Christian Torp-Pedersen; Ian Caterson; Walmir Coutinho; Nick Finer; Luc Van Gaal; Aldo Maggioni; Arya Sharma; Wygenia Brisco; Roger Deaton; Gillian Shepherd; Philip James

Eur Heart J.  2007;28(23):2915-2923.  ©2007 Oxford University Press

Abstract and Introduction

Abstract

Aims: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial is a randomized, double-blind comparison of sibutramine vs. placebo, in addition to standard care for weight management, in overweight/obese subjects with an increased risk of cardiovascular disease. The study had an initial single-blind, 6-week lead-in period with sibutramine plus weight management. We report the cardiovascular responses and weight loss during this period.
Methods and results: A total of 10 742 subjects received treatment in the lead-in period; 97% had cardiovascular disease, 88% hypertension and 84% type 2 diabetes. Body weight decreased (median 2.2 kg [5th, 95th percentile changes –6.2, 0.5]); waist circumference was reduced by 2.0 cm (men: –8.5, 2.9; women: –9.0, 3.0), systolic blood pressure fell by 3.0 mmHg (–23.5, 12.5) and diastolic by 1.0 mmHg (–13.5, 10.0). Pulse rate increased by 1.5 b.p.m. (–11.0, 13.5). All changes were statistically significant (P < 0.001). Two consecutive increases in blood pressure or pulse rate of >10 mmHg/b.p.m. were observed in 4.7 and 3.5% of subjects, respectively. Fifteen subjects (0.1%) died; 10 deaths were attributed to a cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure, respectively.
Conclusion: Six-week treatment with sibutramine appears to be efficacious, tolerable and safe in this high-risk population for whom sibutramine is usually contraindicated.

Introduction

Obesity is an increasing health problem associated with cardiovascular disorders and premature mortality.^[1,2] International guidelines recommend weight loss as the first step in managing cardiovascular risk,^[3] but the value of weight loss in patients with established cardiovascular disease is controversial as judged from epidemiological data.^[4,5]

Most patients have difficulty losing weight and maintaining weight loss by diet and exercise alone.^[6] Pharmacotherapy is an accepted adjunct to traditional weight-loss approaches.^[2] Sibutramine is a serotonin and norepinephrine reuptake inhibitor approved for the management of obesity. It acts centrally to reduce energy intake by promoting early satiety after eating and limiting the fall in energy expenditure during weight loss.^[7] In randomized trials, adding sibutramine to diet and lifestyle advice doubles weight loss and increases three- to four-fold the number of subjects who achieve 5–10% weight loss compared with placebo plus the same diet and exercise advice.^[8,9] Sibutramine has also been shown to increase pulse rate by 3 to 7 b.p.m. and to produce small changes in blood pressure.^[10]

The Sibutramine Cardiovascular OUTcomes (SCOUT) trial is a double-blind, randomized, placebo-controlled, parallel-group study of cardiovascular outcomes in overweight or obese subjects at increased risk of a cardiovascular event. The primary hypothesis is that weight management with sibutramine together with standard care for weight management will reduce cardiovascular morbidity and mortality in high-risk subjects to a greater extent than standard care alone. The study was designed with a 6-week lead-in period during which all subjects would receive single-blind sibutramine to identify those potentially at risk of blood pressure or pulse rate increases. This report describes the cardiovascular responses and main outcomes to sibutramine plus standard care for weight management among subjects during this lead-in period.

Methods

Preliminary details of the rationale for and design of the SCOUT trial have been published previously.^[11] Figure 1 summarizes the trial design. Subjects eligible for enrolment into SCOUT included men and women aged 55 years and older with a body mass index (BMI) ≥27 kg/m² and ≤45 kg/m², or a BMI ≥25 kg/m² and <27 kg/m² with a waist circumference ≥102 cm (men) or ≥88 cm (women). Subjects were also required to have had cardiovascular disease (defined as a history of coronary artery disease, peripheral arterial occlusive disease, or stroke) or diagnosed type 2 diabetes mellitus together with at least one other risk factor (eligible risk factors included hypertension, dyslipidaemia, current smoker, or diabetic nephropathy; see Supplementary material Table A online). Due to a lower than expected overall primary outcome event rate, 15 months after the first enrolment, criteria were modified such that subjects were required to have had both cardiovascular disease and type 2 diabetes with at least one other risk factor. Subjects with heart failure symptoms greater than New York Heart Association Class II, uncontrolled hypertension (blood pressure >160/100 mmHg) or tachycardia (>100 b.p.m.), a recent history of cardiovascular events or symptoms (<3 months), or who were scheduled for cardiac surgery were excluded, as were those with a history of recent weight loss (>3 kg in the 3 months prior to screening). A complete list of other exclusion criteria are presented in Supplementary material online, Table A. All subjects with on-going conditions such as hypertension, diabetes, and any cardiac or vascular condition were to be managed per respective local guidelines.

