STATE OF THE ART
Obesity-Related Hypertension: Epidemiology,
Pathophysiology, and Clinical Management
Theodore A. Kotchen1
The prevalence of obesity, including childhood obesity, is increasing
worldwide. Weight gain is associated with increases in arterial
pressure, and it has been estimated that 6070% of hypertension
in adults is attributable to adiposity. Centrally located body fat,
associated with insulin resistance and dyslipidemia, is a more potent
determinant of blood pressure elevation than peripheral body
fat. Obesity-related hypertension may be a distinct hypertensive
phenotype with distinct genetic determinants. Mechanisms of
obesity-related hypertension include insulin resistance, sodium
retention, increased sympathetic nervous system activity, activation
of reninangiotensinaldosterone, and altered vascular function. In
overweight individuals, weight loss results in a reduction of blood
pressure, however, this effect may be attenuated in the long term.
An increasing number of community-based programs (including
school programs and worksite programs) are being developed
for the prevention and treatment of obesity. Assessment and
Obesity is associated with increased morbidity and mortality
due to hypertension, diabetes, dyslipidemia, and cardiovas-
cular and renal diseases.13 The prevalence of obesity and
obesity-related disease is increasing worldwide. The Centers
for Disease Control and Prevention estimated that obesity cost
the United States at least $147 billion in 2008. Consequently,
strategies for preventing and treating obesity have become
political as well as health-care issues.
Scientific and medical interest in the relationship between
obesity and hypertension is reflected in the number of publi-
cations related to this topic. The number of English language
citations in PubMed for obesity AND hypertension progres-
sively increased from 203 in 1990 to 1,427 in 2009, with most
of the increase occurring in the past decade. The purpose of
this report is to review information about the epidemiology,
pathogenic mechanisms, and strategies for prevention and
treatment of obesity-related hypertension.
Epidemiology of Obesity and Hypertension
In both adults and children, obesity rates have increased over
the past several decades in the United States.4,5 Obesity rates
have increased in both genders, and among all racial, ethnic,
1Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin,
USA. Correspondence:Theodore A. Kotchen (tkotchen@mcw.edu)
Received 6 June 2010; first decision 26 June 2010; accepted 12 July 2010.
2010 American Journal of Hypertension, Ltd.
1170
nature publishing group
treatment of the obese hypertensive patient should address overall
cardiovascular disease (CVD) risk. There are no compelling clinical
trial data to indicate that any one class of antihypertensive agents is
superior to others, and in general the principles of pharmacotherapy
for obese hypertensive patients are not different from nonobese
patients. Future research directions might include: (i) development
of effective, culturally sensitive strategies for the prevention and
treatment of obesity; (ii) clinical trials to identify the most effective
drug therapies for reducing CVD in obese, hypertensive patients;
(iii) continued search for the genetic determinants of the obese,
hypertensive phenotype.
Keywords: adipokines; blood pressure; central obesity; hypertension;
insulin resistance
American Journal of Hypertension, advance online publication 12 August 2010;
doi:10.1038/ajh.2010.172
and socioeconomic groups. Approximately 68% of US adults
are either overweight or obese.6 Based on National Health
and Nutrition Examination Survey data, the prevalence of
obesity in 20072008 was 32.2% among adult men and 35.5%
among adult women.5 Among adults, the prevalence of obesity
increases with age in men. The prevalence of obesity among
African Americans is ~1.5 times that in whites, and Mexican
Americans have an intermediate prevalence.4
During the past three decades, prevalence rates of child-
hood and adolescent obesity (body mass index (BMI) >95th
percentile for age and sex) have more than doubled in the
UnitedStates.7 In 2006, 16.3% of children and adolescents were
reportedly obese,8 and ~32% of children are either overweight
or obese.6 Childhood obesity frequently persists into adult-
hood, with up to 80% of obese children reported to become
obese adults.9 Among adolescents, the prevalence of obesity
is approximately twice as high among African Americans and
Mexican Americans than among non-Hispanic whites.7
Because of the increasing prevalence of obesity in the United
States, it has been projected that the steady increase in life
expectancy during the past two centuries will soon end.10
However, recent reports from the Centers for Disease Control
and Prevention suggest that obesity rates may be stabilizing.5,11
Obesity rates have remained constant for 5 years in men and
closer to 10 years in women and children.
