Review Article

Diabetes, Hypertension, and Cardiovascular Disease

An Update
James R. Sowers, Murray Epstein, Edward D. Frohlich

Abstract—Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors,
including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in
patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive
persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75%
of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie,
reducing blood pressure to ⬍130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk
factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria,
endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and “diabetic cardiomyopathy.” The
cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/
microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those
with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment,
with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy.
This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients
and the impact of interrupting this system on the development of clinical diabetes as well as CVD. (Hypertension. 2001;
37:1053-1059.)
Key Words: diabetes 䡲 cardiovascular diseases 䡲 hypertension, essential 䡲 blood pressure

Hypertension in the Diabetic Patient chronic diseases frequently coexist. Moreover, each patho-
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The subject of diabetes mellitus as a comorbid disease that
frequently confounds hypertension, adding significantly to its
overall morbidity and mortality,1,2 will be updated in the
present review. Among the complications of diabetes, cardio-
vascular and renal vascular diseases are among the most
costly in terms of human suffering and national healthcare
costs. Over the past several years, since the publication of
these foregoing reviews, a number of controlled multicenter
clinical trials have demonstrated the safety and efficacy of
specific antihypertensive therapeutic programs that can sig-
nificantly alter the outcomes of these cardiovascular and renal
complications. The present report summarizes these advances
as well as newer fundamental findings that add importantly to
our overall knowledge of the cardiovascular complications of
diabetes mellitus.
In a recent, large, prospective cohort study that included
12 550 adults, the development of type II diabetes was almost
2.5 times as likely in persons with hypertension than in their
normotensive counterparts.3 This, in conjunction with con-
siderable evidence of the increased prevalence of hyperten-
sion in diabetic persons,1,2 suggests that these 2 common
physiological disease entity, although independent in its own
natural history, serves to exacerbate the other.1,2 In a recent
report of Gress et al,3 hypertensive patients who were taking
␤-blockers had a 28% higher risk of diabetes than did those
taking no medication. In contrast, patients with hypertension
who received thiazide diuretics, ACE inhibitors, or Ca2⫹
antagonists were found not to be at greater risk for subsequent
diabetes than were patients who were not receiving any
antihypertensive medications. However, that study was not
prospective or randomized,3 and other randomized prospec-
tive trials have not shown an increase in the development of
diabetes with ␤-blocker or low-dose diuretic treatment of
hypertension.4 – 6 Recent studies have reported that ACE
inhibitor therapy reduced the propensity of hypertensive
patients to develop type 2 diabetes by 11%7 and 34%8 in trials
extending for 6 and 4 years, respectively, suggesting that
antihypertensive treatment may have a significant impact on
the propensity for the development of diabetes in this popu-
lation.9 These observations are in contrast to a recent report3
in which no reduction in progression to diabetes on ACE
inhibition therapy was observed. Thus, more controlled ran-

Received September 25, 2000; first decision November 8, 2000; revision accepted January 30, 2001.
From the SUNY Downstate Medical Center and VAMC (J.R.S.), Brooklyn, NY; the Alton Ochsner Medical Foundation (E.D.F.), New Orleans, La;
and VAMC (M.E.), Miami, Fla.
Correspondence to James R. Sowers, MD, Professor of Medicine and Cell Biology, Director, Endocrinology, Diabetes and Hypertension, SUNY HSC
at Brooklyn, 450 Clarkson Ave, Box 1205, Brooklyn, NY 11203. E-mail jsowers@netmail.hscbklyn.edu
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

1053
 1054 Hypertension April 2001

domized prospective trials are required to address the poten-

tial for ACE inhibitor therapy to reduce the rate of develop-
ment of diabetes in hypertensive patients.