Figure 1. 

The SCOUT trial design. Wk, week; Mo, month; SIB, sibutramine; PLA, placebo. a, Study drug administered with standard care for weight management; b, subjects could be titrated to 15 mg/day (per investigator) during treatment period; c, to elicit via phone, potential primary/secondary outcome events. Subjects were to return for annual follow-up visit; d, subjects were to take first lead-in period dose the day after the week –6 visit, and the first double-blind dose the day after the baseline/study day –1 visit (study day 1); e, baseline/study day –1 visit was the final visit for all subjects not randomized; f, for all randomized subjects who prematurely discontinued study drug during the treatment period. Standard care for weight management was to be provided throughout follow-up; g, pertained to all subjects that entered the randomization phase and was to be completed once the study was stopped or at the time the subject withdrew consent from the study or had a fatal outcome.

     

Enrolled subjects were classified into one of three cardiovascular risk categories defined as:

Approval was obtained from all relevant scientific ethical committees. All subjects gave written informed consent. The study was done in total compliance with the Declaration of Helsinki.

At the initial screening visit, a medical history and an ECG were obtained and a physical examination performed. Consenting subjects received sibutramine 10 mg with advice for lifestyle change (individualized 500–600 kcal/day [2092–2510 MJ] deficit diet and exercise programme comprising >150 min of moderate exercise per week) for 6 weeks; they were monitored at 2-week intervals for body weight and vital signs; haematology, blood biochemistry, and urinalysis were performed at the screening visit and/or week –6 and 2 weeks prior to randomization. At the end of the 6-week period, a further medical examination was performed and an ECG obtained.

Statistical Analysis

All measurements in this paper relate to data collected at the week –6 visit (or screening if the measurement was not scheduled for week –6) or at scheduled visits during the 6-week single-blind period up to the baseline visit. Final measurements for subjects who prematurely discontinued the lead-in period are reported as baseline visits. Results are summarized using medians and percentiles of the distribution (5th, 25th, 75th, and 95th) or as a percentage of the number of subjects treated, unless indicated otherwise. For summaries of changes, only subjects who provided at least one post-week –6 measurement were included. The last observation carried forward method was used to estimate missing data, such that any missing data following the first scheduled post-week –6 visit measurement were replaced by the last previous scheduled measurement. Median changes from week –6 (or screening visit) to the baseline visit were analysed using the Wilcoxon Signed Rank Test. A 0.05 significance level was assumed, with no adjustments made for multiple testing. The incidence of two consecutive increases from week –6 of >10 units in either diastolic (DBP) or systolic (SBP) blood pressure or pulse rate was assessed in subjects with at least two post-week –6 scheduled visits. Post hoc, blood pressure values at week –6 and at the time of the second consecutive increase of >10 mmHg were categorized according to current European Guidelines for Hypertension,^[12] i.e. normotensive: <140/90 mmHg (non-diabetic); <130/80 mmHg (diabetic); Grade 1 hypertensive: 140 to <160/90 to <100 mmHg (non-diabetic); 130 to <160/80 to <100 mmHg (diabetic); Grade 2 hypertensive: 160 to <180/100 to <110 mmHg; or Grade 3 hypertensive (≥180/110 mmHg).

Serious adverse events and adverse events leading to study drug discontinuation were summarized by preferred term and primary system organ class using the MedDRA coding system. An independent Events Adjudication Committee adjudicated all potential outcome events comprising the study endpoints. The trial is registered at ClinicalTrials.gov number: NCT00234832 [ClinicalTrials.gov].

