Journal of Human Hypertension (2002) 16, 13–19  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by ␤- adrenergic blocking agents: a placebo- controlled, double-blind, randomised trial

JJ Sramek1, MT Leibowitz1, SP Weinstein2, ED Rowe2, CM Mendel2, B Levy3, FG McMahon4, WS Mullican5, PD Toth6 and NR Cutler1 1California Clinical Trials, Beverly Hills, CA, USA; 2Knoll Pharmaceutical Company, Abbott Laboratories, Abbott Park, IL, USA; 3National Medical Research Corporation, Hartford, CT, USA; 4Clinical Research Center, New Orleans, LA, USA; 5Medisphere Medical Research Center, Evansville, IN, USA; 6Midwest Institute for Clinical Research, Indianapolis, IN, USA

Sibutramine is a serotonin-noradrenaline reuptake statistically significantly different between the sibutra- inhibitor that is effective for long-term weight reduction mine group and the placebo group at any post-baseline and maintenance in obese patients when used as an visit during the 12-week trial. At week 12, mean adjunct to dietary and behavioural measures. Because increases from baseline supine SBP and DBP, respect- the inhibition of noradrenaline reuptake may be ively, were 1.6 and 1.7 mm Hg for the sibutramine group expected to increase systolic and diastolic blood pres- vs increases of 0.4 and 1.3 mm Hg for the placebo sure (SBP and DBP) and pulse rate (PR), a 12-week group. At week 12, mean increases from baseline stand- multi-centre, placebo-controlled, double-blind study ing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg was designed to evaluate the efficacy and tolerability of for the sibutramine group vs an increase of 0.3 and a sibutramine for weight loss in obese patients whose decrease of 0.8 mm Hg for the placebo group (P Ͼ 0.05 hypertension was well controlled (DBP р95 mm Hg) by for treatment comparison). A statistically significant adrenergic blocking agents (␤-blockers), with or with- mean increase of 5.6 bpm (؎8.25, s.d.) in supine PR-␤ out concomitant thiazide diuretics. Of the 61 patients from a baseline of 62 bpm was reported in sibutramine- randomised to sibutramine 20 mg once daily or placebo, treated patients at week 12, whereas placebo-treated 55 patients (90%) completed the study. After 12 weeks, patients had a mean supine PR decrease of 2.2 bpm sibutramine-treated patients lost significantly more (؎6.43) (P Ͻ 0.001). In summary, sibutramine was well weight than placebo-treated patients: mean weight tolerated and effective in weight reduction. The addition reductions were 4.2 kg (4.5%) in the sibutramine group of sibutramine did not result in an increase in BP in vs 0.3 kg (0.4%) in the placebo group (P Ͻ0.001). Greater obese patients whose hypertension was well controlled weight reduction on sibutramine was accompanied by by a ␤-blocker. However, based on the potential for trends for greater mean reductions in serum triglycer- changes in BP and PR, obese patients being treated ides and very low density lipoprotein cholesterol. Sibu- with sibutramine should be monitored periodically for tramine was well tolerated, and most adverse events changes in BP and PR and managed appropriately. were mild or moderate in severity. No sibutramine Journal of Human Hypertension (2002) 16, 13–19. DOI: patient discontinued treatment because of an adverse 10.1038/sj/jhh/1001299 event. Mean supine and standing DBP and SBP were not