There is an increasing body of data from controlled clinical
trials indicating that rigorous control of arterial pressure to
levels ⬍140/90 mm Hg markedly reduces cardiovascular
disease (CVD) morbidity and mortality and the development
of end-stage renal disease in persons with type 2 diabetes.6 –13
In the Systolic Hypertension in the Elderly Program (SHEP)
study,4 elderly persons with type 2 diabetes derived more
benefit from aggressive systolic blood pressure lowering in
reduction of CVD than did those without diabetes. Baseline
therapy in the SHEP study used a low-dose diuretic, which is
often a necessary component of the antihypertensive regimen
because of the sodium sensitivity and expanded plasma
volume that is often present in diabetic patients.14 Data from
the subset analysis of type II diabetes in the Hypertension
Optimal Treatment (HOT) trial10 suggest that reduction in
diastolic pressures from ⬍90 mm Hg to values ⬍85 mm Hg
is beneficial in reducing CVD events. The initial drug therapy
in HOT was with a dihydropyridine Ca2⫹ antagonist, but
⬎70% of diabetic patients required at least 3 drugs to control
the diastolic pressure to levels ⬍85 mm Hg. Special benefits
of aggressive blood pressure lowering in the diabetic popu-
lation was observed in a subanalysis of this cohort in the Figure 1. Algorithm for antihypertensive therapy in the diabetic
Systolic Hypertension in Europe (Syst Eur) Trial.11 In that individual. *An adequate response indicates that goal blood
trial, although systolic pressure was reduced by a comparable pressure is achieved or considerable progress is made.
amount in each group (⫺22.0⫾16 mm Hg [nondiabetic
group] versus ⫺22.1⫾14 mm Hg [diabetic group]), the risk ACE inhibitors are currently recognized as first-line anti-
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reduction in mortality from CVD was 13% in nondiabetic
patients versus 76% for the diabetic patients.11 Again, dia-
betic patients required more antihypertensive treatment to
achieve goal blood pressures, with up to two thirds requiring
ⱖ2 medications as previously observed.4,10 Moreover, the
benefit confirmed per mm Hg blood pressure reduction was
greater in diabetic patients than in those patients with hyper-
tension but without concomitant diabetes mellitus, providing
further evidence for rigorous reduction of arterial pressure in
diabetic patients.
United Kingdom Prospective Diabetes
Study Group
In the United Kingdom Prospective Diabetes Study (UKPDS)
group,12,13 blood pressure lowering was similarly effective for
captopril- and atenolol-based regimens in reducing the inci-
dence of both microvascular and macrovascular diabetic
complications. Many of these type 2 diabetic patients re-
quired both drugs plus a diuretic for “tight control” of
pressure (ie, 144/82 mm Hg). The necessity for use of at least
3 drugs for tight control was also observed in the diabetic
cohorts of the HOT and Syst Eur studies as well.10,11 In the
UKPDS, reductions in risk in the group assigned to tight
control were 24% in diabetes-related end points, 32% in
death-related end points to diabetes, 44% in strokes, and 37%
in microvascular end points, especially diabetic retinopathy.
Moreover, in the UKPDS trial, the relative benefit on CVD
risk reduction was conferred in a far more powerful fashion
by intensive blood pressure reduction rather than by tight
glucose control.12
hypertensive therapy in diabetic persons with protein-
uria,2,15,16 and these agents afford unique benefits in modify-
ing the progression and severity of CVD as well as of diabetic
nephropathy (Figure 1). Indeed, a cardioprotective effect of
ACE inhibitors has been suggested from results of the
Fosinopril versus Amlodipine Cardiovascular Events Trial
(FACET),17 the Captopril Prevention Project (CAPPP),7 the
Heart Outcomes Prevention Evaluation (HOPE) trial,8 and the
Shunt Thrombotic Occlusion Prevention by Picotamide
(STOP)-2 Hypertensive Trial.6 FACET16 was an open-label
single-center trial designed to compare the effects of fosino-
pril and amlodipine on serum lipids and glycemic control.
Patients were assigned to treatment with either amlodipine or
fosinopril; if blood pressure was not controlled, the other drug
was added. The incidence of CVD events was less in the
fosinopril-treated group than in the amlodipine-treated group,
but the incidence was least in the group that received both
antihypertensive agents.18 Furthermore, it should be noted
that there was no placebo group in the FACET study, so that
the impact of Ca2⫹ antagonists alone could not be ascertained.
These results, as well as those of the Syst Eur11 and HOT10
studies, suggest that the combination of a dihydropyridine
Ca2⫹ antagonist (such as amlodipine or nitrendipine) and an
ACE inhibitor is an acceptable approach to the treatment of
this high-risk population. It is clear from these recent studies
that reaching goal blood pressure in diabetic patients, espe-
cially if they have renal disease, will require treatment with
several antihypertensive agents. Results of the SHEP8 and the
UKPDS12 trials suggest that diuretics and ␤-blockers as well
as ACE inhibitors are also useful therapeutic agents in

diabetic hypertensive patients who often require ⱖ2 drugs to
control blood pressure adequately19 (Figure 1).
