European Heart Journal Supplements (2005) 7 (Supplement L), L44–L48

doi:10.1093/eurheartj/sui086

Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_L/L44/464333 by Gadjah Mada University user on 10 February 2022

The SCOUT study: risk-benefit profile of sibutramine
in overweight high-risk cardiovascular patients
W. Philip T. James*
London School of Hygiene and Tropical Medicine and International Obesity TaskForce, London, UK

KEYWORDS Moderate weight loss improves metabolic and cardiovascular risk factors and prevents
Cardiovascular risk; the progression to Type 2 diabetes. Furthermore, a healthy lifestyle is associated with
Obesity; lower cardiovascular mortality, whereas sustained weight loss and increased fitness
Randomized trial; are both associated with reduced cardiovascular mortality. Currently available anti-
SCOUT
obesity drugs have been shown to deliver moderate weight loss in more patients
and for longer than diet and exercise alone. In addition, these anti-obesity agents
impact positively on multiple cardiovascular risk factors. The question of whether
the use of weight loss agents can prevent cardiovascular morbidity and mortality
has not been studied so far. The Sibutramine Cardiovascular Outcome Trial (SCOUT)
has been designed to determine whether weight management in cardiovascular
high-risk overweight and obese patients can impact upon cardiovascular endpoints.
Patient enrolment for the SCOUT trial began in December 2002 with the first
patient randomized in February 2003. The study will involve 9000 patients in 16
countries. They will be treated with a novel lifestyle intervention programme and
randomized in a double-blind fashion to receive either sibutramine or placebo.

The previous articles have highlighted the importance of
cardiovascular disease as the biggest killer in the world
and also demonstrated that the new epidemic of
obesity is having a whole array of effects on the risk
factors for cardiovascular disease. The link between
obesity with its associated inappropriate diet and
physical inactivity and premature cardiovascular disease
and death is clear in patients ,75 years of age.1
Furthermore, weight loss limits or corrects high total
and LDL cholesterol, triglycerides, low HDL cholesterol,
and hyperglycaemia and also reduces waist circumfer-
ences, with the result that fewer patients are classified
as having the metabolic syndrome.
Modest, sustained weight loss also provides significant
health benefits. In the Chinese, Finnish, and US
Diabetes Prevention Program trials, overall weight loss
of up to 5% reduced the progression to diabetes in
those with glucose intolerance.2–4 A recent Cochrane
analysis of five epidemiological studies also suggests
*Corresponding author.
E-mail address: JeanHJames@aol.com
that intentional, but not unintentional, weight loss in
women with pre-existing associated disease reduces
total cancer and cardiovascular mortality by 30%,
whereas among men and women with diabetes, mortality
fell by 42%. Although weight loss in obese men did not
reduce cardiovascular mortality, this was suggested as
being a consequence of men avoiding medical care.5
Weight loss of .15% following bariatric surgery
in patients with a body mass index (BMI) exceeding
40 kg/m2 reduces Type 2 diabetes, even though at
present, there are no long-term data to show a reduction
in hypertension rates or mortality.6
However, the case for weight loss is undermined by
observational studies that appear to suggest that
weight loss over a prolonged period enhances mortality
in subjects with pre-existing heart failure.7 Such studies
may be criticized for not differentiating between inten-
tional and unintentional weight loss. Nevertheless,
there are also confusing data on the effect of obesity
on the outcome of different cardiac interventions:
although traditionally considered a risk factor for coron-
ary revascularization, recent data from clinical trials and

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The SCOUT study
registry studies have shown a possible protective effect
of obesity on the outcomes after percutaneous coronary
intervention.8–10 This uncertainty is compounded by the
fact that no formal trials documenting the impact of
weight loss on cardiovascular events and mortality have
yet been published.
