Obesity and Hypertension: A Common Coexistence

In review of the US population for 2007 to 2008, the incidence of being overweight (body mass index [BMI] ≥25–29.99 kg/m²) was 68% and obese (BMI ≥30 kg/m²) 33%. ¹ Depending on what definition is being used, the metabolic syndrome occurred in 33% to 38%. Obesity in the United States was found to be responsible for one third of the shortfall of the longevity relative to other countries with longer life expectancy. ²

Hypertension was present in about 72 million American adults in the period of 1999 to 2004, or about one third of the adults 18 years and older. ³ The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) defines hypertension as a seated blood pressure (BP) of equal to or more than 140/90 mm Hg. Overweight and obesity is present in more than 70% of US adults with hypertension. ⁴

A weight gain of 10 pounds is associated with an average 4.5‐mm Hg increase in systolic BP. ⁵ The mechanism responsible for the development of hypertension in obesity is still not fully elucidated, but 3 major contributing factors have been identified: (1) activation of the sympathetic nervous system, (2) an overactive renin‐angiotensin‐aldosterone system, and (3) increased renal sodium reabsorption leading to volume expansion.

Obesity can be considered a secondary cause of hypertension. Obesity‐hypertension typically is associated with a higher cardiac output and lower systemic vascular resistance compared with essential hypertension. Additionally, in both hypertension and obesity, bioavailability of nitric oxide is reduced and endothelial dysfunction is present.

JNC 7, the International Society on Hypertension in Blacks, the American Society of Hypertension, American Heart Association, American Diabetes Association, and other committees and associations have issued guidelines and goals for the treatment of hypertension in special populations, including African Americans and the elderly and those with chronic kidney disease, diabetes, and coronary artery disease. Despite the high prevalence of obesity‐hypertension, no treatment guidelines for this population exist.

A likely reason for the missing guidelines are the lack of outcome data and long‐term trials in obesity‐hypertension. Completed hypertensive trials have been few and typically of short duration, mostly ending at 12 weeks. Studied antihypertensive drugs in these trials compared lisinopril vs hydrochlorothiazide (the Trial of Preventing Hypertension [TROPHY]), valsartan vs atenolol, candesartan vs hydrochlorothiazide (Candesartan Role on Obesity and on Sympathetic System [CROSS]), and aliskiren vs irbesartan and amlodipine in patients with uncontrolled BP while taking hydrochlorothiazide. These trials showed a similar mean reduction of BP regardless of what drugs were studied. Traditional β‐blockers, despite reducing activity of the sympathetic nervous system and renin‐angiotensin‐aldosterone system (RAAS), have undesirable metabolic consequences, including weight gain, new‐onset diabetes, and worsening lipid parameters; therefore, most have been avoided.

On the contrary, specific trials evaluating vasodilating β‐blockers in obese‐hypertensive patients that studied nebivolol ⁶ or carvedilol ⁷ showed a neutral effect on lipid and carbohydrate metabolism, similar BP reduction in the extended carvedilol vs metoprolol trial, and no difference in BP response in obese vs nonobese hypertensive patients with nebivolol.

Weight reduction in obesity‐hypertension has been shown to be a major benefit in lowering hypertension whether achieved by diets (ie, the Dietary Approaches to Stop Hypertension [DASH] diet), exercise, ⁸ bariatric surgery, or antiobesity medication. The US Food and Drug Administration has approved only 2 anti‐obesity drugs: orlistat, which has been shown to reduce weight by 2.5 kg in 52 weeks in a meta‐analysis of 29 trials, ⁹ and sibutramine, which may increase heart rate as well as worsen hypertension in some patients, rendering it a less desirable choice in obesity‐hypertension.

Because weight reduction is difficult to achieve, as evidenced by the dramatic rise in BMI in the United States over the past 5 decades, ¹⁰ antihypertensive therapy is needed to control hypertension for most of our patients. Moreover, hypertension is more difficult to treat in obese patients and frequently requires combination therapy.

What then is the combination therapy of choice? The study by Kelly and associates in this issue of the Journal is both timely and thought‐provoking in combining a vasodilating β‐blocker with an angiotensin‐converting enzyme inhibitor or hydrochlorothiazide. In a double‐blind crossover trial of 25 centrally obese hypertensive patients with a baseline systolic BP of 138±13 mm Hg and diastolic 85±11 mm Hg, treatment periods of 3 months of lisinopril/carvedilol were followed by a 1‐month washout and 3 months of lisinopril/hydrochlorothiazide. Evaluated were markers of oxidative stress (oxidized low‐density lipoprotein, 8‐isoprostone, and asymmetric dimethylarginine) and endothelial function using a reactive hyperemic index. There was no statistical difference in systolic BP response to either combination. The lisinopril/carvedilol combination, however, improved endothelial function to a greater extent than the lisinopril/hydrochlorothiazide combination. There was no difference in levels of oxidative stress between the two regimens.

While this study was small and of relatively short duration, it nevertheless raises several questions: Does the observed difference in improved endothelial function translate into clinically relevant improvements of cardiovascular outcome in addition to what can be expected from reaching BP goals? Also, would a study of higher baseline BPs, ie, stage II hypertension, show even greater differences in endothelial function between the two studied combination therapies?

A long hypertension trial, using vasodilating β‐blockers and RAAS blockades, is needed to answer these questions and could lead to the first such combination therapy in a single pill.