The prevalence of obesity is increasing not only in the United
States, but also globally.12,13 Socioeconomic and demographic
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Obesity-Related Hypertension STATE OF THE ART

transitions occurring in many developing countries are
contributing to the escalation of obesity despite continuing
nutritional deficiencies. This double burden poses health and
economic challenges in resource-constrained populations. In
1998, the prevalence of obesity in the developing world had
increased from 2.3 to 19.6% over a 10-year period.14 Obesity
rates have increased threefold or more since 1980 in the Middle
East, the Pacific Islands, Australasia, and China. Additionally,
the prevalence of childhood overweight has increased in
almost all countries for which data are available.15 Obesity in
the developing world is no longer a disease of higher socioeco-
nomic status groups; the burden of obesity is shifting toward
groups with lower socioeconomic status as the countrys gross
national product increases.16 The increasing prevalence of
obesity is related to urbanization, major changes in the food
supply, diet, and a reduction in physical activity.12,14
In parallel with increasing obesity rates, cardiovascular
disease (CVD) mortality is rapidly increasing in developing
countries.17 Between 1990 and 2020, mortality from ischemic
heart disease and cerebrovascular disease increased to a con-
siderably greater extent in developing than in developed
countries (Table 1). It is projected that by 2020, low- and
middle-income countries will contribute 19 million of the
annual global mortality of 25 million due to CVD.12
Cross-sectional and longitudinal studies document an
a ssociation of blood pressure with body weight and an asso-
ciation of blood pressure increases over time with weight
gain,1821 even among lean individuals.22 However, the associ-
ation of indices of adiposity with blood pressure is less appar-
ent among hypertensive individuals than among the general
population,23 suggesting that the blood pressureadiposity
relationship in hypertensives is modulated by environmental
and genetic factors. Nevertheless, obese individuals have a 3.5-
fold increased likelihood of having hypertension;19,24) 60%
of hypertensive adults are >20% overweight. It has been esti-
mated that 6070% of hypertension in adults may be directly
attributable to adiposity.19 Possibly related to the increased
prevalence of obesity, in US adults the prevalence of hyper-
tension increased from 25.0 to 28.7% between 19881991 and
19992000.25 Between 19881994 and 20072008, the preva-
lence of both obesity and hypertension increased among all
age groups of adults, although percentage increases of both
were greatest among young adults (Table2).
Similar to adults, the prevalence of hypertension is threefold
higher in obese children than in nonobese children.26 Blood
pressures in children have increased in the past decade, and
this may also be attributable, at least in part, to an increased
prevalence of overweight.26,27 Additionally, longitudinal

Table 1| Global mortality estimates (in thousands) due ischemic heart disease and cerebrovascular disease, by sex, between 1990
and 2020
Women Men
1990 2020 % Increase 1990 2020 % Increase
Ischemic heart disease
Developing countries 1,737 3,825 120 1,828 4,337 137
Developed countries 1,397 1,809 29 1,297 1,921 48
Cerebrovascular Disease
Developing countries 1,499 3,100 107 1,454 3,260 124
Developed countries 867 1,113 28 539 841 56
Adapted from reference 17.

Table 2| Age-specific prevalence of hypertension and obesity in the United States at two time periods, and percent increase over
time
Hypertension prevalence (%) Obesity prevalence (%)
Age (years) 19881991 20052006 Percent increase 19881994 20052008 Percent increase
1839 5.1 7.4 45 17.2 28.7 67
4059 27.0 32.1 19 28.0 35.5 27
>60 57.9 65.8 14 23.9 34.0 42
Based on National Health and Nutrition Examination Survey data obtained from reference 25 and the following Centers for Disease Control and Prevention web sites: www.cdc.gov/
nchs/nhanes/nhanes2007-2008/nhanes07_08.htm and www.cdc.gov/nchs/nhanes/nh3data.htm.
Hypertension = systolic blood pressure >140mmHg or diastolic blood pressure >90mmHg, or taking antihypertensive medication. Obesity = body mass index >30kg/m2.

