The first class of anti-obesity
drugs to capitalize on a clearer understanding of marijuana-related
"munchies" receptors in the brain may soon be approved
in Canada. CB-1 endocannabinoid receptor antagonists
are already available in the European Union in the form
of a drug called rimonabant.
However, two University of Alberta
researchers say the hype about the drug's potential
— weight loss, reduced cardiovascular risk factors
caused by obesity, and even improved smoking cessation
rates and reduced risk of diabetes — is completely
out of proportion with the clinical trials' "modest"
results, and serious concerns about the drug's possible
adverse effects need to be addressed.
"There is a huge question mark,"
said University of Alberta general internist Dr Raj
Padwal. "Is the benefit outweighing the risk? We don't
know."
Dr Padwal and his colleague Dr
Sumit Majumdar published a New Drug Class article in
The Lancet's January 6 issue to draw attention
to the lack of safety data available on rimonabant as
well as two other anti-obesity drugs already approved
in Canada (orlistat, which can have adverse gastrointestinal
effects; and sibutramine, which can increase blood pressure
and pulse rate).
"Yes, these drugs lower weight
in people who take them," said Dr Padwal, "and sometimes
they modestly improve cardiovascular risk factors but
it is a huge extrapolation to say that it will reduce
cardiovascular-caused death."
Rimonabant garnered a great deal
of attention and some favourable findings were published.
A randomized, placebo-controlled trial of 3,045 obese
and overweight patients with hypertension or dyslipidemia,
published in JAMA in early 2006, found weight
loss of 5 to 10% of body weight was sustained over two
years for the higher-dosage treatment group. Those patients
saw reductions in cardiovascular risk factors such as
metabolic syndrome and cholesterol levels.
But data on adverse psychiatric
effects of rimonabant is decidedly lacking, wrote Drs
Padwal and Majumdar. Nearly twice as many patients on
rimonabant dropped out of the JAMA trial as did
the controls because of problems such as nausea, dizziness,
anxiety and an increase in depression. In manufacturer
Sanofi-Aventis's FDA approval application (expected
to be decided this spring) the drug is contraindicated
for patients with a history of psychiatric disorders
— a common pathology of obese patients and a sign
of possible safety issues, warns Dr Padwal.
Blocking the CB-1 receptor appears
to reduce appetite and encourage the perception of having
consumed enough. This action has led some researchers
to investigate rimonabant as a possible nicotine addiction
drug, but such trials have been discontinued. The CB-1
receptor is the most common receptor in the brain, said
Dr Thomas W Wilson, a University of Saskatchewan cardiovascular
risk specialist, and seems to be linked to the things
that give us pleasure, such as eating, smoking and sex.
"I just wonder," mused Dr Wilson, "if it is going to
lead to people not enjoying their life, not getting
pleasure out of the things we get pleasure from. It
could reduce people's joy of living."
In addition to unclear side effects,
said Dr Padwal, studies on the drug's anti-obesity properties
have yet to prove the benefits are long-lasting. "You
don't continue to lose weight after a year," said Dr
Robert Brownsey, a University of British Columbia biochemist,
and the weight you do lose will likely be regained if
treatment is discontinued. "The implication in my mind,"
explained Dr Brownsey, "is that the drug treatment is
resetting the internal balance so the body achieves
a new set point then adjusts to defend that new weight."
MAINSTREAM
APPEAL
Considering its target is obese patients and overweight,
diabetic patients — fully two-thirds of the general
population — and the anticipation with which the
drug is being greeted in the US and Canada, rimonabant
has the potential to reach a vast swath of Canadians;
as great a reach as statins, said Dr Wilson. Some analysts
have reportedly estimated a potential $5 billion per
year market in the US alone.
But before that happens, said Dr
Padwal, we should be sure rimonabant has net benefits.
Dr Padwal described himself as
a pessimist about finding a pharmacological solution
to the obesity epidemic. "Sibutramine and orlistat cost
about $120 to $130 a month. Rimonabant probably will
be priced at the same level. A gym membership costs
20 to 30 bucks a month and the benefits are probably
better," he said. "To ask people to pay that much, we
must be sure the benefits outweigh the risks."
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