Therapeutic Considerations in the Treatment of Obesity Hypertension

Marion R. Wofford, MD, MPH; Margaret Miller Davis, MD; Kimberly G. Harkins, MD; Deborah S. King, PharmD; Sharon B. Wyatt, PhD, RN, CS; Daniel W. Jones, MD

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Pharmacologic Interventions

In general, hypertension in obese patients is more difficult to control and is less responsive to various antihypertensive medications. Even when lifestyle modifications alone are not adequate in controlling or preventing hypertension, their adoption may reduce the number and dosage of antihypertensive medications needed for management. Many patients will need pharmacologic intervention in conjunction with weight loss and other lifestyle modifications. The various mechanisms leading to hypertension and the metabolic abnormalities that characterize the obese patient should be taken into account when selecting antihypertensive agents in the overweight patient.

The JNC VI guidelines[28] make no specific recommendations for treatment of patients with obesity hypertension. As with all patients, evaluation and therapeutic decisions should be based on identification of known causes of high blood pressure, assessment of the presence or absence of target organ damage and CVD, extent of the disease, response to therapy, and identification of other cardiovascular risk factors or concomitant disorders that may define prognosis and guide treatment. There have been few clinical trials designed to determine the best antihypertensive agents for treatment of obesity hypertension.

Diuretics should also be considered, given the association between obesity hypertension and impaired natriuresis.[28] One clinical trial was designed to compare the blood pressure-lowering effect of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, to the diuretic hydrochlorothiazide in obese, hypertensive patients. Both agents were equally effective in lowering blood pressure; however, the response varied with age and race. Hydrochlorothiazide was most effective in African Americans of all ages, while the ACE inhibitor was more effective in young and Caucasian subjects.[44]

Sympathetic nervous system hyperactivity, insulin resistance, and hyperinsulinemia are common metabolic abnormalities in the obese, hypertensive patient. When pharmacologic treatment is required, a case can be made for drugs that lower blood pressure as well as improve insulin sensitivity and other risk factors for coronary heart disease. ACE inhibitors, calcium channel blockers, and -adrenergic blockers may offer potential benefits in the obese hypertensive because of their benefits or lack of adverse effects on insulin sensitivity and sympathetic activity.[28]

Beta blockers may adversely affect the metabolic profile of obese, hypertensive patients by altering the lipid profile and by increasing insulin levels. Furthermore, the use of blockers may impede weight reduction. In the United Kingdom Prospective Diabetes Study (UKPDS),[45] diabetic hypertensive subjects treated with blockers, as compared to those on ACE inhibitors, gained more weight, although they had equally good CVD outcomes. Strong clinical trial evidence supporting the use of these agents in obesity hypertension is not available. In general, a diuretic should probably be included in a treatment regimen if other medications are used.

The potential benefits and side effects of antihypertensive drugs in obesity hypertension are summarized in Table II .

With the increasing incidence of obesity and the recognition of this condition as a chronic disease that responds poorly to dietary and behavioral modification alone, there is continuing pressure from the American public, the pharmaceutical industry, and the medical community to develop antiobesity drugs. In 1996, for the first time in 20 years, the FDA approved the use of an antiobesity drug, dexfenfluramine. Like fenfluramine (marketed since 1973), the agent produced significant weight reduction in overweight subjects, but weight was regained with medication cessation. Dexfenfluramine sales increased dramatically in the year it was marketed, although long-term clinical trials were not available at the time of its approval. In 1997, despite widespread use, dexfenfluramine and fenfluramine were withdrawn from the market when the potentially fatal complications of primary pulmonary hypertension and valvular heart disease were associated with them.[46]

Currently there are two FDA-approved antiobesity agents marketed for long-term use. The NHLBI guidelines recommend (after a 6-month trial of lifestyle modification) that overweight individuals with a BMI of >27 and "concomitant obesity-related risk factors or diseases" or obese persons with a BMI of >30 and no concomitant disease be considered candidates for weight-loss intervention strategies, including pharmacologic treatment.[7] This NHLBI recommendation has far-reaching implications, considering the complexity of weight loss interventions and the prevalence of obesity hypertension in the industrialized world.

Sibutramine hydrochloride monohydrate, a serotonin, dopamine, and norepinephrine reuptake inhibitor, was approved for use in 1997. Clinical trials extending up to 1 year have shown weight reduction to be significant in comparison to placebo. Additional benefits include improved waist-to-hip ratio and lipid profiles.[47] These outcomes may make sibutramine attractive as adjunctive therapy in weight reduction programs and clinics in which a combination of fenfluramine/phentermine was previously used. However, early studies suggest caution in hypertensive patients.

Sibutramine has been associated with increased blood pressure and tachycardia[48] and is, therefore, not recommended by the NHLBI guidelines for use in the hypertensive, obese patient. The FDA states that sibutramine "...substantially increases blood pressure in some patients." A dose-dependent rise in both systolic and diastolic blood pressure and heart rate has been seen, yet the FDA recommends that sibutramine be "given with caution" in hypertensive patients. However, restrictions are placed on the use of sibutramine in patients with known CVD.[49] Thus far, there are no published clinical trials on sibutramine use extending beyond 12 months, and the long-term effects on morbidity and mortality have not been established. Until safety in hypertensive patients has been demonstrated in long-term trials, caution should be exercised with the use of this agent.

Orlistat, a second antiobesity agent, has recently been approved for weight loss. Orlistat inhibits pancreatic lipase, resulting in decreased fat absorption.[50] Although a 10% weight reduction is achieved at 1 year by approximately 20% of orlistat users, careful patient counseling is required to avoid undesirable gastrointestinal effects. As with other approved antiobesity agents, the long-term effects of orlistat on morbidity and mortality are not known. Studies have demonstrated favorable effects on lipids as well as glucose and insulin levels,[51] and reduction of blood pressure in uncontrolled hypertensives on antihypertensive drugs.[52]

The currently approved antiobesity agents have been shown to aid in weight reduction in the short term, but weight regain usually follows discontinuation. Given the magnitude of this public health problem, it is evident that clinical trials to determine long-term risks and benefits of antiobesity pharmacotherapy are critical.


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