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 11 | november 2010 1171

STATE OF THE ART
s tudies document that weight gain is associated with increases
in blood pressure and hypertension incidence. For example,
in the Framingham Heart Study, a 5% weight gain was asso-
ciated with a 2030% increase in hypertension incidence,
and the Harvard Male Alumni study found a weight gain of
25 pounds was associated with a 60% increase in hypertension
incidence.28,29
Visceral obesity or android obesity is in part hormonally
determined. Body fat distribution is also affected by environmen-
tal and genetic factors. Environmental factors include alcohol
intake, cigarette smoking, and the timing of onset of childhood
obesity.30 Most studies suggest that centrally located body fat is
a more important determinant of blood pressure elevation than
peripheral body fat in both men and women.3133 The relation-
ship between waisthip ratio and blood pressure appears to be
independent of BMI.34 Visceral obesity also increases the risks
for insulin resistance and dyslipidemia. Further, insulin resist-
ance and obesity are associated with vascular endothelial dys-
function, manifested by endothelium-dependent coronary and
peripheral vasodilation.35,36 Impaired vasoreactivity, which
may represent the initiation or early phase in the evolution of
atherosclerosis, is more strongly correlated with abdominal
obesity than with BMI.36
The constellation of centripetal obesity (measured as waist
circumference), hypertension, insulin resistance, high serum
triglyceride concentrations, and low levels of high-density lipo-
protein cholesterol constitutes the metabolic syndrome. This
syndrome may be heritable, but as shown in the rodent, it may
be induced by diets high in simple carbohydrates.37 In African
Americans, we have found that insulin resistance is associated
with blood pressure levels and hypertension in men, but not
in women, possibly reflecting the difference between android
and gynecoid obesity.38 In children and adolescents, the preva-
lence of the metabolic syndrome increases with the severity of
obesity, and approaches 50% in severely obese youngsters.39
Although the metabolic syndrome is associated with increased
risk of all cause and cardiovascular morbidity and mortality,
whether the designation of a syndrome provides more risk
information than the individual risk factors by themselves has
been questioned.4042
Evidence for a genetic contribution to both rare monogenic
and to common forms of obesity has recently been reviewed.43
Most genes that have been found to contribute to the patho-
genesis of obesity are expressed in the brain and appear to
exert their effects by modulation of feeding behavior. Obesity-
related hypertension may represent a genetically distinct
hypertensive phenotype. For example, some genes associated
with adiposity may also contribute to the development of
hypertension in overweight and obese individuals, e.g., tumor
necrosis factor-, 3-adrenergic receptor, and G-protein 3
subunit.44 In a relatively isolated French Canadian population,
1172
Obesity-Related Hypertension
Table 3| Putative mechanisms of obesity-related hypertension
Possible underlying
Primary mechanisms mechanisms
Sodium retention Antinatriuretic effect of insulin
Increased renal SNS activity
Increased aldosterone
Increased cortisol activity
Anatomic renal compression
Increased SNS activity Insulin resistance
Reninangiotensin
Leptin/other adipokines
Obstructive sleep apnea
Adrenergic receptor
polymorphisms
Psychological stress
Increased circulating reninangiotensin Increased renal SNS activity
Increased adipose reninangiotensin
Impaired vascular endothelial function Insulin resistance
Other vascular mechanisms Insulin resistance
Altered vascular ion transport
SNS, sympathetic nervous system.
in 120 extended families with at least one sib pair affected with
early onset hypertension and/or dyslipidemia, a total genome
scan identified a cluster of overlapping quantitative trait loci
with significant logarithm (base 10) of odds scores on chro-
mosome 1 for the following phenotypes: BMI, fasting insulin,
leptin, diastolic blood pressure.45 Nevertheless, to date, specific
genetic factors have not been identified to account for the high
heritabilities of hypertension and/or obesity.
Pathophysiology of Obesity-Related Hypertension
Environmental (e.g.diet content, physical activity, level of
stress), physiological, and genetic factors influence the
impact of obesity on arterial pressure. An understanding of
the mechanisms of obesity-related hypertension may have
important therapeutic implications. The putative physiologic
mechanisms of obesity-related hypertension are complex,
interdependent, and redundant (Table3).
