Treatment of Arterial Hypertension in Obese Patients

Treatment of Arterial Hypertension in Obese Patients Ulrich O. Wenzel, MD,* Ralf Benndorf, MD,† and Sascha Lange, PhD* Summary: Obesity is an increasingly observed pathologic entity in the industrialized world and causally linked to the development of hypertension. Consequently, not only the prevalence of obesity but also the prevalence of obesity hypertension is increasing worldwide. In the context of antihypertensive treatment, data from clinical trials indicate that all first-line antihypertensive drugs possess a similar efficacy in reducing systemic blood pressure and hypertension-related end-organ damage in obese hypertensive subjects. Nevertheless, some antihypertensive agents, such as ␤-blockers or thiazide diuretics, may have unwanted side effects on the metabolic and hemodynamic abnormalities that occur in both obesity and hypertension. However, current guidelines still do not include recommendations for state-of-the-art treatment of obese patients with hypertension. Hence, the aim of this article is to provide recommendations for the appropriate use of antihypertensive agents in obese patients mostly based on personal expertise and pathophysiologic assumptions. For instance, thiazide diuretics and ␤-blockers are reported to reduce insulin sensitivity and (at least transiently) increase triglyceride and low-density lipoprotein cholesterol levels, whereas calcium channel blockers are metabolically neutral and angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and renin inhibition may increase insulin sensitivity. The reninangiotensin-aldosterone system in the adipose tissue has been implicated in the development of arterial hypertension and sodium retention plays a central role in the development of obesity-related hypertension. Therefore, treatment with a blocker of the renin-angiotensin-aldosterone-system and a thiazide diuretic should be considered as first-line antihypertensive drug therapy in obesity hypertension. Semin Nephrol 33:66-74 © 2013 Elsevier Inc. All rights reserved. Keywords: Arterial hypertension, obesity, antihypertensive treatment

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ccording to the World Health Organization, “Obesity is one of the most important contributors to ill health.” Worldwide, the prevalence of obesity in industrialized countries and in a substantial number of developing countries is increasing. Overweight or obesity occurs in approximately one third of Americans, with similar estimates for children and adolescents (32%), adult males (32%), and adult females (35%).1 The progressive increase in the prevalence of obesity is accompanied by an increase in the prevalence of hypertension, and it is estimated that 60% to 70% of the risk of hypertension may be attributable to obesity.1 Given the large increase in the number of obese individuals, the proportion of hypertensive patients with obesity is likely to increase sharply in the future.2 Several studies have shown that weight gain increases, whereas weight loss reduces, systemic blood pressure. Blood pressure increases in a linear manner over the whole range of the body mass index or waist circumference. An increase in waist circumference of 4.5 cm for men and 2.5 cm for *III Medizinische Klinik, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany. †Institute of Anatomy and Cell Biology, University of Würzburg, Germany. Financial support: none. Conflict of interest statement: Ulrich Wenzel has received funding and speaker fees from Novartis. Address reprint requests to Ulrich O. Wenzel, MD, III Medizinische Klinik, Universitätsklinikum Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: [email protected] 0270-9295/ - see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2012.12.009

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women or an increase in body mass index of 1.7 kg/m2 for men and 1.25 kg/m2 for woman corresponds to an increase in blood pressure of 1 mm Hg.3 The prevalence of hypertension is higher in obese patients compared with normal weight patients and the rate of patients with adequate blood pressure control decreases with increasing obesity.4 However, the response to antihypertensive drug treatment often is disappointing because obesity is associated with a need for multiple antihypertensive drugs and is one of the most important risk factors for treatment resistance.5 To date, our fundamental and clinical knowledge of therapeutic particularities in the treatment of obesity hypertension is sparse and certainly inadequate,6,7 which in turn may result in inadequate treatment of these patients. The increasing prevalence of hypertension in obese patients and the low control rates in overweight and obese patients reveal the challenge that blood pressure control in obese hypertensive patients imposes on the physician. This article is based on 2 recent articles by us8,9 and additionally summarizes the key content of a comprehensive discussion regarding the differential use of first-line antihypertensive drugs in the pharmacologic management of obesity hypertension.1,2,6-9

