Louisiana State University Health Science Center, New Orleans, LA, USA

Correspondence to: E Reisin, Department of Medicine, Section of Nephrology, Louisiana State University Health Science Center, 1542 Tulane Ave/Rm 354, New Orleans, LA 70112-2822, USA. E-mail: ereisi@lsuhsc.edu

Obesity-associated hypertension is a common disease that involves a complex pathogenesis. Failure to control hypertension (HTN) in obese subjects provides a great threat to their renal and cardiovascular functions. The treatment of obesity-associated HTN is often difficult, and requires nonpharmacological and/or pharmacological approaches. Weight reduction is the cornerstone of the therapies of obesity-HTN, as it reverses the multiple components of its pathogenesis. When weight loss cannot be sustained or fails, pharmacological means should then be used. Angiotensin-converting enzyme inhibitors (ACEI) are the drug of choice: they can reduce blood pressure, protect the kidney and heart, and improve the metabolic abnormalities in obese subjects. Angiotensin-2 type-1 receptor blockers have a renoprotective benefit similar to ACEI, and they provide an important alternative to the use of ACEI. Diuretics are very effective in African-American obese hypertensives, but small doses should be used to avoid adverse effects on metabolic profiles. Long-acting calcium channel blockers are also effective and have the advantage of no adverse metabolic effects. Nondihydropyridine calcium channel blockers may provide additional renal and cardiovascular protective effects. The beta-adrenergic receptor blockers can cause further weight gain and metabolic abnormalities in obese subjects; therefore, careful monitoring is needed. There are few clinical data that support the efficacy and benefit of centrally acting alpha-2 agonists and alpha-adrenergic receptor antagonists in the treatment of obesity-HTN.

Journal of Human Hypertension (2002) 16, 819-827. doi:10.1038/sj.jhh.1001496

obesity; blood pressure; weight control; therapy

Introduction

Obesity, defined as body mass index (BMI) >30 kg/m², is a common disorder that affects over one-third of adult Americans.¹ It is associated with numerous comorbid conditions, such as hypertension (HTN), diabetes, dyslipidaemia, atherosclerosis, focal segmental glomerulosclerosis (FSGS), glomerulomegaly and chronic renal failure (CRF).^2,3,4,5 Up to 50% of obese individuals have concomitant HTN.^3,6 There is cumulating evidence suggesting that obesity per se, is the cause of HTN in obese subjects.^3,7,8,9

Obesity-associated HTN has a complex, multifactorial mechanism, including activation of the sympathetic nervous system (SNS) and the renin-angiotensin systems (RAS), insulin resistance, excess renal sodium reabsorption, leptin-resistance and natriuretic peptides (NPs) downregulation.^7,8,9 Pressure natriuresis normally seen with increased blood pressure (BP) is blunted in obesity.^9,10 Obesity-HTN causes haemodynamic and structural adaptations in the renal and cardiovascular systems. In the kidney, it causes hyperperfusion, hyperfiltration, proteinuria, glomerulosclerosis and CRF. In the heart, it causes concentric-eccentric left ventricular hypertrophy (LVH), development of congestive heart failure (CHF), arrhythmia and cardiac sudden death.^5,7,8

Weight reduction can reverse many of obesity-related metabolic, endocrinologic and haemo-dynamic abnormalities, and it is the most effective nonpharmacological approach for BP control. However, many obese patients have difficulty with dietary compliance and they require pharmacological interventions. Diuretics, angiotensin-converting enzyme inhibitors (ACEI), angiotensin-2 type-1 receptor blockers (ARB), beta-adrenergic receptor blockers (BRB), alpha-adrenergic receptor antagonists (ARA), calcium channel blockers (CCB) and centrally acting alpha-2 agonists have been used to treat obesity-HTN. These drugs have various benefits and adverse effects.

Current guidelines, including the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, do not provide specific recommendations for the pharmacological management of obesity-HTN,¹¹ because the data from clinical studies in obese population are scarce. In this review, we will summarize the available data, discuss the theoretical reasons and clinical approaches for the pharmacological and nonpharmacological treatments of obesity-HTN. We will also emphasize the specific considerations needed for the prevention of renal and cardiovascular damage in these subjects.

Weight reduction as a first-line therapy

Weight reduction may be achieved by behavior modification, diet control, exercise, or use of antiobesity medications. As a result of the side effect of HTN, noradrenergic appetite-suppressant agents (benzphetamine, phendimetrazine, phentermine and diethylpropion) should not be used in hypertensive obese patients. Sibutramine, a mixed noradrenergic and serotonergic agent, can also increase BP. It should be avoided in obese subjects with uncontrolled HTN. The reductions in BP in those who lose weight with sibutramine are usually less than the reductions in BP seen with similar weight loss obtained by other treatments.¹²

Evidence shows that weight reduction is an effective treatment for reducing BP in obesity-HTN.^13,14 In a study in which salt was not restricted, we showed that 75% of obese hypertensive patients returned to normal BP following a weight loss of 10 kg, which indicated that weight loss independent of salt restriction was an effective way in controlling BP.¹³ Additionally, significant reduction of BP can be observed even if the patient's weight loss is less than needed to reach their ideal weight.

