DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ENDOCRINOLOGIC AND METABOLIC DRUGS
Glenn Braunstein, M.D., Acting Chair
LCDR Dornette Spell-LeSane, M.H.A.,
Lynne L. Levitsky, M.D.
Louis J. Aronne, M.D.
Katherine Flegal, Ph.D., M.P.H.
Melanie G. Coffin (Patient Representative)
Frank L. Greenway, M.D.
Jules Hirsch, M.D.
Jack A. Yanovski, M.D., Ph.D.
Susan Z. Yanovski, M.D.
Paul D. Woolf, M.D.
Thomas O. Carpenter, M.D.
Dean A. Follmann, Ph.D.
Steven W. Ryder, M.D.
David S. Schade, M.D.
Morris Schambelan, M.D.
Nelson B. Watts, M.D.
Margaret E. Wierman, M.D.
C O N T E N T S
Call to Order and Introductions, Glenn Braunstein,
of Medicine 4
Conflict of Interest Statement,
LCDR Dornette Spell-LeSane, Executive Secretary 6
Welcome and Introductory Comments, David Orloff,
M.D., Director, DMEDP 9
The Regulatory History of Weight-Loss Drugs,
Eric Colman, M.D., Medical Team Leader, DMEDP 14
The Epidemiology of Overweight and Obesity,
Katherine Flegal, Ph.D., Senior Research
Current Status of Weight-Loss Drugs, Frank
Greenway, M.D., Director, Pennington Biomedical
Patterns of Weight-Loss Drug Use,
Laura A. Governale, Pharm.D., MBA, Drug
Utilization Specialist, Team Leader, Division of
Surveillance Research and Communications
Support, ODS 87
Role of Drugs in the Treatment of Obesity:
Current and Future, Richard L. Atkinson, M.D.,
Director, Obetech Obesity Research Center 106
Charge to the Committee, David Orloff, M.D.,
Director, DMEDP 150
Committee Discussion 186
P R O C E E D I N G S
Call to Order and Introductions
DR. BRAUNSTEIN: We will call the meeting
to order. This is the Food and Drug
Administration, Center for Drug Evaluation and
Research, Endocrinologic and Metabolic Drugs
Advisory Committee meeting, on
The agenda today is to discuss the FDA draft
guidance document entitled, "Guidance for the
Clinical Evaluation of Weight Control Drugs." The
original guidance was dated
I am Glenn Braunstein, Professor and
Chair, Department of Medicine, Cedars-Sinai Medical
Center. I am an endocrinologist. I would like to
go around the table and ask people to introduce
themselves and tell us where they are from. We
will start with Dr. Orloff.
DR. ORLOFF: I am David Orloff. I am
Director, Division of Metabolic and Endocrine Drugs
DR. COLMAN: I am Eric Colman, a medical
officer from Metabolic and Endocrine
Drugs at FDA.
DR. HIRSCH: Jules Hirsch, Rockefeller
DR. SCHAMBELAN: Morris Schambelan, from
DR. FOLLMANN: Dean Follmann, from NIH.
DR. YANOVSKI: Jack Yanovski, from NIH.
DR. LEVITSKY: Lynne Levitsky, Pediatric
Endocrinology Unit, Massachusetts General.
MS. COFFIN: I am Melanie Coffin, patient
LCDR SPELL-LESANE: Dornette Spell-LeSane,
executive secretary for the committee.
DR. GREENWAY: I am Frank Greenway, from
DR. FLEGAL: I am Katherine Flegal, from
DR. YANOVSKI: Susan Yanovski, NIH.
DR. CARPENTER: Tom Carpenter, pediatric
DR. WIERMAN: I am Maggie Wierman,
endocrinologist at the
WOOLF: Paul Woolf, endocrinologist,
DR. WATTS: Nelson Watts, endocrinology,
DR. SCHADE: Dave Schade, endocrinology,
DR. ARONNE: Louis Aronne,
DR. RYDER: Steve Ryder, Pfizer Research
and Development. I am the industry representative.
DR. BRAUNSTEIN: Thank you. I will now
turn the meeting over to LCDR Dornette
Conflict of Interest Statement
LCDR SPELL-LESANE: Good morning. The
following announcement addresses the issue of
conflict of interest with respect to this meeting
and is made a part of the record to preclude even
the appearance of such at this meeting.