Keywords: sibutramine; weight loss; controlled hypertension; pulse rate

Introduction tion has been shown to have a favourable impact on 1–3 Obesity is an important risk factor for developing the risk of hypertension and its management. Sibutramine (sibutramine hydrochloride mono- hypertension and is a confounding factor in the   effective treatment of hypertension. Weight reduc- hydrate; Meridia , Reductil ) taken orally once daily enhances satiety and produces significant, dose-related weight reduction in obese patients Correspondence: Dr NR Cutler, California Clinical Trials, 8501 when used as an adjunct to dietary and behavioural Wilshire Blvd. 2nd Floor, Beverly Hills, CA 90211, USA 4–6 Ȱ measures. At doses of 5 to 20 mg once daily, sibu- E-mail: ncutler cctrials.com tramine is safe and well tolerated, and weight Sibutramine in obese patients with hypertension JJ Sramek et al 14 reduction is maintained while treatment continues.7 five clinical research centres. The Institutional The current recommended dosage of sibutramine is Review Board at each centre approved the protocol, 10 or 15 mg once daily. and all patients gave oral and written informed con- Sibutramine is a tertiary amine that undergoes sent prior to participation. demethylation in the liver, generating two active At the initial screening visit, a physical exami- metabolites with potent inhibitory activity on sero- nation was conducted, height and weight measured, tonin and noradrenaline reuptake.8,9 Its mechanism body mass index (BMI) calculated, a 12-lead electro- as a serotonin-noradrenaline reuptake inhibitor is cardiogram (ECG) recorded, supine and standing BP distinct from the mechanisms of fenfluramine, and PR measured, and blood and urine samples col- dexfenfluramine, and the amphetamines. Sibutra- lected for routine laboratory evaluations. Qualifying mine and its metabolites do not stimulate neuronal patients entered a single-blind, 2-week minimum monoamine release, lack the abuse potential associa- run-in period, during which placebo medication ted with amphetamines,8,10,11 and have not been was dispensed to the patients, who were instructed associated with the cardiovascular pathologies to take one capsule each morning. Run-in visits were which have been seen with fenfluramine.12,13 Both separated by a minimum of 7 days. Enrolment was preclinical and clinical studies strongly suggest that limited to patients whose hypertension was well dopamine is not a target for sibutramine at pharma- controlled. Eligible patients were randomised into cologically relevant concentrations.8,10,11,14 the 12-week, double-blind phase of the study. Consistent with its enhancement of noradrenergic Patients randomised to sibutramine were titrated activity relative to placebo, normotensive obese from 5 to 20 mg once daily in 5-mg increments per patients on sibutramine treatment have experienced week. Patients were given a standardised pro- small mean increases in systolic blood pressure gramme of dietary advice with exercise and behav- (SBP) and diastolic blood pressure (DBP). Increases ioural recommendations. of 1 to 3 mm Hg and increases in pulse rate (PR) of At each run-in visit, the baseline randomisation 4 to 5 beats per minute (bpm) at doses up to 20 mg visit, and weeks 1, 2, 3, 4, 8, and 12, BP and PR were have been reported.8 In a dose-ranging study, at a measured, adverse events and concomitant medi- sibutramine treatment dose of 15 mg, the current cations were documented, and weight (except at the maximum recommended dose, changes in BP (+2.7 run-in visits) was measured. At the baseline visit, a mm Hg, SBP; +3.4 mm Hg, DBP) were not statisti- 12-lead ECG was recorded. At week 12, or at the cally significantly different from BP changes time of premature termination of treatment, a physi- observed with placebo treatment.5 In recent, large, cal examination was performed, a 12-lead ECG was placebo-controlled trials with sibutramine, how- recorded, and samples were collected for laboratory ever, the numbers of patients in whom an increase evaluations. Haematology, serum chemistry (in- in BP became clinically significant, or in whom cluding lipid profile), and urinalysis were performed mild hypertension appeared, leading to withdrawal at screening and week 12. Serum pregnancy tests from treatment, were generally not significantly dif- were performed at screening, baseline, and week 12, ferent between sibutramine- and placebo-treated when appropriate. patients.6,7,15–17 Supine and then standing BP and PR were meas- The objective of this study was to evaluate the ured after 5 min supine and 1 min standing, respect- efficacy of sibutramine on weight loss, BP, and PR ively. At all visits, measurements of supine and in hypertensive obese patients whose BP was well standing BP and PR were taken, from which average controlled by stable doses of a ␤-adrenergic blocking values were calculated. BP was measured after PR. agent (␤-blocker). This study was part of a series of If a patient developed a mean increase in supine PR three studies evaluating the efficacy and tolerability Ͼ20 bpm over the baseline mean PR, or if PR was of sibutramine in patients with hypertension well Ͼ105 bpm at any visit during the study, the protocol controlled with angiotensin-converting enzyme in- mandated that the patient be discontinued from hibitors, calcium channel blockers, or ␤-blockers. the study. Based on results available at the time of design of Safety and adverse events were monitored at each the studies, a dose of 20 mg was selected for evalu- visit or as reported. Adverse events were recorded ation, which is higher than the maximum 15 mg according to the COSTART classification system.18 dose currently recommended. A study design flowchart is shown in Figure 1.