CAPPP Trial
CAPPP7 was an unblinded prospective trial that enrolled
10 985 patients aged 25 to 66 years with diastolic pressure of
at least 100 mm Hg. Patients were randomized to receive
either captopril (in 1 or 2 doses up to 100 mg/d), with a
thiazide diuretic added if necessary, or the clinician’s choice
of a thiazide diuretic or ␤-blocker, with the alternative agent
as add-on therapy if necessary. Over a follow-up period of
⬇6.1 years, in part because of inadequate randomization for
baseline blood pressure, there was a small increase in stroke
in the captopril group and a slight reduction in myocardial
infarction and other cardiovascular deaths in this treatment
group for the nondiabetic cohort. However, the risk of
developing new diabetes was 11% less in the captopril-
treated group. In diabetic patients (n⫽572), there was a
reduction in the CVD end points (P⫽0.02) in the group
receiving captopril. In the diabetic cohort, there was a better
outcome with regard to all outcomes in patients randomized
to captopril.7 The study suggested that although overall
events may be similar to ␤-blocker/diuretic treatment com-
pared with an ACE/diuretic regimen, there appears to be an
advantage to the latter regimen in diabetic persons.
HOPE Trial
HOPE was a randomized double-blind evaluation of the ACE
inhibitor ramipril in patients at high risk for vascular disease
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complications but without clinically evident heart failure.8
The HOPE trial tested the hypothesis that ACE inhibitors in
general, and ramipril in particular, have beneficial effects on
vascular disease complications above and beyond their ef-
fects on blood pressure. However, the small reduction in
blood pressure with ramipril may have contributed to its
beneficial effects.8
All patients enrolled in the HOPE trial had documented
vascular disease, ie, a history of coronary artery disease,
stroke, peripheral vascular disease, or diabetes, with 1 addi-
tional cardiovascular risk factor. A total of 9297 patients were
randomized to either ramipril or matching placebo and were
followed for a mean duration of 5 years. The primary end
points were myocardial infarction, stroke, or death from a
cardiovascular cause. Secondary outcomes were death from
all causes, need for coronary artery revascularization, hospi-
talization for unstable angina, heart failure, and complications
related to diabetes.
The 3577 diabetic patients enrolled in the HOPE trial were
also examined separately in a substudy of microalbuminuria
and cardiovascular and renal outcomes (MICRO-HOPE).20 In
keeping with the findings of the major trial, the primary
outcome (a composite of myocardial infarction, stroke, or
death from a cardiovascular cause) was reduced by 25% (95%
CI 12% to 36%, P⬍0.0004) in diabetic patients treated with
ramipril compared with diabetic patients receiving placebo.
Secondary outcomes of total mortality and need for revascu-
larization were also significantly lower among diabetic pa-
tients receiving ramipril. Admissions to the hospital for
unstable angina or heart failure did not differ between
Sowers et al Diabetes and Hypertension 1055
Figure 2. Intracellular signaling pathways of insulin/IGF-1. PKB
indicates protein kinase B; NOS, NO synthase.
patients receiving ramipril and those receiving placebo.
However, there was a significant 16% reduction in progres-
sion to overt nephropathy (95% CI 1% to 29%, P⫽0.036),
and there were nonsignificant trends toward less laser therapy
for retinopathy and less progression to end-stage renal disease
in the ramipril group as well.
One of the most striking observations from the HOPE trial
is that relatively large reductions in risk were achieved in the
face of comparatively small reductions in blood pressure.