GUIDELINES Guidelines for the management of hypertension provide specific recommendations for a variety of special populations, including African or African American patients, patients with heart failure, pregnancy, coronary heart disease, diabetes mellitus, chronic kidney disease, or the elderly.10 However, specific recommendations for antiSeminars in Nephrology, Vol 33, No 1, January 2013, pp 66-74

Arterial hypertension and obesity

hypertensive therapy of obese hypertensive patients are not included in these guidelines. This is quite astonishing because most physicians treat more obese hypertensive patients than, for example, pregnant hypertensive patients. Most guidelines in general do not recognize obese patients as being “special” with regard to antihypertensive treatment and only recommend that these patients lose weight.11,12 This indeed seems to be the most effective measure for the treatment of hypertension in obese patients, but, in practice, long-term outcome of weight management programs for obesity are generally poor and most obese patients need additional medical treatment for blood pressure control. It should be emphasized that if hypertensive obese patients reduce their weight they need significantly fewer antihypertensive agents than those with stable obesity. Therefore, weight loss not only lowers blood pressure but appears to be a useful tool in blood pressure management in patients who require medication to control their blood pressure.13 Moreover, the World Health Organization technical report on prevention and management of the global epidemic of obesity does not contain any specific recommendations or guidelines for antihypertensive therapy in obesity hypertension.12 This lack of specific recommendations may originate from the paucity of data from prospective intervention studies involving obese hypertensive patients. Large outcome studies investigating the management of hypertension in obese patients have not been performed to date. Moreover, obese patients frequently are excluded from large intervention trials and although obese patients may have been included in some of the large intervention trials, no subgroup analysis for these patients has been presented to date.11,12 In conclusion, clinical trials urgently are needed to determine the most effective antihypertensive drugs for obese hypertensive patients. Because of the lack of clinical data, recommendations or guidelines for antihypertensive treatment of obesity hypertension are based mostly on subjective expert opinion. In this review, we provide the reader with general recommendations that rely on widely accepted mechanistic or pathophysiologic assumptions in the field of hypertension and obesity. Each class of first-line antihypertensive drugs and potential advantages/disadvantages in the treatment of obese hypertensive subjects is discussed. The general principles of pharmacotherapy for obese patients are not different than those for nonobese patients.

RANDOMIZED TRIALS WITH ANTIHYPERTENSIVE AGENTS IN OBESITY HYPERTENSION Usually, randomized studies evaluating the effect of specific classes of antihypertensive agents are small and of short duration.14 The Treatment in Obese Patients with Hypertension trial was the first randomized trial comparing the effect of the ACE inhibitor lisinopril and the diuretic hydrochlorothiazide on systemic blood pressure control in obese hypertensive subjects. After 12 weeks of

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treatment, blood pressure was reduced to a similar extent with both regimens.15 Also, in the Candesartan Role on Obesity and on Sympathetic System study, blood pressure reduction was very similar in patients treated with either hydrochlorothiazide (HCT) or candesartan. Nevertheless, insulin sensitivity was improved and sympathetic nerve activity was reduced in candesartan-treated patients.16 Diastolic blood pressure reduction was slightly better in atenolol- than in valsartan-treated patients, but a similar reduction was achieved after additional treatment of the nonresponders in both groups with HCT. Insulin sensitivity was slightly better in valsartan- than in atenolol-treated patients.17 Aliskiren and irbesartan combined with HCT achieved a higher responder rate (57% and 55%) than the combination of amlodipine with HCT (45%) in patients with obesity.18