Based on the agenda, it has been
determined that the topic of today's meeting is an
issue of broad applicability, and there are no
products being approved at this
issues before a committee in which a particular
product is discussed, issues of broader
applicability involve many industrial sponsors and
All special government employees have been
screened for their financial interests as they may
apply to the general topic at hand. To determine
if any conflict of interest existed, the agency has
reviewed the agenda and all relevant financial
interests reported by the meeting participants.
The Food and Drug Administration has granted
general matters waivers to the special government
employees participating in this meeting who require
a waiver under Title 18, United States Code,
A copy of the waiver statements may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building.
Because general topics impact so many
entities, it is not practical to recite all
potential conflicts of interest as they
each member, consultant and guest speaker.
FDA acknowledges that there may be
potential conflicts of interest but, because of the
general nature of the discussion before the
committee, these potential conflicts are mitigated.
With respect to FDA's invited industry
representative, we would like to disclose that Dr.
Steven Ryder is participating in this meeting as a
non-voting industry representative, acting on
behalf of regulated industry. Dr. Ryder is
employed by Pfizer Global Research and Development
as senior vice president and global
cardiovascular/metabolism/GI/GU development head.
And, although Pfizer conducts research in
therapeutic areas possibly covered by today's
discussion, Dr. Ryder's role on this committee is
to represent industry interests in general and not
any one particular company.
In the event that the discussions involve
any other products or firms not already on the
agenda for which FDA participants have a financial
interest, the participant's involvement
exclusion will be noted for the record.
With respect to all other participants, we
ask in the interest of fairness, that they address
any current or previous financial involvement with
any firm whose product they may wish to comment
upon. Thank you.
DR. BRAUNSTEIN: Thank you. Dr. David
Orloff with give the welcome and introductory
Welcome and Introductory Comments
DR. ORLOFF: Good morning. The first
thing I want to say actually before I get to the
introductory comments is that I believe, Dornette,
if I am not mistaken, we do not have any speakers
for the open public hearing. Is that correct?
LCDR SPELL-LESANE: That is correct.
DR. ORLOFF: As a result of that, time
permitting, we may try to push Dr. Atkinson's talk
up to the morning before we break for lunch. I
leave that up to Dr. Braunstein and to the clock.
I want to wish everyone a good morning and
welcome our advisors, our guest
staff and interested public.
The purpose of today's meeting of the
Metabolic and Endocrine Advisory Committee is to
revisit the division's 1996 draft guidance on the
development of drugs for the treatment of obesity.
As everyone present knows, the FDA's public health
mission includes the charge to assure that safe and
effective drugs are efficiently, but without
cutting crucial corners, brought forward through
development to the marketplace in order to
diagnose, cure, treat, prevent or mitigate disease.
That, broadly speaking, explains our purpose here
More specifically, in August of 2003 the
then Commissioner McClellan established the FDA
obesity working group and asked that group to
develop a plan of action to address critical
aspects of the burgeoning obesity problem in the
U.S. within the authorities of the Food and Drug
Germane to our work here today, he charged
the so-called therapeutic subgroup, which
by our division, to assess real or perceived
barriers to obesity drug development and to make
recommendations on ways to encourage the
development of new or enhanced therapeutics for
In the face of this growing public health
problem, advances in the understanding of the
physiology and pathophysiology of obesity and the
activity within the pharmaceutical industry in this
therapeutic area, we took the opportunity to plan a
discussion of the current guidance and its
potential modification. Today's meeting is further
timely in light of the recent release by NIH,
announced on August 24th, of the final version of
its own strategic plan for obesity research which
includes intensification of efforts on
pharmacologic approaches to the prevention and
treatment of obesity in both children and adults.
In early 2004 we published a formal call
for comments on the guidance in the Federal
Register, with an open comment period until late
Today, with the help of our advisors and
consultants, we will review what we consider to be
the salient issues raised in the comments we
received, as well as others that we believe are
critical to ensuring that FDA's evidentiary
standards for safety and efficacy of obesity drugs
are, to the extent possible, in line with the
science of the day.
We look forward to the formal
presentations and what we trust will be a fruitful
discussion to follow. I should make clear, as I
believe is apparent from the agenda, that this
meeting is not intended to discuss any specific
drug products, approved or in development.
Furthermore, in a manner distinct from a meeting of
that type, we will not ask the committee and guests
to vote per se on the questions we will pose.