Sympathetic nervous system
Depending on populations studied and methods of measure-
ment, most evidence indicate that sympathetic nervous sys-
tem activity is increased in obesity, particularly sympathetic
activity to the kidney and skeletal muscle, as measured by
regional norepinephrine kinetic studies and microneuro
graphy, respectively.4648 Neural activity to skeletal muscle is
more closely related to abdominal visceral fat than to total fat
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Obesity-Related Hypertension
mass or abdominal subcutaneous fat.47 However, hypertension
is not an invariable consequence of obesity-related increases
of neural activity. Neural activity to the kidney and skeletal
muscle is elevated in obese normotensive, as well as in obese
hypertensive humans.46,47 These observations raise the possi-
bility that the impact of obesity-related neural activity on arte-
rial pressure is modified by environmental and genetic factors,
including race and gender. For example, muscle sympathetic
nerve activity is primarily related to BMI in men, but to blood
pressure in women.49 In Pima Indians, despite a high preva-
lence of obesity, muscle sympathetic nerve activity is low.49,50
This may provide a clue for the relatively low prevalence of
hypertension in Pima Indians.
The causes for activation of the sympathetic nervous system
in obesity remain uncertain and may be multiple.49 Putative
mechanisms include hyperinsulinemia and/or insulin resist-
ance; leptin or other adipokines; reninangiotensin; lifestyle
factors. Additionally, obesity, especially upper body obesity, is
a risk factor for obstructive sleep apnea. Hypertension is caus-
ally related to sleep apnea, possibly due to sympathetic outflow
as a consequence of intermittent hypoxia.51
Renal and adrenal mechanisms
Obesity-related hypertension is associated with renal sodium
retention and impaired pressure natriuresis.52 Obese humans
and subjects with the metabolic syndrome tend to be relatively
salt sensitive.53,54 Increased renal tubular reabsorption of
sodium has been attributed to increased sympathetic outflow
to the kidney. In the dog, renal denervation blunts sodium
retention and attenuates the rise in blood pressure associated
with dietary-induced obesity. It has also been suggested that
increased intrarenal pressures caused by fat surrounding the
kidneys and increased abdominal pressure associated with
visceral obesity may impair natriuresis.
Impaired pressure-natriuresis may also be related to
increased mineralocorticoid activity. We and others have
reported that plasma aldosterone is associated with blood pres-
sure, BMI, waist circumference, and insulin resistance.5558
Among African Americans, aldosterone is independently
associated with hypertension, and plasma aldosterone con-
centrations are relatively high in African Americans with the
metabolic syndrome.57 These observations suggest that the
mineralocorticoid action of aldosterone contributes to obesity-
related hypertension, particularly among African Americans.
Consistent with a pathogenic role for aldosterone, the miner-
alocorticoid antagonist, eplerenone, attenuates sodium reten-
tion and hypertension associated with the development of
obesity in dogs fed a high-fat diet.59 Somewhat paradoxically,
plasma aldosterone concentrations in obese and hyperten-
sive African Americans are relatively high despite low plasma
renin activity. The stimulus for increased aldosterone remains
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 11 | november 2010
STATE OF THE ART
a matter of conjecture, however, recent reports indicate that
adipokines may directly stimulate aldosterone production.60
Although not as potent a mineralocorticoid as aldosterone,
in high concentrations, cortisol may increase arterial pressure
by activating the mineralocorticoid receptor. Circulating lev-
els of cortisol are variable in obesity; however, they may not
reflect cortisols activity in target tissues.57 11-Hydroxysteroid
dehydrogenase type 1 activates cortisone (a functionally inert
glucocorticoid) to cortisol (an active glucocorticoid) in target
tissues, including adipose tissue. This conversion is more pro-
nounced in visceral than in subcutaneous adipose tissue.61
The P2-HSD1 mouse with overexpression of HSD1 develops
hypertension, features of the clinical metabolic syndrome, and
activation of the circulating reninangiotensinaldosterone
system.62 Although these observations are provocative, a role
for cortisol in the pathogenesis of obesity-related hypertension
and the metabolic syndrome remains to be established.
Activation of the reninangiotensin system may also con-
tribute to obesity-related hypertension. Several reports indi-
cate that plasma renin activity and plasma angiotensin II
concentrations are elevated in obesity, possibly as a conse-
quence of increased sympathetic outflow to the kidney.63,64
In obese hypertensive patients, pharmacologic blockade with
angiotensin-converting enzymes (ACEs) or angiotensin II
receptor blockers ameliorate hypertension and associated
metabolic derangements, and reduce the incidence of type
2 diabetes.65 Additionally, adipose tissue expresses all com-
ponents of the reninangiotensin system (angiotensino-
gen, renin, ACE, angiotensin type 1 and type 2 receptors).