OBESITY HYPERTENSION Mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of the renin-angiotensin-aldosterone system (RAAS), and altered vascular function. There is extensive overlap among factors that induce these abnormalities, but growing evidence links abnormalities in the adipose tissue to blood pressure control. Dysfunctional adipose tissue in obesity is hypertrophied and characterized by increased macrophage infiltration and by marked changes in secretion of adipokines.19 Three excellent recent review articles discuss this in detail.1,20,21 Obesity-related hypertension is associated with renal sodium retention and impaired pressure natriuresis. The renal sodium retention in obesity occurs despite an increase in glomerular filtration rate, indicating increased renal fractional tubular sodium reabsorption. Driving forces for this sodium retention are an increase in renal sympathetic tone and activation of the renin-angiotensin-system (RAS). In the dog, renal denervation blunts sodium retention and attenuates the increase in blood pressure associated with dietary-induced obesity. It also has 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 also may be related to increased mineralocorticoid activity.1 Somewhat paradoxically, plasma aldosterone concentrations in obese patients are relatively high despite low renin activity in the plasma. The stimulus for increased aldosterone remains a matter of conjecture, however, recent reports have indicated that adipokines may stimulate aldosterone production directly.22 Obesity hypertension is characterized hemodynamically by expanded intravascular volume associated with increased cardiopulmonary volume and cardiac output.23 Because obese patients have sodium retention, even normal levels of renin activity must be considered as inappropriate.24 Serum levels of almost all components of the RAS are increased in obesity and the adipose tissue is an impor-

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tant source of the RAS components.20 Hypertension in obese patients also is associated with increased inflammation, left ventricular hypertrophy, sleep apnea, endothelial dysfunction, renal hyperfiltration, and microalbuminuria. Obese patients often have metabolic abnormalities ranging from hyperinsulinemia to full-blown type 2 diabetes. In addition, obesity per se may cause end-stage organ damage.24 Although it is incompletely understood which mechanisms of obesity alter blood pressure and renal function, there are 3 factors that seem to be of particular importance: (1) activation of the reninangiotensin-aldosterone system, (2) increased sympathetic activity, and (3) structural changes in the kidney itself.25

U.O. Wenzel, R. Benndorf, and S. Lange

Renin inhibitor Angiotensinogen

Renin

Angiotensin I Angiotensin Conversions Enzym

ACE inhibitor

Angiotensin II AT1Rezeptor

AT1 antagonist

CHILDREN AND ADOLESCENTS

Adrenal gland

The prevalence rates of childhood and adolescent obesity have more than doubled26 in recent years. Similar to adults, the prevalence of hypertension is 3-fold higher in obese children than in nonobese children. The average blood pressure of children has been reported to increase in the past decade, and this may be attributable, at least in part, to an increased prevalence of overweight.1

Aldosterone

Aldosterone antagonist

BLOOD PRESSURE TREATMENT GOALS There are currently no specific treatments goals for obese hypertensive patients. These goals probably should be similar to those recommended for other high-risk patients, including patients with diabetes (130/80 mm Hg).

WEIGHT REDUCTION: FACT OR FICTION? Reviews of randomized trials reported a diastolic reduction of 0.92 mm Hg and a systolic reduction of 1 mm Hg for each kilogram of weight loss.27 However, the effect of weight loss on blood pressure may be less consistent than previously believed.2 In short-term studies blood pressure decreased substantially with weight loss. Increased physical activity as well as a reduction of alcohol consumption and sodium uptake during weight loss programs may contribute considerably to blood pressure reduction. Overall, blood pressure reductions attributed to weight loss may be overly optimistic because they are based on short-term weight loss studies. Indeed, blood pressure changes may differ between periods with active weight loss, weight maintenance, and subsequent weight regain. Furthermore, individual blood pressure responses to weight loss are variable given that blood pressure may be fat-sensitive or fat-resistant. Individual blood pressure responses also depend on the actual blood pressure at baseline. Weight loss influences on blood pressure may be modified by a number of concurrent factors including energy balance, dietary composition, physical exercise, comorbidities, genetic profile, and concurrent pharmacologic treatments. Finally, in most obesity studies, blood pressure is not the primary outcome measure, and consequently may not have been measured properly.2

Aldosterone receptor

Figure 1. The renin angiotensin system can be inhibited at all relevant steps of the cascade. Renin inhibition, ACE inhibition, AT1receptor antagonism, and aldosterone antagonist can inhibit the RAS.

