Sibutramine and Blood Pressure: a Therapeutic Dilemma

GA Bray Pennington Biomedical Research Center Baton Rouge, LA 70808, USA

Journal of Human Hypertension (2002) 16, 1–3. DOI: 10.1038/sj/jhh/1001297

Keywords: sibutramine; blood pressure

The prevalence of obesity has increased dramati- where14 that used sibutramine to treat the obesity in cally over the past two decades.1 This epidemic has patients whose blood pressure was controlled with already shown its impact through the increasing calcium channel blockers, with beta-blockers, or prevalence of type 2 diabetes in adolescents. We can with angiotensin-converting enzyme inhibitors. A also anticipate a major epidemic of diabetes in rise in heart rate is characteristic of patients treated adults and more hypertension and heart disease with sibutramine and might be a response to the unless the tide is turned. Preventive strategies are sympathomimetic properties of this drug. The fact the ﬁrst line of defence, but when these fail, treat- this rise was not attenuated by the beta-blockers, ment is the primary option. At present only two however, suggests that a ‘sympathomimetic’ mech- drugs are approved for long-term use in the treat- anism may not be the explanation for the rise in ment of obesity, and both have troublesome side heart rate. The other possible, and untested, hypoth- effects. The two papers2,3 in this issue of the Journal esis would be that sibutramine had lowered vagal of Human Hypertension focus on the effect of the activity to the heart leading to the rise in heart rate. anti-obesity drug sibutramine on the blood pressure The failure of blood pressure to fall with weight of hypertensive patients treated for their hyperten- loss in normotensive and hypertensive patients sion. treated with sibutramine differs from the decline A positive relationship of blood pressure and seen with orlistat15–18 or weight loss induced by life- overweight has been demonstrated in most stud- style6–8 (Table 1). In the 18 months trial with sibutra- ies.4,5 Moreover, weight loss induced by non-pharm- mine the 4.5% weight loss in the placebo-treated acologic means reduces blood pressure6–8 and this patients was associated with a 1.6 mm Hg decrease reduction is maintained while the blood pressure in diastolic blood pressure in contrast to the 2.3 remains down.9 However, a note of caution was mm Hg increase in the sibutramine-treated patients, recently raised by the Swedish Obese Subjects study even though they lost more weight (10.0%). From where weight loss of 20% from baseline was epidemiological studies Stamler et al19 have esti- induced by gastric surgical operations. Although mated that for each 3 mm change in diastolic blood body weight and blood pressure initially fell as pressure there is a 4–8% reduction in cardiovascu- expected, by the fourth year of post-operative lar mortality. In the case with sibutramine, the follow-up blood pressure had returned to control potentially detrimental effect due to the failure of levels, even though body weight remained reduced blood pressure to fall with weight loss that might 10 from baseline. occur with continued use of sibutramine may be off- The observation that sibutramine, a drug that set by the reduction in lipids, insulin, and uric acid blocks the reuptake of noradrenaline and serotonin that do occur with weight loss.11–13 There are at least and to a lesser degree dopamine, raises blood press- two strategies that might reduce the potential con- 11–13 ure has been troubling. We can get some insight cerns about the rise in blood pressure during treat- into this problem and its importance from the two ment with sibutramine. The ﬁrst would be to use papers published in this issue of the Journal of sibutramine intermittently. In a 9-month trial Munro 2,3 Human Hypertension, and another published else- et al20 compared continuous vs alternating monthly use of phentermine and found that the weight loss Correspondence: GA Bray, MD Pennington Biomedical Research of both groups was the same. If this applied to sibu- Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA. tramine, then the exposure to drug would only be E-mail: BrayGAȰpbrc.edu half as much and might have less effect on blood Sibutramine and blood pressure GA Bray 2 Table 1 Changes in weight and blood pressure during weight loss with diet, sibutramine and orlistat

Clinical trial Duration Drug or diet Placebo or control months ⌬wt (%) ⌬DBP (mm Hg) ⌬Wt (%) ⌬DBP (mm Hg)

Hypertensive patients Sibutramine (Ca Channel 12 −4.7 +2.0 −0.7 −1.3 Blockers)14 Sibutramine (ACE inhibitors)3 12 −4.8 +3.0 −0.3 −0.1 Sibutramine (␤-Blockers)2 3 −4.5 +1.7 −0.4 +1.3 HPT7 12 −4.7 −4.3 +0.4 −3.1 TOHP8,9 12 −3.6 −5.8 +0.4 −3.8

Normotensive patients Sibutramine11 6 −5.8 +3.4 −0.9 +1.7 Sibutramine12 6 −8.7 +0.8 −4.2 −1.1 Orlistat15 12 −10.2 −2.1 −6.1 +0.2 Orlistat16 12 −9.7 −0.9 −6.6 −1.3 Orlistat17 12 −8.8 −1.0 −5.8 +1.3 Orlistat18 12 −7.9 −1.0 −4.2 +2.0

For the sibutramine hypertensive studies: In reference 13 data obtained from Tables 2 and 4 using intent-to-treat analysis; In reference 3 data were obtained from 3 and 4 using intent-to-treat analysis; In reference 2 data were obtained from the results section; For sibutramine normotensive studies: data in reference 11 are for 15 mg dose; For reference 12 weight loss was intention-to-treat (LOCF) from Table 3 and diastolic blood pressure was changed from day 0 to day 180 in Table 4; For the Orlistat studies (references 15–18), data are intention-to-treat with the 120 mg three times a day dose; diastolic blood pressure is week 52 minus day 1; HPT, Hypertension Preven- tion Trial (reference 7) weight extrapolated from data in Figure 2 at 12 months and divided by baseline weight, DBP from Figure 3 at the 12 month point; TOPH, Trials of Hypertension Prevention (references 8,9) weight extrapolated from data from Figure 1 at 12 months (reference 9) and divided by baseline weight in Table 1 (reference 8), DBP from Table 2 (reference 8) at the 12-month point.

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