Obesity-Related Hypertension: Epidemiology, Pathophysiology, and Clinical Management

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1 nature publishing group Obesity-Related Hypertension: Epidemiology, Pathophysiology, and Clinical Management Theodore A. Kotchen 1 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 60 70% 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 renin angiotensin aldosterone, 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 cardiovascular and renal diseases. 1 3 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 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 publications related to this topic. The number of English language citations in PubMed for obesity AND hypertension progressively 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, 1 Department 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 American Journal of Hypertension, Ltd. 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: /ajh 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 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 childhood and adolescent obesity (body mass index (BMI) >95th percentile for age and sex) have more than doubled in the United States. 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 adulthood, 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 1170 November 2010 VOLUME 23 NUMBER AMERICAN JOURNAL OF HYPERTENSION

2 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 socioeconomic status groups; the burden of obesity is shifting toward groups with lower socioeconomic status as the country s 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 considerably 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 association of blood pressure with body weight and an association of blood pressure increases over time with weight gain, even among lean individuals. 22 However, the association of indices of adiposity with blood pressure is less apparent among hypertensive individuals than among the general population, 23 suggesting that the blood pressure adiposity 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 estimated that 60 70% 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 hypertension increased from 25.0 to 28.7% between and Between and , the prevalence of both obesity and hypertension increased among all age groups of adults, although percentage increases of both were greatest among young adults (Table 2). 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 Ischemic heart disease Women % Increase % Increase Developing countries 1,737 3, ,828 4, Developed countries 1,397 1, ,297 1, Cerebrovascular Disease Developing countries 1,499 3, ,454 3, Developed countries 867 1, Adapted from reference 17. Men Table 2 Age-specific prevalence of hypertension and obesity in the United States at two time periods, and percent increase over time Age (years) Hypertension prevalence (%) Obesity prevalence (%) Percent increase Percent increase > Based on National Health and Nutrition Examination Survey data obtained from reference 25 and the following Centers for Disease Control and Prevention web sites: nchs/nhanes/nhanes /nhanes07_08.htm and Hypertension = systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, or taking antihypertensive medication. Obesity = body mass index >30 kg/m 2. AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER 11 november

3 Obesity-Related Hypertension studies 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 associated with a 20 30% 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 environmental 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 The relationship between waist hip ratio and blood pressure appears to be independent of BMI. 34 Visceral obesity also increases the risks for insulin resistance and dyslipidemia. Further, insulin resistance and obesity are associated with vascular endothelial dysfunction, 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 lipoprotein 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 prevalence 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 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 pathogenesis of obesity are expressed in the brain and appear to exert their effects by modulation of feeding behavior. Obesityrelated 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-α, β3-adrenergic receptor, and G-protein β3 subunit. 44 In a relatively isolated French Canadian population, Table 3 Putative mechanisms of obesity-related hypertension Primary mechanisms Sodium retention Increased SNS activity Increased circulating renin angiotensin Increased adipose renin angiotensin Impaired vascular endothelial function Other vascular mechanisms SNS, sympathetic nervous system. Possible underlying mechanisms Antinatriuretic effect of insulin Increased renal SNS activity Increased aldosterone Increased cortisol activity Anatomic renal compression Insulin resistance Renin angiotensin Leptin/other adipokines Obstructive sleep apnea β Adrenergic receptor polymorphisms Psychological stress Increased renal SNS activity Insulin resistance Insulin resistance Altered vascular ion transport 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 chromosome 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 (Table 3). Sympathetic nervous system Depending on populations studied and methods of measurement, most evidence indicate that sympathetic nervous system activity is increased in obesity, particularly sympathetic activity to the kidney and skeletal muscle, as measured by regional norepinephrine kinetic studies and microneurography, respectively Neural activity to skeletal muscle is more closely related to abdominal visceral fat than to total fat 1172 november 2010 VOLUME 23 NUMBER 11 AMERICAN JOURNAL OF HYPERTENSION

4 Obesity-Related Hypertension STATE OF THE ART 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 possibility that the impact of obesity-related neural activity on arterial 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 prevalence 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 resistance; leptin or other adipokines; renin angiotensin; lifestyle factors. Additionally, obesity, especially upper body obesity, is a risk factor for obstructive sleep apnea. Hypertension is causally 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 pressure, BMI, waist circumference, and insulin resistance Among African Americans, aldosterone is independently associated with hypertension, and plasma aldosterone concentrations are relatively high in African Americans with the metabolic syndrome. 57 These observations suggest that the mineralocorticoid action of aldosterone contributes to obesityrelated hypertension, particularly among African Americans. Consistent with a pathogenic role for aldosterone, the mineralocorticoid antagonist, eplerenone, attenuates sodium retention and hypertension associated with the development of obesity in dogs fed a high-fat diet. 59 Somewhat paradoxically, plasma aldosterone concentrations in obese and hypertensive African Americans are relatively high despite low plasma renin activity. The stimulus for increased aldosterone remains 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 levels of cortisol are variable in obesity; however, they may not reflect cortisol s activity in target tissues β-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 pronounced 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 renin angiotensin aldosterone 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 renin angiotensin system may also contribute to obesity-related hypertension. Several reports indicate that plasma renin activity and plasma angiotensin II concentrations are elevated in obesity, possibly as a consequence 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 components of the renin angiotensin system (angiotensinogen, renin, ACE, angiotensin type 1 and type 2 receptors). Preliminary evidence suggests that activation of an adipose renin angiotensin system is associated with high blood pressure in a model of visceral obesity 66,67 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 bioactivation is an important determinant of vascular relaxation. Vascular endothelial dysfunction is associated with a number of cardiovascular risk factors, including obesity, insulin resistance, 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 AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER 11 november