Given the clear benefits in terms of cardiovascular risk
factors but confusion relating to cardiovascular out-
comes, the challenge is to assess the value of modest
but sustained weight loss rather than extreme weight
changes in the millions of middle aged and elderly who
have obesity-related diabetes and cardiovascular
disease. The validity of using pharmacotherapy to aid
this approach to weight management also needs to be
tested.
Sibutramine and weight loss
Sibutramine was first marketed in the USA in 1997. It is
now registered in over 80 countries and has been pre-
scribed to over 16 million people.
A number of randomized placebo-controlled studies
have shown that sibutramine given in conjunction with
lifestyle and dietary advice can induce dose-dependent
weight loss of 5–10% in most patients,11–15 including
those with Type 2 diabetes.16,17 Overall, sibutramine
increases by three to four times the proportion of
patients sustaining 5% weight loss.18
The Summary of Product Characteristics for sibutra-
mine notes that a mean increase in resting systolic and
diastolic blood pressures of 2–3 mmHg and a mean
increase in heart rate of 3–7 b.p.m. have been
observed.19 These effects have been noted in the
combined analysis of dose-finding studies conducted in
normotensive subjects with doses of up to 30 mg. As
noted by the previous presentation,20 the effect is con-
siderably less marked in the licensed dosages of 10 and
15 mg. Furthermore, sibutramine is not contraindicated
in patients with well-controlled hypertension, and
several studies have shown that treatment for periods
of up to 12 months is safe and effective in these
patients.21–25
However, there is a widespread belief that sibutramine
should not be used in patients who have hypertension.
In March 2002, the Italian regulatory authorities tem-
porarily suspended market authorization of sibutramine
following reported adverse reactions, which included
two cardiovascular deaths purportedly linked to sibutra-
mine. A subsequent independent review by the
European Committee for Proprietary Medicinal Products
concluded that the risk-benefit profile of the drug
remained positive and that clinicians could continue
using it in clinical practice. Significantly, extensive
post-marketing data, collected over the last 7 years,
have revealed no significant problems.26
In fact, there is reason to suggest that patients who
lose weight with sibutramine may derive additional
benefit in terms of cardiovascular protection. Studies
suggest that the drug increases serum concentrations of
HDL cholesterol independently of weight loss,13 and
L45
there is also evidence that sibutramine-induced weight
loss causes regression of left ventricular mass indepen-
dent of blood pressure.27 In obese hypertensive subjects,
sibutramine appears to block the enhanced central
adrenergic drive of the sympathetic nervous system
(SNS) while stimulating the peripheral SNS.28
It is increasingly clear that patients with cardiovascular
disease benefit from weight management,29 and yet
Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_L/L44/464333 by Gadjah Mada University user on 10 February 2022
losing weight is a challenge to most individuals.30
Although the possible additional effects of sibutramine
suggest a wider role for the drug, doctors have an over-
whelming responsibility to ‘first do no harm’.
Therefore, the Sibutramine Cardiovascular Outcomes
Trial (SCOUT) has been designed to determine the
impact of weight loss with sibutramine on cardiovascular
endpoints in a large group of overweight and obese
subjects at high risk for cardiovascular disease.
The SCOUT trial
The SCOUT trial is a multi-centre, double-blind, placebo-
controlled trial designed to evaluate the potential
benefits of weight management on cardiovascular out-
comes in overweight and obese patients at high risk for
cardiovascular events. Weight management in SCOUT
includes weight loss and weight maintenance induced
by a novel lifestyle intervention programme. In addition,
the 9000 patients will be randomized in a double-blind
fashion to receive either sibutramine (10–15 mg daily)
or matching placebo.
Unlike most obesity trials, which include patients aged
18–65, SCOUT is designed to assess higher risk patients
and, therefore, includes patients aged 55 years and
older. The trial uses standard WHO BMI criteria for over-
weight and obese.31 Patients, both men and women, are
eligible for inclusion in SCOUT if they have a BMI of 27
and 45 kg/m2 or 25 and ,27 kg/m2 with a waist
circumference of 102 cm (men) or 88 cm (women).
