Diabetes, Hypertension, and

Cardiovascular Derangements:
Pathophysiology and Management
Fadi El-Atat, MD, Samy I. McFarlane, MD, and James R. Sowers, MD
Address
Department of Internal Medicine, University of Missouri-Columbia,
MA410 Health Science Center, One Hospital Drive, Columbia, MO
65212, USA.
E-mail: Sowersj@health.missouri.edu
Current Hypertension Reports 2004, 6:215223
Current Science Inc. ISSN 1522-6417
Copyright 2004 by Current Science Inc.
Introduction
Cardiovascular disease (CVD) is the major cause of prema-
ture mortality in patients with diabetes, accounting for up
to 80% of deaths in this population. The age-adjusted rela-
tive risk (RR) of death due to CV events in diabetes is three-
fold higher than that in the general population [13]. Risk
factors for CVD that cluster in diabetes include hyperten-
sion, central obesity, dyslipidemia, microalbuminuria,
coagulation abnormalities, loss of nocturnal dipping of
blood pressure (BP) and pulse, and left-ventricular hyper-
trophy (LVH) (Table 1) [3,4]. Among those risk factors,
hypertension is approximately twice as frequent in patients
with diabetes than in those without the disease and is a
powerful risk factor for CVD in this population [5]. A 10
mm Hg increase in systolic BP (SBP) in diabetic persons
leads to a 15% increase in death related to diabetes, 11% in
myocardial infarctions, 19% in stroke, and 12% in conges-
tive heart failure (CHF) [6,7]. Furthermore, when hyper-
tension confounds diabetes, the risk for developing end-
stage renal disease increases to five to six times compared
with hypertensive patients without diabetes [8].
Conversely, the estimated prevalence of insulin (INS)
resistance and/or impaired glucose tolerance (IGT) is up to
50% of patients with essential hypertension [46]. In a
large, prospective study of 12,550 adults, the development
of type 2 diabetes was almost 2.5 times as frequent in
patients with hypertension as in their normotensive coun-
terparts after adjustment for age, sex, race, education, adi-
posity, family history, physical-activity level, and other
health-related behavior [9]. Possible reasons for increased
INS resistance and development of diabetes in patients
with essential hypertension have been discussed [6].
Pathogenesis of Hypertension in Insulin
Resistance/Hyperinsulinemia and Diabetes
The association of hypertension, INS resistance, and resultant
hyperinsulinemia is well established [1,36,816,17,18
21,22,23,24,25,2632]. In untreated essential hyperten-
sive patients, fasting and postprandial INS levels are higher
than in normotensive controls, regardless of the body mass
index (BMI), with a direct correlation between plasma INS
concentrations and BP. INS resistance and hyperinsulinemia
also exist in rats with genetic hypertension, such as the Dahl
hypertensive and spontaneously hypertensive rat (SHR)
strains [10,11]. However, the association of INS resistance and
essential hypertension does not occur in secondary hyperten-
sion [12]. This suggests a common genetic predisposition for
Hypertension frequently coexists with diabetes mellitus,
occurring twice as frequently in diabetic as in nondiabetic
persons. It accounts for up to 75%of added cardiovascular
disease (CVD) risk in people with diabetes, contributing
significantly to the overall morbidity and mortality in this
high-risk population. Patients with hypertension are two
times more prone to have diabetes than are normotensive
persons. Hypertension substantially increases the risk for
coronary heart disease (CHD), stroke, retinopathy, and
nephropathy. In patients with type 2 diabetes, hypertension
usually clusters with the other components of the cardio-
metabolic syndrome, such as microalbuminuria, central
obesity, insulin resistance, dyslipidemia, hypercoagulation,
increased inflammation, and left ventricular hypertrophy
(LVH). In type 1 diabetes, hypertension often occurs subse-
quent to the development of diabetic nephropathy. Hyper-
tension in people with diabetes is characterized by volume
expansion, increased salt sensitivity, isolated systolic blood
pressure (BP) elevation, loss of the nocturnal dipping of BP
and pulse, and increased propensity toward orthostatic
hypotension and albuminuria. Among the treatment strate-
gies tested in hypertensive diabetic persons, low-density
lipoprotein (LDL)-cholesterol lowering to less than 100 mg/
dL and aggressive BP control to less than 130/80 mm Hg
have proven effective in CVD risk reduction. The combina-
tion of two or more drugs is usually necessary to achieve
the target BP.
