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Therapeutics in hypertension: Treatment of Obesity-Hypertension

Efrain Reisin, M.D.
Professor of Medicine
Chief, Section of Nephrology
Louisiana State University, School of Medicine
New Orleans, Louisiana, USA

Several cross-sectional and longitudinal epidemiological studies have found that obesity—specifically central adiposity—is a strong determinant of hypertension. In fact, up to 30% of hypertension cases can be attributed to obesity. Numerous studies have demonstrated a dramatic drop in blood pressure with weight loss. Knowledge of the important differences in the metabolic, endocrinologic, and hemodynamic mechanisms of obesity and the related morphological changes that occur in obesity-hypertension is essential to understanding the positive effects of weight loss and to determining the best approach to the treatment of hypertension in obese individuals.

Mechanisms of Obesity-Induced Hypertension

Some studies consider insulin resistance and hyperinsulinemia to be the initial triggers in obesity-hypertension. Others, however, do cast some doubt on a clearly established cause-and-effect relationship between hyperinsulinemia and chronic hypertension. Chronic overeating may induce adrenergic stimulation via increased insulin concentration, which increases the reactivity of tissues to catecholamines. The increased sympathetic activity may raise the aldosterone-to-plasma renin activity ratio, a change that may trigger sodium and water retention in obese-hypertensive patients, with consequent hypervolemia and increased cardiac output. Additionally, decreased Na+, K+ AT-PASE activity in obese- hypertensive patients may decrease calcium efflux, which may enhance smooth muscle tone and vascular resistance (Figure1).

Fig. 1

Cardiac and Renal Morphological Changes

Obesity-hypertension will induce both eccentric and concentric left ventricular hypertrophy (Figure 2), changes that may increase the risk for congestive heart failure. Hemodynamic changes described in obesity hypertension include increased renal flow and increased glomerular filtration rate with a high filtered sodium load. These renal hemodynamic changes will cause glomerular hyperfiltration and proteinuria. In obese experimental animals, renal morphological changes induced by the previously described hemodynamic changes are increased glomerular volume and changes in the renal medulla with increased intra-renal pressure.

Fig. 2

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Effects of Weight Reduction

Multiple large cooperative studies have shown the positive effects of weight reduction on the management of hypertension. Moderate weight loss (10 Kg) in obese-hypertensive patients improved insulin sensitivity as a result of an increase in the number of insulin-binding receptors in the target cells. Weight reduction also has been shown to drop levels of plasma norepinephrine, plasma renin activity, and aldosterone. Additionally, recent investigations show a decrease in free cytolytic platelet calcium levels with a consequent decrease in forearm resistance and a subsequent increase in blood flow. Hemodynamic studies performed after weight loss (10 Kg) have shown a reduction in oxygen consumption, cardiac output, and left ventricular stroke, without changes in peripheral resistance. Weight loss may also decrease intra-ventricular, septal, and posterior wall thickness and left ventricular mass in humans (Figure 3); in experimental animals, it may decrease proteinuria, glomerular volume, and glomerular and interstitial damage.

Fig.3

Pharmacological Interventions

In obese-hypertensive patients who are unable to lose weight or in those with initial moderate or severe hypertension, a pharmacological approach that meets the specific requirements of this complex pathological condition is recommended (Figure 4)

Fig.4

Diuretics

A large prospective double-blind placebo-controlled cooperative study comparing hydroclorothiazide (HCTZ) with lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, in obese-hypertensive subjects demonstrated that HCTZ effectively lowered systolic and diastolic blood pressure (Figure 5), but 46% of these patients required the highest dosage (50 mg/day) to achieve effective blood pressure control. HCTZ was more effective in African-American subjects than in Caucasian subjects. Treatment increased plasma glucose and reduced plasma potassium, suggesting that long-term therapy with HCTZ may generate undesirable side effects.

Fig.5

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Centrally Acting Agents

A small prospective double-blind study comparing the effect of clonidine, a centrally acting alpha-adrenergic stimulator, with that of chlorthalidone, a diuretic, demonstrated that the latter was more effective than clonidine in the control of blood pressure in obese-hypertensive subjects.

Adrenergic Blocking Agents

Three different studies of adrenergic blocking agents yielded conflicting results, but metoprolol up to 100 mg/day and atenolol have shown beneficial effects on blood pressure in obese-hypertensive subjects. Adrenergic blocking agents, however, may reduce glucose tolerance and worsen insulin resistance.

Alpha-Adrenergic Receptor Blockers

An early study in a small number of obese-hypertensive subjects showed that prazosin significantly decreased blood pressure, increased insulin-mediated glucose disposal, and decreased insulin response to an intravenous glucose load. However, studies of large numbers of obese-hypertensive patients treated with alpha-adrenergic receptor blockers are lacking.

Calcium Antagonists

A large study of the calcium antagonist nifedipine showed equal efficacy in lean, overweight, and obese-hypertensive patients (Figure 6).

Fig. 6

Angiotensin-Converting Enzyme (ACE) Inhibitors

A large prospective cooperative study mentioned above showed that compared with HCTZ, the ACE inhibitor lisinopril significantly lowered systolic and diastolic blood pressure in obese-hypertensive subjects. Treatment with lisinopril was more effective in Caucasians than in African-Americans, and had similar effects in young and elderly subjects and in "dipper" and "non-dipper" individuals (Figure 7).

Fig. 7

Conclusion

Moderate weight reduction of 10 Kg in obese-hypertensive individuals is an effective and well-tolerated treatment for reducing blood pressure. When a pharmacological approach is necessary, ACE inhibitors, calcium antagonists, and perhaps adrenergic receptor blocking agents, may have safe and efficient antihypertensive effects.

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