RAAS BLOCKADE Meanwhile, 4 different elements of the RAAS cascade have been established as therapeutic targets for the treatment of cardiovascular and renal diseases and hypertension (Fig. 1). Angiotensin-Converting Enzyme Inhibitors More than 110 years ago renin was discovered by Tigerstedt and Bergman and more than 70 years ago angiotensin was identified by Braun-Menendez and Page.28 Much insight has been gained from the synthesis of biologically active molecules that antagonize the biosynthesis and effect of angiotensin II. Angiotensin-converting enzyme (ACE) inhibitors block the catalytic activity of the angiotensin-converting enzyme and thereby inhibit conversion of angiotensin I to angiotensin II. ACE inhibitors reduce morbidity and mortality in patients with myocardial infarction and heart failure. In addition, they slow progression of renal disease in patients with chronic kidney disease.29,30 These data and the results of the HOPE study (Heart Outcomes Prevention Evaluation study) indicate that ACE inhibitors confer vascular and renal protection that are independent of their systemic

Arterial hypertension and obesity

antihypertensive action.31 ACE inhibitors do not promote metabolic abnormalities and may improve insulin sensitivity to reduce the risk of new-onset type 2 diabetes. Indeed, use of ACE inhibitors has been associated in several studies with a lower rate of newly diagnosed diabetes.32 However, the DREAM study (Diabetes Reduction Assessment With Ramipril And Rosiglitazone Medication) suggests that the reduction of diabetes risk with ACE inhibition may not be as pronounced as expected. However, the DREAM study did not target obese patients so this conclusion may not hold true for obese patients with hypertension.33 Moreover, use of full doses of these agents is suggested before a second agent of another class is added. The co-administration of a diuretic may be extremely valuable, especially in the patients who are more volume-dependent. In conclusion, ACE inhibitors currently are considered the most appropriate form of antihypertensive treatment for obese hypertensive patients.2,34,35 Angiotensin-Receptor Blockers Angiotensin-receptor blockers (ARBs) directly inhibit the binding of angiotensin II to the angiotensin II type 1 (AT1) receptor and provide a more specific blockade of the renin-angiotensin system than ACE inhibitors. The binding of angiotensin II to the AT2 receptor still remains intact. Their tolerability, particularly the absence of cough, makes them an alternative to ACE inhibitors.36 The most frequent indication for ARB use is for patients who have had side effects from ACE inhibitors. ARBs may share some of the beneficial properties of ACE inhibition. ARBs significantly reduce the progression of diabetic nephropathy in type 2 diabetes.37 Similar to ACE inhibitors, treatment with ARBs reduces the rate of newonset diabetes compared with other antihypertensive drugs.38 A relevant number of reports deal with the combined use of ACE inhibitors and ARBs39 and there is a certain rationale for the concomitant use of ACE inhibitors and ARBs with regard to an almost complete blockade of the renin angiotensin system.6 However, the ONTARGET (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) trial clearly showed that the dual RAS blockade (ramipril ⫹ telmisartan) is not significantly better than the respective monotherapies but clearly has more side effects.40 In addition, the ALTITUDE (Aliskiren Trial In Type 2 Diabetes Using Cardiovascular And Renal Disease Endpoints) study also did not reveal advantages by adding a renin inhibitor on top of an ACE inhibitor or an ARB in patients with diabetes (see later). Ongoing trials are examining whether double blockade of the RAS may have certain effects in patients with heart failure.41 In summary, ARBs provide an important and interesting alternative to the use of ACE inhibitors in hypertensive obese patients.36 Because ARB generics are available in many countries, more widespread use is anticipated.