Results

The study was conducted under International Conference on Harmonisation Good Clinical Practice guidelines in 316 centres in 16 countries. Between January 2003 and November 2005, 10 783 subjects were eligible to enter the single-blind period. Overall, 10 742 of the 10 783 subjects took at least one dose of sibutramine and are the subjects reported in this paper. The screening/week –6 subject characteristics are shown in Table 1 . Overall, 97% of subjects had cardiovascular disease, 88% hypertension, and 84% type 2 diabetes. Table 2 summarizes the cardiovascular characteristics of subjects within the enrolled population by risk category. Approximately 61% of these subjects were taking a beta-blocker at entry and median pulse rate was lower in these subjects (68.0 b.p.m.) compared with those not taking beta-blockers (74.5 b.p.m.). There was no other clinically relevant baseline difference between these two subgroups.

During the lead-in period, 96% of subjects took at least 85% of the study medication. Single-blind treatment with sibutramine plus standard care for weight management resulted in early reductions in body weight and waist circumference ( Table 3 ). There was, as expected, a range in response but only 1171 (11%) of subjects failed to lose or gained weight during this period.

Of the 10 742 subjects who received sibutramine, 732 (6.8%) did not complete the 6-week period. Primary reasons for discontinuation are presented in Table 4 . Fifteen (0.1%) subjects died during the lead-in period and 10 deaths were attributed to a cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure, respectively. Twenty-six subjects experienced one of the events comprising the study's primary composite endpoint. These events included the 10 cardiovascular deaths noted above, plus eight subjects who had a non-fatal stroke, and eight subjects who had a non-fatal myocardial infarction. Silent myocardial infarctions identified from ECG records for 15 additional subjects are awaiting final adjudication.

Overall, 287 (2.7%) subjects reported at least one serious adverse event that met pre-defined regulatory criteria. Serious cardiac disorders were reported for 105 (1.0%) subjects; those reported by at least 10 subjects included atrial fibrillation (18 subjects), unstable angina (17 subjects), angina pectoris (15 subjects), and coronary artery disease (13 subjects). No other serious adverse event in any other primary system organ class was reported by at least 10 subjects.

Adverse events contributed to or were the primary reason for discontinuation in 329 (3.1%) of the subjects. Cardiac disorders were cited as a reason for discontinuation in 60 (0.6%) subjects; those reported by at least five subjects included a tachycardia-related event in 13 subjects, symptoms of angina pectoris or unstable angina (12 subjects), atrial fibrillation (7 subjects), coronary artery disease (6 subjects), myocardial infarction (6 subjects), and palpitations (5 subjects). Hypertension/blood pressure increase was cited as a reason for discontinuation in 21 subjects. An additional 49 subjects reported a haemodynamic event which contributed to or was the primary reason for discontinuation; however, the individual investigators did not consider these findings to be adverse events and therefore, they have not been reported as such in this paper.

Other adverse events resulting in discontinuation were similar to those reported previously with sibutramine therapy^[10] and reflect its mode of action. Seventy (0.7%) subjects discontinued with gastrointestinal disorders; those reported by at least five subjects included constipation (22 subjects), nausea (15 subjects), dry mouth (12 subjects), vomiting (6 subjects), diarrhea (6 subjects) or upper abdominal pain (5 subjects). Fourteen subjects stopped because of insomnia and 23 subjects cited headache as a reason for discontinuation. Twenty-five (0.2%) subjects indicated drug intolerance as a reason for discontinuation. Other adverse events that occurred in at least five subjects and resulted in discontinuation included dizziness (8 subjects), sleep disorder (8 subjects), vertigo (8 subjects), increased sweating (8 subjects), urinary retention (7 subjects), dysuria (6 subjects), and chest pain (5 subjects). In 19 subjects, the adverse event cited as a reason for discontinuation is unknown.

Two consecutive increases in blood pressure >10 mmHg were reported by 487 (4.7%) subjects (at week –6, 287/487 [59%] were categorized as normotensive, 194 [40%] Grade 1, and 6 [1%] Grade 2). Of the 287 normotensive subjects, 31% remained normotensive and 68% shifted to Grade 1 hypertension at the time of the second increase. Of the 200 subjects who were originally hypertensive, 78% showed no change in their blood pressure category following their second increase. An increase in pulse rate exceeding 10 b.p.m. at two consecutive visits was reported for 364 (3.5%) subjects. As shown in Table 5 , some subjects reported two consecutive increases of >10 in both pulse rate and blood pressure so the total number of subjects with at least one of these increases was 791 (7.6%).