Weight loss can frequently obviate the need of antihypertensive drugs.^13,14 In the Dietary Intervention Study in Hypertension (DISH), obese hypertensives were separated into three groups: weight reduction, dietary sodium restriction, or no intervention as controls. The average weight loss in the weight reduction group was 4.5 kg after 1 year, and 60% of them remained normotensive without any antihypertensive medication. When daily sodium intake was reduced to 40 meq, 46% of them maintained normotensive. Only 30% of the control group remained normotensive without medication. The beneficial effects of weight reduction occurred in both sexes, and also in Caucasian and African-American subjects.¹⁴ It was concluded that weight loss was the best nonpharmacological intervention for obese-HTN.¹⁴ For those requiring antihypertensive medications, weight loss can help to decrease the number and dosage of drugs and thereby decrease both the side effects and treatment cost.

The trial of nonpharmacological interventions in the elderly (TONE) has shown that elderly hypertensive subjects benefit from weight reduction, and have fewer cardiovascular events and HTN, compared with subjects treated with the usual care.¹⁵ Weight loss also decreases the incidence of HTN in longitudinal studies of normotensive populations. A trial of HTN prevention, which recruited about 2400 overweight adults with high-normal BP, concluded that the incidence of HTN after 2 years was lower in those patients treated with weight loss, with reduction in salt intake or with both approaches, than in those managed with usual care only.¹⁶

Haemodynamic and cardiovascular changes

Decrease in BP following weight loss is associated with a rapid fall in insulin level,^17,18 reduced SNS and RAS activity,^19,20 and accelerated natriuresis.^,22 Therefore, the benefits of weight loss are likely because of the reversal of many of the haemodynamic abnormalities in obese subjects. In an earlier study, we showed that a weight loss of only 10 kg caused lower total circulating and cardiopulmonary blood volumes without changing total peripheral resistance. These changes were related to decreased venous return, cardiac output and oxygen consumption.²²

The haemodynamic changes after weight loss are associated with reduced left ventricular internal dimension during diastole, decreased septal and left ventricular systolic wall thickness. The reduction of LVH is correlated with the decrease in systolic BP,^23,24 These haemodynamic and cardiac structural changes following weight loss significantly reduced left ventricular stroke work and led to improved cardiac function.²⁵

Renal changes

Recently, Kambham et al⁵ reported a 10-fold increase in the incidence of obesity-related glomerulopathy over 15 years (0.2% in 1986-1990, 2% in 1996-2000) in a large renal biopsy-based study, suggesting an emerging epidemic of obesity-glomerulopathy, which includes obesity-associated FSGS and glomerulomegaly.

In animal studies of Fisher rats with only 1/6 of their kidney left after nephrectomy²⁶ and in our study of uninephrectomized spontaneously hypertensive rats,²⁷ calorie restriction without protein restriction was found to lower urinary protein excretion and protect kidney function (GFR). A low-calorie diet also decreased the glomerular injury and mesangial expansion in the remaining kidney. Recently, we further demonstrated that in uninephrectomized spontaneously hypertensive rats, low-calorie diets without restriction of protein could prevent renal injury by reducing glomerular growth, mesangial expansion and interstitial infiltration,²⁸ which supports Hall's hypothesis that obesity-HTN and nephropathy may be related to the physical compression of kidney by intrarenal fat accumulation and extracellular matrix proliferation.⁹These animal data suggest that weight loss improves glomerular hyperfiltration, lessens proteinuria and renal injury, and therefore, may prevent the develop-ment of glomerular sclerosis in obesity.^26,27,28

In humans, obesity was reported to increase the risk for development of proteinuria and CRF after unilateral nephrectomy.²⁹ Weight loss by hypo-caloric diet without protein restriction was shown to decrease proteinuria in obese patients with chronic proteinuric nephropathies that included diabetic nephropathy, chronic glomerulonephritis and hyperfiltration diseases.³⁰ More human studies are necessary to explore further the beneficial effects of weight loss on the kidney of obese patients.

