В продолжение разговора об изъятии сибутрамина в БМЖ состоялся еще один
горячий обмен:
Участники СКАУТа отстаивают: у них хороший трайал.
Видьямс им отвечает - не очень хороший, а лекарство еще хуже
А другой читатель обращает внимание на то, что тайал должен был
закончиться в марте 2009 - где же данные, чтоб можно было понять, что
хорошо, и что плохо.
ввв
BMJ 2010;340:c1346
Letters
Withdrawal of sibutramine
Editorial is judgment in advance of the facts
Williams's negative, even nihilistic, approach to obesity treatment and
to sibutramine in particular is ill judged and inaccurate.1 His
editorial seems to be based mainly on the limited data from the
Sibutramine Cardiovascular Outcomes Trial (SCOUT) released by the
European Medicines Agency, and perhaps data not in the public domain. It
would have been better to await full details of the trial findings
before writing an editorial.
To say that the trial has left a "mess of data that are impossible to
interpret"1 is wrong. We, the Executive Steering Committee, delayed the
final closure of the database expressly to ensure that the data
collection is as robust as that of other cardiovascular trials. We are
now analysing for publication unique data on the impact of therapeutic
weight loss in obese people.
The cardiovascular effects of sibutramine are complex: for most patients
in SCOUT it reduced blood pressure during a six week active run-in,2 as
well as increasing HDL cholesterol.3 SCOUT was not "an act of faith"1
but required by the European regulatory authorities when sibutramine
received its product licence. To say that no other manufacturer signed
up for such a long study is also not true: Sanofi-aventis did just this
for rimonabant until its withdrawal (CRESCENDO trial).
Williams is dismissive of small percentages of weight loss: the newly
published SIGN guidelines,4 among others, contradict him. He seems twice
to endorse the concept of a magic bullet for obesity, which few in the
discipline subscribe to because of the well known complexities of neural
defences against body weight loss.5
Most involved doctors hope for progressive advances in treatment
strategies, perhaps akin to hypertension treatment. Sibutramine
withdrawal needs to be considered carefully once all the data are
formally published. Given the need for better obesity treatments, a more
appropriate editorial would have been in order.
Cite this as: BMJ 2010;340:c1346
Nick Finer, consultant endocrinologist and honorary professor1, On
behalf of the Executive Steering Committee of the Sibutramine
Cardiovascular Outcome Trial (SCOUT): Ian Caterson, Walmir Coutinho, Luc
Van Gaal, Aldo Maggioni, Christian Torp-Pedersen, Arya Sharma, and
Philip James.
1 University College Hospitals London, London WC1T 7DN
n.finer@ucl.ac.uk
Competing interests: The authors are members of the SCOUT Executive
Steering Committee, for which they have received payment from Abbott. In
addition NF, IC, WC, LVG, AS, and CT-P have received lecture fees from
Abbott.
References
1. Williams G. Withdrawal of sibutramine in Europe. BMJ
2010;340:c824. (9 February.)[Free Full Text]
2. Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L,
Maggioni A, et al; SCOUT Investigators. Cardiovascular responses to
weight management and sibutramine in high-risk subjects: an analysis
from the SCOUT trial. Eur Heart J 2007;28:2915-23.[Abstract/Free Full Text]
3. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Ro"ssner S, et
al; STORM Study Group. Effect of sibutramine on weight maintenance after
weight loss: a randomised trial. Lancet 2000;356:2119-25.[CrossRef][Web
of Science][Medline]
4. Scottish Intercollegiate Guidelines Network. Management of
obesity. Guideline No 115. February 2010. Available at:
www.sign.ac.uk/guidelines/fulltext/115/index.html.
5. Adan RA, Vanderschuren LJ, la Fleur SE. Anti-obesity drugs and
neural circuits of feeding. Trends Pharmacol Sci
2008;29:208-17.[CrossRef][Medline]
Author's reply
Finer and colleagues' spirited letter might stimulate a wider and long
overdue debate on the lasting benefits of the modest reduction in fat
mass achievable with any of the anti-obesity drugs in clinical practice.1
For an obese adult weighing 70 kg aged 20 who gains 30 kg of fat through
adult life, a 10% loss of weight lasting two years is only a 3%
reduction in the total excess fat carried until the age of 60. Whether
such drug induced weight loss prolongs life or reduces the
cardiovascular damage of obesity is still not known.2 This crucial
question could be answered by long term trials in which all participants
are followed up to death (not the intention of SCOUT or CRESCENDO), and
provided that the drug has no intrinsic impact on the cardiovascular
system. Sibutramine clearly has intrinsic sympathomimetic effects,
causing tachycardia and hypertension in some patients.3 Thus the cause
of the excess cardiovascular risk in the pre-terminal analysis of SCOUT
cannot be determined, and this outcome is uninterpretable.
Ideally, a magic bullet that is effective, safe to be given for life,
and cheap should be possible. Orlistat, "the only drug specifically
licensed for use in obesity"2, probably falls short of this mark, even
if given for longer than its licensed duration. We shall never know how
good orlistat is because the necessary lifelong study will never be
done. Meanwhile, obesity gains momentum so fast that whatever we are
doing to try to stop it is not working.
As my editorial shows, I think that the idea of a magic bullet is
untenable because of physiology and human nature. Sibutramine is just
the latest in a long line of drugs that had to be withdrawn because of
risk or inefficacy. The writing on the wall is all too clear; perhaps
standing back a little would allow Finer and colleagues to see what it's
trying to tell us.
Cite this as: BMJ 2010;340:c1349
Gareth Williams, professor of medicine1
1 Faculty of Medicine and Dentistry, University of Bristol, Bristol BS10 5NB
gareth.williams@bristol.ac.uk
Competing interests: GW previously (up to 2003) had support for
preclinical and clinical research, accepted honorariums to speak at
meetings, and acted as a paid scientific and medical adviser to various
drug companies, including the manufacturers of sibutramine.
References
1. Finer N, Executive Steering Committee of the Sibutramine
Cardiovascular Outcome Trial (SCOUT). Editorial is judgment in advance
of the facts. BMJ 2010;340:c1346.[Free Full Text]
2. Scottish Intercollegiate Guidelines Network. Management of
obesity. Guideline No 115. February 2010. Available at:
www.sign.ac.uk/guidelines/fulltext/115/index.html.
3. McNulty SJ, Ur E, Williams G, for the Multicenter Sibutramine
Study Group. A randomised trial of sibutramine in the management of
obese type 2 diabetic patients treated with metformin. Diabetes Care
2003;26:125-31.[Abstract/Free Full Text]
Confusing SCOUT timeline 12 March 2010
Top
Matthew Robinson,
Clinical Pharmacist
Newton Drive Surgery, FY3 8LZ
Finer et al state that final closure of SCOUT was delayed to allow for
robust data collection and analysis.
I wonder why a trial with a planned completion date of March 2009(1) has
not yet been published in peer review literature while the data are
available to regulatory authorities who have made the decision to
suspend the drug!.
William's editorial may well be in advance of the facts - but that
raises the thorny question as to why the data are not yet in the public
domain after almost a year has passed.
1/ http://www.clinicaltrial.gov/ct2/show/NCT00234832
Competing interests: None declared