Preliminary evidence suggests that activation of an adipose
reninangiotensin system is associated with high blood pres-
sure in a model of visceral obesity66,67 and in adipose tissue
from obese hypertensive patients.68
Impaired endothelial function
The vascular endothelium plays a major role in the regulation
of vascular resistance. Endothelium-derived nitric oxide bio-
activation is an important determinant of vascular relaxation.
Vascular endothelial dysfunction is associated with a number
of cardiovascular risk factors, including obesity, insulin resist-
ance, and hypertension.35,36 Reduced endothelium-dependent
coronary and peripheral arterial vasodilation are more strongly
correlated with waist-to-hip ratio than with BMI. Visceral fat,
quantified by abdominal computed tomography or ultrasound
is independently linked to impaired vasoreactivity. Weight loss
improves endothelial function.69
Adipokines
Adipose tissue is increasingly recognized as an endocrine
organ with many secretory products. Over 50 different
adipocyte-derived substances have been identified, and many
1173
STATE OF THE ART
of these substances have been implicated in blood pressure
control. To date, leptin has been the most thoroughly studied.
Leptin is a 167 amino acid peptide that promotes weight loss
by reducing appetite and by increasing energy expenditure
through sympathetic stimulation to thermogenic tissue.70 The
effects of leptin are primarily mediated by receptors located in
the central nervous system. The absence of leptin or a muta-
tion in the leptin receptor induces hyperphagia and obesity in
both rodents and humans. Circulating levels of leptin parallel
fat cell mass. Blood pressure and leptin are modestly correlated
in normotensive and hypertensive individuals after adjust-
ment for fat mass.71 Two prospective studies have reported
that plasma leptin concentration independently predicts the
onset of hypertension.72,73 Although these associations do
not necessarily indicate causality, chronic systemic and intra
cerebral administration of leptin increases blood pressure in
rats.71 Transgenic mice overexpressing leptin develop hyper-
tension, despite weight loss, and conversely, blood pressure is
not increased in the obese, leptin deficient ob/ob mouse71 or
in obese, leptin deficient humans.74
Increased sympathetic outflow is a putative mechanism by
which leptin may increase arterial pressure. Leptin activates
the sympathetic nervous system both by centrally medi-
ated effects on the hypothalamus and by local peripheral
actions.75 In humans, results of studies of the association of
plasma leptin with skeletal muscle nerve activity (measured
by peroneal nerve microneurography) are conflicting. High
circulating levels of leptin reportedly account for much of the
increase in renal sympathetic tone observed in obese human
subjects.76 Because obesity is almost invariably associated with
leptin resistance, it has been postulated that the resistance to
the weight-reducing effect of leptin is selective, and does not
extend to leptins potential sympathetic and cardiovascular
actions. Although acute infusion of leptin produces natriure-
sis in normotensive rats, the natriuretic effect is attenuated in
hypertensive and obese Zucker rats, possibly as a consequence
of leptin resistance.77
Preliminary evidence suggest that other adipocyte-derived
peptides may also affect arterial pressure. Circulating adipo
nectin levels are decreased in obesity-induced insulin
resistance,70 and some studies suggest that adiponectin is pro-
tective against hypertension through an endothelial-dependent
mechanism.78 A positive relationship between resistin and
hypertension has recently been described.
Insulin resistance
Insulin resistance may be a link between obesity and hyperten-
sion. Obesity is associated with resistance to insulin-stimulated
glucose uptake and hyperinsulinemia, and weight loss increases
insulin sensitivity.37 Independent of obesity, centripetal dis-
tribution of body fat is associated with insulin resistance and
1174
Obesity-Related Hypertension
blood pressure. A metabolic consequence of insulin resistance
is an impaired capacity of postprandial hyperinsulinemia to
suppress lipolysis, resulting in greater free fatty acid release,
particularly in upper body/visceral obesity compared with the
nonobese or lower body obesity. Release of free fatty acids due
to excess adipose tissue lipolysis in upper body obesity contrib-
utes to the metabolic abnormalities and possibly to the vascular
dysfunction associate with upper body obesity.30 Experimental
evidence suggests that systemic free fatty acids, derived pri-
marily from subcutaneous adipose tissue, may mediate hyper-
tensive mechanisms attributed to insulin resistance. However,
many of these studies have been conducted at supraphysiologic
concentrations of free fatty acids, and consequently these obser-
vations should be considered tentative.
