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Appropriate blood pressure control
in hypertensive and normotensive type 2 diabetes
mellitus: a summary of the ABCD trial
Robert W Schrier*, Raymond O Estacio, Philip S Mehler and William R Hiatt
S U M M A RY
The hypertensive and normotensive Appropriate Blood Pressure Control in
Diabetes (ABCD) studies were prospective, randomized, interventional clinical
trials with 5years 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 24h creatinine
clearance) remained stable during 5years of either intensive or standard blood
pressure intervention in patients with normoalbuminuria (<30mg/24h)
or microalbuminuria (30300mg/24h) at baseline. By contrast, the rate of
creatinine clearance in patients with overt diabetic nephropathy (>300mg/24h;
albuminuria) at baseline decreased by an average of 5ml/min/year in spite
of either intensive or standard blood pressure control. Analysis of the results
of 5years 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, reninangiotensin system, urinary albumin excretion
Review criteria
The PubMed database was searched for all articles related to the ABCD trial.
cme
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
robert.schrier@uchsc.edu
Received 10 April 2007 Accepted 25 May 2007
www.nature.com/clinicalpractice
doi:10.1038/ncpneph0559
428 nature clinical practice NEPHROLOGY
2007 Nature Publishing Group
Continuing Medical Education online
Medscape, 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
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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 objectives
Upon 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.
Introduction
A worldwide epidemic of diabetes mellitus is
emerging. It has been estimated that by 2010
there will be 221million 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 blindnessboth
are microvascular complicationsin 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
august 2007 vol 3 no 8

substantial morbidity, mortality and health-
care costs. Nevertheless, it is the macrovascular
complicationsstroke, heart attack and periph-
eral vascular diseasethat account for 7580%
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 2.6mmol/l (100mg/dl) has been
recommended. In high-risk diabetic patients
with cardiovascular disease, an even lower LDL
cholesterol goal of 1.8mmol/l (70mg/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
august 2007 vol 3 no 8 SCHRIER ET AL. 
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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
9years 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 15years 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 7580% of diabetes-related deaths are
due to macrovascular complications. Because
3540% 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 8090%
when diabetic nephropathy (urinary albumin
excretion>300mg/24h) 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 type2
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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70 Normotensive
P = 0.005
63
Proportion of patients with complication (%)
60
Hypertensive
P = 0.001
54
P = 0.05a
P = 0.005
50 48 49
47
45
40 37
30
20 19
10
0 pathy;17 the cause and effect of this relation-
Renal Retinopathy CVD Neuropathy
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: 152161.
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 Enrollees
Baseline 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 >90mmHg)
than among those with normotensive diastolic
blood pressure (8090mmHg; 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
ncpneph_2007_065f1.eps
430 nature clinical practice NEPHROLOGY
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of retinopathy (P<0.001), neuropathy (P<0.001)
and cardiovascular disease (P<0.001), accor
ding to 2 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
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-
linenamely, overt albuminuria and autonomic
neuropathywas a strong predictor of future
cardiovascular events over 5years of follow-up.
Overt albuminuria (>300mg/24h) 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 cohort
The 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 (58years for both
groups); gender (58% male for both groups);
duration of diabetes (11.9 vs 11.5years);
glycosylated hemoglobin (11.6 vs 11.5%); BMI
SCHRIER ET AL. august 2007 vol 3 no 8