Leptin change

The hormone leptin is secreted from adipocytes. After binding to the leptin receptor (Ob-R) at hypothalamus, activating multiple neuropeptide pathways, leptin decreases appetite and increases energy expenditure, and therefore, reduces adipose tissue mass and body weight.⁷ Leptin also has other actions, such as activating the sympathetic system, increasing renal sodium and water excretion, improving insulin sensitivity and inhibiting glucose-mediated insulin secretion.⁷

A strong correlation between serum leptin level and body fat mass has been documented, which suggests a leptin-resistant mechanism in obesity.³¹ Leptin resistance in obese patients may contribute to their clinical profile, such as low-energy ex-penditure, sodium retention, intravascular volume expansion and insulin resistance.⁷ Weight loss is accompanied with a decrease in leptin levels,³² which suggests that weight loss probably 'reverses' the leptin resistance, and improves the clinical profiles of obese subjects. Leptin was demostrated to stimulate expression of TGF-beta1 and proliferation of glomerular endothelial cells, and to increase proteinuria in rat, which suggest that leptin is a renal growth and profibrogenic factor contributing to renal injury and glomerulosclerosis.³³

NPs changes

NPs are important regulators of volume homeostasis and arterial pressure.^7,34 In the kidneys, NPs modulate renal vascular resistance and increase GFR; they decrease inner medullary hypertonicity and inhibit sodium reabsorption. NPs also inhibit RAS, decrease vascular resistance and BP. Several studies suggest that relative overexpression of inactive receptor (Npr-C) in adipose tissue may trap and clear more ANP from circulation and reduce its biological effects on the kidney,^34,35,36 which may contribute to the sodium retention in obesity.

Weight loss increases the biological activity of NPs. In rats, fasting suppressed Npr-C expression in adipose tissue accompanied with increased biological activity of atrial natriuretic peptide (ANP).³⁶ Obese subjects were reported to have delayed urinary sodium excretion and a blunted response of plasma ANP to saline load.³⁷ Weight loss induced by caloric restriction led to significant natriuresis and diuresis, together with an early increase of circulating ANP levels.³⁸ Dessi-Fulgheri et al³⁹ reported that after caloric restriction for 4 days in obese hypertensive patients, ANP infusion caused more profound diuresis, natriuresis, reduction of BP, than ANP infusion did before caloric restriction. Thus, weight loss seems to increase the biological activity of NPs that are abnormally suppressed in obesity.

In summary, weight reduction should be the first choice to treat obesity-HTN. It reverses the multiple pathogenic factors implicated in obesity-HTN. The benefits of weight loss in obese patients include (but are not limited to) improvement of insulin sensitivity, reduced SNS and RAS activities, restored leptin sensitivity, increased biological activity of NPs, accelerated natriuresis, and most importantly, decreased glomerular hyperfiltration, proteinuria and renal injury, regression of LVH and improved cardiac function.

Pharmacological treatment

The majority of obese patients find that weight reduction is difficult to maintain, and a high drop-out rate in 1-2 years in weight loss program has been reported⁴⁰ When obese patients are unable to tolerate, or are unwilling to comply with weight reduction, or when weight reduction alone cannot control HTN, then antihypertensive drug therapy should be used. The ideal medications to treat HTN in obese patients would be those that specifically target to the pathogenic factors, protect the renal and cardiovascular end organs, and do not further enhance the existing metabolic abnormalities. However, there are currently no long-term studies examining the efficacy of any antihypertensive agents in reducing mortality in obese patients.

ACEI

ACEI appear to be the most appropriate drug for treat-ing obesity-HTN. ACEI block the RAS, facilitates natriuresis and diuresis. ACEI control glomerular hyperfiltration by reversal of angiotensin-2-induced efferent arteriolar restriction, improve perm-selectivity, decrease proteinuria and protect kidney function.^41,42 It has no adverse effects on lipid profiles. ACEI also improves insulin sensitivity and reduces plasma levels of insulin, norepinephrine and leptin in obese hypertensives.³³

In the first large prospective multicenter double-blind trial performed in obese hypertensive patients (TROPHY),⁴² we studied the efficacy and safety of lisinopril compared with the hydrochlorothiazide (HCTZ). A total of 60% of patients treated with lisinopril for 3 months had diastolic BP <90 mmHg, compared with 43% of patients treated with HCTZ (P<0.05). We also found that lisinopril was more effective than HCTZ in Caucasians and young obese patients, while HCTZ was more effective in obese African-American patients. Furthermore, among those whose BP were controlled, more than half of the patients (57%) only needed low-dose lisinopril (10 mg/day), whereas 46% of patients required a high-dose HCTZ (50 mg/day) to maintain BP control. Neither treatment significantly affected insulin and lipid levels after 12 weeks, but plasma glucose increased and plasma potassium decreased significantly in patients treated with HCTZ.

In a previous small study, Reaven et al⁴³ noted that lisinopril was more effective than HCTZ in lowering BP in obese patients and lisinopril was not associated with adverse metabolic effects. Also, the combination of lisinopril and HCTZ could control BP in those who failed monotherapy. Another ACEI moexipril was used to treat obese postmenopausal women. It was found that moexipril was equally as effective as atenolol in reducing BP without adversely affecting lipid and carbohydrate metabolism.⁴⁴ Recently, Masuo et al³² reported 1-year treatment of young obese hypertensives: enalapril groups (with or without weight reduction) have a greater reduction in plasma insulin, NE and particularly leptin levels than amlodipine groups (with or without weight reduction) or weight reduction alone.