216 Secondary Hypertension: Adrenal and Nervous System Mechanisms
essential hypertension and INS resistance, a concept that is
also supported by the finding of altered glucose metabolism
in normotensive offspring of hypertensive patients [13,14].
This relation between hypertension and INS resistance/
hyperglycemia has evolved during the past two decades
from coexistence to a common genetic predisposition to
these diseases. Hyperinsulinemia was hypothesized to be
the cause of hypertension in INS-resistant states, with the
sympathetic nervous system (SNS) as the major link. Other
putative effects of hyperinsulinemia, such as enhanced
sodium retention; volume expansion; an altered kallikrein-
kinin system and cell membrane ion exchange; cardiac
hyperreactivity; and suppressed atrial natriuretic peptide
(ANP) activity might contribute to this causal relation
between hypertension and diabetes.
Currently, it is thought that hypertension in type 1 dia-
betes mellitus is often secondary to overt nephropathy. Ele-
vated BP, in turn, promotes nephropathy, and, therefore,
these comorbid states exacerbate each other [1,3]. In type 2
diabetes mellitus, however, elevated BP is primarily due to
essential hypertension, with a genetic predisposition to
both INS resistance and hypertension.
Furthermore, a cluster of cardiometabolic derangements
is frequently present in hypertensive diabetic patients, includ-
ing central obesity, microalbuminuria, dyslipidemia,
increased oxidative stress, LVH, hyperuricemia, and hyperco-
agulability (Table 1), although the coexistence of hyperten-
sion and diabetes occur in lean individuals as well.
Several abnormalities of INS signaling contribute indi-
vidually and interdependently to hypertension in INS-
resistant states (ie, in the cardiometabolic syndrome). The
mechanisms through which INS affects BP in INS-resistant
states are among the maladaptive cardiometabolic path-
ways involved.
Insulin and hypertension
The selective resistance to INS and its homologous auto-
crine/paracrine peptide insulin-like growth factor-1 (IGF-
1) signaling at the cellular level, namely the endothelial,
vascular smooth muscle cell (VSMC) and skeletal muscle
cells, is due, in part, to the antagonistic action of angio-
tensin II (Ang II) [1,3]. Ang II, acting through its angio-
tensin II type 1 receptor (AT1R), inhibits the actions of
INS in vascular and skeletal muscle tissue, in part, by
interfering with INS signaling through phosphatidylinos-
itol 3-kinase (PI3-K) and protein kinase (AKT) meta-
bolic pathways (Fig. 1). This leads to decreases in nitric
oxide (NO) production in endothelial cells, increased
myosin light-chain activation/vasoconstriction in VSMCs,
and reduced skeletal muscle glucose transport. In fact,
one mechanism by which INS and IGF-1 attenuate vascu-
lar contractility is through effects on VSMC divalent cat-
ion metabolism [4,15,16]. These hormones reduce Ca
2+
influx into VSMCs by attenuating both voltage- and
receptor-operated Ca
2+
channels, limit the release of Ca
2+
from intracellular organelles, and stimulate the Na
+
,K
+
-
ATPase pump, leading ultimately to reduced intracellular
Ca
2+
concentration ([Ca
2+
]i) and, thus, contributing to
vascular relaxation [1]. Also, INS and IGF-1 increase the
cellular uptake of Mg
2+
, which produces a vasorelaxant
effect. Ang II, through increasing oxidative stress and
RhoA activity, inhibits these effects, thus contributing to
vasoconstriction [16,17,18,19].
Furthermore, both insulin and IGF-1 exert their effects
on vascular tone via metabolic actions exerted on endothe-
lial cells (EC) [16,17]. Both peptides stimulate NO pro-
duction [16,18,19], a process mediated via PI3-K/AKT
signaling pathways, and Ang II inhibits this vasorelaxant
effect of INS/IGF-1.
In addition, Ang II antagonizes the INS-induced increase
in glutamine (GLUT)-4 transport to the skeletal muscle cell
membrane, thereby reducing cellular glucose uptake.
