Rush Toward New Weight-Loss Drugs Tramples Patients' Health

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Rush Toward New Weight-Loss Drugs Tramples Patients' Health

By Susan Kelleher

The Seattle Times

 

Sunday 26 June 2005

 

When Tami Melum hugs her heart-shaped pillow, she can feel the pain of

the past three years seep into the surgical scar on her chest.

 

" It reminds me of how the kids and my husband suffered, " Melum

said of the pillow, which was given to her after open-heart surgery

and usually sits on a bedroom dresser in her Sedro-Woolley home. " I

keep it there as a reminder. "

 

Melum, 39, took weight-loss drugs so she could feel healthier and

keep up with her two boys, now 11 and 13. The drugs nearly killed her.

 

After being prescribed Redux and a drug combination known as

" phen-fen, " Melum developed heart damage so severe that in 2002

surgeons had to cut open her chest and heart and install an artificial

valve.

 

She is a tragic testament to what can go wrong in a system where

the powerful pharmaceutical industry influences what constitutes a

disease, who has it, and how it should be treated.

 

Before taking the drugs, Melum was overweight but healthy: Her

cholesterol, blood pressure and blood sugar were all normal.

 

But that wasn't enough. By the mid-1990s, the medical

establishment had changed its mind about people such as Melum. Some of

the world's most prominent obesity experts, with backing from the drug

industry and medical societies, defined obesity as a stand-alone

" disease " that caused premature death and needed to be treated with drugs.

 

Suddenly, Tami Melum and millions like her were, by definition, sick.

 

In making obesity a disease, these experts helped create a

billion-dollar market for the drugs that maimed Melum, killed

hundreds, and damaged the hearts and lungs of tens of thousands.

 

The story of obesity shows how it became acceptable for doctors to

risk killing or injuring people on the premise that it would save them

from illnesses they might never get.

 

How Fat Hit the Fire

 

Body Mass Index helped fan the flames of diet craze.

 

How did the fight against fat reach this point?

 

It started more than a decade ago as drug companies and their

scientific consultants increasingly promoted using a Body Mass Index

(BMI) of 30 as the trigger point for when someone should be treated

for obesity, including being prescribed weight-loss drugs.

 

The BMI is a height-to-weight ratio that provides a rough estimate

of body fat. Adapted from life-insurance company measures three

decades ago, the BMI not only measures obesity but also sets ranges

for " ideal weight " and " overweight. "

 

With the dividing line between being overweight and obese set at a

BMI of 30, a 5-foot-10 person would be obese once he weighed 209

pounds or more. About 30 percent of the nation's adults are estimated

to be obese.

 

 

 

At the time the BMI standard was being promoted as a disease, only

two prescription weight-loss drugs were available in the United

States: phentermine, approved by the Food and Drug Administration

(FDA) in 1959, and fenfluramine, sold as Pondimin, approved in 1973.

 

In the early 1990s, doctors began prescribing them together for

weight loss, and a diet craze took off. The FDA had not signed off on

the safety of the two being used together. This " off-label " use of

phen-fen therefore carried unknown risks for patients and their

prescribing doctors.

 

With the patent on Pondimin soon to expire, a drug company formulated

a blend of molecules in the two drugs and created Redux,

dexfenfluramine. Like phen-fen, it gave its users the feeling of being

full.

 

With a new drug in the pipeline, the industry and its experts

demonstrated a new urgency to define obesity as a chronic disease that

should be treated with its own drug.

 

In May 1995, the National Institutes of Health (NIH) asked 24

experts to write guidelines for diagnosing and treating obesity. The

expert panel officially defined obesity as a BMI of 30 or higher, and

overweight as a BMI above 25 and below 30. The panel, which included

the pharmacologist who created the phen-fen combo, was criticized for

its ties to the drug and weight-loss industries.

 

In fall 1995, the FDA first took up the approval of Redux, owned

at the time by Interneuron Pharmaceuticals. If approved, Redux would

be the first new weight-loss drug in more than 20 years.

 

At the hearings, Interneuron presented data showing an obesity

pandemic and said desperate measures were required to stop it from

prematurely killing 300,000 Americans a year.

 

That controversial figure came from weight-loss experts and

researchers who used epidemiological data from decades-old health

studies to build the case that excess body fat was a crisis more

urgent than even AIDS. They estimated the economic cost in health

care, including associated heart attacks, diabetes and other diseases,

to be more than $60 billion a year.

 

The high costs and daunting death toll bolstered support for

physicians to apply risky treatments to the obese, such as gastric

bypass surgery, stomach banding or long-term courses of drugs that

would be too dangerous to give to healthy people.

 

Although phen-fen and Redux were billed as lifesavers, they also

were known to have fatal side effects in certain cases.