Patients enrolled in the HOPE trial were not required to be
hypertensive, and the average blood pressure on admission
was 139/79 mm Hg. By 2 years, when the trends in end points
first reached statistical significance, the average reduction in
blood pressure was only 3/2 mm Hg. This striking finding
points toward possible direct effects of ramipril (and ACE
inhibitors as a class) on the heart and vasculature in addition
to their additional effect on blood pressure. In the HOPE trial,
diabetic patients derived an even greater reduction in CVD
than did the rest of the high-risk population.8
The HOPE study also showed a 34% reduction in the
development of diabetes in those patients without diabetes at
the onset of the study. Furthermore, in another study, the
ACE inhibitor perindopril was reported to reduce insulin
resistance in obese hypertensive patients without diabetes.21
Thus, the lessons learned from these 3 studies suggest that
ACE inhibitor therapy can improve insulin sensitivity and
also delay the development of diabetes in patients at high risk
for the development of this disease. The mechanism whereby
ACE inhibitors improve glucose metabolism and protect
against the development of clinical diabetes may involve the
improvement of blood flow through the microcirculation to
fat and skeletal muscle tissue and/or the improvement of
insulin action at the cellular level (by interfering with the
angiotensin II [Ang II] antagonism of insulin signaling)
(Figure 2). The fact that ACE inhibitors, but not Ang II
receptor antagonists, improve insulin resistance21 suggests
that their action on glucose metabolism may be mediated via
(at least in part) bradykinin metabolism. Significant improve-
ment of insulin responsiveness, which was achieved by the
addition of an ACE inhibitor to a tissue culture,22 indicated
 1056 Hypertension April 2001
that the protective effect of ACE inhibition on diabetes is not
(or is not solely) related to changes in blood flow. This
improvement is also likely mediated at a cellular level, as
shown by increases in glucose transporter (GLUT-4) protein
and the activity of hexokinase, one of the major enzymes of
glucose metabolism, in skeletal muscle of obese rats treated
with an ACE inhibitor (Figure 2).
Interrupting the effects of the renin-angiotensin system
(RAS) may improve the cellular actions of insulin by several
mechanisms. Ang II in vascular and heart tissue interferes
with insulin stimulation of phosphatidylinositol 3-kinase
(PI3-kinase) activation, a major pathway for insulin signal
transduction23–25 (Figure 2). The relationship between the
RAS and insulin is complex and includes several intracellular
mechanisms and signaling pathways. Normally, insulin binds
to its receptor (IR) on the surface of the insulin-sensitive cell
and triggers autophosphorylation of the IR ␤-subunit, which,
in turn, phosphorylates tyrosine in the IR substrate (IRS)
molecules. This allows the regulating p85 subunit of PI3-
kinase to connect to the IRS-1 and form an IRS-1/PI3-kinase
complex, which is involved in many of the actions of insulin,
including chemotaxis, translocation of cellular elements, and
glucose transport.26 This pathway has also been implicated in
mediating the activation of NO synthase and the Na2⫹ pump
activity in vascular tissue26,27 and in facilitating vascular
relaxation.
Ang II, acting via an Ang II type 1 G-protein–linked
receptor, phosphorylates a number of proteins, including
IRS-1 and -2. Such phosphorylation leads to the activation of
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catalytic activity of the p110 subunit of PI3-kinase, the same
enzyme that belongs to the insulin-signaling pathway. Para-
doxically, this process interferes with insulin-dependent ac-
tivation of PI3-kinase and, therefore, inhibits this major
pathway of insulin signaling and decreases the ability of the
cell to consume glucose in response to insulin.12 Precise
mechanisms of such inhibition remain unclear, but it has been
shown that Ang II inhibits the insulin-stimulated association
between IRS-1 and the regulatory p85 subunit of PI3-kinase
by 30% to 50% in a dose-dependent manner,23,24 interrupts
the insulin-signaling cascade, and, therefore, contributes to
the development of insulin resistance. This insulin resistance
can be manifested as diminished glucose transport in skeletal
muscle tissues and adipocytes and impaired vascular
relaxation.27
Even though they are not completely understood, the cellular
actions of ACE inhibitors on glucose metabolism lead to
increases in GLUT-4 concentration and activation of one of the
major enzymes of glucose pathway, hexokinase.27 These
changes are probably secondary to activation of the PI3-kinase
signaling pathway by the enhancement of tyrosine phosphory-
lation of IRS-1 and the improvement of PI3-kinase/IRS-1
complexing.28 ACE inhibitors are also able to facilitate blood
flow through the microcirculation in skeletal muscles.29 This
effect is bradykinin dependent and occurs through the activation
of cell surface ␤2-adrenergic receptors.29 ACE inhibitors prolong
the action of bradykinin by blocking its enzymatic breakdown
and facilitating its action.29 Facilitation of blood flow to insulin-
sensitive tissues, such as skeletal muscle, would lead to an
increase in glucose delivery to these tissues. In turn, bradykinin
Figure 3. Incidence of death from cardiovascular causes in dia-
betic and nondiabetic individuals after a 7-year follow-up. MI
indicates myocardial infarction.