Although there are currently no 'hard data' from long-term prospective studies in obese population, ACEI has been shown to have additional renal protective effects beyond the degree of BP control in patients with proteinuria, diabetic nephropathy or renal insufficiency. ACEI has been shown to decrease cardiac enlargement and preserve cardiac function in asymptomatic patients with CHF,⁴⁵ and improve both symptoms and survival in patients with overt CHF.^46,47. ACEI also can reduce the morbidity and mortality in patients with myocardial infarction⁴⁸ and can cause the regression of LVH.⁴⁹ As obese hypertensives are commonly associated with these renal and cardiovascular comorbid conditions (diabetes, proteinuria, renal insufficiency, LVH, CHF and coronary artery disease), they should benefit from both the renal and cardiovascular protective effects of ACEI.

ARB

ARB antagonize angiotensin-2 type-1 receptor mediated biological actions, including vasoconstriction, vascular remodelling, aldosterone release and proximal sodium reabsorption. They are well tolerated and have less side effects than ACEI. ARB also improve insulin sensitivity and have no adverse effects on lipid profiles.⁵⁰

Recently, ARB irbesartan was shown to protect against the progression of type-II diabetes nephropathy (proteinuria >0.9 g/day), independent of the reduction of BP.⁵¹ Another ARB losartan was reported to have similar renal benefits.⁵² Furthermore, irbesartan was shown to have renoprotective effect on the development of diabetic nephropathy in type-II diabetic patients with microalbuminuria.⁵³ ARB may also provide an additive antiproteinuric effect in the combination therapy with ACEI.⁵⁴

Although there is no published trial in treating obesity-HTN, type-II diabetes and proteinuria are the common comorbid conditions in these patients, we believe that ARB could be very useful and beneficial in treating obese hypertensive patients. It provides an important alternative to the use of ACEI.

Diuretics

The hypotensive effect of thiazides is attributed initially to a reduction of intravascular and extracellular fluid volumes. Over time, this action on volume becomes less important, and the more chronic action of thiazides results chiefly from a reduction in peripheral vascular resistance.

In an early study of black obese women with HTN, we reported that chlothalidone was more effective than clonidine in reducing BP.⁵⁵ Then, in the TROPHY trial, we found that HCTZ was more effective than lisinopril in African-American obese patients in controlling HTN.⁴²

All the studies that have used HCTZ in obesity-HTN were short-term, and most patients required a high dose of thiazides (HCTZ, 50 mg/day) for good pressure control.⁴² The prolonged use of such a high dose of thiazides will not only cause electrolyte imbalances (hypokalaemia, hypomagnesemia), but can also exacerbate some pre-existing metabolic abnormalities in obese patients, such as hyperlipidaemia, hyperglycaemia, insulin resistance and activated RAS. High doses of diuretics may be associated with an increased risk of sudden death, especially if patients have underline heart disease, or diabetes mellitus.^56,57 However, low-dose therapy (12.5-25 mg of HCTZ or chlorthalidone) is usually safe and more cost-effective. It has been shown to decrease the incidence of stroke, AMI and coronary death in the elderly with isolated systolic HTN.⁵⁸ Diuretics also can cause moderate regression of LVH, not as much as ACEI or CCD, but more than BRB.⁴⁹

We therefore propose (Figure 1) for the pharmacological treatment of obesity-HTN, ACEI would be used first to control BP and decrease the cardiovascular and renal morbidity that characterized obesity-HTN. If just ACEI do not control BP adequately, then a diuretics in low dose is added as a second choice. Combination with a diuretics can be very helpful in patients with fluid overload or renal function damage. Diuretics may also restore the antiproteinuric effect of ACEI in patients without adequate antiproteinuric response to ACEI because of the failure of dietary salt restriction.⁵⁹

CCB

CCB inhibit the slow inward calcium channels, which cause relaxation of smooth muscle arterial wall and myocardial cells. CCB also induce a mild natriuresis by direct action on renal tubules. However, short-acting CCB can increase SNS and RAS activity,⁶⁰ precipitate ischaemic events and increase mortality in patients with CAD.⁶¹ Long-acting CCB seem to be safe, and should be chosen in hyper-tensive patients.

Long-acting nifedipine gastrointestinal therapeutic system (GITS) was found to effectively control BP in 76% of extremely obese and 72% of moderately obese patients. The responsive rate was similar in obese and nonobese hypertensive patients.⁶² Other CCB, including amlodipine, diltiazem, and nitredipine, were also found to be effective in obese patients.^63,64,65

CCB are considered metabolically neutral, as it does not affect insulin sensitivity or the levels of serum insulin, glucose and lipid.^8,63,65 CCB can reduce LVH more effectively than diuretics and BRB.⁴⁹ Nondihydropyridine CCB (diltiazem, verapamil) can also lower the heart rate, may reduce the rate of reinfarction and increase the patient survival after an AMI.⁶⁶

In the kidney, dihydropyridine CCB appear to dilate the preglomerular afferent arteriole,⁶⁷ which allows more of the systemic pressure to be translated to the glomerulus. Despite the reduction in systemic pressure by dihydropyridine CCB, the intraglomerular pressure may not be changed or even elevated. They have a variable effect on proteinuria.^67,68,69 Only the nondihydropyridine CCB (diltiazem, verapamil) consistently have been shown to reduce proteinuria and diabetic nephropathy progression.^69,70,71 These may be because of the reduction in the efferent arteriolar resistance,⁶⁷ similar to ACEI.