Materials and methods Patients у Study design Male and female hypertensive patients 18 years of age with a BMI from 27 to 40 kg/m2 were eligible to This was a 12-week, double-blind, placebo-con- participate in this study. Patients had to have been trolled, parallel-group, randomised study in obese diagnosed with hypertension у12 months before the patients whose hypertension was well controlled screening visit, and they must have had a mean DBP with a ␤-blocker, with or without concomitant thia- р95 mm Hg that was well controlled. Patients were zide diuretic therapy. The study was carried out at defined as having well-controlled DBP if their mean

Journal of Human Hypertension Sibutramine in obese patients with hypertension JJ Sramek et al 15

Figure 1 Study design flowchart. supine DBP did not fluctuate у10 mm Hg over three procedure. The Wilcoxon test for two samples was consecutive visits of the run-in period, if individual used for comparison of changes in lipid profile. measurements within each visit during the run-in Analysis of categoric data was done using the period stayed within a 10-mm Hg range, and if they Cochran-Mantel-Haenszel test. Discontinued pa- had no dosage changes in either the ␤-blocker or thi- tients were included in most analyses until the time azide diuretic during the run-in period. Patients of their withdrawal. Unless noted otherwise, con- could also be taking a fixed maintenance dose of a tinuous variables are presented as mean (± stan- potassium-sparing diuretic, potassium supplements, dard deviation). or lipid-lowering agents along with the ␤-blocker. Patients were excluded from the study if their hypertension was secondary to a concurrent medical Results condition (other than obesity) or drug therapy. Patient demographics and disposition Patients with a mean supine PR Ͼ95 bpm at baseline or a mean supine DBP Ͼ95 mm Hg at any run-in A total of 61 eligible patients were randomised into visit were also excluded. A history of convulsions, the study, 29 to sibutramine and 32 to placebo. Fifty- severe cerebral trauma, stroke, significant endocrine five patients (90%) completed the 12-week study. abnormalities, a significant history of cardiac dis- Hypertension in all randomised patients was well р ␤ ease, or any clinically significant abnormal cardiac controlled (DBP 95 mm Hg) with a -blocker. ␤ condition other than hypertension was also cause Atenolol was the -blocker most frequently used, for exclusion. In addition, patients with clinically being taken by 59% of the sibutramine group and significant laboratory abnormalities or a history of 63% of the placebo group. In addition, 62% of the gastric surgery to reduce obesity were excluded, as sibutramine-treated patients and 69% of placebo- were those who had participated in a weight loss treated patients were also receiving thiazide programme within 3 months prior to the screening diuretics. Baseline and demographic characteristics visit. of randomised patients, including supine DBP and SBP and PR, are shown in Table 1. No statistically significant differences were found between the sibu- Statistical analyses tramine and placebo treatment groups at baseline. The study was powered to determine a difference of 3 kg in weight loss between treatment groups. Based Weight loss efficacy on previous studies, this would require a sample size of 30 patients per treatment group. Statistical After 12 weeks of treatment, body weight in patients tests were two-tailed at the P Ͻ 0.05 level of signifi- treated with sibutramine had decreased by a mean cance. Inferential analyses on continuous variables of 4.2 kg (±3.8), or 4.5% (±4.0), compared to 0.3 kg were done using a two-way analysis of variance pro- (±2.0), or 0.4% (±2.0), for placebo-treated patients cedure. Repeated measure analysis was not used, (P Ͻ 0.001 for both total weight lost and percentage and the treatment groups were compared at each of body weight lost, all randomised patients). At the scheduled visit. The normality of residuals was follow-up visit 10–14 days after treatment was assessed using the Shapiro-Wilk procedure, and stopped, patients in the sibutramine treatment group homogeneity of variance was tested using Levene’s had maintained a weight reduction of −3.5 kg (±4.25)

Journal of Human Hypertension Sibutramine in obese patients with hypertension JJ Sramek et al 16 Table 1 Baseline and demographic characteristics of random- seen with placebo from weeks 2–12 (P р 0.002, all a ised patients randomised patients). Greater weight loss over 12 weeks in patients on Characteristic Sibutramine Placebo (n = 29) (n = 32) sibutramine treatment was generally accompanied by greater mean changes in lipid profile, including Age (yr) mean ± s.d. 51.9 ± 9.9 53.4 ± 9.2 greater reductions in serum triglycerides and very (range) (29–68) (31–69) low density lipoprotein (VLDL) cholesterol levels Gender, female/male (%) 79.3/20.7 65.6/34.4 and greater increases in high-density lipoprotein Race, Caucasian/black (%) 75.9/24.1 81.3/18.8 (HDL) cholesterol levels. However the trends favour- Weight (kg) 94.2 ± 14.3 95.9 ± 15.4 BMI (kg/m2) 33.5 ± 3.4 34.3 ± 3.8 ing sibutramine treatment did not reach statistical significance in this modestly sized trial. Supine SBP (mm Hg) 130.8 ± 9.7 132.7 ± 14.7 Supine DBP (mm Hg) 82.7 ± 6.4 82.0 ± 6.7 Supine PR (bpm) 62.2 ± 7.2 63.9 ± 7.1 Increases and decreases in BP and heart rate

