(23-08-10) Elsevier Global Medical News By Mitchel L. Zoler Weight-Loss Drug Sibutramine Fails Safety Trial

STOCKHOLM (EGMN) ? When European drug regulators called for a study to push
the safety profile of the sympathomimetic weight-loss drug sibutramine to its
limit, sibutramine failed the test.

Stephen R?ssner

W. Philip T. James
In a randomized, placebo-controlled trial with nearly 10,000 patients, most of
whom had a history of cardiovascular disease, an average of nearly 4 years of
treatment with 10-15 mg sibutramine daily produced a 1.4% absolute increased
rate of cardiovascular events, especially nonfatal myocardial infarction and
stroke, compared with placebo patients ? a 16% relative increased risk that was
statistically significant, Dr. Luc van Gaal said at the eleventh International
Congress on Obesity. This excess risk from sibutramine seemed linked to a
consistent rise in recipient?s blood pressure of 1.5-2.0 mm Hg, and heart rate
by 2-4 beats per minute.
Results from the Sibutramine Cardiovascular Outcome Trial (SCOUT) also showed
that the drug effectively aided weight loss, producing a significant loss of at
least 5% of baseline weight in 42% of treated patients, and these bigger losers
had their risk for a cardiovascular event substantially blunted.
Preliminary results of SCOUT were given to the Food and Drug Administration
and the European Medicines Agency (EMA) last fall, and in January both
regulators took action: the U.S. Food and Drug Administration contraindicated
sibutramine in people with a history of cardiovascular disease, and EMA
withdrew its marketing approval.
The drug remains available in several other countries including Australia and
Brazil.
This inconsistent approach to the new data appeared to rankle European
physicians who treat obesity and heard the SCOUT results reported for the first
time at the meeting. They seemed especially puzzled by SCOUT?s design, with its
enrollment largely including patients with cardiovascular-disease history or
risk even though these are label contraindications, and by continuing patients
on chronic sibutramine even when they lacked a weight-loss response.
?Some of us feel we could use sibutramine in a responsible way to benefit
patients? despite the safety problem that SCOUT revealed, said Dr. Stephen
R?ssner, an obesity specialist and professor of health-related behavioral
science at the Karolinska Institute in Stockholm, who spoke as a discussant of
SCOUT and was not involved in the study. ?For many patients, on an individual
basis, sibutramine would be very beneficial. We had desperate patients calling
when they found out that they would not be able to get the drug anymore.?
Currently, The European Union gives marketing approval to just one drug for
obesity treatment, orlistat (Xenical), he noted.
?Everyone agrees that sibutramine has cardiologic effects that you need to
control for. But many patients without cardiology problems need weight-loss
maintenance for treating sleep apnea or osteoarthritis. Sibutramine could be
very helpful provided you can control the risks, but I think that can be done
by a responsible physician,? Dr. R?ssner said in an interview.
SCOUT was sponsored by Abbott, which markets sibutramine, to address questions
about the drug?s safety from the EMA. An independent steering committee formed
to run the study, led by Dr. W. Philip T. James, of the London School of
Hygiene and Tropical Health and president of the International Association for
the Study of Obesity, the meeting organizer. Dr. James has been a consultant to
and served on an advisory board for Abbott and for Sanofi-Aventis and
GlaxoSmithKline, and he has been a speaker for Roche and Sanofi-Aventis. Dr.
R?ssner said he has received research and travel support from Abbott,
GlaxoSmithKline, Novo Nordisk, Pfizer Inc., and Roche.
The trial ran at 297 sites in 16 countries, including Australia, Brazil, and
Mexico as well as several European countries. The first patient randomized in
February 2003, the last patient in December 2005, and the follow-up database
closed in November 2009.
When SCOUT began it enrolled three types of patients in equal numbers:
patients with type 2 diabetes and at least one cardiovascular risk factor ?
controlled hypertension, dyslipidemia, smoking, or diabetic nephropathy with
microalbuminuria; patients only with diagnosed coronary artery disease or
peripheral arterial disease; and patients who fulfilled both of these two
criteria. Less than a year into the study, the steering committee decided to
boost the event rate in the trial by narrowing enrollment to only patients with
a history of cardiovascular disease, either alone or with type 2 diabetes. The
