Article on Weight Loss Pills: A high price for lost pounds

A high price for lost pounds
Woman now suffers heart failure
Pills off market, but others are available

RITA DALY AND KAREN PALMER
Toronto Star STAFF REPORTERS

When Sheila Wilson was prescribed a diet pill to help her lose weight,
it never occurred to her it might not be safe. After a year on the
medication she could barely walk, or breathe.

Wilson would eventually join hundreds of other women and men worldwide
who became permanently injured or died after taking fenfluramine
(marketed as Ponderal in Canada) and dexfenfluramine (Redux), two
popular and closely related diet drugs used to treat obesity. More than
155,000 Canadians were on the drugs.

Highly promoted to be safe and effective, the drugs were found to cause
a rare, but fatal, heart-lung disease called primary pulmonary
hypertension.

Both were pulled off the global market in 1997.

Today, Wilson, a once active mother of five, is in a state of heart
failure, hooked up to oxygen nightly and on a daily regimen of pills to
keep her alive. Doctors have told her she could die in three years.

She is part of a class action settlement reached with Servier Canada,
which marketed the drugs in Canada. Servier has settled with no
admission of liability.

Wilson is the first to acknowledge that all medicines carry a risk.

In this case, she says it wasn't one she would have taken if she had
known about the drug's damaging effects.

"I understand all drugs have a risk and a benefit," says the
68-year-old Scarborough resident.

"But for a drug to be on the market, the benefits have to far outweigh
the risks, especially when there's a risk you're going to get a fatal
illness."

Obesity is being called the world's fastest growing health problem,
with two-thirds of Americans and half of Canadians said to be
overweight or obese.

Two to 3 per cent of Canadians are considered morbidly obese: defined
as more than 100 pounds overweight.

It is also one of the hottest areas of pharmaceutical research, with
more than a dozen prospective obesity pills moving through the
pipeline.

But developing a drug that is both safe and effective for a condition
that carries a risk of diabetes, heart disease and certain types of
cancer has so far had limited success.

There is no standard formula for approving any drug.

Each is assessed on its own merits and there are varying levels of
safety, depending on how sick the population is that the drug is
intended for.

In the case of obesity drugs, the decision has been particularly
challenging.

Following the withdrawal of Ponderal and Redux, Health Canada and the
Food and Drug Administration in the United States approved two new
obesity pills, Meridia and Xenical. Though safer than their
predecessors, both are suspected of causing potentially serious side
effects for some patients.

In addition, in approving drugs to help those facing life-threatening
obesity, regulators have opened the door for those seeking ways to lose
a few pounds and for whom the drugs' benefit may not be worth the risk.

Meridia, originally tested as an antidepressant, works by creating a
feeling of fullness and is known to cause high blood pressure and
increase the heart rate, both of which can lead to cardiac events.

Xenical can cause vitamin deficiency, severe cramping and possibly
pancreatitis, and has another unpleasant, less serious "side effect"
that is actually its mechanism of action: it bars the body from
absorbing fat, meaning fats consumed are expelled in the form of oily,
orange diarrhea.

Government regulators have been pressured for more than a decade by
obesity experts and patients to approve drugs whose safety, in some
cases, was questioned from the start.

Scientific reviewers at the FDA, for example, initially rejected
Redux's application in a 5-3 vote, saying there wasn't enough evidence
to support its claims of safety and efficacy.

Warnings coming out of Europe in 1995 said the drug raised the risk of
the heart-lung disease if used longer than three months.

Its U.S. application seeking approval to sell the drug was amended
seven times until a second vote in April 1996 ended up 6-5 in favour,
upsetting researchers concerned about its safety.

Three months later, Health Canada also approved the drug.

Both regulators licensed the drug's use for up to one year because
obesity experts argued long-term treatment was sorely needed.

Shortly after, an international study published in the New England
Journal of Medicine revealed an even higher risk of primary pulmonary
hypertension than previously reported for patients on fenfluramine or
Redux for longer than three months.

A year later, another study resulted in the drugs being pulled.

Wilson said the most agonizing part is that she was given no indication
of fenfluramine's harmful effects.

It had been on the market since the 1970s but had not been widely used
until the mid-'90s, when it was marketed in combination with another
appetite suppressant as Fen-Phen, or alone as Ponderal.

"I had no warning and was told of no side effects," Wilson said. "I
don't even know if my doctor knew."