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Renin Inhibition As mentioned earlier, angiotensin II is strongly implicated in the development of cardiovascular and renal disease as well as obesity hypertension. Therefore, inhibition of the renin angiotensin system is a highly successful pharmacologic strategy. However, compensatory increases in plasma renin levels in response to ACE inhibitors or ARBs may lead to adjustments in angiotensin II formation, and may limit the blockade of the renin angiotensin system.42 The concept of blocking the renin angiotensin system at its origin by inhibition of renin was proposed 30 years ago. However, the first generation of orally active renin inhibitors never entered the clinic because of their low bioavailability and weak blood pressure–lowering efficacy. An orally effective renin inhibitor, aliskiren, now is available to address angiotensin production directly at its rate-limiting step. Combination treatment with a renin inhibitor and a diuretic is an attractive approach for patients with an insufficient response to first-line diuretic treatment. The renin inhibitor blocks the effects of the counterregulatory increase in renin release from the kidney that occurs in response to sodium depletion and thereby enhances the blood pressure–lowering effects of diuretic treatment. A recent trial with aliskiren in obese patients with arterial hypertension was mentioned earlier. In addition, aliskiren penetrates adipose tissue.43 To verify the hypothesis that renin inhibition is a valuable contribution to available first-line antihypertensives, end point studies have been initiated. However, the value of renin inhibition on top of another RAS inhibitor recently was challenged by early termination of the ALTITUDE study. The ALTITUDE trial, in which aliskiren was given to high-risk patients with diabetes and renal impairment on top of ACE inhibition or AT1-receptor antagonism, was terminated prematurely because of increased morbidity and side effects, such as hyperkalemia, in the double-blockade group.41 In cases of volume depletion (ie, by diarrhea), complete and longlasting RAS blockade may aggravate acute renal failure. A similar observation was made by combining ramipril and telmisartan in the ONTARGET study.40 Therefore, the addition of aliskiren to an ACE inhibitor or ARB is no longer recommended in diabetic patients and may have no advantage in nondiabetic patients. Renin inhibition alone or in combination with a calcium channel blocker or diuretic shows excellent blood pressure reduction but whether it is superior to other RAS inhibitors remains to be proven. AT2-Receptor Antagonism Research about the angiotensin AT2 receptor has been hampered in the past by the lack of specific and selective agonists with in vivo stability. The situation fundamentally changed as the first nonpeptide AT2-receptor agonist, compound 21, was introduced in 2004.44 Now there is a nonpeptidic, orally active, specific, and selective AT2-receptor agonist available that not only serves as a

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new tool for AT2-receptor research, but that is being taken through a drug developmental program and expected to enter a clinical phase I study in 2012. AT2receptor stimulation has been studied with promising results in disease models of hypertension, renal disease, stroke, Alzheimer’s disease, myocardial infarction, and metabolic disease. Hence, AT2-receptor agonism could be an interesting tool in arterial hypertension and obesity.44 Diuretics As discussed earlier, sodium and volume retention play a central role in the development of obesity-related hypertension. Diuretics reduce blood pressure levels by decreasing intravascular volume and cardiac output and thus should be beneficial in obese patients. Therefore, diuretics should be considered in antihypertensive drug treatment of obese patients.6 Moreover, diuretics have been shown to decrease cardiovascular morbidity and mortality in patients with arterial hypertension.45 However, higher doses of diuretics may stimulate the renin angiotensin system, increase sympathetic nerve activity, and promote insulin resistance as well as dyslipidemia. Moreover, despite improved clinical outcomes, diureticbased antihypertensive therapy is associated with an increase in new-onset diabetes. It has been proposed that the duration of clinical trials, such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), has been too short to detect the adverse effects of diuretic-induced diabetes and its complications. During a mean follow-up period of 14 years for patients enrolled in the systolic hypertension in the elderly program, patients given chlorthalidone who developed new-onset diabetes had no increase in cardiovascular or total mortality rates, whereas there was an increased morbidity and mortality in those who developed diabetes while on placebo. The systolic hypertension in the elderly program data may reflect a more benign course of diabetes induced by a diuretic than for diabetes that develops spontaneously.46 This was confirmed by recent data from the Valsartan Antihypertensive LongTerm Use Evaluation trial showing that patients who develop diabetes during antihypertensive treatment have a cardiac morbidity rate between diabetic subjects and those who never had diabetes.47 It should be noted that thiazides are more potent to lower blood pressure than loop diuretics in hypertensive patients and should be preferred. Loop diuretics are indicated if the diuretic response to thiazides is inadequate and in patients with heart failure or decreased renal function. The usual starting dose of diuretics, such as chlorthalidone or hydrochlorothiazide, should be titrated around 12.5 or 25 mg, respectively. Controversy exists regarding the choice of the thiazide diuretic. In contrast to chlorthalidone, typically applied doses of hydrochlorothiazide (12.5 or 25 mg) have never been shown to reduce hard cardiovascular end points.2