In addition, patients must also have experienced a
cardiovascular event or have diagnosed Type 2 diabetes
and another cardiovascular risk factor.
Patients with a history of coronary artery disease,
peripheral arterial occlusive disease, cerebrovascular
disease (stroke or transient ischaemic attack), controlled
hypertension, or New York Heart Association classes I and
II heart failure are eligible for inclusion in SCOUT.
The primary endpoint of the trial will include a compo-
site of myocardial infarction, stroke, resuscitated cardiac
arrest, and cardiovascular death.
SCOUT is an event-driven trial and estimated event
rates have been modelled on the basis of those reported
in trials recruiting subjects at similar levels of risk.32–35
Study design
Patients recruited to SCOUT will first undergo a 2-week
screening phase before entering a 6-week single-blind
lead-in period, during which all patients will receive sibu-
tramine 10 mg daily in addition to the study’s unique diet
and lifestyle programme (Figure 1).
L46
Figure 1
Figure 2 The multi-national SCOUT will be the first study to report the potential benefits of weight management on cardiovascular outcomes in over-
weight and obese patients at high risk for cardiovascular events.
The lead-in phase is designed to ensure the safety of
study patients: it allows evaluation of study patients for
safety and tolerability including blood pressure and
heart rate changes. It also serves to familiarize patients
with the diet and exercise programme prior to randomi-
zation and permits an assessment of compliance; patients
who take ,85% of study drug during this phase are not
eligible for further inclusion in the trial.
It is estimated that the study will continue for 3 years
after the last patient is recruited. Treatment will be con-
tinued throughout this period, and all patients will be
monitored at regular intervals (trimonthly and annual
visits are scheduled), together with a final analysis of
every patient, including those who discontinue study
drug.
SCOUT includes a novel lifestyle intervention pro-
gramme comprising an individualized 600 kcal per day
deficit diet and at least 150 min per week of moderate
physical activity (e.g. walking/cycling). The exercise pro-
tocol was developed in conjunction with the Mexico City
Cardiac Rehabilitation Centre and was originally designed
W.P.T. James
Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_L/L44/464333 by Gadjah Mada University user on 10 February 2022
The SCOUT study design.
for use in a high-risk group of patients exercising at high
altitude, with a compromised cardiovascular system. The
diet and exercise programme has been translated into
appropriate languages and adapted in terms of food
types and traditions to fit all 16 countries taking part in
the trial. It includes detailed explanations and advice
on how to engage patients in both diet and physical
activity.
Conduct of the trial
The SCOUT trial is being conducted in over 300 centres in
16 countries. It is predominantly a European trial, with
centres in Belgium, Czech Republic, Denmark, France,
Germany, Hungary, Italy, Poland, Portugal, Romania,
Slovakia, Spain, and the UK. However, the trial also
includes centres in Mexico, Brazil, and Australia
(Figure 2). The study does not include Asia where differ-
ent criteria apply for overweight and obesity.
The SCOUT study
An Executive Steering Committee is leading SCOUT,
while an independent Data Safety Monitoring Board is
monitoring all data collected, and potential outcome
events are adjudicated by an independent Event
Adjudication Committee. Both the Executive Steering
Committee and the Data Safety Monitoring Board are
providing regular and detailed updates on the progress
of the study to the European regulatory agencies.
Patient enrolment for SCOUT began in late December
2002 with the first patient randomized in February
2003; it is expected that randomization will be complete
in mid-2005. All patients will be followed for 3 years, thus
the trial will continue till 2008. The Executive Steering
Committee is confident that SCOUT will then be able to
provide the evidence needed to transform the clinical
management of overweight and obesity in high-risk cardi-
ovascular patients.
Key points
. Cardiovascular disease is the leading cause of death
worldwide; obesity is associated with a number of
risk factors for cardiovascular disease.