We, therefore, propose that nondihydropyridine CCB should be used as the third choice for patients with obesity-HTN when ACEI and low-dose diuretics fail to control BP. If necessary, a dihydropyridine CCB may also be added later. It has been shown that the combination of a nondihydropyridine and a dihydropyridine CCB has additive and even synergistic effects in BP reduction.⁷²

BRB

The haemodynamic and hormonal profiles of obesity-HTN, which includes activated SNS and RAS and high cardiac output,⁷ may justify the use of BRB.

MacMahon et al⁷³ reported that metoprolol was as effective as weight reduction of >7 kg in lowering BP. Metoprolol was also reported to reduce BP more effectively in obese than in lean hypertensive patients, while CCB isradipine was more effective in controlling BP in lean than in obese hypertensive patients.⁷⁴ Another BRB atenolol was shown to be as effective as ACEI moexipril in obese postmenopausal women.⁴⁴ However, atenolol had negative effects on the glucose metabolism after 12 weeks therapy in nondiabetic obese hypertensive patients.⁴⁴

Long-term use of BRB in obese subjects may worsen their metabolic abnormalities. It increases triglycerides, decreases HDL cholesterol levels, decreases insulin sensitivity and increases insulin level.⁷⁵ BRB also interferes with a diabetic patient's awareness of hypoglycaemia. Another potential problem is that weight reduction may become difficult with BRB, which is more evident in African-American women.⁷⁶ BRB inhibits the effect of catecholamines on fatty acid metabolism, which decreases the availability of fatty acid and decreases feedback to the appetite center, and therefore leads to overeating and weight gain.⁷⁵

BRB may not reverse intraglomerular hyperfiltration and they usually have little or a lesser antiproteinuric effect.⁶⁹ BRB are also lesser effective than ACE, CCB or diuretics in causing regression of LVH.⁴⁹ However, BRB were found to improve long-term survival if they were administrated following an AMI.⁷⁷

We propose that BRB may not be a good choice for uncomplicated young obese subjects. However, for those complicated with angina, CAD, CHF or arrhythmia, BRB should be considered, as its benefits may out weigh its side effects.

Centrally acting alpha-2 agonists

The most commonly used agent of this class is clonidine. It inhibits the release of norepinephrine (NE) at central ganglionic junctions, which decreases sympathetic outflow, peripheral vascular resistance and heart rate. Sustained inhibition of SNS by clonidine leads to reductions of total body sodium and plasma volume.⁷⁸

Tuck et al⁶⁰ reported that clonidine effectively lowered BP and plasma NE levels in obese hypertensive patients. In a small prospective study of obese hypertensive African-American women, we found that clonidine failed to control BP in most patients using a daily dosage of up to 0.4 mg, and that chlothalidone controlled BP more effectively than clonidine.⁵⁵ Larger studies with a higher daily dose may be necessary to evaluate its efficacy in treating obesity-HTN. Clonidine has no adverse effects on metabolic profiles. No data suggest that clonidine offer any specific renal or cardiovascular protective effects.

ARA

The hypotensive effect of ARA is because of vasodilatation by inhibiting the postsynaptic alpha-receptor. It improves insulin sensitivity and induces early insulin response. ARA also decrease triglycerides and LDL cholesterol levels.^41,79 Clinical data in obese patients are very limited.

One small study reported that prazosin significantly decreased both systolic and diastolic pressures and also increased insulin sensitivity.⁸⁰ Another small study compared ARA bunazosin with BRB atenolol in treating nondiabetic obese-HTN. Bunazosin and atenolol were equally effective in lowering BP, but bunazosin had a significantly better profile with glucose metabolism than atenolol.⁸¹ Recently, Wofford et al⁸² reported that BP in obesity is more sensitive to adrenergic blockades (combination of doxazosin and atenolol) than in lean hypertensive patients.

Our hesitation about the use of ARA in obesity-HTN comes from the conclusions of the ALLHAT study.⁸³ Compared with those who received clorthalidone, patients treated with doxazosin had a 25% increase in cardiovascular events and a doubling in the risk of CHF, which led to the discontinuation of the doxazosin arm in this trial. Like BRB and diuretics, ARA do not preferentially dilate the efferent arteriole, may not improve intraglomerular hypertension, and have a lesser antiproteinuric effect.⁸⁴ We propose that ARA should be used as a last-line agent for obesity-HTN except for those patients complicated with benign prostatic hypertrophy.