 

At the FDA hearing, Interneuron and its experts presented grisly

calculations in support of Redux's approval: For every nine people who

died from the drug in a given year, 280 people would be saved from

premature deaths.

 

The company's chief scientific officer, Dr. Bobby Sandage, told

the FDA panel that, despite expected deaths, the drug had " a highly

favorable safety profile given the morbidity and mortality of obesity. "

 

Dr. JoAnn Manson, a Harvard medical professor, making a

presentation on behalf of the drug maker, said her research showed

that even modest weight loss - as little as 11 pounds - would

" substantially reduce morbidity and mortality. "

 

One of the leading obesity experts supporting Redux and the effort

to classify obesity as a disease was Dr. George Bray, a physician and

medical researcher at Louisiana State University. A consultant for

numerous drug companies for more than three decades, Bray holds

patents for such things as low-fat potato chips, a cream to reduce fat

thighs, and treatment for metabolic disorders.

 

Also at the hearing was a newly formed group, the American Obesity

Association, which built a case for treating obesity as a chronic

disease. Funded largely by drug companies, including two involved with

Redux, the association was headed by Dr. Richard Atkinson, an

internist who advocated gastric bypass for severe obesity and who

later founded a company to test for what he believed might be an

" obesity virus. "

 

At the hearing, the association positioned itself as a

patient-advocacy organization, though it offered no patients to

testify for the drug.

 

Dr. Leo Lutwak, the FDA scientist who evaluated Redux, opposed its

approval, saying it was too risky for what he thought were only modest

weight losses. He said he was concerned about the drug's effect on the

brain and its " frightening " association with pulmonary hypertension,

an irreparable and often fatal lung disease.

 

Although few in the field questioned that obesity in its extreme

form posed substantial health risks, less was known about the health

risks for those who were marginally obese.

 

When drugs are given to people on the margins of disease, the

number of people harmed with little benefit increases exponentially,

critics said.

 

The FDA committee members discussed the troubling data surrounding

Redux for nine hours and voted 5-3 against its approval. After

impassioned pleas from one member, the committee took a second vote,

but the 3-2 vote for approval was voided because some members had

left. Another meeting was scheduled for November.

 

Judith Stern, vice president of the American Obesity Association

and a nutritionist at the University of California, Davis, was

disappointed the panel members had not voted to approve Redux. Stern

told reporters, " If they recommend 'no,' these doctors ought to be shot. "

 

The committee voted 6-5 in November to recommend approval, and in

April the FDA gave the drug clearance for long-term use.

 

The drug went on sale in May 1996. Prescriptions for the drug that

year topped 18 million.

 

Pills' High Cost

 

Woman learns weight-loss drugs have damaged her heart.

 

Melum, then a 30-year-old mother of two in Skagit County, was

swept into the anti-fat fervor by her doctor, who shared the same

health club and noticed how hard Melum was working to lose the weight

she had gained during her second pregnancy.

 

Getting into better shape was important to Melum, who wanted to be

the kind of mom who played sports with her kids. The extra weight made

her feel slow, she said, and her blood pressure, while still in a

healthy range, began creeping up.

 

Melum took the phen-fen combination for six months starting in

February 1996. In one month, she lost 22 pounds from her 5-foot-5-inch

frame, dropping to 203. She lost another 13 pounds over the next six

months. " It worked great, I have to admit, " she said.

 

She took Redux for two or three months, and when it seemed to stop

working, resumed taking phen-fen for about five more months. Melum

said she doesn't recall discussing the known risks with her doctor

when she began taking phen-fen and Redux.

 

At the time, the drug maker noted what it said were rare instances

of lung damage but nothing else of significance. But across the

country, Redux users were suffering heart damage, a side effect the

drug maker never mentioned.

 

The first outsider to publicly warn about Redux and heart damage

was a medical technician at a Fargo, N.D., clinic. She noticed that

echocardiograms of younger women, with no history of heart disease,

showed severely damaged heart valves after taking the diet drugs. The

doctor she worked for sent two dozen case files to the Mayo Clinic.

 

There at the clinic, cardiologists researched the matter and

concluded that Redux and phen-fen were linked to heart-valve damage.

The clinic announced this startling finding in summer 1997, and the

FDA followed up with its own warning about the drugs to doctors,

hospitals and the public.

 

 

Unaware, Melum took the drugs until September 1997, when a local

pharmacist told her they had been pulled from the market. He told her

she might be able to get her prescription filled elsewhere.

 

She tried without success but went on with her workouts.

 

In fact, Wyeth, which by then held the license to Redux, had

pulled the drug from the market that month. It also stopped selling

Pondimin, its brand-name fenfluramine, half of the phen-fen combo.

 

Melum said her doctor, Nadine Burrington in Mount Vernon, never

contacted her after news broke of the potentially deadly side effects.