Hyperinsulinemia, secondary to INS resistance, also
contributes to hypertension in the INS-resistant state by
enhancing sympathetic nervous system (SNS) activity, in
which INS action is selectively preserved. This, in turn,
stimulates renal sodium absorption, with subsequent vol-
ume expansion, and increases cardiac output (CO), thus
contributing to elevated BP [4,20]. Another role for INS in
the etiology of hypertension related to INS resistance is the
upregulation of AT1Rs by post-transcriptional mecha-
nisms, such as stabilization of messenger RNA (mRNA)
and prolongation of its half-life [21]. This potentiates the
physiologic actions of Ang II, which include peripheral vas-
oconstriction and plasma volume expansion.
In concert with actions of INS on vasculature, described
earlier, clinical studies have shown that modification of INS
resistance improves BP control. For instance, aerobic exer-
cise training has been shown to improve INS sensitivity and
lower BP among sedentary, nondiabetic, hypertensive sub-
jects [22]. Following an 8-week treatment with troglita-
Table 1. Cardiovascular and renal risk factors
associated with the cardiometabolic syndrome
Hypertension
Central obesity
Hyperinsulinemia/insulin resistance
Endothelial dysfunction
Microalbuminuria
Low HDL-cholesterol levels
High triglyceride levels
Small, dense LDL cholesterol particles
Increased Apo-lipoprotein B particles
Increased fibrinogen levels
Increased plasma activator inhibitor -1 levels
Increased C-reactive protein and other
inflammatory markers
Reduced vascular compliance
Absent nocturnal dipping of blood pressure and pulse
Salt sensitivity
Left ventricular hypertrophy
Hyperuricemia
HDLhigh-density lipoprotein; LDLlow-density lipoprotein.
Diabetes, Hypertension, and Cardiovascular Derangements El-Atat et al. 217
zone, an INS-sensitizing agent, patients with essential
hypertension and mild diabetes had a significant improve-
ment in BP control and glucose metabolism [23]. These
findings were supported by a recent study using another
INS-sensitizing agent, in which treatment of nondiabetic,
hypertensive patients increased INS sensitivity, reduced sys-
tolic and diastolic BP, and induced favorable changes in
markers of CV risk [24]. Another oral hypoglycemic agent,
metformin, improved BP control in a rodent model of INS
resistance. Collectively, these findings suggest that INS resis-
tance and hypertension are interrelated processes that are
responsive to drugs that target INS sensitivity.
Other putative mechanisms of hypertension in
insulin resistance
Other maladaptive pathways that contribute to the etiol-
ogy of hypertension and CV complications in INS-resistant
and obese individuals include an enhanced renin-angio-
tensin-aldosterone system (RAAS); hyperleptinemia;
al tered renal and vascul ar structure and functi on;
enhanced SNS activity; and blunted ANP activity [25].
Obesity contributes significantly to the development of
hypertension, especially in younger individuals [25,26].
It is associated with increased SNS activity, abnormal
VSMC cation metabolism, and reduced ability of the kid-
ney to excrete salt [25,2628]. Other mechanisms
through which increased RAAS and SNS activities contrib-
ute to elevated BP in obesity are increased peripheral vas-
cular resistance (PVR), concentric LVH, and increased heart
rate (HR) [25,2628].
Another key player in linking obesity and hypertension
is leptin. It is a 167amino acid peptide secreted by white
adipocytes and involved in the regulation of energy bal-
ance. Higher BMI is associated with elevated leptin levels,
which enhance SNS activity through alteration in neuro-
chemical mediators, such as neuropeptide-Y (NPY) and
melanocortin receptor-4 (MC4-R), contributing to elevated
BP [25,29].
Diminished activity of natriuretic/vasodilatory pep-
tides might also contribute to increased BP associated with
obesity. In fact, the natriuretic peptide system normally has
a protective role against the development of hypertension,
due to its natriuretic and vasodilator effects, as well as its
SNS and RAAS inhibitory effects [30]. With elevated BMI,
the activity of the natriuretic peptide system is dampened,
contributing to the development of hypertension [25].