For the 10 742 subjects overall, median blood pressure changes across time ranged from –3.0 to –2.0 mmHg for SBP and from –1.0 to 0.0 mmHg for DBP, whereas median pulse rate changes ranged from 1.0 to 1.5 b.p.m. during the course of the 6 weeks' monitoring. In subjects (12%) who lost >5% of week –6 body weight, median SBP/DBP changes to the baseline visit were –7.5/–2.5 mmHg (P < 0.001 for both) for subjects who were hypertensive at entry and –2.0/+0.25 for normotensive subjects (P < 0.001 and P = 0.591, respectively). In subjects who lost ≤5% body weight, median changes for hypertensive subjects were –4.5/–1.5 (both P < 0.001) and for normotensive subjects were +1.5/+1.5 mmHg (both P < 0.001).

Figure 2 displays the overall changes in SBP and DBP with week –6 values graded according to the categories of current European Society of Hypertension guidelines.^[12]

Figure 2. 

Median changes from week –6 in systolic blood pressure and diastolic blood pressure categorized by blood pressure category at week –6—(last observation carried forward analysis). SBP, systolic blood pressure; DBP, diastolic blood pressure; NT, normotensive; BL, baseline. Median blood pressure (mmHg) at week –6 by grade of hypertension: NT = 124/71; Grade 1 hypertension = 142.5/80.5; Grade 2 hypertension = 161.5/84.5.

     

We also performed analyses in subgroups by gender and beta-blocker treatment. Female/male subjects had median SBP reduction of 3.5/3.0 mmHg, median increase in pulse rate of 1.5/2.0 b.p.m. and median weight loss of 2.3/2.1 kg. Subjects treated with beta-blockers had identical median weight loss as those not treated, median SBP reduction was 3.5 or 2.5 mmHg with or without beta-blocker therapy, respectively, and pulse rate was increased by median 1.0 or 2.5 b.p.m., respectively. These differences could not be explained by differences in other baseline characteristics.

Discussion

Clinical Events and Safety Issues

The single-blind, 6-week lead-in period of the SCOUT trial was designed as a safety screen in this population because of the original concern from early animal and pre-registration clinical studies that sibutramine may induce blood pressure and pulse rate increases. These clinical observations were in keeping with the assumption that sibutramine as a norepinephrine reuptake inhibitor could conceivably exacerbate arterial hypertension and disadvantage subjects with cardiovascular disease. The data from this period show that treatment with sibutramine at the currently accepted therapeutic dose of 10 mg once daily was tolerated well in these obese and overweight subjects with a high risk of cardiovascular events. When the trial was conceived and designed, it was thought that as many as 25% of these high-risk subjects might be withdrawn during the single-blind period as a result of increases in blood pressure and/or pulse rate. However, as the trial progressed and as the present report demonstrates, <5% of these subjects experienced sustained increases (defined as two consecutive increases of >10 mmHg irrespective of initial blood pressure value) in SBP or DPB. Sustained increases in pulse rate of >10 b.p.m. were recorded by <4%.

The overall death rate observed during this initial 6-week period of 1.2 per 100 years of exposure was low. This was less than the death rates observed in the placebo arms of the HOPE^[13] and LIPID^[14] studies (approximately 2.6–2.8 per 100 years of exposure) but similar to that in the more recent ASCOT-LLA study (approximately 1.3 per 100 years of exposure),^[15] three studies with subject populations similar to SCOUT.

Pulse Rate Effects of Sibutramine

Sibutramine is recognized to increase mean pulse rate by 3–7 b.p.m.,^[10] which is consistent with the peripheral action of the drug (see below). Those individuals in SCOUT with unstable angina or arrhythmias may be especially affected. Subjects with chronic atrial fibrillation and/or unstable angina were eligible for inclusion and could be expected to be at greater risk of such pulse rate changes. Review of subjects' previous medical history indicated that six of the seven subjects who withdrew due to atrial fibrillation had a positive medical history for this event. All 12 subjects who withdrew due to anginal symptoms or unstable angina had a previous history of angina pectoris; in 11 of these, the condition was ongoing at study entry. In addition, the requirement for optimal medical management throughout SCOUT meant that 61% of the subjects overall were taking a beta-blocker at entry, which would not only affect blood pressure and pulse rate but might also dampen any effects of sibutramine in stimulating the cardiovascular system.^[16] In those subjects who reported ongoing cardiac arrhythmias at study entry, the majority (563/838 [67%]) were taking concomitant beta-blockers.