. Modest, sustained weight loss has a beneficial impact
on a range of cardiovascular risk factors; in contrast,
extreme weight change appears to have a detrimental
impact.
. No formal clinical trials documenting the impact
of modest weight loss on cardiovascular events and
mortality have yet been published.
. The ongoing SCOUT trial has been designed to deter-
mine the impact of weight loss with sibutramine on
cardiovascular endpoints in a large group of over-
weight and obese subjects at high risk for cardio-
vascular disease.
Conflict of interest: The author has consulted for Abbott and
lectured at Abbott-sponsored symposia. He chairs the Executive
Steering Committee of the Abbott-sponsored SCOUT trial.
References
1. James WPT, Jackson-Leach R, Ni Mhurchu C et al. Overweight and
obesity (high body mass index). In: Ezzati M, Lopez AD, Rodgers A,
Murray CJL, eds. Comparative Quantification of Health Risks.
Global and Regional Burden of Disease Attributable to Selected
Major Risk Factors. Chapter 8, Vol 1. Geneva: World Health
Organization; 2004.
2. Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing
NIDDM in people with impaired glucose tolerance. The Da Qing IGT
and Diabetes Study. Diabetes Care 1997;20:537–544.
3. Tuomilehto J, Lindstrom J, Eriksson JG et al; Finnish Diabetes
Prevention Study Group. Prevention of Type 2 diabetes mellitus by
changes in lifestyle among subjects with impaired glucose tolerance.
N Engl J Med 2001;344:1343–1350.
4. Knowler WC, Barrett-Connor E, Fowler SE et al; Diabetes Prevention
Program Research Group. Reduction in the incidence of Type 2 dia-
betes with lifestyle intervention or metformin. N Engl J Med
2002;346:393–403.
5. Avenell A, Broom J, Brown TJ et al. Systematic review of the long
term effects and economic consequences of treatments for obesity
and implications for health improvements. Health Technol Assess
2004;8:1–182.
L47
6. Sjostrom L, Lindroos AK, Peltonen M et al; Swedish Obese Subjects Study
Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10
years after bariatric surgery. N Engl J Med 2004;351:2683–2693.
7. Anker SD, Negassa A, Coats AJ et al. 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.
8. Gurm HS, Whitlow PL, Kip KE; BARI Investigators. The impact of body
mass index on short- and long-term outcomes inpatients undergoing
coronary revascularization. Insights from the bypass angioplasty
Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_L/L44/464333 by Gadjah Mada University user on 10 February 2022
revascularization investigation (BARI). J Am Coll Cardiol 2002;39:
834–840.
9. Gruberg L, Mercado N, Milo S et al.; Arterial Revascularization
Therapies Study Investigators. Impact of body mass index on the
outcome of patients with multivessel disease randomized to either
coronary artery bypass grafting or stenting in the ARTS trial: The
obesity paradox II? Am J Cardiol 2005;95:439–444.
10. Minutello RM, Chou ET, Hong MK et al. Impact of body mass index on
in-hospital outcomes following percutaneous coronary intervention
(report from the New York State Angioplasty Registry). Am J
Cardiol 2004;93:1229–1232.
11. Bray GA, Blackburn GL, Ferguson JM et al. Sibutramine produces
dose-related weight loss. Obes Res 1999;7:189–198.
12. Apfelbaum M, Vague P, Ziegler O et al. Long-term maintenance of
weight loss after a very-low-calorie diet: a randomized blinded
trial of the efficacy and tolerability of sibutramine. Am J Med 1999;
106:179–184.
13. James WP, Astrup A, Finer N et al. Effect of sibutramine on weight
maintenance after weight loss: a randomised trial. STORM Study
Group. Sibutramine trial of obesity reduction and maintenance.
Lancet 2000;356:2119–2125.
14. Smith IG, Goulder MA, on behalf of the Members of the Sibutramine
Clinical Study 1047 Team. Randomized placebo-controlled trial of
long-term treatment with sibutramine in mild to moderate obesity.