U.O. Wenzel, R. Benndorf, and S. Lange

In the case of high sodium consumption, blood pressure reduction by blockade of the renin angiotensin system alone is often not very satisfying. Therefore, lowdose diuretics are excellent in combination with ACE inhibitors and ARBs. As we learned from clinical practice, it is almost impossible to control blood pressure in obese patients without the use of diuretics.35 Taken together, in the management of obese hypertensive patients, diuretics most frequently are needed to control blood pressure. They also play a central role as a combination partner of other first-line agents in the treatment of obese hypertensive patients.34 Aldosterone Antagonists There is accumulating evidence of the role of aldosterone excess in the pathogenesis of obesity hypertension.9 Spironolactone and eplerenone are steroid analogues with structural similarity to aldosterone and thereby function as competitive antagonists.9 Compared with spironolactone, eplerenone is equally potent but more specific for the mineralocorticoid receptor by virtue of a 9,11-epoxy moiety that decreases its binding to androgen and progesterone receptors. Several trials have shown that spironolactone and eplerenone reduce blood pressure effectively. Recent clinical studies have indicated that aldosterone antagonists provide especially significant additional blood pressure reduction when added to treatment regimens of patients with therapy-resistant hypertension.48 This does not mean that aldosterone antagonists are first-line antihypertensive drugs. However, they may be useful add-on antihypertensive drugs producing a fairly predictable additional pressure-lowering effect in all patients. An issue left largely unresolved by the studies in patients with arterial hypertension is whether the benefit of spironolactone is mediated via its diuretic effect or via its ability to modify the non–volume-mediated effects of aldosterone.9,48 Therefore, it is very interesting to compare spironolactone with the potassiumsparing diuretic amiloride or triamterene. Amiloride and triamterene indirectly inhibit the effect of aldosterone on basolateral Na-K-adenosine triphosphatase by blocking luminal epithelial sodium channels in the distal collecting duct. The epithelial sodium channel is up-regulated by aldosterone, such that amiloride and triamterene function as indirect aldosterone antagonists. If actions outside the epithelial sodium channel activity were provoked by aldosterone, then one would predict that the aldosteronereceptor blockers would be more widely effective than amiloride or triamterene. However, use of amiloride mimics quite successfully the effects of spironolactone in patients with resistant hypertension, raising doubts that, at least in therapy-resistant hypertension, the beneficial effects of spironolactone are caused by nondiuretic effects.49 In addition, after intake of the potassium-sparing diuretic triamterene, this rather short-acting agent and its 2 main metabolites are excreted in the urine and can be detected easily by fluorescence. Thus, intake of tri-

Arterial hypertension and obesity

Figure 2. Spot urine sample under ultraviolet light. Left side: control patient; right side: patient taking 50 mg triamterene. Adapted with permission from Wenzel 2012.

amterene can be monitored effectively by a fluorescence signal because the urine glows under ultraviolet light as described by us and shown in Fig. 2. Treatment with triamterene allows the physician to monitor compliance and adherence.50 A recent prospective study performed in patients with resistant hypertension who had an average body mass index of 30 kg/m2 and waist circumference of 100 cm showed that waist circumference was an independent predictor of systolic blood pressure response to spironolactone.51 Based on this study and the knowledge that plasma aldosterone levels are increased in obesity, more liberal use of aldosterone antagonists in obesity-related hypertension has been advocated.14