consequence was that of the 9,996 patients randomized in SCOUT 76% had a
history of cardiovascular disease, and 84% had type 2 diabetes; 60% had both.
Their average age was 63, older than is typical in a weight-loss study, and 58%
were men, more than is typical in a weight-loss trial. Their average baseline
body mass index was 34 kg/m2.
All patients began on 10 mg sibutramine daily for a 6-week run-in to screen
out patients whose blood pressure rose too high. Most patients also lost weight
during this phase, an average of 2.2 kg.
After 6 weeks, randomization assigned patients to either 10 mg sibutramine or
placebo. Those in the active-treatment arm could have their dosage raised to 15
mg/day, which happened for a third of the sibutramine patients.
The intention-to-treat primary end point analysis included 4,906 patients
treated with sibutramine and 4,898 who received placebo followed for an average
of 3.8 years on treatment. In addition to the primary end point, the combined
rate of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac
arrest, and cardiovascular death, the SCOUT investigators reported several
other important outcomes.
In the 24% of patients with diabetes and one risk factor, the primary end-
point rate ran 6.5% in both the sibutramine and placebo groups. In contrast, in
patients with cardiovascular disease history and diabetes sibutramine added 2%
to the placebo risk, and in those with cardiovascular disease history only
sibutramine produced an added 1.8% of event rates over placebo.
The results also documented sibutramine?s efficacy for weight loss. Forty-two
percent of patients in the sibutramine group lost at least 5% of their baseline
weight, compared with 24% of the placebo patients. The percent of patients who
gained weight on the regimen was 24% on sibutramine and 38% on placebo.
Patients who responded to sibutramine by losing weight also had an improved
prognosis. For each 1 kg lost during the 6-week sibutramine-treatment phase for
all patients, patients had a 0.8% reduction in their incidence of a primary-
outcome event during follow-up, said Dr. Ian Caterson, professor of human
nutrition at the University of Sydney and another collaborator on the study.
In addition, patients who lost weight had a significant reduction in their
blood pressure. The average blood pressure of patients who lost at least 5% of
their baseline weight closely tracked with the placebo level throughout the 5
years of the study. Only patients on sibutramine who failed to lose at least 5%
had significantly increased blood pressure, compared with the placebo group,
reported Dr. Arya M. Sharma, professor of medicine and chairman of obesity
research and management at the University of Alberta, Edmonton, and another
member of the SCOUT steering committee.
Despite the positive weight-loss results, the known action of sibutramine as a
serotonin-noradrenalin reuptake inhibitor, its discernable blood pressure
effect, and the excess of cardiovascular events it caused in SCOUT together
create a ?causal train? between the drug and clinically meaningful adverse
events, said Dr. Steven B. Heymsfield. ?Drug companies will stay away from
this,? said Dr. Heymsfield, who spoke as the session?s second invited
discussant and is executive director of clinical sciences and head of obesity
drug development at Merck in Rahway, New Jersey.
?The question is risk benefit, and they haven?t shown the benefit of
[sibutramine.] It?s critical to show a medical benefit? from sibutramine, Dr.
Heymsfield said.
Despite Dr. Heymsfield?s skepticism about regulators accepting a future role
for sibutramine in routine practice, one member of the steering committee
voiced his support of countries that have kept sibutramine available.
?In Brazil sibutramine is still on the market and widely used, with a million
prescriptions per year,? said Dr. Walmir Coutinho, an endocrinologist at
Catholic University in Rio de Janeiro, and a member of the SCOUT steering
committee. ?Brazilian physicians believe it should remain on the market,? he
said, citing a recent statement from the society of Brazilian endocrinologists.
?The event rates in patients without cardiovascular disease were very low.?
Aside from Dr. Coutinho?s statement of support for the Brazilian approach to
regulating sibutramine, the SCOUT steering committee members who presented the
study?s data deliberately avoided commenting on the EMA?s action. The closest
anyone came was when Dr. James, in response to a question, referred back to
what Dr. Coutinho had said. He ?said effectively that [the EMA?s decision] wasn?
t appropriate,? Dr. James said.

Source: univadis.it

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