J Fam Pract 2001;50:505–512.
15. Wirth A, Krause J. Long-term weight loss with sibutramine: a random-
ized controlled trial. JAMA 2001;286:1331–1339.
16. Finer N, Bloom SR, Frost GS et al. Sibutramine is effective for weight
loss and diabetic control in obesity with Type 2 diabetes: a random-
ised, double-blind, placebo-controlled study. Diabetes Obes Metab
2000;2:105–112.
17. McNulty SJ, Ur E, Williams G; Multicenter Sibutramine Study Group. A
randomized trial of sibutramine in the management of obese Type 2
diabetic patients treated with metformin. Diabetes Care 2003;
26:125–131.
18. Astrup A, Chong E. Weight loss produced by sibutramine: a meta-
analysis. Int J Obes Relat Metab Disord 2001;25(Suppl. 2):S104.
19. Abbott Laboratories. Sibutramine Summary of Product Characteristics.
20. Sharma AM. Sibutramine pharmacology and the cardiovascular
system. Eur Heart J Suppl 2005;7:L39–43.
21. Hazenberg BP. Randomized, double-blind, placebo-controlled, multi-
center study of sibutramine in obese hypertensive patients.
Cardiology 2000;94:152–158.
22. McMahon FG, Fujioka K, Singh BN et al. Efficacy and safety of sibutra-
mine in obese white and African American patients with hyperten-
sion: a 1-year, double-blind, placebo-controlled, multicenter trial.
Arch Intern Med 2000;160:2185–2191.
23. McMahon FG, Weinstein SP, Rowe E et al. Sibutramine is safe and
effective for weight loss in obese patients whose hypertension
is well controlled with angiotensin-converting enzyme inhibitors.
J Hum Hypertens 2002;16:5–11.
24. Sramek JJ, Leibowitz MT, Weinstein SP et al. 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.
25. Fanghanel G, Cortinas L, Sanchez-Reyes L et al. Safety and efficacy of
sibutramine in overweight Hispanic patients with hypertension.
Adv Ther 2003;20:101–113.
26. Scholze J. Adipositasbehandlung mit sibutramin unter praxisbedin-
gungen. Deutsche Medizinische Wochenschrift 2002; 127:606–610.
27. Zannad F, Gille B, Grentzinger A et al. Effects of sibutramine on
ventricular dimensions and heart valves in obese patients during
weight reduction. Am Heart J 2002;144:508–515.
L48
28. Birkenfeld AL, Schroeder C, Boschmann M et al. Paradoxical effect
of sibutramine on autonomic cardiovascular regulation. Circulation
2002;106:2459–2465.
29. The World Health Report 2002. Reducing risks, promoting healthy
life. WHO Technical Report Series, no. 916. Geneva: World Health
Organization; 2002.
30. Williamson DF, Serdula MK, Anda RF et al. Weight loss attempts in
adults: goals, duration, and rate of weight loss. Am J Public Health
1992;82:1251–1257.
31. World Health Organization. Obesity: Preventing and Managing the
Global Epidemic. (WHO Obesity Technical Report Series No. 894.)
World Health Organization: Geneva, 2000.
32. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart
disease in subjects with Type 2 diabetes and in nondiabetic subjects
W.P.T. James
with and without prior myocardial infarction. N Engl J Med
1998;339:229–234.
33. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and
of antioxidant vitamin supplementation in a wide range of patients
at increased risk of coronary heart disease death: early safety and
efficacy experience. Eur Heart J 1999;20:725–741.
34. Collins R, Armitage J, Parish S et al; Heart Protection Study
Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-
lowering with simvastatin in 5963 people with diabetes: a randomised
placebo-controlled trial. Lancet 2003;361:2005–2016.
Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_L/L44/464333 by Gadjah Mada University user on 10 February 2022
35. Yusuf S, Sleight P, Pogue J et al. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000;342:145–153.