The prevalence of obesity has increased dramatically over the past two decades.1 This epidemic has already shown its impact through the increasing prevalence of type 2 diabetes in adolescents. We can also anticipate a major epidemic of diabetes in adults and more hypertension and heart disease unless the tide is turned. Preventive strategies are the first line of defence, but when these fail, treatment is the primary option. At present only two drugs are approved for long-term use in the treatment of obesity, and both have troublesome side effects. The two papers2,3 in this issue of the Journal of Human Hypertension focus on the effect of the anti-obesity drug sibutramine on the blood pressure of hypertensive patients treated for their hypertension.
A positive relationship of blood pressure and overweight has been demonstrated in most studies.4,5 Moreover, weight loss induced by non-pharmacologic means reduces blood pressure6,7,8 and this reduction is maintained while the blood pressure remains down.9 However, a note of caution was recently raised by the Swedish Obese Subjects study where weight loss of 20% from baseline was induced by gastric surgical operations. Although body weight and blood pressure initially fell as expected, by the fourth year of post-operative follow-up blood pressure had returned to control levels, even though body weight remained reduced from baseline.10
The observation that sibutramine, a drug that blocks the reuptake of noradrenaline and serotonin and to a lesser degree dopamine, raises blood pressure has been troubling.11,12,13 We can get some insight into this problem and its importance from the two papers published in this issue of the Journal of Human Hypertension,2,3 and another published elsewhere14 that used sibutramine to treat the obesity in patients whose blood pressure was controlled with calcium channel blockers, with beta-blockers, or with angiotensin-converting enzyme inhibitors. A rise in heart rate is characteristic of patients treated with sibutramine and might be a response to the sympathomimetic properties of this drug. The fact this rise was not attenuated by the beta-blockers, however, suggests that a 'sympathomimetic' mechanism may not be the explanation for the rise in heart rate. The other possible, and untested, hypothesis would be that sibutramine had lowered vagal activity to the heart leading to the rise in heart rate.
The failure of blood pressure to fall with weight loss in normotensive and hypertensive patients treated with sibutramine differs from the decline seen with orlistat15,16,17,18 or weight loss induced by lifestyle6,7,8 (Table 1). In the 18 months trial with sibutramine the 4.5% weight loss in the placebo-treated patients was associated with a 1.6 mm Hg decrease in diastolic blood pressure in contrast to the 2.3 mm Hg increase in the sibutramine-treated patients, even though they lost more weight (10.0%). From epidemiological studies Stamler et al19 have estimated that for each 3 mm change in diastolic blood pressure there is a 4-8% reduction in cardiovascular mortality. In the case with sibutramine, the potentially detrimental effect due to the failure of blood pressure to fall with weight loss that might occur with continued use of sibutramine may be offset by the reduction in lipids, insulin, and uric acid that do occur with weight loss.11,12,13 There are at least two strategies that might reduce the potential concerns about the rise in blood pressure during treatment with sibutramine. The first would be to use sibutramine intermittently. In a 9-month trial Munro et al20 compared continuous vs alternating monthly use of phentermine and found that the weight loss of both groups was the same. If this applied to sibutramine, then the exposure to drug would only be half as much and might have less effect on blood pressure. A second strategy would be to identify those patients who respond to sibutramine with weight loss, but who have minimal change in blood pressure. This too could serve to reduce the concerns about using a drug that otherwise has a good safety record and is effective in maintaining weight reductions for 12 to 18 months.12,21
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-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial. J Hum Hypertens 2002; 16: 13-19.