Hypertensive patients
(DBP >89 mmHg)
n = 470
Intensive Moderate
blood pressure control blood pressure control
DBP 75 mmHg DBP 8090 mmHg
n = 237 n = 233
Nisoldipine Enalapril Nisoldipine Enalapril
n = 116 n = 121 n = 119 n = 114
Figure 2 Randomization protocol for the
hypertensive ABCD study. Abbreviation: DBP,
diastolic blood pressure.
(31.8 vs 31.7kg/m2); total cholesterol (5.6 [215] vs
5.7mmol/l [221mg/dl]); blood pressure (156/98
vs 154/98mmHg); and duration of hypertension
(11.9 vs 11.5years). After 4years 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
(Figure3).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
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40
Enalapril 2: P = 0.003
35
35 Nisoldipine
2: P = 0.002
30
2: P = 0.007 27
Number of events
25 24
20
24
15
9
10 9
5
0
Nonfatal All MI MI plus CV death
Figure 3 Cardiovascular complications in patients receiving enalapril or
nisoldipine. After 4years 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.
The KaplanMeier 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 3/2mmHg 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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Table 1 Effect of intensive versus moderate blood pressure control on the (>300mg/24h; albuminuria) at baseline,
renal function of hypertensive and normotensive patients with overt diabetic neither moderate nor intensive blood pressure
nephropathy in the ABCD trial.30 control stabilized renal function, regardless of
Degree of blood Mean creatinine clearance P value the initial antihypertensive agent used (Table1).
pressure control (ml/min/1.73m2SE) Hypertensive patients with diabetes with overt
Baseline 5years nephropathy lost kidney function at a rate of
Hypertensive patients
approximately 5ml/min/year of creatinine
clearance.31 Although this rate of loss is clearly
Intensive 75.04.4 56.95.8 0.035
better than the loss of kidney function of 10
Moderate 77.55.5 52.65.8 0.006 12ml/min/year in patients with type 2 diabetes
Normotensive patients whose hypertension is untreated,32 it indicates
Intensive 84.57.2 57.79.2 0.032 that prevention of diabetic nephropathyin
contrast to slowing its progressionrequires
Moderate 76.06.3 52.99.7 0.042
early intervention at the normoalbuminuric or
microalbuminuric stage.
All-cause mortality over the 5years of the
hypertensive ABCD study was significantly
lower in the intensive than in the moderate
Obesity
blood pressure control group (5.5% vs 10.7%;
P<0.037).31 It is important to emphasize that
Insulin resistance this beneficial effect on mortality of intensive
(mean 133/78mmHg) versus moderate (mean
139/86mmHg) blood pressure control was
Smooth muscle Hyperinsulinemia Kidney noted in the absence of any differences between
cell proliferation treatment groups in blood glucose concentra-
tion, lipid levels or smoking prevalence. During
SNS activity Na+ the ABCD study, blood pressure control was
reabsorption
managed by nurse practitioners under physician
Vessels Heart supervision, whereas blood glucose and treat-
ment of lipid abnormalities remained under
the management of the patients primary care
Vasoconstriction Cardiac output
physician. The potential mechanisms by which
obesity and insulin resistance might increase
? Blood pressure blood pressure in patients with type 2 diabetes
are illustrated in Figure 4.
Figure 4 Interactions by which obesity and insulin resistance might lead to
hypertension in patients with type 2 diabetes. Abbreviations: Na+, sodium;
Intervention phase of the ABCD
SNS, sympathetic nervous system.
trial: normotensive cohort
The randomization protocol for the normo-
tensive ABCD study is shown in Figure 5. The
control groups. Although these patients with following baseline demographics of the inten-
diabetes were in their 60s, their mean renal sive (n=237) and moderate (n=243) blood
function after 5years (as assessed by 24h creati- pressure therapy groups were comparable: age
nine clearance) remained stable for those with (58.5 vs 59.6years); gender (53 vs 56% male);
either normoalbuminuria (<30mg/24h) or duration of diabetes (8.8 vs 9.2years); glycosyl-
microalbuminuria (30300mg/24h) at base- ated hemoglobin (11.5 vs 11.6%); BMI (11.5
line.31 This effect occurred in both the moderate vs 11.6kg/m2); total cholesterol (5.6 [216] vs
and intensive blood pressure control groups, 5.5mmol/l [214mg/dl]); blood pressure (136/84
and was independent of initial therapy (i.e. vs 137/84mmHg); and creatinine clearance (84
either nisoldipine or enalapril). This finding [1.4] vs 83ml/min [1.4ml/s]). The goal of inten-
indicates that reported declines in renal function sive intervention was to reduce diastolic blood
with increasing age might be due to inadequate pressure by 10mmHg using either nisoldipine or
blood pressure control in elderly patients. In enalapril; the moderate blood pressure control
patients with overt diabetic nephropathy group received placebo.

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Normotensive patients Table 2 Effect of intensive versus moderate blood pressure control on
DBP 8089 mmHg the progression of complications in patients with type 2 diabetes in the
n = 480 normotensive ABCD study.
Disease state Blood pressure control (% of patients P value
who progressed)

Intensive Moderate Intensive Moderate

blood pressure blood pressure Normoalbuminuria 17 28 0.02
control control to microalbuminuria
10 mmHg decrease No change
n = 237 n = 243 Incipient to overt diabetic 18 37 0.02
nephropathy
Retinopathy 35 46.5 0.02

Nisoldipine Enalapril Stroke 1.75 5.5 0.03

Placebo
n = 118 n = 119

Figure 5 Randomization protocol for the

normotensive ABCD study. Abbreviation: DBP, 100
diastolic blood pressure. Permission obtained
from Nature Publishing Group Schrier RW et al. Normoalbuminuria (n = 191)
(2002) Kidney Int 61: 10861097.
90

Microalbuminuria (n = 86)
Patient survival (%)