a No statistically significant differences in supine or No significant differences between groups. standing DBP or SBP were found between the sibu- tramine and placebo groups at any post-baseline compared to maintenance of −0.5 kg (±2.23) for pla- visit during the 12-week double-blind trial. Mean cebo treatment (P Ͻ 0.01). Patients in the sibutra- changes in supine DBP during the 12-week double- mine treatment group also experienced a greater blind treatment period ranged from a decease of 1.2 mean percentage weight reduction from baseline to an increase of 1.7 mm Hg for the sibutramine than the placebo treatment group at all time points. group and from a decrease of 1.1 to an increase of The difference between the treatment groups was 1.3 mm Hg for the placebo group. Mean changes in statistically significant from week 2 (P Ͻ 0.01) to postural DBP ranged from a decrease of 0.4 to an week 12 (P р 0.001) and at the follow-up visit, when increase of 1.8 mm Hg for the sibutramine group and patients were no longer on treatment for obesity (P from a decrease of 1.3 to an increase of 1.4 mm Hg Ͻ 0.01). The mean percentage decreases in weight for the placebo group (P Ͼ 0.05). Mean changes in from baseline during the course of the study are supine SBP ranged from a decrease of 2.3 to an shown in Figure 2. increase of 1.6 mm Hg for sibutramine-treated Patients in the sibutramine treatment group also patients (95% CI, −2.99, 6.19) and from a decrease of had a greater mean decrease in BMI at all time 3.1 to an increase of 0.6 mm Hg for placebo-treated points from week 2 (P р 0.002) compared to pla- patients (95% CI, −3.59, 4.39; P Ͼ 0.05). Mean cebo. At week 12, patients in the sibutramine treat- changes in standing SBP ranged from a decrease of ment group had a mean reduction in BMI of 1.1 to an increase of 2.3 mm Hg for the sibutramine 1.5 kg/m2 (±1.3) compared to a mean reduction of group and from a decrease of 0.2 to an increase of 0.1 (±0.7) for placebo (P Ͻ 0.001, all randomised 3.3 mm Hg for the placebo group. At week 12, mean patients). The sibutramine treatment group had increases from baseline supine SBP and DBP, greater mean decreases in BMI at all time points, and respectively, were 1.6 and 1.7 mm Hg for the sibutra- these decreases were significantly greater than those mine group vs 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P Ͼ 0.05 for treatment comparison). None of the above treatment comparisons for supine BP were statistically significant (P Ͼ 0.05). Mean supine PR for the sibutramine and placebo treatment groups at baseline was 62.2 and 63.9 bpm, respectively, indicating that patients were on aver- age treated adequately with ␤-blockers. Mean increases and decreases from baseline supine PR during the study are shown in Figure 3. The data presented in Figure 3 possibly suggest an upward trend for heart rate over time among patients treated with sibutramine. Statistically significant differ- ences in mean supine PR for sibutramine-treated Figure 2 Mean percent change from baseline weight during treat- patients compared to placebo-treated patients were ment with sibutramine (circles) or placebo (squares). The statisti- found at weeks 4, 8, 12, and at the follow-up visit cal significance of the treatment-group difference is indicated р above each time point. Error bars indicate standard error of the (P 0.022). Mean PR at week 12 were sibutramine mean. NS, not statistically significantly different, placebo treat- treatment, 67.1 bpm and placebo treatment, ment vs sibutramine treatment. 61.5 bpm (difference, 5.6 bpm; P Ͻ 0.01 sibutramine

Journal of Human Hypertension Sibutramine in obese patients with hypertension JJ Sramek et al 17 Table 2 Adverse events occurring with a frequency of у10% in either treatment group*

Adverse event Sibutramine Placebo (n = 29) (n = 32) n(%) n(%)