not only causes vasodilation but also independently increases the
basal and insulin-stimulated rate of glucose uptake in skeletal
muscle in insulin-resistant obese Zucker rats30 by improving
postreceptor insulin signaling and enhancing GLUT-4 translo-
cation to the cell membrane.30 Thus, in addition to blocking the
negative effect of Ang II on PI3-kinase signaling, there are
additional mechanisms by which ACE inhibitor therapy may
improve the insulin sensitivity associated with hypertension.31
Other Factors Contributing to Increased CVD
in Diabetic Patients
CVD accounts for up to 80% of the deaths in persons with
type 2 diabetes31 (Figure 3). Indeed, age-adjusted relative risk
of death due to cardiovascular events in persons with type 2
diabetes is 3-fold higher than in the general population.14,31 A
recent population-based study showed that CVD mortality
was 7.5 times greater among persons with type 2 diabetes
without a previous myocardial infarction than in those with-
out diabetes31 (Figure 3). Furthermore, the incidence of CVD
mortality was 3-fold higher among individuals with diabetes
who had suffered a myocardial infarction than among nondi-
abetic individuals.31 Diabetes is associated with a relatively
greater risk for CVD in women than in men.32 Moreover,
diabetes negates the normal gender differences in the preva-
lence of CVD, and when adjusted for other risk factors, the
risk rate for increased mortality is 2.4 times greater for
diabetic men and 3.5 times greater for diabetic women.32,33
A number of factors, in addition to hypertension, contrib-
ute to the high prevalence of CVD in type 2 diabetic persons.
Within the Multiple Risk Factor Intervention Trial (MR-
FIT),34 ⬎5000 diabetic patients were followed for 12 years
and were compared with ⬎350 000 persons without diabetes.
The occurrence of CVD death at the 12-year follow-up was
⬇3 times more in diabetic men than in their nondiabetic
controls, regardless of systolic pressure, age, cholesterol,
ethnic group, or use of tobacco. This study also confirmed
that systolic hypertension, elevated cholesterol, and cigarette
smoking were independent predictors of mortality and that
the presence of ⱖ1 of these risk factors had a greater impact
on increasing CVD mortality in persons with diabetes than in
those without diabetes.
Other risk factors that are involved in the cardiometabolic
syndrome, which includes persons with prediabetes, include

the following: obesity, hyperlipidemia, hyperuricemia, and
albuminuria.15,16,25 The hyperuricemia that occurs in essential
hypertension (when not ascribed to gout, diuretic therapy, or
other factors known to produce hyperuricemia) is related to
reduced renal blood flow and increased renal vascular resis-
tance.25 This elevation in serum uric acid not only accompa-
nies the vascular alterations associated with nephrosclerosis
but also follows the development of left ventricular hypertro-
phy (echocardiographically) and accompanies the foregoing
renal hemodynamic involvement in patients with the early
stages of essential hypertension, even before the development
of proteinuria or impaired renal excretory function.25 On the
other hand, microalbuminuria has been reported to develop
before any clinical evidence of coronary heart disease (eg,
myocardial infarction and cardiac failure) or intrarenal vas-
cular disease in patients having diabetes with or without
hypertension.15,16 Nephrosclerosis associated with hyperten-
sion and renal diabetic vascular disease affects the intrarenal
arterioles, whereas CHD, associated with occlusive epicardial
coronary artery disease, as manifested by myocardial infarc-
tion, is an arterial disease. In the case of the latter, both
hypertension and diabetes exacerbate the atherosclerotic oc-
clusive disease.