In summary, the challenge for a clinician to treat obesity-HTN is to select the drug or drug combinations that can specifically target the underlying pathogenesis, effectively control the HTN, not worsen existing metabolic abnormalities, and protect the targeted end organs: renal and cardiovascular systems. ACEI seem to be the most appropriate drugs. It not only can effectively lower BP, but also has favourable renal and cardiovascular protective effects and improves the metabolic abnormalities in obesity. ARB has renoprotective effects apparently similar to ACEI in type-II diabetics. It should be used as an alternative to ACEI, especially in obese diabetic patients. Thiazide diuretics seem to be particularly useful in African-American obese hypertensives, but high doses should be avoided because of its metabolic adverse effects. For many obese patients who failed the single-drug regimen, the combination of an ACEI and a low-dose thiazide diuretics may represent the 'combination of choice'. Long-acting CCB is also effective and has the advantage of no adverse metabolic effects. Nondihydropyridine CCB can provide additional renal protective effect and possible cardiovascular benefit. The major concern for using BRB in obese patients is its adverse metabolic effects and the tendency of further weight gain, though, it continues to be an important drug for those patients complicated with CAD, CHF, or arrhythmia. There is little clinical data supporting the efficacy of centrally acting alpha-2 agonists and the benefit of ARA in treating HTN in obese patients.

With consideration of both the limited clinical data on obesity-HTN and the large amount of data from essential HTN,⁸⁵ we propose the approach described in Figure 1 to treat the HTN in uncomplicated obese subjects.

Acknowledgements

We thank Ms Tami Hotard, for her excellent job in editing this manuscript.

1 Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. The national health and nutrition examination surveys, 1960 to 1991. JAMA 1994; 272: 205-211. MEDLINE

2 Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardio-vascular disease: a 26-year follow-up of participants in the Framingham heart study. Circulation 1983; 72: 53-60.

3 Kannel WB et al. The relation of adiposity to blood pressure and development of hypertension. The Framingham Study. Ann Intern Med 1967; 67: 48-59. MEDLINE

4 Stevens J et al. The effect of age on the association between body-mass index and mortality. N Engl J Med 1997; 338: 1-7. Article

5 Kambham N et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 2001; 59: 1498-1509. Article

6 Johnson AL et al. Influence of race, sex and weight on blood pressure behavior in young adults. Am J Cardial 1975; 35: 523-530.

7 Zhang R, Reisin E. Obesity hypertension: the effects on cardiovascular and renal systems. Am J Hypertens 2000; 13: 1308-1314. Article

8 Mikhail N, Golub MS, Tuck ML. Obesity and hypertension. Prog Cardiovasc Dis 1999; 42: 39-58.

9 Hall JE. Mechanism of abnormal renal sodium handling in obesity hypertension. Am J Hypertens 1997; 10: 49S-55S.

10 Hall J, Brands M, Dixon W. Obesity-induced hypertension: renal function and systemic hemodynamics. Hypertension 1993; 22: 292-299.

11 The Sixth Report of the Joint National Committee on the prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157: 2413-2446.

12 Yanovski SZ, Yanovski JA. Drug therapy: obesity. N Engl J Med 2002; 346: 591-602. Article

13 Reisin E et al. Effect of weight loss without salt restriction on the reduction of blood pressure in overweight hypertensive patients. N Engl J Med 1978; 298: 1-6.

14 Landgford HG et al. Dietary therapy slows the return of hypertension after stopping prolonged medication. JAMA 1985; 253: 657-664.

15 Whelton PK et al. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE collaborative research group. JAMA 1998; 279: 839-846. MEDLINE

16 Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The trials of hypertension prevention, phase 2. The trials of hypertension prevention collaborative research group. Arch Intern Med 1997; 157: 657-667.

17 Genet SM. Insulin secretion in obesity and diabetes: an illustrative case. Ann Intern Med 1977; 87: 714-716.

18 Grey N, Kilns DM. Effect of diet composition on the hyperinsulinemia of obesity. N Engl J Med 1971; 285: 827-831.

19 Eggena P et al. Hormonal correlates of weight loss associated with blood pressure reduction. Clin Exp Hypertens 1991; 13: 1447-1456.

20 Tuck ML et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930-933.

21 Alexander JK, Peterson KL. Cardiovascular effects of weight reduction. Circulation 1972; 45: 310-318.

22 Reisin E et al. Cardiovascular changes after weight reduction in obesity hypertension. Ann Intern Med 1983; 98: 315-319. MEDLINE

23 de Simon G et al. Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension 1994; 23: 600-606. MEDLINE

24 MacMahon SW, Wilcken DE, MacDonald GJ. The effect of weight reduction on left ventricular mass: a randomized controlled trial in young, overweight hypertensive patients. N Engl J Med 1986; 314: 334-339.

25 Backman L, Freyschuss V, Hallberg D, Melcher A. Reversibility of cardiovascular changes in extreme obesity. Acta Med Scand 1979; 205: 367-373.