Evaluating pulse rate responses to sibutramine therapy is further complicated by the fact that the majority of subjects, albeit long-standing attendees in cardiovascular and diabetes clinics and in receipt of diet and physical activity advice, were asked to engage in a programme of weight management with prescriptive changes in diet and exercise. In one small study assessing the value of explicit exercise advice in addition to dietary counselling, sibutramine did not induce an increase in pulse rate, a finding consistent with the vagal training effect of exercise.^[17] It is too soon to know whether compliance with the physical activity programme within the SCOUT protocol will be sufficient to counter any pulse rate stimulation.

Blood Pressure Effects of Sibutramine

While there were no significant overall increases in blood pressure, approximately 5% of subjects experienced an increase in blood pressure of >10 mmHg on two consecutive occasions during the 6-week lead-in period. The majority (86% [297/345]) of subjects with these two consecutive increases in SBP originally had blood pressures below 140/90 mmHg. In contrast, despite the rather modest reduction in body weight of only 2 kg, the subjects who had increased blood pressure (i.e. classified as ≥Grade 1 hypertension) on entry to the 6-week period showed an appreciable reduction in blood pressure, particularly evident in those with the highest blood pressure (≥Grade 2 hypertension; Figure 2). These changes could reflect regression to the mean; however, the fall in blood pressure in hypertensive subjects, together with the modest increase in blood pressure in normotensive subjects, is in agreement with previously reported (albeit uncontrolled) observations in an open-label, 12-week post-marketing study of over 6000 German subjects in a general practice setting.^[18] As in the present study, subjects with Grade 1 hypertension in the post-marketing study experienced a reduction in blood pressure of 9.9/5.0 mmHg, whereas for those with Grade 2 hypertension, the decline was 24/10.6 mmHg. Few (0.16%) subjects in this German study withdrew from treatment because of an increase in blood pressure.

Together, these blood pressure lowering effects of sibutramine are fully compatible with the emerging concept regarding the complex and opposing peripheral and central actions of sibutramine on sympathetic activity. The peripheral sympathomimetic effects of norepinephrine uptake may increase blood pressure in a small proportion of normotensive individuals with relatively low central sympathetic drive; however, the central sympatholytic effects of sibutramine may predominate in hypertensive individuals with elevated sympathetic nerve activity so that appreciable and sustained reductions in blood pressure can occur. This hypothesis is compatible with the direct microneurography analyses in normotensive and hypertensive individuals with increased sympathetic activity at baseline showing the blocking of sympathetic nerve activity by sibutramine.^[19,20] This central ‘clonidine-like’ sympatholytic effect of norepinephrine inhibition with sibutramine is also compatible with the marked sympatholytic effect observed during treatment with the potent norepinephrine inhibitor, reboxetine.^[21,22]

In this study, the blood pressure as well as the pulse rate effects were modified by the use of beta-blockers. Almost 40% of the disadvantageous changes among subjects with normal blood pressure occurred in those who were not on beta-blockers. As shown in a previous study, sibutramine at a higher 20 mg dose did not result in an increase in blood pressure in obese patients whose hypertension was well controlled by beta-blockers, with or without concomitant thiazide diuretics.^[23] Thus, the current data from the SCOUT trial clearly challenge the current notion that sibutramine should be used with particular caution in patients with pre-existing hypertension.

The SCOUT trial is treating subjects, most of whom have conditions that are explicitly contraindicated for therapy under the current label because it was considered that sibutramine's cardiological effects might be disadvantageous. Data from the 6-week single-blind period of the SCOUT trial indicate that weight management with the addition of sibutramine is well tolerated by a broad range of high-risk subjects with cardiovascular disease.

Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA (2002) 288:1723–1727. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. Obes Res (1998) 6(Suppl. 2):51S–209S. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Cats VM, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D., European Society of Cardiology Committee for Practice Guidelines. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil (2003) 10(Suppl. 1):S1–S78. Anker SD, Negassa A, Coats AJ, Afzal R, Poole-Wilson PA, Cohn JN, Yusuf S. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet (2003) 361:1077–1083. Kennedy LMA, Dickstein K, Anker SD, James M, Cook TJ, Kristianson K, Willenheimer R. Weight-change as a prognostic marker in 12 550 patients following acute myocardial infarction or with stable coronary artery disease. Eur Heart J (2006) doi:10.1093/eurheartj/ehl182. Wadden TA, Foster GD. Behavioral treatment of obesity. Med Clin North Am (2000) 84:441–461. Hansen DL, Toubro S, Stock MJ, Macdonald IA, Astrup A. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obes Relat Metab Disord (1999) 23:1016–1024. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, Hesson LA, Osei SY, Kaplan R, Stunkard AJ. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med (2005) 353:2111–2120. Astrup A, Chong E. Weight loss produced by sibutramine: a meta-analysis. Int J Obes Relat Metab Disord (2001) 23:S104. Sharma AM. Does pharmacologically induced weight loss improve cardiovascular outcome? Sibutramine pharmacology and the cardiovascular system. Eur Heart J (2005) 7(Suppl. L):L39–L43. James WPT. The SCOUT study: risk-benefit profile of sibutramine in overweight high risk cardiovascular patients. Eur Heart J (2005) 7(Suppl. L):L44–L48. Guidelines Committee. 2003 European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens (2003) 21:1011–1053. HOPE Study Investigators. The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple randomized trial of an angiotension-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Can J Cardiol (1996) 12:127–137. Simes RJ, Marschner IC, Hunt D, Colquhoun D, Sullivan D, Stewart RAH, Hague W, Keech A, Thompson P, White H, Shaw J, Tonkin A. Relationship between lipid levels and clinical outcomes in the long-term intervention with pravastatin in ischemic disease (LIPID) trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels? Circulation (2002) 105:1162–1169. Sever PS, Poulter NR, Dahlöf B, Wedel H, for the Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Different time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA). Am J Cardiol (2005) 96(Suppl.):39F–44F. Ersoz HO, Ukinc K, Baykan M, Erem C, Durmus I, Hacihasanoglu A, Telatar M. Effect of low-dose metoprolol in combination with sibutramine therapy in normotensive obese patients: a randomized controlled study. Int J Obes Relat Metab Disord (2004) 28:378–383. Berube-Parent S, Prud'homme D, St-Pierre S, Doucet E, Tremblay A. Obesity treatment with a progressive clinical tri-therapy combining sibutramine and a supervised diet—exercise intervention. Int J Obes Relat Metab Disord (2001) 25:1144–1153. Scholze J. Adipositasbehandlung mit Sibutramin unter Praxisbedingungen. Deutsche Medizinische Wochenschrift (2002) 127:606–610. Birkenfeld AL, Schroeder C, Pischon T, Tank J, Luft FC, Sharma AM, Jordan J. Paradoxical effect of sibutramine on autonomic cardiovascular regulation in obese hypertensive patients—sibutramine and blood pressure. Clin Auton Res (2005) 15:200–206. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, Biaggioni I, Sharma AM, Jordan J. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation (2002) 106:2459–2465. Tank J, Schroeder C, Diedrich A, Szczech E, Haertter S, Sharma AM, Luft FC, Jordan J. Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition. Circulation (2003) 107:2949–2954. Heusser K, Tank J, Diedrich A, Engeli S, Klaua S, Krüger N, Srauss A, Stoffels G, Luft FC, Jordan J. Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Clin Pharmacol Ther (2006) 79:500–508. Sramek JJ, Leibowitz MT, Weinstein SP, Rowe ED, Mendel CM, Levy B, McMahon FG, Mullican WS, Toth PD, Cutler NR. Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial. J Hum Hypertens (2002) 16:13–19.

Appendix: Executive Steering Committee: Philip James (Chair), Ian Caterson, Walmir Coutinho, Nick Finer, Luc Van Gaal, Aldo Maggioni, Arya Sharma, Christian Torp-Pedersen.

Data and Safety Monitoring Board: Carl Pepine (Chair), Stuart Pocock, Helmut Drexler, Karl Swedberg, Peter Sleight, Paul Armstrong, David Kerr.

Event Adjudication Committee: Gilles Dagenais (Chair), James Brophy, Alvaro Avezum, Peter Bogaty, Gianna Fabbri, Michele Galli, Per Hildebrandt, Johannes Mann, Jan Ostergren, David Sherman, Faiez Zannad.

National Leaders: David Colquhoun, Geert Hollanders, Adriana Costa e Forti, Renata Cifkova, Soren Toubro, Olivier Ziegler, Werner A. Scherbaum, Jens Jordan, Lazlo Halmy, Eleuterio Ferrannini, Ferruccio Santini, Clicerio Gonzalez, Krzysztof Narkiewicz, Nicolae Hancu, Juraj Payer, Jose Pascual, John Wilding.