Melum said the doctor eventually apologized and told her she had no

idea the drugs would harm her.

 

Melum gave Burrington permission to discuss all aspects of her

treatment with The Seattle Times. The doctor declined to be interviewed.

 

The first information Melum received about potential problems with

her heart came in early 2001 in the form of an information packet

Wyeth sent her. The mailing was part of its proposed legal settlement

with hundreds of thousands of patients in a class-action lawsuit.

Melum said she kept the information but ignored it until fall 2001. At

a friend's urging, she applied for Wyeth's free testing, which

discovered her valve damage.

 

" The doctor told me if I had waited much longer, I would be a

candidate for [a heart] transplant, " Melum said.

 

In May 2002, a surgeon sawed through Melum's sternum, cut into her

heart and replaced a valve that controls blood flow on the left side

of her heart.

 

Within three weeks, she suffered an allergic reaction to the

anesthesia and was hospitalized. Two days later, she was near death.

 

In emergency surgery at the University of Washington Medical

Center, doctors inserted a tube in her chest and siphoned more than

three quarts of fluid from her heart. Her husband, Glenn, watched and

wondered how he was going to raise the boys by himself.

 

" I was standing there watching her just slip away from me, " he

said in an interview, looking to the ceiling to keep tears at bay.

 

The medical bills related to her surgeries topped $140,000.

 

Wyeth established a $3.7 billion trust fund for injured patients

in 2000 as part of a proposed settlement and created a $1.2 billion

supplemental fund for patients earlier this year. Wyeth said it

expects to pay $21.1 billion to settle legal claims involving phen-fen

and Redux.

 

Melum joined the lawsuit and settled her claim in December. After

fees, she received $500,000. She now weighs more than when she started

the drugs, has an eight-inch scar down her chest, and will have to

take a daily blood thinner for life.

 

Pushing Ahead

 

Weight-loss industry works to forge treatment guidelines.

 

The industry lost a blockbuster obesity drug, but more were in

development. In the years after the Redux fiasco, the weight-loss

industry - doctors, nutritionists, weight-loss clinics, drug makers -

supported efforts to keep obesity classified as a disease and

successfully lobbied for insurance to cover its treatment.

 

Industry-sponsored obesity experts continued to support treatment

guidelines for obesity that included prescribing drugs. Guidelines are

essentially detailed steps for doctors in diagnosing and treating an

ailment, including recommended drugs to prescribe.

 

The doctors who write guidelines are a powerful force in health

care because their opinions become the blueprints that drug companies

and medical societies use to teach doctors in the trenches how to

prescribe newly approved drugs.

 

Many of the doctors who supported Redux, including Bray of

Louisiana State University and others, worked on the obesity

guidelines for the NIH and the World Health Organization.

 

These experts ended up endorsing the notion that doctors should

encourage obese patients to lose weight at almost any cost.

 

The guidelines also discussed the approval of future weight-loss

drugs. New anti-obesity drugs should be approved if significant

numbers of people taking them lost at least 5 percent of their body

weight and kept it off, compared to those taking placebos.

 

The FDA agreed with that target.

 

The world's leading weight-loss experts also argued that

weight-loss drugs should be given to marginally obese people who could

not lose weight by other means and even to overweight people who had

at least two other " at risk " conditions such as high cholesterol and

elevated blood pressure.

 

Some of them argued that the FDA should approve new weight-loss

drugs even if obese people lost only 7 pounds on them.

 

Critics of the guidelines, notably those not associated with the

drug industry, argued that physical activity and fitness play a

greater role in health than body fat. People can be fat and fit.

 

Those experts also said the drive to classify excessive body fat

as a disease and develop rules for its treatment would make more sense

if there were effective treatments and proof that losing weight would

enable someone to live a longer, healthier life. But there are no

effective long-term methods for significant weight loss, studies show.

 

Some doctors say obesity can be modified, but " there's no evidence

it can be easily changed, " said Paul Ernsberger, a nutrition professor

and drug researcher at Case Western Reserve University. Everything

tried so far, he said, has " an abysmal success rate. "

 

Like most others with dissenting views on obesity, Ernsberger was

not invited to sit on the expert medical panels that wrote guidelines

for the treatment of obesity. At the Redux approval hearings, he came

on his own and testified about its dangers during a public-comment period.

 

" There's this fantasy of taking 160 million overweight Americans

and instantly converting them to the mythical ideal weight, "

Ernsberger said in an interview.

 

Recently, a study by the federal Centers for Disease Control and

Prevention challenged the conventional wisdom that the nation faces a

medical crisis caused by fat.

 

In fact, carrying a few extra pounds may prolong life, especially

in the elderly, the study shows. People who are overweight, but not

obese, have a lower death risk than people of normal weight, according

to the study. Obese people, except for those who are extremely obese,

face only a slightly increased risk of death from their weight, the

study shows.