26 Kovayashi S, Venkatachalam MA. Differential effects of calorie restriction on glomeruli and tubules of the remnant kidney. Kidney Int 1992; 42: 710-717.

27 Reisin E et al. Low caloric unrestricted protein diet attenuates renal injury in hypertensive rats. Hyper-tension 1993; 21: 710-717.

28 Reisin E et al. A low-calorie unrestricted protein diet attenuates kidney damage in uninephrectomized spontaneously hypertensive rats. Am J Nephrol 1999; 19: 433-440. Article

29 Praga M et al. Influence of obesity on the appearance of proteinuria and renal insufficiency after unilateral nephrectomy. Kidney Int 2000; 58: 2111-2118. Article

30 Morales E et al. Antiproteinuric effect of weight loss in obese patients with chronic proteinuric nephropathies. J Am Soc Nephrol 2001; 12: 231A.

31 Considine RV et al. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295. Article MEDLINE

32 Masuo K, Mikami H, Ogihara T, Tuck ML. Weight reduction and pharmacologic treatment in obese hypertensives. Am J Hypertens 2001; 14: 530-538. Article

33 Wolf G et al. Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int 1999; 56: 860-872. Article MEDLINE

34 Dessi-Fulgheri P, Sarzani R, Rappelli A. The natriuretic peptide system in obesity-related hypertension: new pathophysiology aspects. J Nephrol 1998; 11: 296-299.

35 Sarzani R et al. Expression of natriuretic peptide receptors in human adipose and other tissues. J Endocrinol Invest 1996; 19: 581-585. MEDLINE

36 Sarzani R et al. A comparative analysis of atrial natriuretic peptide receptor expression on rat tissue. J Hypertens 1993; 11: ((Suppl 5)) S114-S116.

37 Licata G, Volpe M, Scaglione R, Rubattu S. Salt-retaining hormones in young normotensive obese subjects. Effects of saline load. Hypertension 1994; 23: ((Suppl 1)) 120-124.

38 Maoz E et al. The role of atrial natriuretic peptide in the natriuresis of fasting. J Hypertens 1992; 10: 1041-1044.

39 Dessi-Fulgheri P, Sarzani R, Tamburrini P, Moraca A et al. Plasma atrial natriuretic peptide and natriuretic peptide receptor gene expression in adipose tissue of normotensive and hypertensive obese patients. J Hypertens 1997; 15: 1695-1699.

40 Dunbar J. Practical aspects of dietary management of hypertension compliance. Can J Physiol Pharmacol 1986; 64: 831-835.

41 Richard RJ, Thakur V, Reisin E. Obesity related hypertension: its physiology basis and pharmacological approaches to its treatment. J Hum Hypertens 1996; 10: ((Suppl 3)) S59-S64.

42 Reisin E et al. Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multi center placebo-controlled trial. Treatment in obese patients with hypertension (TROPHY). Hypertension 1997; 30: 140-145.

43 Reaven GM et al. Comparison of the hemodynamic and metabolic effects of low-dose hydrochlorothiazide and lisinopril treatment in obese patients with high blood pressure. Am J Hypertens 1995; 8: 461-466. Article

44 Stimpel M, Koch B, Weber MA. Comparison between moexipril and atenolol in obese postmenopausal women with hypertension. Maturitas 1998; 30: 67-77. Article

45 The SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685.

46 The CONSENSUS trial group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavia Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429.

47 Swedberg K, Kjekshus J, Snapinn S and for the CONSENSUS investigators. Long-term survival in severe heart failure in patients treated with enalapril. Ten year follow-up of CONSENSUS 1. Eur Heart J 1999; 20: 136. Article

48 The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of Ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821.

49 Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 1996; 275: 1507. MEDLINE

50 Paolisso G et al. Losartan mediated improvement in insulin action is mainly due to an increase in non-oxidative glucose metabolism and blood flow in insulin-resistant hypertensive patients. J Hum Hypertens 1997; 11: 307-312. Article

51 Lewis EJ et al. Collaborative study group: renal protective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-860. Article MEDLINE

52 Brenner BM et al. and RENAAL study investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-879. Article MEDLINE

53 Parving HH et al. Irbesartan in patients with type 2 diabetes and microalbuminuria study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870-878. Article MEDLINE

54 Ruilope LM, Aldigier JC, Ponticelli C. Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European group for the investigation of valsartan in chronic renal disease. J Hypertens 2000; 18: 89.

55 Reisin E, Weed SG. The treatment of obese hypertensive black women: a comparative study of chlorthalidone versus clonidine. J Hypertens 1992; 10: 489-493.

56 Hoes AW, Grobbee DE, Lubsen JL. Diuretics, beta blockers, and the risk for sudden cardiac death in hypertensive patients. Ann Intern Med 1995; 123: 481.

57 Warram JH, Laffel LM, Valsania P. Excess mortality associated with diuretics theraphy in diabetes mellitus. Arch Intern Med 1991; 151: 1350.