Unique Features of Hypertension in Diabetes
Hypertension in patients with diabetes, compared with
those without diabetes, has unique characteristics such as
i ncreased propensi ty to protei nuri a and orthostati c
hypotension, increased salt sensitivity and volume expan-
sion, loss of nocturnal dipping of BP, and isolated systolic
Figure 1. Putative mechanisms of hypertension and cardiovascular diseases in insulin resistance and obesity. ANPatrial natriuretic peptide; BP
blood pressure; COcardiac output; EDRFendothelium-derived relaxing factor; HDLhigh-density lipoprotein; HRheart rate; LVHleft-ven-
tricular hypertrophy; PVRperipheral vascular resistance; RAASrenin-angiotensin-aldosterone system; RFrenal failure; SNSsympathetic ner-
vous system; TGtriglycerides.
218 Secondary Hypertension: Adrenal and Nervous System Mechanisms
hypertension [3]. Most of these features are risk factors for
CVD (Table 1) and are particularly important for selecting
the appropriate antihypertensive medicationfor exam-
ple, low-dose diuretics for treatment of volume expansion;
angiotensin-converting enzyme (ACE) inhibitors or angio-
tensin-receptor blockers (ARBs) in patients with pro-
tei nuri a; and di ureti cs and cal ci um antagoni sts to
accomplish appropriate lowering of systolic pressures.
Alterations in sodium balance and extracellular
fluid volume
Salt intake has heterogeneous effects on BP in both normo-
tensive and hypertensive subjects [31]. Sensitivity to dietary
salt intake is greatest in hypertensive patients with diabe-
tes, obesity, renal insufficiency, and low renin status, and in
black and elderly patients [32,33]. Indeed, salt sensitivity
in normotensive subjects is associated with a greater subse-
quent age-related increase in BP [34]. This is particularly
important to consider in the early stages of hypertension in
patients with diabetes, especially elderly persons, because
the preval ence of both di abetes and sal t sensiti vity
increases with increasing age and obesity.
Nondipping blood pressure/pulse pattern
There is a reproducible circadian BP pattern in normoten-
sive individuals and many patients with hypertension [35].
Typically, the BP is highest when the patient is awake and
lowest during sleep, a pattern called dipping, in which
BP decreases by 10% to 15%. Patients with loss of noctur-
nal decline in BP, non-dippers, have less than a 10%
decline of BP during the night compared with daytime BP
values [36]. In patients with diabetes, there is a loss of noc-
turnal dipping as demonstrated by 24-hour ambulatory
monitoring of BP. This is particularly important because
the loss of nocturnal dipping conveys excessive risk for
stroke and myocardial infarction, and ambulatory BP was
found to be superior to office BP in predicting target-organ
involvement, such as LVH [37,38]. Approximately 30% of
myocardial infarctions and 50% of strokes occur between
6:00 AM and noon. This is particularly important in decid-
ing the optimal dosing strategies for antihypertensive med-
ications, where drugs that provide consistent and sustained
24-hour BP control will be advantageous [39].
Microalbuminuria
Hypertension in type 1 diabetes is often a consequence,
rather than a cause, of renal disease, and this nephropa-
thy precedes the rise in BP [1,3,40]. Persistent hyper-
tensi on i n pati ents wi th type 1 di abetes i s often a
manifestation of diabetic nephropathy, as indicated by
the accompanying elevation of the urinary albumin [40].
In type 2 diabetes, microalbuminuria is correlated with
INS resistance [41], salt sensitivity, loss of nocturnal
dipping, and LVH [42]. Elevated systolic BP is a signifi-
cant determining factor in the progression of micro-
albuminuria [43,44]. There is increasing evidence that
microalbuminuria is an integral component of the meta-
bolic syndrome associated with hypertension [1,3,42,44].
This concept is important to consider in selecting the
pharmacologic therapy for hypertension in patients with
diabetes, because medications that decrease both pro-
teinuria and BP, such as ACE inhibitors and ARBS, have
evolved as increasingly important tools in reducing the
progression of nephropathy in such patients [1,3].
Systolic hypertension
Isolated systolic hypertension is more common and occurs
at a relatively younger age in patients with diabetes
[1,3,45]. This is believed to be secondary to atherosclerosis
in patients with diabetes in whom the larger arteries lose
elasticity and become rigid, and the systolic BP elevation
occurs because the arterial system is incapable of expan-
sion for any given volume of blood ejected from the left
ventricle [1].