Dry mouth 11 (37.9) 0 (0) Headache 10 (34.5) 6 (18.8) Infection 6 (20.7) 1 (3.1) Dyspepsia 5 (17.2) 2 (6.3) Constipation 4 (13.8) 2 (6.3) Back pain 4 (13.8) 2 (6.3) Pain 3 (10.3) 7 (21.9) Insomnia 3 (10.3) 3 (9.4) Asthenia 3 (10.3) 1 (3.1) Diarrhoea 1 (3.4) 4 (12.5)

*Difference in frequency of occurrences of adverse events were Figure 3 Mean change from baseline supine PR during treatment not statistically significant. with sibutramine (circles) or placebo (squares). The statistical sig- nificance of the treatment-group difference is indicated above each time point. Error bars indicate standard error of the mean. different from the rate in the placebo treatment NS, not statistically significantly different, placebo treatment vs sibutramine treatment. group. Most adverse events reported were mild to moderate in intensity. Clinical laboratory evalu- ations did not reveal any changes indicative of a del- compared with placebo). One patient in the sibutra- eterious treatment effect. mine treatment group had a PR increase Ͼ20 bpm No patients in the sibutramine group discon- to 74 bpm from baseline (52 bpm) at week 4. This tinued treatment because of adverse events. Three patient was allowed to remain in the study, as no patients receiving placebo treatment (9%) were dis- deleterious effects were noted, and subsequent PR continued from the study because of adverse events changes in this patient were Ͻ20 bpm throughout (diarrhoea, pancreatitis, and pharyngitis). the remainder of the study. No statistically signifi- cant increases or decreases in mean postural PR Discussion were found in either treatment group during the study. In the present 12-week study, sibutramine was Mean heart rates calculated from ECG readings found to be an effective weight loss agent, with sta- were consistent with the findings of treatment- tistically significant reductions observed within 2 related increases in PR. At week 12, the changes in weeks of treatment initiation in absolute weight, ECG heart rate for individual patients in each treat- percent reduction from baseline weight, and BMI ment group ranged from a decrease of 8.0 to an compared to placebo. At week 12, a mean 4.5% increase of 25.0 bpm for the sibutramine treatment reduction from baseline weight was observed in group and ranged from a decrease of 18.0 to an patients treated with sibutramine 20 mg once daily increase 15.0 bpm for the placebo treatment group. compared to a 0.4% reduction for placebo treatment No possibly clinically significant abnormal values (P р 0.001, all randomised patients). In a previous for heart rate (р50 bpm with a у15 bpm decrease 24-week dose-ranging study in normotensive obese from baseline or у120 bpm with a у15 bpm patients, weight loss at week 12 in patients on sibu- increase from baseline) occurred. No conduction tramine 20 mg once daily was 5.7% of body weight.7 abnormalities were observed on ECG readings dur- These losses are comparable to those observed with ing the study. the treatment duration in the present study, indicat- ing that the concomitant use of ␤-blockers does not appear to diminish the efficacy of the compound. Safety Sibutramine, a monoamine neurotransmitter Sibutramine was safe and well tolerated during the reuptake inhibitor, inhibits food intake by promot- 12-week trial. Adverse events occurring in у10% of ing satiety via the synergistic interaction of patients in at least one treatment group are shown increased serotonergic and noradrenergic activity in in Table 2. Overall, adverse events were reported by the central nervous system.8,14 Additionally, sibutra- 93% (27/29) of the patients receiving sibutramine mine has been shown to increase energy utili- and 87.5% (28/32) of those receiving placebo, the sation.19,20 The increased energy utilisation activity difference between the groups not being statistically of sibutramine may be indirectly generated by cen- significant. The most common adverse events tral stimulation of efferent sympathetic output to the ␤ 20,21 reported by patients in the sibutramine treatment 3-adrenoceptors in brown adipose tissue. group were dry mouth and headache, but the rate Increase in energy expenditure with sibutramine of their reporting was not statistically significantly treatment has been reported in two studies19,20