 

The study's federal scientists discounted previous estimates of

300,000 annual deaths due to obesity, the controversial figure used by

pharmaceutical companies to justify selling the risky weight-loss

drugs. Authors of the new study said the 300,000 figure had been

exaggerated by selective data and faulty analysis.

 

Instead, obesity was associated with 112,000 deaths each year -

most of them in extremely obese people, the study said. Being

underweight had risks, too, and was said to be responsible for 34,000

premature deaths a year.

 

More Drugs on Way

 

More than 70 new medicines in development; industry wages

terminology battle.

 

Whether anyone is becoming healthier because of all the activity

remains to be seen. What is clear is that people continue to gain

weight, that governments are worried about what that could mean for

the future of health-care spending, and that more weight-loss drugs

will continue to hit the FDA pipeline.

 

Currently, two prescription weight-loss drugs are sold in the

U.S., and more than 70 are in development.

 

Meanwhile, the lobbying arm of the drug industry, Pharmaceutical

Research and Manufacturers of America (PhRMA), continues to press the

FDA to allow overweight people to enroll in drug trials for new

weight-loss drugs.

 

PhRMA also asked the FDA to stop referring to obese people as

" relatively healthy " or " otherwise healthy. " The industry group said

such language " sends the wrong message " and does not reflect its view

that obesity is a chronic disease requiring life-long intervention.

 

One person who will be paying close attention to the debate is

Tami Melum.

 

Had she known then what she knows now, she never would have taken

the risk that the drug-company experts minimized in their battle

against fat.

 

" You may be a little overweight, " she said, " but at least you have

your health. "

 

 

 

 

 

 

 

Overweight Who Diet Risk Dying Earlier, Says Study

By Ian Sample

The Guardian UK

 

Monday 27 June 2005

 

Overweight people who diet to reach a healthier weight are more

likely to die young than those who remain fat, according to a study.

 

The finding needs to be backed up by further research before

sweeping changes are made to public health strategies, the authors

warn, but it highlights how poorly the long-term health effects of

dieting are understood.

 

It is well proven that losing weight reduces the risk of heart

disease and diabetes among the obese, but the new study suggests that

dieting also causes physiological damage that in the long term can

outweigh the benefits.

 

The authors stressed that very overweight people and those with

weight-related illnesses should not be deterred from dieting, but

added that researchers should in future consider the short-term

advantages of weight loss against the potential long-term risks.

 

" We need to study the effects of weight loss on the body much

better than we have done so far, " said the study's lead researcher,

Thorkild Sorensen, of the Institute of Preventive Medicine at

Copenhagen University hospital.

 

The study, which was carried out in Finland, followed 2,957

overweight or obese people who had been screened to ensure they had no

underlying illnesses.

 

Overweight people have body mass indexes (BMIs) greater than 25,

while obese people have BMIs greater than 30.

 

Each participant was questioned about their desire to lose weight

in 1975 and again in 1981. Records of their weight and general health

were kept for the next 18 years, during which 268 of the participants

died.

 

Analysis of the data showed that those who wanted to lose weight

and succeeded were significantly more likely to die young than those

who stayed fat.

 

" Healthy overweight or obese subjects who try to lose weight and

succeed in doing so over a six-year period suffer from almost double

the risk of dying during the next 18 years compared with subjects who

do not try to lose weight and whose weight remains stable, " said Dr

Sorensen.

 

Those who gained weight also had a greater risk of dying young.

 

The researchers were unable to identify why the dieters were at a

greater risk of dying younger, but believe it is caused by fat being

lost from lean organs as well as other body tissues.

 

" It seems as if the long-term effect of the weight loss is a

general weakening of the body that leads to an increased risk of dying

from several different causes, " said Dr Sorensen. " The adverse effects

of losing lean body mass may overrule the beneficial effects of losing

fat mass when dieting, " he added.

 

The finding is supported by an earlier study by researchers at the

US National Centre for Chronic Disease Prevention and Health Promotion

in Atlanta.

 

It followed 6,391 overweight or obese people for nine years and

found that those who had no intention of losing weight and even gained

weight were least at risk of dying young.

 

If the latest study is confirmed, it emphasises the need to

prevent people becoming overweight and obese, the authors say.

 

" If people are overweight, their main priority should be to stop

gaining weight and then work on losing some rather than chasing a low

body mass index, " said Tom Sanders, professor of nutrition and

dietetics at King's College London. " If you can stop people gaining

weight in their 20s and 30s, it seems to have the best outcome in the

long term. "

 

Adult obesity has nearly quadrupled in Britain in the past 25

years with around 22% now obese and three quarters overweight.

 

A National Audit Office report into obesity in 2002 estimated that

the condition cost the NHS £500m a year.

 

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