Dysautonomia
In patients with diabetes and autonomic dysfunction,
excessive venous pooling can cause orthostatic hypoten-
sion, with secondary reduction in cerebral blood flow,
l eadi ng to i ntermi ttent li ghtheadedness, weakness,
unsteady gait, and syncope [4648]. This has several diag-
nostic and therapeutic implications in patients with diabe-
tes and concomitant hypertension. Discontinuation of
diuretic therapy and volume repletion, for instance, might
be necessary for the treatment of chronic orthostasis. Also,
increased propensity for orthostatic hypertension in
patients with diabetes renders -adrenergic receptor block-
ers less desirable and relegates them to second-line agent
status for these patients [1]. In addition, doses of all anti-
hypertensive agents must be titrated more carefully in
patients with diabetes, who have a greater propensity for
orthostatic hypertension.
Goal blood pressure in diabetic persons
Patients assigned to lower BP targets showed improved
outcomes, particularly in preventing stroke, in The Hyper-
tension Optimal Treatment (HOT) [49] and the United
Kingdom Prospective Diabetes Study (UKPDS) [50]. In the
HOT trial, improved outcomes were achieved in the group
assigned to a target diastolic BP of less than 80 mm Hg
[49]. Epidemiologic studies also suggested greater CVD
events and mortality with a BP higher than 120/70 mm Hg.
Therefore, a target BP less than 130/80 mm Hg is currently
recommended by the Joint National Committee VII (JNC
VII) [51] and American Diabetes Association (ADA) [52].
The treatment algorithm reflects the new treatment goal of
BP less than 130/80 mm Hg, as well as the latest recom-
mendations regarding drug therapy and the results of the
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack (ALLHAT) study [53,54].
Diabetes, Hypertension, and Cardiovascular Derangements El-Atat et al. 219
Treatment of Hypertension in the
Diabetic Population
Dietary and lifestyle modifications
Lifestyle and dietary modifications are an integral part of
the management of hypertension in patients with diabetes.
Addressing other CVD risk factors, such as smoking, inac-
tivity, and elevated low-density lipoprotein (LDL) choles-
terol is also emphasized [51,53]. Dietary and lifestyle
modifications recommended for patients with hyperten-
sion are listed in Table 2. Based on the results of the
Dietary Approaches to Stop Hypertension (DASH) study
[55], the reduction of sodium intake to levels below the
current recommendation of 100 mmol per day and the
DASH diet both lower BP substantially, with greater effects
in combination than singly [56]. Dietary management and
aerobic exercise in patients with diabetes should be inte-
grated in the overall nutritional and lifestyle management
of these patients. Although lifestyle modifications are
important for all patients with diabetes, pharmacotherapy
for hypertension is often necessary (Table 2).
Pharmacotherapy for Hypertensive
Diabetic Individuals
Angiotensin-converting enzyme inhibitors
The ability of ACE inhibitors to attenuate albuminuria and
renal disease progression led to their use as renoprotective
agents in diabetic nephropathy [57,58]. More recently, ran-
domized, controlled trials have shown that ACE inhibitors
provide cardiovascular and microvascular benefits that
were even greater than those attributable to the decrease in
BP and were particularly demonstrated in people with dia-
betes [5961]. Also, as we learned from the Heart Out-
comes Prevention Evaluation (HOPE) and the Captopril
Prevention Project (CAPPP) trials, ACE inhibitors improve
INS sensitivity and reduce the rate of development of dia-
betes [5961]. Two putative mechanisms through which
ACE inhibitors exert this effect include increases in blood
flow through the microcirculation to fat and skeletal mus-
cle tissue, with a special role for bradykinin and NO, and
improvement of INS action at the cellular level by reversing
the Ang II inhibition of INS signaling [60].
In patients with type 1 diabetes and proteinuria, ACE-
inhibitor treatment was associated with a 50% reduction in
the risk of the combined end points of death, dialysis, and
transplantation [57]. Furthermore, ACE inhibitors provide
considerable benefits in diabetic patients with heart fail-
ure. In the Studies of Left Ventricular Dysfunction (SOLVD)
trial, ACE inhibitors reduced left ventricular mass and left
ventricular dilation and significantly reduced mortality
and hospitalization for heart failure [62].