Whether hypertension is causally related to insulin resist-
ance and/or hyperinsulinemia remains an unresolved issue. In
several rodent models of experimental hypertension, hyper-
tension can be ameliorated or prevented by chemically diverse
agents that increase insulin sensitivity or have a primary lipid-
lowering effect (e.g., thiazolidinediones, metformin, clofibrate,
lovastatin).79 Putative mechanisms by which insulin resistance
and/or hyperinsulinemia may increase blood pressure include
an antinatriuretic effect of insulin, increased sympathetic
nervous system activity, augmented responses to endogenous
vasoconstrictors, altered vascular membrane cation transport,
impaired endothelium-dependent vasodilatation, and stimula-
tion of vascular smooth muscle growth by insulin.
Clinical Management
Lifestyle interventions for treatment of obesity include emphasis
on nutrition, physical activity, and behavior modification. The
increasing prevalence of obesity, including childhood obesity,
has stimulated interest in developing and evaluating strate-
gies for obesity prevention. Effective strategies for preventing
and controlling overweight and obesity over a short term have
been implemented in worksite settings. These interventions
have combined instruction in healthier eating with a structured
approach to increasing physical activity in the workplace.80
Interventions for preventing obesity in children have recently
been reviewed.81 Nineteen of 22 studies included in the review
were school/preschool-based interventions. The majority of
studies were of short term. Nearly all studies resulted in some
improvement in diet and physical activity. Some studies that
focused on either diet or physical activity alone, but not in com-
bination, had a small but positive impact on BMI.
In two small towns in France, a comprehensive and innova-
tive community-based program to prevent obesity in school-
children involved the mayor, teachers, health-care providers,
food providers, sports associations, the media, scientists, and
various branches of town government.82 The towns built sporting
facilities, playgrounds, mapped out walking itineraries, and hired
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Obesity-Related Hypertension
sports instructors. Families were offered cooking workshops
and families at risk were offered individual counseling. Between
2000 and 2005, the prevalence of overweight in children had
fallen to 8.8%, whereas it had risen to 17.8% in neighbor-
ing comparison towns. This total community approach is
now being extended to 200 towns in Europe under the name
EPODE (Ensemble, prevenons lobesite des enfants (Together,
lets prevent obesity in children)).83
Several different diets have been advocated for the treat-
ment of obesity (e.g., very-low-calorie diets, balanced-deficit
diets, low-fat diets, low-carbohydrate diets, high-protein
diets), and weight loss occurs with each of them.84 A number
of behavioral strategies, administered either individually or
groups, may assist with adherence. As recently reviewed,83
behavioral packages may include food diaries and activity
records, control of stimuli that activate eating, slower rate
of eating, goal setting, behavioral contracting and reinforce-
ment, nutrition education, meal planning, social support,
cognitive restructuring and problem solving. Incorporation
of increased physical activity (e.g., activity that expends
~2,500 kcal/week) in the regimen increases the likelihood of
maintaining weight loss. Nevertheless, the recidivism rate is
high. Approximately 90% of people who lose weight by diet-
ing regain it within 35years.85
For patients with BMI >27kg/m2 who do not respond to a
trial of diet, exercise, and behavior therapy, pharmacotherapy
can be tried. Two medications are currently available in the
United States for the treatment of obesity: (i) orlistatan
inhibitor of pancreatic lipase that reduces intestinal diges-
tion of fat and (ii) sibutraminea serotoninnorepinephrine
reuptake inhibitor.84 Orlistat is associated with steatorrhea,
and sibutramine may actually increase blood pressure and
blunt the decrease associated with weight loss. In adolescents,
metformin has recently been shown to cause a small but sta-
tistically significant decrease in BMI when added to a life-
style intervention program.86 Bariatric procedures are being
performed with increasing frequency for patients with BMI
>40kg/m2 or BMI >35kg/m2 with associated comorbidities.87
In the short term, blood pressure has been shown to decrease
in response to orlistat and to bariatric surgery.88,89 However,
hypertension per se is generally not considered an indication
for these pharmacologic or surgical approaches.