In the case of Meridia, submitted for approval in the U.S. in 1995,
regulators were aware of the drug's risk of high blood pressure, which
could subject a significant number of overweight people to cardiac
events.

The FDA ignored a 5-4 expert vote against approving Meridia and a year
later, in November 1997, allowed the drug on the U.S. market, two
months after it recalled Redux and fenfluramine.

Canadian experts also cautioned against extensive use of the drug.

According to Access to Information documents obtained by the Star,
Health Canada drug reviewer Joanne Goh, of the central nervous system
committee, noted that because Meridia could raise a person's blood
pressure and possibly their pulse rate, it shouldn't be used in
patients with or at risk of "poorly controlled hypertension, coronary
artery disease, angina pectoris, congestive heart failure, stroke,
transient ischemic attacks, cardiac tachyarrhythmias, Type II diabetes,
hyperthroidism, peripheral vascular disease and known or suspected
cardiovascular disease."

Dr. Stuart Connolly, a Hamilton cardiologist, was asked to give an
independent review and also cautioned against its use in most of the
general obese population.

In December 2000, four years after its application, Meridia was
approved by Health Canada on condition the drug only be used in
patients whose blood pressure is well controlled.

Sarah Henderson, spokesperson for Abbott Laboratories Inc., maker of
Meridia, said the drug has been proven to be safe and, when used in
combination with diet and exercise, "can produce and maintain a
statistically significant weight loss in patients."

The drug, she added, includes instructions to doctors on how to
supervise patients over the course of their treatment.

Doctors are required to monitor patients' blood pressure every two
weeks for the first three months, and regularly thereafter, she said.

"It's really a decision between a doctor and a patient regarding the
appropriate therapy."

Since it came on the market, Meridia has been dogged by controversy.

Public Citizen, an American patient advocacy group, has twice
petitioned the FDA to ban the drug, recently citing 49 cardiovascular
deaths.

Abbott has rejected the claims, saying Meridia's safety record is sound
and supported by an extensive integrated safety database representing
dozens of clinical studies. The petition, the company said, is based on
few facts and no coherent analysis.


In 2002, the drug was temporarily banned in Italy following a series of
cardiovascular events including two deaths, triggering a European
review.

It was reinstated after the review concluded the drug was not linked to
the deaths. Abbott has since launched its own cardiovascular outcomes
study on the drug.

Health Canada conducted its own safety review, concluding 53 adverse
reaction reports in its database from March 1, 2002 to Nov. 13, 2002
were consistent with known reactions such as increased blood pressure
and heart rate, chest pain, stroke and bleeding from the eyes.

No deaths had been reported.

Dr. David Graham, a veteran FDA researcher who questioned the safety of
the anti-arthritic drug Vioxx before it was recalled in September,
singled out at a recent Senate hearing five other medicines currently
on the market as needing closer scrutiny for safety: one was Meridia.

Graham claims Abbott's Meridia works only if used long-term, but many
people stop taking it early because of side effects. The FDA said it
does not share his views.

Abbott also responded, saying 15 million people have used its drug
worldwide and studies continue to support its safety.

Carolyn Sawler, a 40-year-old mother of three, said she went off the
drug after five weeks because she experienced so many side effects,
including headaches, dry mouth, insomnia, an increase in heart rate,
chest pain, nausea, increased sweating, increased blood pressure and
shortness of breath.

Sawler, who recently advised against taking the drug on the Weight
Watchers website, said in an interview that at least she was aware of
the risks.

"When my doctor read off all the potential side effects, I believe
there were 21 of them. I think I got 19 of them."

An analysis of Canadian adverse drug reaction report data, obtained by
the Toronto Star, shows there have been 150 reports filed where Meridia
was suspected in an adverse reaction, 68 of which were deemed serious.

There have been 148 reports for Roche's Xenical, 133 deemed serious.
Xenical was suspected of contributing to three deaths, but Health
Canada and drug makers warn no causal links can be established from the
data alone.

The reports are based on suspicions and are not intended, nor do they
prove, a causal link, but they are nonetheless entered into a database,
which is used as a surveillance tool by Health Canada.

Complicating the issue of the risks associated with obesity drugs is an
ongoing debate over obesity's impact on public health and how effective
weight-loss treatments are in battling it.