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cause weight reduction is an important aspect of hypertension management, it may be hampered by the use of a ␤-blocker.36 Indeed, in the recent Hypertension-ObesitySibutramine Study, the sibutramine-induced weight loss was significantly less in metoprolol/hydrochlorothiazidetreated patients (-4 kg) than in felodipine/ramipril- (-7 kg) or verapamil/trandolapril-treated individuals (-6 kg).52 In addition, ␤-blockers may disturb carbohydrate and lipid metabolism, leading to impaired glucose tolerance as well as increased lipid levels. ␤-blockers with vasodilating properties, such as carvedilol, may be less likely to worsen glucose metabolism.2 The first choice role of ␤-blockers in the treatment of arterial hypertension has been challenged. Meta-analysis data showed that in comparison with other antihypertensive drugs, the effect of ␤-blockers is less than optimal, with an increased risk of stroke. Hence, ␤-blockers are no longer the first choice in the treatment of arterial hypertension.53 Indeed, the recent guideline of the British National Institute for Health and Clinical Excellence no longer recommends ␤-blockers for treatment steps 1, 2, or 3 in newly diagnosed arterial hypertension. ␤-blockers should be given when they are specifically indicated (ie, in obese patients with atrial fibrillation, ischemic heart disease, or heart failure). However, without these specific indications other antihypertensive drugs should be taken first to lower blood pressure in obese patients.34 Calcium Channel Blockers Calcium channel blockers are very efficacious in lowering blood pressure. Calcium channel blockers lower blood pressure through a decrease in peripheral vascular

␤-Blockers ␤-blockers may decrease blood pressure more effectively in obese rather than in lean hypertensive patients, perhaps because they decrease cardiac output and plasma renin activity, both of which are increased in obese patients.1 The effects of ␤-blockers are controversial. ␤-blockers have been used widely in the treatment of hypertension but are no longer recommended as first-line drugs in most hypertension guidelines.10 ␤-blockers have been shown to decrease cardiovascular morbidity and mortality in patients with arterial hypertension. Increased sympathetic activity may play an important role in obesity hypertension because ␤-blockers are more effective in lowering blood pressure in obese than in lean hypertensive subjects. ␤-blocker therapy is associated with weight gain in the first month.36 This may be caused by changes in energy metabolism. ␤-blocker treatment reduces energy expenditure by 4% to 9%.36 Obese patients with hypertension are advised to exercise regularly for weight loss. However, at the same time, ␤-blockers may negatively influence exercise capacity. This has to be considered before prescribing these drugs to obese patients.34 Be-

Figure 3. Shown is the renal ablation catheter in the renal artery after application of heat. A small notch is visible below the tip, showing a temporary reaction of the vessel wall. Reprinted with permission from the Department of Radiology, UKE, Hamburg, Germany.

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U.O. Wenzel, R. Benndorf, and S. Lange

resistance. Dihydropyridine calcium channel blockers also promote natriuresis and therefore may work well in obese patients. Calcium channel blockers do not have adverse metabolic effects, making them suitable for obese hypertensive patients. Nevertheless, smaller studies have shown that calcium channel blockers may be less effective in obese individuals.54 This may be caused by the fact that peripheral resistance often is reduced in these patients. A trial with verapamil showed that this drug is effective in reducing blood pressure and heart rate in obese hypertensive patients.55 The precise role of calcium channel blockers is still rather controversial with respect to hypertension, especially in patients with cardiac complications. But this controversy probably has been overstated similar to the earlier-mentioned discussion about the first choice use of ␤-blockers in the management of uncomplicated hypertension.6 The AngloScandinavian Cardiac Outcomes Trial compared the effect of combinations of ␤-blocker with a thiazide versus long-acting calcium channel blockers with an ACE inhibitor on cardiovascular events. The calcium antagonist-based regimen lowered blood pressure slightly better and prevented more major cardiovascular events and induced fewer cases of diabetes than the ␤-blocker– based regimen.56 The observation that obese patients are more likely to experience peripheral edema with dihydropyridine calcium antagonist treatment compared with lean patients is a potential limitation.2 However, calcium

channel blockers, especially in combination with, for example, ACE inhibitors or an ARB, are useful antihypertensive drugs for obese hypertensive patients.