In a minority of patients, the use of ACE inhibitors is asso-
ciated with cough, angioedema, and hyperkalemia. Addition-
ally, these agents are contraindicated in patients with renal
insufficiency, bilateral renal artery stenosis, and unilateral
renal artery stenosis in those with one kidney because of the
risk of renal failure. However, if used with caution and appro-
priate follow-up, ACE inhibitors are still among the most
beneficial pharmacologic agents in the treatment of hyperten-
sionespecially for those with coexisting diabetes.
Angiotensin II-receptor blockers
These agents, otherwise referred to as AT1R blockers, are
very well-tolerated, with lower incidence of side effects,
such as cough and angioedema, than ACE inhibitors [63].
Renal side effects, however, are similar to those with ACE
inhibitors. The JNC VII recommended the use of ARBs as
one of several alternative first-line therapies for patients
with hypertension who cannot tolerate or do not respond
to the recommended first-line medications [51]. In addi-
tion, ARBS were also recommended as an initial therapy
for those who could not tolerate ACE inhibitors (usually
because of cough) and in whom ACE inhibitors are recom-
mended [64], such as patients with diabetes and pro-
tei nuri a, heart fai l ure, systol i c dysfuncti on, post
myocardial infarction, and those with mild renal insuffi-
ciency. However, three major studiesthe Reduction of
Endpoints in NIDDM with the Angiotensin II Antagonist
Losartan (RENAAL) Study [65]; the Irbesartan Microalbu-
minuria Type 2 Diabetes in Hypertensive Patients (IRMA
II) Study [66]; and the Irbesartan in Diabetic Nephropathy
Trial (IDNT) [67]showed that ARBs are effective in
reducing the progression of renal disease in patients with
type 2 diabetes and hypertension. Therefore, based on the
evidence and because of the better tolerability, ARBs are
recommended as a first-line therapy for patients with dia-
betes, hypertension, and significant proteinuria [51].
-Blockers
-Blockers are very useful agents in the treatment of hyper-
tension in patients with diabetes [1,3]. In the UKPDS
study, atenolol reduced CVD morbidity and mortality in
patients with diabetes as efficiently as ACE inhibitors [68].
Hence, despite potentially adverse metabolic effects of -
blockers, namely, worsening of glucose tolerance [6], they
have proved to have significant long-term, favorable effects
on CVD in hypertensive patients with diabetes and, there-
fore, should be used in patients with diabetes, particularly
those with coronary disease.
Calcium channel blockers
To achieve a target BP of 130/80 mm Hg, clinical studies
suggest that at least 65% of patients require two or more
different antihypertensive agents [6971]. Additional ther-
apies in people with diabetes, besides ACE inhibitors/ARBs
and diuretics, include longacting calcium channel block-
ers (CCBs) [1,3,45]. It is important to note that the Appro-
priate Blood Pressure Control in Diabetes (ABCD) trial
demonstrated a superiority of ACE inhibitors over CCBs in
reducing CVD events; however, these differences are likely
the result of the beneficial effects of ACE inhibitors rather
than the negative effects of the CCBs. Furthermore, the use
220 Secondary Hypertension: Adrenal and Nervous System Mechanisms
of these agents is particularly helpful in achieving the tar-
get BP, especially in patients with isolated systolic BP that is
not responding to the addition of low-dose diuretic ther-
apy. In fact, the Systolic Hypertension in Europe Treated
with Nitrendipine-based Antihypertensive Therapy (Syst-
Eur) Trial demonstrated that the added risk for CVD events
and stroke associated with diabetes was abolished by rigor-
ous antihypertensive treatment for older patients with type
2 diabetes and isolated systolic hypertension [72]. Further-
more, the HOT trial demonstrated a reduction in major
CVD events with diastolic BP control in patients with dia-
betes using felodipine, a CCB, as a first-line therapy [73].
