH et al. (1983) Early aggressive antihypertensive treatment reduces the rate of decline in kidney function in diabetic nephropathy. Lancet 1: 1175–1179

33 Schrier RW et al. (2002) Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int 61: 1086–1097

34 Gall MA et al. (1995) Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes 44: 1303–1309

35 Turner R et al. for the UK Prospective Diabetes Study Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317: 703–713

36 Hansson L et al. for the HOT Study Group (1998) 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 351: 1755–1762

37 Mehler PS et al. (2003) Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation 107: 753–756

38 Nobakhthaghighi N et al. (2006) Relationship between urinary albumin excretion and left ventricular mass with mortality in patients with type 2 diabetes. Clin J Am Soc Nephrol 1: 1187–1190

39 Seyoum B et al. (2006) Exercise capacity is a predictor of cardiovascular events in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 3: 197–201

40 Kamgar M et al. (2006) Impaired fibrinolytic activity in type II diabetes: correlation with urinary albumin excretion and progression of renal disease. Kidney Int 69: 1899–1903

41 Estacio RO et al. (2006) Effect of intensive blood pressure control with valsartan on urinary albumin excretion in normotensive patients with type 2 diabetes. Am J Hypertens 19: 1241–1248



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