Diabetic Cardiomyopathy
Diabetic cardiomyopathy, a diabetes-related myopathic state,
is characterized mainly by impaired diastolic function.35–38 In
experimental diabetes, the mechanical properties of the myo-
cardium and cardiomyocytes in vitro involve prolongation of
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contraction and relaxation as well as considerable slowing in
relaxation velocity.36 –38 Diabetic cardiomyopathy is observed
in chemically induced insulinopenic36,37 as well as in genet-
ically predisposed insulin-resistant38 rodent models. Potential
abnormalities underlying this cardiomyopathic state include
altered K⫹ channel function,39 – 41 alterations in Na⫹ pump
function,42 alterations in sarcoplasmic (endoplasmic) reticu-
lum Ca2⫹-ATPase,43,44 Na⫹-Ca2⫹ exchanger45 function, and
abnormalities of protein kinase C metabolism.46
Diabetic cardiomyopathy may be associated with a balance
between the cardiac RAS and the autocrine/paracrine actions
of insulin-like growth factor (IGF)-1. The peptides, Ang II
and IGF are generated by cardiomyocytes and exert pleiotro-
pic effects in an autocrine/paracrine fashion.27,47 IGF-1 also
has been demonstrated to increase myocardial contractility by
increasing [Ca2⫹]i and cardiomyocyte myofilament Ca2⫹ sen-
sitivity.47 IGF-1 is synthesized by cardiomyocytes under the
control of insulin, Ang II, mechanical stress, and increased
total peripheral resistance.47 IGF-1 and Ang II have opposing
actions on key signaling pathways of the heart but work
synergistically in promoting growth.47 One of the major
pathways of IGF-1 signaling involves the activation of the
PI3-kinase/IRS-1 complex.48,49 The PI3-kinase pathway is
known to mediate many insulin/IGF-1 actions, including
receptor trafficking, glucose transport, cytoskeletal reorgani-
zation, the Na⫹,K⫹-ATPase and K⫹ channel expression/
activity, and myofilament-Ca2⫹ sensitivity.23,24,27
Ang II, acting via its G-protein–linked receptor, also
induces tyrosine phosphorylation of IRS-1.23,24 In cardiac
tissue in contrast to insulin/IGF-1, Ang II acutely inhibits
Sowers et al Diabetes and Hypertension 1057
Cardiovascular Risk Factors That Cluster
With Microalbuminuria
Central obesity
Insulin resistance
Low HDL cholesterol levels
High triglyceride levels
Systolic hypertension
Absent nocturnal drop in blood pressure
Salt sensitivity
Male sex
Increased cardiovascular oxidative stress
Impaired endothelial function
Abnormal coagulation/fibrinolytic profiles
basal as well as insulin/IGF-1–stimulated PI3-kinase activi-
ty23,47 (Figure 2). Thus, it has been proposed that overexpres-
sion of the RAS, as occurs in the diabetic heart, would
predispose one to a resistance to the actions of insulin/IGF-1
on the PI3-kinase–mediated activation of K⫹ channel and Na⫹
pump expression/activation as well as myofilament-Ca2⫹
sensitivity.47 Indeed, reduced cardiomyocyte glucose trans-
port and attenuated PI3-kinase response to insulin IGF-1 have
been observed in insulin-resistant rodent models.36,50 These
abnormalities are associated with decreased expression/acti-
vation of the K⫹ channel and Na⫹ pump in both type I and
type II diabetic states.36,47,51 Resistance to the PI3-kinase–
mediated actions of IGF-1 and insulin50 (Figure 2) could
explain the abnormalities of both diastolic and systolic
function and left ventricular hypertrophy,52 which character-
ize “diabetic cardiomyopathy.” However, unabated action of
both IGF-1 and Ang II could help explain why patients with
diabetes appear to have greater left ventricular mass than do
nondiabetic cohorts with comparable blood pressures.52
Microalbuminuria and CVD in Diabetes
There is considerable evidence that the presence of hyperten-
sion in type 1 diabetes is a consequence rather than a cause of
renal disease. For example, with low levels of microalbumin-
uria, the arterial pressure remains normal, a finding that
suggests that nephropathy precedes the raise in blood pres-
sure.2,14 Regardless of whether hypertension in type 1 diabe-
tes is the etiologic factor of nephropathy or a complication of
it, it is clear that a genetic predisposition to hypertension is
important in the development of nephropathy in those 30% of
type 1 diabetics who develop this complication and that
nephropathy and hypertension exacerbate each other.53 On
the other hand, microalbuminuria is an independent risk
factor for the development of CVD and a predictor of
cardiovascular mortality in the diabetic population. It is
associated with insulin resistance,54 atherogenic dyslipid-
emia,54 central obesity,54 and the absence of nocturnal drop in
both systolic and diastolic pressures55,56 and is a part of the