Over the course of the 5-year follow-up 80

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 24h creatinine clearance)
of patients with either normoalbuminuria or
microalbuminuria at enrollment remained
stable for the 5years 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 5ml/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;>300mg/24h)
was markedly slower in the intensive than in
the moderate blood pressure control group
(Table2). 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
ncpneph_2007_065f5.eps
august 2007 vol 3 no 8 SCHRIER ET AL. 
70
Macroalbuminuria (n = 51)a
60
50
0 1 2 3 4 5 6
Time (years)
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.
To summarize, in the normotensive ABCD
study, both intensive (mean blood pressure
128/75mmHg) and moderate (mean blood
pressure 137/81mmHg) control of blood pres-
sure stabilized creatinine clearance over 5years
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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0 Optimal Treatment (HOT) randomized trial
0
10
10
12
Decrease in incidence (%)
20
24
25
30
32
37
40
44
50
Stroke Diabetes-related Diabetes-related Microvascular
deaths endpoints complications
Strict blood glucose control Strict blood pressure control
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.
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 144/82mmHg) and
less-strict (mean blood pressure 154/87mmHg)
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
ncpneph_2007_065f7.eps
434 nature clinical practice NEPHROLOGY
2007 Nature Publishing Group
(total n=18,790), a substantial decrease in
cardiovascular mortality (by 51%; P=0.016)
was detected when a diastolic blood pressure
goal of 80mmHg, as opposed to 90mmHg,
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 90mmHg
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
130/80mmHg 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 trial
Effect of increased LVM on cardiovascular
mortality
Prospective 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 (Figure9). 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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170
SBP DBP
154
150 144 144 141 140
Mean blood pressure (mmHg)

138 137
132
130 128

JNC goal <130/80

110

90 87 85 86
82 83 81 81
78 75
70

50
UKPDS UKPDS HOT goal HOT goal HOT goal Hypertensive Normotensive Hypertensive Normotensive
Less-strict Strict <90 DBP <85 DPB <80 DPB ABCD ABCD ABCD ABCD
blood blood Moderate Moderate Intensive Intensive
pressure pressure blood blood blood blood
control control pressure pressure pressure pressure
control control control control

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 <130/80mmHg.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

heart disease, systolic and diastolic heart failure, 10.5

arrhythmias and sudden death.
Adjusted Cornell voltage

10.0

Effect of decreased exercise peak oxygen 9.5

consumption on rate of cardiovascular
9.0
events
A cohort of 468 patients with type 2 diabetes 8.5
in the ABCD trial underwent graded exercise
8.0
testing at baseline to measure peak VO2.39 These
patients were then followed up for 5years. 7.5
<20 20200 >200
Those with the lowest peak VO2 experienced
Stage of albuminuria (g/min)
significantly more cardiovascular disease events
than those with a higher peak VO2. Multiple Figure 9 Left ventricular mass (as adjusted
Cox regression analysis showed that low Cornell voltage) across the three stages of
peak VO2 was an independent risk factor for albuminuria (P<0.0001) in patients from the
ABCD trial with type 2 diabetes. Permission
cardiovascular events.
obtained from Lippincott, Williams and Wilkins
Nobakhthaghighi N et al. (2006) Clin J Am Soc
Cardiovascular and renal implications Nephrol 1: 11871190.
of impaired fibrinolysis
The increased levels of plasminogen activator
inhibitor and the associated impairment of
fibrinolytic activity that occurs in type 2 diabetes activator inhibitor in type 2 diabetes could be a
mellitus40 might be related to insulin resistance. crucial factor in the thrombosis and fibrosis that
A correlation between impaired fibrinolysis occur in diabetic cardiovascular and renal disease.
and urinary albumin excretion, as well as progres
sion of renal disease, was observed in patients ABCD-2 Valsartan trial
with type 2 diabetes. As proposed in Figure 10, Data from the normotensive ABCD study
the observed increase in levels of plasminogen support a blood pressure goal of less than
ncpneph_2007_065f8.eps

august 2007 vol 3 no 8 SCHRIER ET AL.  nature clinical practice NEPHROLOGY 435

2007 Nature Publishing Group

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Type 2 diabetes

LDL and VLDL Insulin Adipocytes Glucose Angiotensin II

PAI-1

APC tPA and uPA TGF-

Plasmin
Extracellular matrix
synthesis

Fibrinolysis Proteolysis

Thrombosis Extracellular matrix degradation Fibrosis

Myocardial infarction, stroke, Cardiovascular Cardiomyopathy and

peripheral vascular disease and renal mortality 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-, transforming growth factor ;
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: 18991903.

130/80mmHg in type 2 diabetes. Results of
a more-recent investigation, the ABCD-2
Valsartan trial, provide some support for a
blood pressure goal of 120/80mmHg.41 During
this study, 129 normotensive patients with
type 2 diabetes with a mean baseline blood
pressure of 128mmHg were randomly assigned
to receive either placebo or the angiotensin-
receptor blocker valsartan. The blood pres-
sure goals were less than 120/80mmHg in the
valsartan group and less than 140/90mmHg
in the placebo group. After a mean of approxi
mately 2years, those who had received
placebo had a mean (SE) blood pressure of
12411/806.5mmHg. The blood pressure
of patients in the valsartan group was signifi-
cantly lower, at 11811/756 (P<0.001).
During follow-up, no difference in creatinine
ncpneph_2007_065f10.eps
436 nature clinical practice NEPHROLOGY
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).
Conclusions
A 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.
SCHRIER ET AL. august 2007 vol 3 no 8

2007 Nature Publishing Group


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 90mmHg;
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
4years 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 5years 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
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Acknowledgments
The 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. Dsire
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.
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