Many predominantly short-term (6-week to 6-month dura-
tion) clinical trials document that even moderate weight loss
(510%) results in reduction of blood pressure and hyperten-
sion incidence, and improvement in insulin sensitivity and vas-
cular endothelial function.36,69 Reviews of randomized trials
reported a diastolic reduction of 0.92mmHg and a systolic
reduction of 1mmHg/kg of weight loss.90 However, review of
longer term trials, including trials of bariatric surgery, suggests
that the maximum effect of weight loss on blood pressure
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 11 | november 2010
STATE OF THE ART
occurs during and soon after weight loss and that this effect is
attenuated in the long term.91
In addition to weight loss and other lifestyle modifications,
many if not most obese, hypertensive patients ultimately
require treatment with one or more antihypertensive agents
for blood pressure control. There is little clinical trial data to
indicate that any one class of agents is superior to others. Most
guidelines do not recognize obese patients as a special popula-
tion, and do not make specific recommendations for the phar-
macologic treatment of hypertension associated with obesity.
The general principles of pharmacotherapy for obese patients
are not different from nonobese patients, but there are a few
caveats. The capacity of thiazide diuretics to lower blood pres-
sure in obese hypertensive patients is well established,92 and
the adverse metabolic effects of diuretics (insulin resistance,
dyslipidemia, hypokalemia) are dose related. ACE inhibitors,
and possibly angiotensin II receptor blockers, increase insulin
sensitivity and reduce diabetes risk.93,94 Some consider ACE
inhibitors to be the most appropriate medication for blood
pressure control in obese hypertensive patients.95,96 Although
the recent DREAM (Diabetes Reduction Assessment with
Ramipril and Rosiglitazone Medication) study suggests that the
reduction in diabetes risk with ACE inhibition in patients with
low cardiovascular risk was not as pronounced as expected,
that study did not target an obese hypertensive population.97
In the PROGRESS (Perindopril Protection Against Recurrent
Stroke Study) trial, compared to placebo, blood pressure low-
ering with perindopril resulted in comparable risk reductions
in vascular disease in normal weight, overweight, and obese
individuals with a history of stroke.98 The greatest benefit was
observed in those with higher BMIs, possibly because they had
higher levels of cardiovascular risk at baseline, including higher
blood pressures. The antihypertensive potencies of lisinopril
and hydrochlorothiazide were reportedly similar in a study
of 223 predominantly white, obese, hypertensive patients.99
Several trials have documented the efficacy of the combina-
tion of hydrochlorothiazide with either an ACE, an ARB, or the
renin inhibitor aliskiren in obese hypertensive patients.100
-Blockers may more effectively decrease blood pressure
in obese than in lean hypertensives, perhaps because they
decrease cardiac output and plasma renin activity, both of
which are increased in obese patients. However, -blockers
may be associated with weight gain and have negative effects
on glucose metabolism.101 The use of -blockers as first line
agents has been questioned because their effect on stroke
protection does not compare favorably with other antihyper-
tensive agents.100 Although calcium antagonists do not have
adverse metabolic side effects, and -blockers have been asso-
ciated with improved insulin sensitivity and lipid metabolism,
there is no compelling reason to use these as first line agents in
obesity-related hypertension.
1175
 STATE OF THE ART
In the final analysis, similar to treatment of all hypertensive
patients, combinations of agents with complimentary mech-
anisms may be required to achieve blood pressure goals.
Selection of drugs should be individualized, taking into
account the severity of hypertension, other CVD risk factors,
comorbid conditions, and practical considerations related to
cost, side effects, and frequency of dosing.
Summary
Obesity-related hypertension is a multifactorial phenotype
determined by the interaction of genes and environments.
However, currently identified genomic factors account for
only a small percent of the heritable risk of this phenotype.
The association of hypertension with obesity is primarily
related to visceral obesity, which in turn is associated with
insulin resistance and dyslipidemia. Lifestyle and pharma-
cologic approaches for treating obesity-related hypertension
should address overall CVD risk, not simply hypertension.
More work is required to identify culturally sensitive strate-
gies for obesity prevention and their impact not only on body
weight, but also on blood pressure, the metabolic phenotypes
associated with obesity, and subsequent CVD. Although
several mechanisms have been identified that may account
for elevated arterial pressure, currently, there is no compelling
evidence to indicate that any one class of antihypertensive
agents is particularly advantageous for the treatment of
obesity-related hypertension.
Disclosure: The author declared no conflict of interest.
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