Investigators:Australia: Lesley Campbell, David Carey, David Colquhoun, Murray Gerstman, Jeff Karrasch, Jeffrey Lefkovits, Jonathan Marks, Sharon Marks, Robert Moses, Patrick Phillips, Joseph Proietto, David Roberts, Philip Roberts-Thomson, JE Shaw, Richard Simpson, Bhuwan Singh, Bronwyn Stuckey. Belgium: Jean Boland, Christian Brohet, Francis Coucke, Paul Dendale, Geert Hollanders, Guy Jouret, Jaroslaw Kolanowski, Maximilien Kutnowski, Frank Martens, Erik Muls, Frida Peiffer, Hubert Penninckx, Andre Scheen, Danny Schoors, Vaerenberg Marc, Johan Van Cleemput, Paul Van Crombrugge, Marc Van Kuyk, Ann Verhaegen, Bart Wollaert. Brazil: Denilson Campos de Albuquerque, Jose Appolinario. Adriana Costa e Forti, Amelio Fernando de Godoy Matos, Jorge Luiz Gross, Alfredo Halpern, Jose Francisco Kerr Saraiva, Rosangela Milagres, Giuseppe Repetto, Henrique Lacerda Suplicy, Maria Tereza Zanella. Czech Republic: Jana Bednarova, Vaclav Cepelak, Petr Cerny, Renata Cifkova, Vojtech Hainer, Pavel Havranek, Miroslav Homza, Pavel Jansa, Milan Karlicek, Jan Kolesar, Ilja Kotik, Jiri Kuchar, Martin Kunc, Milan Kvapil, Ales Linhart, Vilma Machova, Jaroslav Matuska, Jan Pavlas, Svatava Pesatova, Jiri Povolny, Borivoj Semrad, Karel Smetana, Stepan Svacina, Pavel Tesinsky, Robin Urbanek, Bedrich Wasserburger, Richard Zachoval, Emil Zahumensky, Eva Zidkova. Denmark: Arne Astrup, Helena Dominguez, Jens Faber, Christian Hassager, Per Hilderbrant, Lars Kober, Bjorn Richelsen, Peter Sogaard, Ole Lander Svendsen, Soren Toubro, Soren Urhammer. France: Arnaud Basdevant, Jean-Michel Borys, Jacques Bringer, Catherine Brunetiere, Guillaume Charpentier, Magali Cocaul-André, Henry Dabadie, Bruno Estour, Jean-François Gautier, Thierry Gibault, Jean-Pierre Hespel, Michel Issa Sayegh, Michel Krempf, Jean-Michel Lecerf, Jean-Pierre Louvet, Alfred Penfornis, Patrick Ritz, Jean-Louis Schlienger, Bernard Schmitt, Paul Valensi, Olivier Ziegler. Germany: Markus Baar, Jens Beermann, Manfred Bock, Gerd Boenner, Hanns-Gerd Dammann, Herwig Ditschuneit, Siegfried Gehlhar, Sigrid Geßner, Achim Guthersohn, Andreas Hamann, Markolf Hanefeld, Gerd Hasenfuß, Annette Herzner, Klaus-Christoph Heun, Hartmut Hohensee, Stephan Jacob, Jens Jordan, Peter Krings, Bernhard Krätzig, Reiner Thorsten Lehmann, Susanne Mindt-Prüfert, Andreas F.H. Pfeiffer, Frank Richard, Werner A. Scherbaum, Ekkehard Schmidt, Juergen Scholze, Andreas Schreckenberg, Petra Stuebler, Jörg Walter, Alfred Wirth, Joachim Wunderlich. Hungary: Gyorgy Abraham, Andras Altorjay, Gabor Augusztin, Albert Csaszar, Istvan Czuriga, Laszlo Gero, Andras Gyimesi, Laszlo Halmy, Andras Janosi, Imre Kovacs, Imre Liziczai, Anna Majtenyi, Mihaly Medvegy, Zoltan Nadhazi, Gyula Pados, Gyula Polak, Aladar Ronaszeki, Zoltan Sido, Kornel Simon. Italy: Claudio Anzà, Maurizio Bevilacqua, Ottavio Bosello, Massimo Chiariello, Luca Chiovato, Renzo Cordera, Ettore Ferrari, Eleuterio Ferrannini, Lucia Frittitta, Riccardo Giorgino, Antonio Liuzzi, Claudio Malinverni, Nazario Melchionda, Giuseppe Occhi, Francesco Perticone, Aldo Pinchera, Giuseppe