Journal of Human Hypertension Sibutramine in obese patients with hypertension JJ Sramek et al 18 although not in one other.22 This possible dual sympathetic activity induced by sibutramine could mechanism of action may enhance the efficacy of possibly counteract the normal BP-lowering effect of sibutramine by diminishing the decrease in meta- weight loss. On the other hand, the small increases bolic rate normally encountered upon initial weight in BP and PR may be offset by reductions in other loss. Because the cardiovascular side effects of sibu- risk factors achieved by more efficient weight loss tramine can be attributed, in part, to stimulation of with sibutramine, such as improvement in lipid pro- the sympathetic nervous system, blocking of the car- files seen in this and other studies.4–6,15 Neverthe- ␤ ␤ diac 1-adrenoceptors with -blockers can be less, because BP and PR changes may occur as a expected to reduce the magnitude of these effects. result of the pharmacologic activity of sibutramine, Most patients in this study were taking atenolol, a these parameters should be periodically monitored ␤ ␤ -blocker with specificity for 1-adrenoceptors. during treatment. Sibutramine is not recommended Although this compound penetrates the central ner- for use in patients with uncontrolled or poorly con- vous system poorly and thus would not be expected trolled hypertension, nor in patients with a history to counteract the central adrenergic effects of sibu- of serious cardiovascular disease (coronary artery ␤ tramine, 1-adrenoceptor blockade in the periphery disease, cardiac arrhythmia, congestive heart failure, might reduce sympathetic cardiovascular effects or stroke).26 Rates of reported adverse events in this while not disrupting any potential, beneficial, poss- study were not statistically different for the sibutra- ␤ ibly 3-receptor-mediated peripheral effects of sibu- mine treatment group compared to the placebo treat- tramine. Some evidence exists that nonselective ␤- ment group. adrenoceptor blockade during treatment for hyper- In summary, this study indicates that sibutramine tension can result in decreased energy utilisation is an effective, well-tolerated weight management and weight gain,23,24 which could complicate the agent in obese patients and does not exacerbate pre- interpretation of the results of this study. While this existing hypertension controlled with ␤-blockers. study did not specifically compare patients treated Although the effects of sibutramine on decreasing with ␤-blockers to those not so treated, this study BP may not be entirely commensurate with the shows that sibutramine produces significant weight extent of the weight loss achieved, obesity itself has loss in overweight patients taking ␤-blockers, a recently been recognised as a major, independent, mainstay of treatment for hypertension. It is interest- modifiable risk factor for coronary heart disease,27 ing to note that atenolol effectively prevented the and weight loss and the maintenance of weight are modest increase in BP that can be seen with the use clearly superior when adjunctive sibutramine ther- of sibutramine, but atenolol did not appear to pre- apy is used.6–8,15–17,28 In the present study, improve- vent the increase in PR. The reason for the differing ments associated with weight loss resulting from effects is not known. A recently published report25 sibutramine use included greater improvement in assessing the effect of sibutramine on sympathetic BMI, greater reduction in serum triglyceride and and parasympathetic activity showed the expected VLDL cholesterol, and increase in HDL cholesterol. increase in sympathetic activity. It did not show a Greater improvements in lipids paralleled greater diminution in parasympathetic control. weight loss, as reported previously.4–6,15 Despite the In the present study, although the 20-mg dose of presence of apparently effective ␤-adrenoceptor sibutramine was greater than the 15-mg maximum blockade, modest increases in PR were observed in daily dose currently recommended for clinical use, sibutramine-treated obese hypertensive patients in the increases in BP observed in these obese hyper- the present study, perhaps suggesting that mech- tensive patients taking ␤-blockers were not statisti- anisms other than increased sympathetic tone may, cally significant. The PR increases, however, were at least in part, mediate this effect. Based on the significant. At week 12, the mean increase in PR potential for increases in BP and PR, obese patients over the baseline value of 62 bpm was 5.6 bpm, a with well-controlled hypertension who are treated statistically significantly greater increase than that for weight loss with sibutramine should be moni- seen in the placebo group (P Ͻ 0.01). These results tored periodically for possible BP and PR effects. differ from those observed in a previous study, a 52- week placebo-controlled trial of sibutramine given at a 10-mg dose,6 in which the increases in PR in Acknowledgements normotensive individuals treated with sibutramine The authors wish to thank Wanda J Krall, PhD, for were generally not significantly different from the assistance in writing this manuscript. This study PR changes seen in the placebo group. However, was supported by Abbott Laboratories, Abbott Park, another study of sibutramine given at the 20-mg IL, USA. once daily for 24 weeks15 reported statistically sig- nificant increases in DBP (5.0 mm Hg) and PR (7.0 bpm) compared with placebo (P Ͻ 0.05). References The present study shows that hypertension con- 1 Joint National Committee on Prevention, Detection, trolled through ␤-adrenoceptor blockade in obese Evaluation and Treatment of High Blood Pressure. The individuals remains well controlled when weight is sixth report of the Joint National Committee on Pre- lost with sibutramine treatment. The increase in vention, Detection, Evaluation, and Treatment of High

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