␣-Blockers ␣-blockers have been associated with improved insulin sensitivity and lipid metabolism. Positive effects on insulin sensitivity also have been reported in obesity hypertension.57 In addition, ␣-blockers are used to treat benign prostatic hyperplasia. Noradrenaline acts on ␣1adrenoceptors to contract the smooth muscle in the prostate and bladder and by opposing these actions, ␣-blockers are beneficial in prostatic hypertrophy. The ALLHAT trial has severely challenged the use of ␣-blockers for initial therapy in hypertension. Patients treated with doxazosine had a 25% increase in risk of cardiovascular disease events in the ALLHAT trial, especially congestive heart failure, compared with patients treated with the thiazide diuretic chlorthalidone.58 This study very nicely underlined that it is difficult to rely on studies that show substantial advantages of ␣-blockers on surrogate parameters such as insulin sensitivity or lipid levels. Particular care also must be exercised in patients with postural hypotension and frequent falls. Therefore, ␣-blockers are not first-line antihypertensive drugs.10 However, they may be useful in combination with other antihypertensive drugs or in patients with benign prostatic hyperplasia.

Table 1. Summary of First Choice Use of Antihypertensive Drug Classes in Obesity Hypertension Antihypertensive Drug Class

ACE inhibitors

ARBs Renin inhibition Diuretics

Aldosterone antagonists ␤-blockers

Advantage

Improve insulin sensitivity Decrease rate of new-onset diabetes mellitus Vascular and renal protection Similar to ACE inhibitors Good tolerability Similar to ACE inhibitors Sodium and volume retention are pathogenic in obesity hypertension Good in combination with other classes Not expensive Aldosterone excess is pathogenetic in obesity hypertension Beneficial for patients with coronary heart disease, atrial fibrillation, and heart failure Not expensive

Calcium antagonists

Metabolic neutral Good combination with ACE inhibitor

␣-blockers

Improve insulin sensitivity, improve lipid metabolism, and beneficial in patients with benign prostatic hyperplasia

Disadvantage

Recommendation

Cough

First choice

Expensive but generics are available

Alternative to ACE inhibitor or first choice Unclear at the present time First choice (especially in combination with ACE inhibitors)

Expensive, end point studies ongoing Decrease insulin sensitivity Disturb lipid metabolism

Hyperkalemia gynecomastia Weight gain Decrease insulin sensitivity Disturb lipid metabolism Discussion about first-choice treatment of hypertension ongoing Dihydropyridines are less efficient in obesity hypertension Increases risk of congestive heart failure

Good addition to other antihypertensive drugs Not first choice but should be given when specifically indicated

Not first choice but good in combination with ACE inhibitors Not first choice anymore but is acceptable in combination therapy or in patients with prostatic hypertrophy

Arterial hypertension and obesity

Renal Nerve Ablation Catheter-based renal denervation is a new approach for the treatment of resistant hypertension that was developed in 2008 (Fig. 3). Clinical studies have shown that it decreases blood pressure in the short and midterm and has a good tolerability profile. However, the blood pressure response after this intervention has been evaluated only in a small number of highly selected patients in open-label studies. Catheter-based renal denervation opens new interesting therapeutic perspectives. Moreover, renal denervation also improves glucose metabolism, insulin sensitivity,59 and sleep apnea severity.60 This novel procedure therefore may provide protection in patients with obesity hypertension. However, at this stage of development, the technique still should be evaluated carefully and widespread clinical use cannot be recommended thus far.61

SUMMARY Diuretics and ␤-blockers are reported to reduce insulin sensitivity and increase lipid levels, whereas calcium antagonists are metabolically neutral and ACE inhibitors as well as ARBs and renin inhibition increase insulin sensitivity. Sodium and volume retention play a central role in the development of obesity-related hypertension. A summary of first-choice treatment of obese hypertensive patients is shown in Table 1. Treatment with an ACE inhibitor or a diuretic should be considered as first-line antihypertensive drug therapy in obese patients. In most cases, combination therapy of a RAS inhibitor with lowdose diuretics may be the first choice to lower blood pressure. If such a treatment does not lower blood pressure sufficiently, the addition or substitution of a calcium antagonist, an ␣- or ␤-blocker, or an aldosterone antagonist may be considered. Clearly, additional studies are needed to determine the long-term efficacy of antihypertensive drugs in obesity hypertension.

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