Pinelli, Giuseppe Rovera, Fausto Santeusanio, Stefano Urbinati. Mexico: Melchor Alpizar, Elmo Carrillo-Ortega, Guillermo Fanghanel, Clicerio Gonzalez, Hugo Antonio Laviada-Molina, Miguel Agustin Madero, Gilberto Rodriguez, Cristina Saldate, Claudia P. Sanchez-Castillo, Rafael M. Violante, Niels Wacher, Francisco J. Zayas-Jaime, Sergio Zuniga-Guajardo. Poland: Rajmund Adamiec, Waldemar Banasiak, Pawel Chrusciel, Boguslaw Derlaga, Andrzej Gebala, Jacek Gessek, Krzysztof Janik, Marianna Janion, Zbigniew Kalina, Artur Kozlowski, Barbara Kusnierz, Zbigniew Majcher, Stanislaw Mazur, Pawel Miekus, Krzysztof Narkiewicz, Joanna Niegowska, Boguslaw Okopien, Lucyna Ostrowska, Mieczyslaw Pasowicz, Marek Piepiorka, Wladyslaw Pluta, Miroslawa Polaszewska-Muszynska, Danuta Pupek-Musialik, Andrzej Sawicki, Henryk Sobocik, Andrzej Stankiewicz, Michal Szpajer, Ryszard Trojnar, Andrzej Tykarski, Krzysztof Wrabec, Bogdan Wyrzkowski, Barbara Zahorska-Markiewicz, Marek Zalewski. Portugal: Maria Monica Mendes Pedro, Lelita dos Santos. Romania: Aurel Babes, Gabriela Creteanu, Gheorghe Andrei Dan, Stefan Iosif Dragulescu, Mariana Graur, Nicolae Hancu, Constantin Ionescu Tirgoviste, Magdalena Morosanu, Maria Mota, Fraga Silvia Paveliu, Mariana Radoi, Aurelian Ranetti, Ion Totoian. Slovakia: Igor Andre, Viliam Bugan, Juraj Cencarik, Ludovit Csala, Stefan Farsky, Josef Gonsorcik, Gabriel Kamensky, Jan Kmec, Boris Krahulec, Vladimir Macek, Ivan Majercak, Karol Micko, Marian Mokan, Igor Riecansky, Gabriel Sojka, Rudolf Uhliar, Lubica Urgeova, Juraj Vancik. Spain: Francisco Moreno Baro, Antonio Barrios Merino, Jose-Luis Griera Borras, Assumpta Caixas, Guillermo Cuatrecasas Cambra, Jose Ramon Dominguez Escribano, Santiago Duran Garcia, Luis Escobar-Jimenez, Isabel Esteva, Xavier Formiguera Sala, Pedro-Pablo Garcia-Luna, Rafael Garcia Robles, Olga Gonzalez Albarran, Antonio Hernandez-Mijares, Alberto Martin Hidalgo, Lluis Masmiquel Comas, Francisco Morales Perez, Basilio Moreno Esteban, Jose M Pascual Izuel, Wifredo Ricart, Miguel-Angel Rubio, Luis Miguel Ruilope, Jordi Salas-Salvado, M. Terroba Larumbe, Francisco Tinahones, Martin Lopez de la Torre Casares, Josep Vidal Cortada, Manuel Zuniga-Perez Lemaur. UK: Amanda Adler, Anthony H. Barnett, Charles Bodmer, Ian W. Campbell, Tahseen Chowdhury, John Cleland, Robert.C. Cook, Sean Dinneen, David W. Haslam, Morag Horne, David J. Howarth, Elizabeth Hughes, Stephen Jackson, Stephen C. Jones, T. Hugh Jones, Sudhesh Kumar, Mike Lean, Jacqui Maroni, Gordon McInnes, Alan Middleton, Andrew Morris, Guy Newcombe, Kevin P J O'Kane, Irina Constantina Pavel, Ravi Pawa, Colin Perry, Chris Pitts, John Reckless, John Robinson, Mansur Salman, Shiu-Ching Soo, Sue Taylor, Hawys Olwen Thomas, Margaret Ann Thomson, John Wilding, Martin Wilkins.

Acknowledgements

Supplementary material is available at European Heart Journal online.

Funding Information

Abbott Laboratories provided funding for all aspects of this clinical study.

Reprint Address

Christian Torp-Pedersen: Tel: +45 356 316 161; fax: +45 3976 0107. E-mail address: ctp@heart.dk