58 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991; 265: 3255.

59 Buter H, Hemmelder MH, Navis G. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 1998; 13: 1682. Article MEDLINE

60 Tuck ML. Obesity, the sympathetic nervous system, and essential hypertension. Hypertension 1992; ((Suppl I)) 19: 1-67, 1-77.

61 Furberg CD, Psaty BM, Meyer JV. Nifedipine, dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326-1331.

62 Tuck ML, Bravo EL, Krakoff LR, Friedman CP. Endocrine and renal effects of nifedipine gastrointestinal therapeutic system in patients with essential hypertension: results of a multicenter trial. The modern approach to the treatment of hypertension study group. Am J Hypertens 1990; 3: S333-S341.

63 de Courten M et al. Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension. Eur J Clin Pharmacol 1993; 44: 457-462.

64 Cabezas-Cerrato J, Garcia-Estevez DA, Arujo D, Iglesias M. Insulin sensitivity, glucose effectiveness and B-cell function in obese males with essential hypertension: investigation of the effects of treatment with a calcium channel blocker diltiazem or an angiotensin-converting enzyme inhibitor quinopril metabolism. Metabolism 1997; 46: 173-178.

65 Beer NA et al. Effects of nitredipine on glucose tolerance and serum insulin and dehydroepiandrosterone sulfate levels in insulin resistant obese and hypertensive men. J Clin Endocrinol Metab 1993; 76: 178-183.

66 Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial and other recent studies. Am J Cardiol 1991; 67: 1295.

67 Bakris GL. The effects of calcium antagonists on renal hemodynamics, urinary protein excretion, and glomerular morphology in diabetic states. J Am Soc Nephrol 1991; 2: S21.

68 Ruggenenti P, Perna A, Benini R, Remuzzi G and for the GISEN group. Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors and blood pressure control on chronic, nondiabetic nephropathies. J Am Soc Nephrol 1998; 9: 2096.

69 Gansevoort RT, Sluiter WJ, Hemmelder MH. Antiproteinuric effect of blood pressure lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant 1995; 10: 1963.

70 Bakris GL et al. Calcium channel blockers versus other antihypertensive therapies on progression of non-insulin-dependent diabetes mellitus associated nephropathy. Kidney Int 1996; 56: 1641-1650.

71 Griffin KA, Picken MM, Bakris GL, Bidani AK. Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int 1999; 55: 1849-1860. Article

72 Saseen JJ et al. Comparison of nifedipine alone and with diltiazem or verapamil in hypertension. Hypertension 1996; 28: 109-114.

73 MacMahon SW et al. Comparison of weight reduction with metoprolol in treatment of hypertension in young overweight patients. Lancet 1985; 1: 1233-1236. MEDLINE

74 Schmieder RE et al. Obesity as a determinant for response to antihypertensive treatment. BMJ 1993; 307: 537-540.

75 Reisin E, Tuck ML. Obesity-associated hypertension: hypothesized link between etiology and selection of therapy. Blood Pres Monit 1999; 4: S23-S26.

76 Davis BR et al. Effect of antihypertensive therapy on weightloss. Hypertension 1992; 19: 393-399.

77 Freemamtle N, Cleland J, Young P. Beta-blockade after myocardial infarction: systemic review and meta regression analysis. BMJ 1999; 318: 1730.

78 Campese VM et al. Role of sympathetic nerve inhibition and body sodium volume state in the antihypertensive action of clonidine in essential hypertension. Kidney Int 1980; 18: 351-357.

79 Koch-Weser J, Graham RM, Pettinger WAS. Drug therapy: prazosin. N Engl J Med 1979; 300: 232-236.

80 Pollare T, Lithell H, Selinus L, Berne C. Application of prozosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 1988; 31: 415-420.

81 Bonner G, Schmieder R, Chrosch R, Weidinger G. Effect of bunazosin and atenolol on glucose metabolism in obese, nondiabetic patients with primary hypertension. Cardiovasc Drugs Ther 1997; 11: 21-26. Article

82 Wofford MR et al. Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects. Am J Hypertens 2001; 14: 694-698. Article

83 ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlothalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000; 283: 1967-1975.

84 Rosenberg ME, Hostetter TH. Comparative effects of antihypertensive on proteinuria: Angiotensin-converting enzyme inhibitor versus alpha1-antagonist. Am J Kidney Dis 1991; 18: 472.

85 Bakris GL et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000; 36: 646-661. MEDLINE

Figure 1 The suggested approach to treat obesity-HTN. HTN: hypertension; BMI: body mass index; BP: blood pressure; ACEI: angiotensin-converting enzyme inhibitors; ARB: angiotensin-2 type-1 receptor blockers; HCTZ: hydrochlorothiazide; SCr: serum creatinine level; CCB: calcium channel blockers; ARA: alpha-adrenergic receptor antagonists; BRB: beta-adrenergic receptor blockers.