Critics have argued obesity experts have gone too far in medicalizing
the notion of fat, and have called into question the "inflated"
hundreds of thousands of Americans claimed to be dying of obesity.

Two weeks ago, the U.S. Centers for Disease Control and Prevention
admitted that because of statistical errors it had overestimated the
numbers of obesity-related deaths in a study commonly cited to bolster
arguments that obesity was overtaking tobacco as the primary cause of
preventable death.

Others debate whether body mass index, used to measure one's body fat,
is even accurate since it ignores fat distribution in the body and the
fat-muscle proportion of total weight.

The index, created in the 19th century by a Belgian statistician, was
revised downward in 1998, in a single day moving millions of people
into the realm of overweight status.

A person is overweight if their BMI is between 25 and 29.9. A BMI of 30
or more is considered obese.

Still others point out that while obesity can be attributed to a
genetic predisposition, poor diet or lack of exercise, the growing use
of prescription drugs, like anti-psychotics and antidepressants, are
causing significant weight gain among more people.

Physicians treating obese patients say there is still no denying the
fact, obesity is a health condition requiring urgent treatment.

Dr. Arya Sharma, a Canadian expert in cardiovascular obesity and
professor at Hamilton's McMaster University, says an estimated 200,000
severely obese patients in Ontario face such a dangerous health risk
that any drug is worth trying. For many, whose body mass index is 40 or
above, exercise isn't even an option.

"If obesity is contributing to your ill health and you're not able to
deal with obesity any other way, then maybe a pill is the answer,
because it's solving the medical problem," he says.

Robert Ross, an obesity expert at the School of Physical and Health
Education at Queen's University, says drugs like Meridia and Xenical
are meant as a last-gasp effort for the obese.

"If we can get a 5 per cent weight loss in someone who's morbidly obese
where lifestyle therapy tends to be less effective, let's try it.

``There's a place for obesity reduction through pharmacological
therapy."

The far bigger problem, he says, is that while the drugs are approved
for obese patients, they have become instantly popular among mildly
overweight women anxious to lose a few pounds and, in some cases,
unaware of the potentially serious side effects.

When Xenical came out, women were clamouring for it.

"If they didn't have a doctor willing to prescribe it, they found one
who did," he says.

Jennifer Lamond, a 31-year-old policy analyst in Etobicoke, says she
heard about the drug on a bridal chat board where diet pills are often
discussed.

She decided to try Xenical to help her lose 30 pounds before her
wedding.

Almost immediately Lamond says she had out-of-control diarrhea.

Even after she began to watch her fat intake, she found herself
constantly running to the washroom.

Worse, she says, "I tried the drug for a month and didn't lose a thing."

New obesity drugs were approved by drug regulators after clinical
trials ‹ which test a medication's effectiveness and safety ‹ showed
volunteer subjects lost at least 5 per cent of their body weight while
on the pill, compared to those on a placebo.

That patients gained their weight back after going off the pills hasn't
been factored into their approval.

With little proven long-term benefit and potential serious side
effects, critics have been calling for regulators both in Canada and
the U.S. to raise the risk and benefit threshold for approving new
drugs.

They point out that pre-approval studies are carried out by the drug
company, which has an obvious commercial interest, and aren't generally
designed to test a product's safety.

The process is also carried out behind closed doors, although Health
Canada officials now agree it must be opened up to public scrutiny.

That happens already in the United States, where the Food and Drug
Administration holds public hearings on new drug approvals.

Critics also point out that clinical studies are carried out on small
populations and are too short to detect serious side effects, despite
the drug eventually being prescribed to millions, often for long-term
treatment.

"If the drug is going to be used by everyone, including healthy people,
then you really want to be sure these products are safe before you put
it on the market," says Joel Lexchin, a health policy professor at York
University.

Studies submitted to Health Canada for Meridia, for example, showed
that while patients lost up to 6 kilograms, long-term follow-up showed
they gained almost all the weight back once they stopped taking
Meridia. Some studies lasted as little as eight weeks; another, which
lasted a year, saw almost half of participants drop out.

Abbott's Henderson says what many fail to recognize is that obesity
drugs have been on the market now for several years and have helped
millions.

Obviously, adds Ross, people believe it's worth trying the drugs even
though they eventually gain back their weight.

After all, "why do we continue to look for diets that work when all the
evidence for 50 years is to the contrary?"

--
Diva
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There is no substitute for the right food