5 Obesity-Related Hypertension 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 mutation 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 adjustment 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 intracerebral administration of leptin increases blood pressure in rats. 71 Transgenic mice overexpressing leptin develop hypertension, despite weight loss, and conversely, blood pressure is not increased in the obese, leptin deficient ob/ob mouse 71 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 mediated 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 leptin s potential sympathetic and cardiovascular actions. Although acute infusion of leptin produces natriuresis 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 adiponectin levels are decreased in obesity-induced insulin resistance, 70 and some studies suggest that adiponectin is protective 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 hypertension. Obesity is associated with resistance to insulin-stimulated glucose uptake and hyperinsulinemia, and weight loss increases insulin sensitivity. 37 Independent of obesity, centripetal distribution of body fat is associated with insulin resistance and 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 contributes 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 primarily from subcutaneous adipose tissue, may mediate hypertensive mechanisms attributed to insulin resistance. However, many of these studies have been conducted at supraphysiologic concentrations of free fatty acids, and consequently these observations should be considered tentative. Whether hypertension is causally related to insulin resistance and/or hyperinsulinemia remains an unresolved issue. In several rodent models of experimental hypertension, hypertension can be ameliorated or prevented by chemically diverse agents that increase insulin sensitivity or have a primary lipidlowering 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 stimulation 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 strategies 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 combination, had a small but positive impact on BMI. In two small towns in France, a comprehensive and innovative community-based program to prevent obesity in schoolchildren 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 1174 november 2010 VOLUME 23 NUMBER 11 AMERICAN JOURNAL OF HYPERTENSION

6 Obesity-Related Hypertension STATE OF THE ART 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 neighboring comparison towns. This total community approach is now being extended to 200 towns in Europe under the name EPODE (Ensemble, prevenons l obesite des enfants (Together, let s prevent obesity in children)). 83 Several different diets have been advocated for the treatment 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 reinforcement, 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 dieting regain it within 3 5 years. 85 For patients with BMI >27 kg/m 2 who do not respond to a trial of diet, exercise, and behavior therapy, pharmaco therapy can be tried. Two medications are currently available in the United States for the treatment of obesity: (i) orlistat an inhibitor of pancreatic lipase that reduces intestinal digestion of fat and (ii) sibutramine a serotonin norepinephrine 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 statistically significant decrease in BMI when added to a lifestyle intervention program. 86 Bariatric procedures are being performed with increasing frequency for patients with BMI >40 kg/m 2 or BMI >35 kg/m 2 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 duration) clinical trials document that even moderate weight loss (5 10%) results in reduction of blood pressure and hypertension incidence, and improvement in insulin sensitivity and vascular endothelial function. 36,69 Reviews of randomized trials reported a diastolic reduction of 0.92 mm Hg and a systolic reduction of 1 mm Hg/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 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 population, and do not make specific recommendations for the pharmacologic 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 pressure 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 lowering 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 combination of hydrochlorothiazide with either an ACE, an ARB, or the renin inhibitor aliskiren in obese hypertensive patients. 100 β-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, β-blockers may be associated with weight gain and have negative effects on glucose metabolism. 101 The use of β-blockers as first line agents has been questioned because their effect on stroke protection does not compare favorably with other antihypertensive agents. 100 Although calcium antagonists do not have adverse metabolic side effects, and α-blockers have been associated with improved insulin sensitivity and lipid metabolism, there is no compelling reason to use these as first line agents in obesity-related hypertension. AMERICAN JOURNAL OF HYPERTENSION VOLUME 23 NUMBER 11 november

7 Obesity-Related Hypertension In the final analysis, similar to treatment of all hypertensive patients, combinations of agents with complimentary mechanisms 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 pharmacologic approaches for treating obesity-related hypertension should address overall CVD risk, not simply hypertension. More work is required to identify culturally sensitive strategies 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. 1. Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE. Body weight and mortality among women. N Engl J Med 1995; 333: Corrigan SA, Raczynski JM, Swencionis C, Jennings SG. Weight reduction in the prevention and treatment of hypertension: a review of representative clinical trials. 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