These are intended to raise the issues that we wish
to hear discussed. We, the FDA staff, will listen
and contribute as we see fit and, of course,
respond to questions directed at us as we are able.
We intend to take the information we have gleaned
today back for consideration in drafting
revisions to our guidance for industry.
It is important for those participating
and listening today to understand that by this
meeting we make no formal commitment to changes in
the guidance. We view this as an information
gathering step in a process that may lead to
changes. I know you all have the agenda and I will
not review it. I have already announced the
Finally, before we start, I would like to
thank Dr. Lynne Levitsky, valued advisor
particularly on pediatric matters whose term has
recently expired, for service to us over the last
term. She is here today formally speaking as a
consultant. By her agreement to stay on in that
capacity, we hope to continue to engage her in the
future and look forward to her additional input
into the work of the division and the agency.
Finally, special recognition goes to Dr.
Glenn Braunstein who has kindly agreed to serve as
the chair of today's meeting. Dr. Braunstein's
second term as a member expired in June,
him here today is particularly fitting given that
he chaired the 1995 meeting that led to the
drafting of the '96 guidance under discussion.
Glenn's association with the committee and the
division dates to late 1991, including two stints
as an extremely effective chair. We thank him once
again for his invaluable service. Indeed, we are
not releasing him. He too has agreed to remain a
consultant. Glenn, thank you for your generosity
with your precious time and for your contributions
over many years to this committee, to the division
and to the work of the agency. With that, I will
turn it over to you.
DR. BRAUNSTEIN: Thank you, David. I
appreciate that. The first speaker this morning as
far as presentations are concerned is Dr. Eric
Colman, who is medical team leader, and he is going
to speak about the regulatory history of weight
The Regulatory History of Weight-Loss Drugs
DR. COLMAN: What I plan to do for the
next 20 minutes or so is to give you an
the FDA regulation of obesity drugs from roughly
the years 1938 through 1999. Before I get to that,
I did want to mention two milestones in the history
of drug regulatory.
These were, first, the signature in 1906
of the original Food and Drugs Act and that was
signed by President Teddy Roosevelt. Roughly
30-plus years later another Roosevelt, Franklin,
signed the Food, Drug and Cosmetic Act of 1938.
This Act has quite an influence on drug regulation.
It affected the labeling provisions, the
advertising provisions for drugs, and it was also
the first time that drug companies had to submit
evidence of a drug's safety before it was allowed
to go onto the market. It also marked the
beginning of the new drug application, or NDA,
process that we have all come to appreciate over
Getting started with the obesity drugs, in
1938 Myerson and colleagues reported the paper in
The New England Journal of Medicine, "Benzedrine
sulfate as an aid in the treatment of
These two colleagues treated roughly 17 obese
patients with 30 mg of amphetamine sulfate, which
is what Benzedrine is. They reported that the
patients lost anywhere from 9-54 lbs. This was
just one of a number of studies that started to
appear in the medical literature that suggested
that amphetamines may be an effective way to treat
The following year, in 1939, the agency
approved Benzedrine for a host of different
indications, however, obesity was not one of them.
Several years later the agency approved another
amphetamine. This one was desoxyephedrine. Again,
there was a list of indications--narcolepsy, mild
depression, alcoholism, even hay fever at one
point, but again obesity was not in the list.
Now, it took four more years before the
agency finally felt comfortable and granted an
obesity indication for desoxyephedrine. To the
best of my knowledge, this was the first drug that
the agency approved for the treatment of obesity.
I have shown you here some of
from the labeling at that time to give you a flavor
of what people were thinking. For this drug the
labeling stated that the sympathomimetic amines
have been found of value, when administered under
the supervision of a physician, as an adjunct to
the dietary management of obesity. That was the
The labeling also warned, however, against
its use in persons with cardiovascular disease,
hypertension or insomnia, and in those who were
neurotic or hyperexcitable. So, clearly, there was
an awareness that these drugs were stimulatory to
the central nervous system, to the cardiovascular
On this last point regarding the
amphetamines I want to just highlight--this is just
to remind you that I will be talking a lot about
amphetamines and I will be talking about
amphetamine-like drugs in a moment. But when I
refer to the amphetamines I am including a large
number of compounds which include amphetamine
sulfate, desoxyephedrine, also referred
methamphetamine, dextroamphetamine and a number of
Soon after the amphetamines were approved
in the '40s and early '50s companies began to work
to try to develop compounds that, on the one hand,
maintained the anorectic properties of the
amphetamines but had less of the stimulatory
properties. They were successful to varying
By 1960 the agency had approved five new
what I refer to as amphetamine-like drugs. These
are also referred to as the amphetamine cogeners.
