How to treat hypertension in the obese

Background

Large scale epidemiological studies have shown that hypertension is two to three times more present in the obese than in lean individuals. Moreover, blood pressure values and body weight are directly related at any age of life.
These findings denote a close association between obesity and hypertension (1-2).
More specifically, obese individuals with central (or visceral) fat dominant distribution tend to have higher hypertension than those with non-central fat dominant distribution (2).
Additionally, obesity appears to be an important cause of difficult-to-treat hypertension and of treatment-resistant or refractory arterial hypertension (1,3).

1 - Obesity as a cause of treatment-resistant or difficult-to-control hypertension

Resistant hypertension is a clinical state in which a therapeutic plan that has included 1) Attention to lifestyle measures and 2) Prescription of at least three drugs in adequate doses including a diuretic have failed to lower systolic and diastolic blood pressure at goal (1). 
It is associated with a variety of conditions: 1) Obstructive sleep apnea, cigarette smoking and most importantly 2)The obese state, probably as a result of the peculiar pathophysiological background of obesity-related hypertension (2). 
Obesity-related hypertension often is accompanied by: 1) Blood volume overload 2) Rennin-angiotensin stimulation with inappropriately high circulating plasma levels of aldosterone 3) Insulin resistant state 4) Stimulation of the sympathetic nervous system and 5) Obstructive sleep apnea syndrome (further complicating the obese state).

2 - Therapeutic interventions

Obesity

• Can raise blood pressure and may add metabolic and cardiovascular risk.

Therefore, a cardiovascular and metabolic risk assessment - through evaluation of blood pressure, body weight, body fat and body mass index - revealing both obesity and hypertension must give way to a carefully considered treatment strategy in order to attain adapted, optimal risk reduction.
Weight loss may improve hypertension-associated target organ damage independently from blood pressure - for example, weight loss reduces urinary albumin excretion and may favor regression of left ventricular hypertrophy. Interventions based on weight loss should be primary treatment (4-5). 
The ESH/ESC guidelines 2013 recommend that weight reduction or weight stabilisation should be instituted in overweight patients. Evidence that weight reduction may have a beneficial effect on overall risk and that weight reduction may lower blood pressure are the rationale for this recommendation. Adequate behavioral and expert support are needed to ensure a patient's weight reduction, the guidelines go on to state, however the latest guidelines still do not provide details as to what patients should do to lose weight. 

3 - Treatment of hypertension

What is recommended in the guidelines, is that a flexible approach taking into consideration 1) associated risk factors, such as presence of the metabolic syndrome, as well as 2) target organ damage or 3) cardiovascular disease is recommended.
While many obese hypertensive patients ultimately require antihypertensive medication, here are their needs more specifically addressed. Our current understanding of the mechanisms involved in obesity-associated arterial hypertension are that obesity-associated arterial hypertension comes with volume expansion and increased neurohumoral activation. As such:

• Diuretics, renin-angiotensin system inhibitors, and betablockers: are reasonable first choices – if you factor in the metabolic side effects.
• Inhibitors of the renin-angiotensin-system: are first-line antihypertensives for most patients. Because of their broad spectrum of beneficial effects, angiotensin-converting enzyme inhibitors are currently the most appropriate drug for these patients (1-2,6). 
• Angiotensin receptor blockers can be used in patients who do not tolerate angiotensin-converting enzyme inhibition. Clearly, renin-angiotensin system blockade in patients with obesity-related hypertension is unlikely to worsen glucose or lipid metabolism (1-2,6).
• Beta-blockers: reduce cardiac output and renin activity, both of which are frequently increased in obese patients. Beta-blockers alone, or in combination with alpha-adrenoreceptor blockers, were more effective in decreasing blood pressure in obese than in lean hypertensive individuals (1-2,6). 

Limitations for the use of beta-blockers, however, especially in young obese hypertensive patients without cardiac and renal complications, are their potential negative effects on glucose metabolism and body weight. 

• Diuretic agents: could be used with respect to the well described hypervolemia and sodium retention in obesity (1-2,6). 
• Thiazide diuretics: combination of low-dose thiazide diuretics with renin–angiotensin system blockers may reduce hyperkalemia risk while improving blood pressure control. Consideration should be given to the impairment of insulin sensitivity and deterioration of glucose metabolism that could be caused by high dose thiazide diuretics. Overall, thiazide diuretics may not be the first choice for most obese hypertensive patients (1,6). However, in patients not responding to monotherapy, thiazide diuretics are a reasonable second or third antihypertensive drug. 
• Dihydropyridine calcium channel blockers: dihydropyridine calcium channel blockers are effective in lowering blood pressure.The observation that obese patients are more likely to experience peripheral edema with dihydropyridine calcium channel blocker treatment compared with lean patients is a potential limitations.

4 - Treatment of resistant hypertension

Data on how to treat obese patients with resistant arterial hypertension are scarce. 

• Special role of aldosterone in obesity associated hypertension

Spironolactone: A recent study suggests that, adding the mineralocorticoid antagonist spironolactone may be useful in these patients (7). In another study, true resistant hypertension patients diagnosed by ambulatory blood pressure monitoring, were treated with spironolactone treatment in doses of 25–100 mg/day. A second ambulatory blood pressure monitoring performed after a median interval of 7 months showed a 16/9 mmHg reduction in blood pressure. Remarkably, higher waist circumference was associated with better response to spironolactone. These findings point to the special role of aldosterone in obesity associated hypertension. 

• Direct renin inhibition effective alternative treatment approach in obese hypertensive patients 

Direct renin inhibition: It may be an effective alternative treatment approach in obese hypertensive patients. However, this medication should be used with caution, particularly in combination with other renin-angiotensin system inhibitors or renal disease (8).

• Devices for treatment of resistant arterial hypertension have recently undergone clinical testing (3-9).

Many of the patients included in these trials were overweight or obese. Renal sympathetic denervation through a novel catheter based approach substantially reduced clinic blood pressure in patients with treatment-resistant arterial hypertension with an overweight or an obese state (3-9). 
Ambulatory blood pressure values appear to be also reduced by the intervention, although the magnitude of the blood pressure lowering effects appear to be less pronounced compared to effects on clinic blood pressure (3-9). The response may be mediated in part through ablation of renal afferent nerves decreasing centrally generated sympathetic activity. 

• Baroreflex activation therapy: It reduces blood pressure through sympathetic inhibition and evidence exists indicating that the approach may improve blood pressure control in resistant hypertension and in obesity related high blood pressure. (3-9). 

This treatment requires surgical implantation of an electrical stimulatory device and electrodes located at the level of the carotid sinus. Although promising, renal sympathetic denervation through a novel catheter based approach and electrical stiumation of carotid baroreceptor approaches need in to be tested in large scale clinical trials a near future.

Conclusions

The data discussed in this brief review article addresses the difficulties in achieving blood pressure control in treated obese hypertensive patients. They also underline the need for using combination drug treatment in these patients, along with non pharmacological interventions aimed at reducing body weight.
Combination drug treatment based on ace-inhibitors or angiotensin II receptor blockers, anti-aldosterone drugs as well as calcium channel blockers appears mandatory in the obese hypertensive patient, before considering renal denervation or carotid baroreceptor stimulation. 
Appealing, but still requiring further evaluation, are the initial results obtained with interventions aimed at reducing symapthetic overdrive, such as renal nerve radiofrequency ablation and carotid baroreceptor stimulation.