Diuretics
The diabetic cohort in the ALLHAT study provided valuable
information about the treatment of hypertension in older
diabetic patients at risk for incident CVD [54,74]. Thiazide-
type diuretics were comparable with ACE inhibitors and
CCBs in reducing CVD events and are less expensive than
CCBs and ACE inhibitors. Therefore, they are recom-
mended as first-step antihypertensive therapy. Diuretics
generally have been shown to prevent CVD complications
and usually enhance the antihypertensive efficacy of multi-
drug regimens.
Effective blood pressure control
To achieve the recommended target BP of 130/80 mm Hg,
patients with hypertension and diabetes will require two or
more drugs. Data from our group and others indicate that
multiple medications are usually necessary to achieve such
a goal [6971]. The addition of a second drug from a differ-
ent class should be initiated when the use of a single drug
in adequate doses fails to achieve the BP goal. The JNC VII
recommends initiation of therapy with two drugs when BP
pressure is 20/10 mm Hg above goal [51]. This will proba-
bly increase the likelihood of achieving the BP goal. In fact,
Table 2. Cardiovascular and metabolic abnormalities and treatment strategies in the
cardiometabolic syndrome
Cardiovascular and metabolic disorders
in the cardiometabolic syndrome Treatment strategies
Hypertension, especially SBP elevation Physical activity, weight reduction
Rigorous BP control to <130/80 (with ACEIs, ARBs, thiazide diuretics,
adrenergic blockers, insulin sensitizers, and calcium channel blockers)
Dyslipidemia Physical activity, weight reduction
Low cholesterol diet, HMG-CoA reductase inhibitors to LDL<100 mg/dL
Microalbuminuria Physical activity, weight reduction
Blood pressure control to <130/80 with ACEIs and ARBs
Glycemic control
Lipid-loweringtherapy with HMG-CoA reductase inhibitors
Insulin sensitization
Hypercoagulability and enhanced
platelet aggregation
Physical activity, weight reduction
Antiplatelet therapy (ASA, ASA +dipyridamole, thienopyridines)
Insulin sensitization
Congestive heart disease Physical activity, weight reduction
Blood pressure control,
Glycemic control,
Antiplatelet therapy
Correction of dyslipidemia
Dysglycemia Physical activity, weight reduction
Glycemic control to HBA1c <7.0
Enhanced RAAS activity Physical activity, weight reduction
ACE inhibitors
ARBs
Endothelial dysfunction Physical activity
Blood pressure control
Glycemic control
Abnormal divalent cation metabolism
and vascular insulin/IGF1 resistance
Physical activity, weight loss
Insulin sensitization
Improved endothelial function
Visceral obesity and physical inactivity Exercise (minimum of 20 min, 3/wk)
Weight reduction
Behavioral modification
ACEIangiotensin-convertingenzyme inhibitor; ARBangiotensin-receptor blocker; ASAaspirin; HbA1chemoglobin A1c; HMG-CoA3-
hydroxy-3-methylglutaryl coenzyme A; IGFinsulin-growth factor; LDLlow-density lipoprotein; RAASrenin-angiotensin-aldosterone system;
SBPsystolic blood pressure.
Diabetes, Hypertension, and Cardiovascular Derangements El-Atat et al. 221
the use of a fixed-dose combination therapy is becoming
increasingly popular because it has the potential for
enhancing compliance, and reducing side effects and cost
of medications [75,76]. Several diuretic-based combina-
tions are available, including those with -blockers, ACE
inhibitors, and ARBs.
Conclusions
Diabetes and hypertension frequently coexist secondary to
common genetic and environmental predisposing factors.
This coexistence markedly increases CVD risk. Multiple
maladaptive cardiometabolic pathways are involved in the
etiology of hypertension in INS-resistant states as well as in
diabetes. Awareness and thorough understanding of these
fundamental abnormalities are required for optimal man-
agement of hypertension and CVD and renal disease risk
reduction in people with hypertension and diabetes. Life-
style modifications and pharmacotherapy, commonly with
two or more antihypertensive agents, are necessary for
effective BP control and reduction of CVD events and mor-
tality in this patient population. Other strategies to reduce
CVD risk include rigorous control of lipids and glucose lev-
els and the use of aspirin prophylactically (Table 2). A
recent report from Denmark [77] underscores the value of
addressing CVD risk in patients with coexistent diabetes
and hypertension.
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Papers of particular interest, published recently, have been
highlighted as:
Of importance
Of major importance
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