metabolic cardiovascular syndrome associated with hyperten-
sion55,57 (Table). Because microalbuminuria is part of the
cardiometabolic syndrome54,57 and is related to endothelial
dysfunction and increased oxidative stress, it is not surprising
that diabetic glomerulosclerosis parallels diabetic atheroscle-
 1058 Hypertension April 2001
rosis and is a very powerful risk factor for coronary heart
disease and stroke in diabetic persons.15,16,57
Therapeutic Implications
It is clear from the foregoing review of newer information
concerning the CVD complications of diabetes mellitus and
their interaction with hypertension and its complications that
the recent national recommendations concerning the treat-
ment of patients with hypertension19 are all the more impor-
tant. Thus, although there is a necessity for risk stratification
of patients with hypertension according to the stage of blood
pressure elevation, it is apparent that the inclusion of all
patients with hypertension whose systolic and diastolic pres-
sures exceed 130 and/or 85 mm Hg, respectively, should
probably receive antihypertensive drug therapy. Although a
goal blood pressure of 130/85 mm Hg is relatively arbitrary,
it is also recognized by other organizations, such as the
Canadian Hypertension Society,58 as a reasonable goal to
maximally preserve function and reduce CVD morbidity and
mortality. Clearly, lifestyle modifications are important for
all patients with diabetes, but in those with even high normal
levels of blood pressure elevation, pharmacotherapy of hy-
pertension is particularly important. It is further evident from
these Joint National Committee-6 recommendations and re-
cent clinical trial data cited in the present report that the first
choice in antihypertensive agents is the selection of an ACE
inhibitor. Indeed, ACE inhibitor therapy has been shown to
reduce the progression of renal disease20,59 and CVD8 in
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diabetic persons with “normal blood pressure.”
Although it is clearly not our purpose to review the
pharmacological treatment of diabetes and hypertension, a
few compelling observations are in order. A review of
recently completed clinical trials indicates that ⬎65% of
people with diabetes and hypertension will require ⱖ2
different antihypertensive medications to achieve the new
suggested target blood pressure of ⬍130/85 mm Hg.19 ACE
inhibitor therapy should be an integral component of any
antihypertensive regime in patients with diabetes, inasmuch
as these agents have been demonstrated to reduce CVD7,8 and
renal disease53 in this population. Not every patient with
diabetes and hypertension can take an ACE inhibitor either
because of specific side effects from therapy or because of
absolute contraindications. Thus, if a persistent cough sec-
ondary to the ACE is intolerable and precludes its further use,
then selection of an Ang II (type 1) receptor antagonist
appears appropriate. A number of multicenter trials are
ongoing and are directed to support this recommendation.
However, because results supporting their use are not yet
available, it is not unreasonable to conclude that Ang II
receptor antagonists are appropriate choices. Other compli-
cations of ACE inhibitor therapy, particularly in patients with
diabetes, may be the progression of renal functional impair-
ment and/or hyperkalemia. In these patients, a number of
studies have supported the use of Ca2⫹ antagonists.19 Finally,
the use of ACE inhibitors or Ang II antagonists in any
pregnant woman (including one with diabetes) is definitely
contraindicated.
Over and above the foregoing therapeutic recommenda-
tions, it is also important to assess the status of the diabetic
patient’s serum concentration of LDL cholesterol and gly-
cated hemoglobin.1,2,10,19,59 Thus, in those patients with an
LDL cholesterol of 100 mg/dL and glycated hemoglobin of
ⱖ6.5, more vigorous control of both lipids and of glycated
hemoglobin levels is particularly indicated. Finally, all dia-
betic patients should receive aspirin unless there is absolute
contraindication.60
Acknowledgments
Work from Dr Sowers’ laboratory was supported by grants from the
National Institutes of Health (grant HL-63904-01), American Dia-
betes Association, and Veterans Administration. The authors wish to
thank Paddy McGowan for her excellent work in preparing this
review.
References
1. The National High Blood Pressure Education Program Working Group.
National high blood pressure education program working group report on
hypertension in diabetes. Hypertension. 1994;23:145–158.
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