These drugs were phenmetrazine, phendimetrazine,
phentermine, benzphetamine and diethylpropion.
Again to give you a sense of what people
were thinking during this time, I have shown you
some of the language from the labeling for
diethylpropion. This drug was indicated for any
obese patient, including the adolescent, the
geriatric and the gravid, as well as the special
high-risk situations of the cardiac, hypertensive
and diabetic patient. That is probably an
indication section that most drug companies would
die for at this point.
The labeling also stated that because
tolerance, habituation or addiction did not
develop, this drug was ideal for long-term use.
Again, it is interesting to look at the labeling
language from back in the late '50s.
Against the backdrop of the approval of
the amphetamines and amphetamine-like drugs, there
was a problem growing in this country and some
people were referring to it as an epidemic. That
was an epidemic of the abuse of amphetamines.
I have shown three figures here to give
you a sense of the amount of use of these
compounds. In 1958 there were approximately 3.5
billion tablets of amphetamines manufactured
legally in this country. Approximately a decade
later that had more than doubled to 8 billion
tablets. Expressed another way, in 1967 there were
approximately 23 million prescriptions for
amphetamines, 80 percent were for women and of all
the indications, these drugs were most
prescribed for obesity.
The government tried to intervene to slow
or stop the spread of this abuse by passing two
laws, one was the Drug Abuse Control Amendments, in
1965. The second was the Controlled Substances Act
of 1970. This is when the scheduling of drugs was
Moving from 1970 back to the early '60s,
in 1962 there was a very important addition made to
the '38 Food, Drug and Cosmetic Act. These were
the Kefauver-Harris Amendments, also known as the
Drug Efficacy Amendments. This legislation for the
first time mandated that new drug applications
contain substantial evidence of a dug's
You recall, I mentioned that in '38 the
law said you had to have evidence of safety. This
law now said you had to have evidence of efficacy.
So the loop had now been closed. And, this
effectiveness was to come from adequate and
This raised a problem
legislation took care of drugs approved in '62
forward but there were literally thousands of drugs
that were approved between '38 and '62. The
question came up what do we do about the efficacy
assessment of these drugs approved before 1962?
The answer came when the Commissioner called upon
the National Research Council of the National
Academy of Sciences to take this task on. This
endeavor became known as the Drug Efficacy Study
Implementation, or the DESI review process.
The formal portion of the Drug Efficacy
Study was conducted between 1966 and 1969. There
were a host of different drug panels, depending on
expertise, and it was the psychiatric drug panel
that was charged with reviewing the available data
on the efficacy of the amphetamines and
amphetamine-like drugs. They were told after they
completed their analyses of the available data that
they should classify the efficacy using one of
these five descriptors, starting at the top with
effective; effective but; probably effective;
possibly effective; or ineffective.
They completed their analyses in 1969 and
sent the results outcome the FDA Commissioner, and
this is what they concluded. They felt the
efficacy data supported a statement saying that the
amphetamines were possibly effective for the
treatment of obesity.
Regarding the amphetamine-like drugs, a
little bit better--they thought that this was
effective but... so, again, one step below
effective. The reasons they cited for not
classifying these compounds as effective were the
following: Many of the studies that they looked at
were of short duration. There was no evidence
available that the drugs altered the natural
history of obesity. There was some evidence that
the anorectic effects may have been strongly
influenced by the suggestibility of the patient.
And, there were concerns about the adequacy of the
controls in some of the clinical studies.
What were the regulatory consequences of
DESI review of the obesity drugs? In 1970 the FDA
concluded that the amphetamines were,
possibly effective in the treatment of obesity, and
basically mimicked what the DESI review panel
recommended. However, because this was short of
the category of effective, the FDA directed
industry to submit evidence of weight-loss efficacy
from adequate and well-controlled trials and,
ideally, of more than a few weeks duration. I
would point out here that at this time the FDA made
no comment about the efficacy of the
amphetamine-like drugs. That wouldn't come for a
few more years.
After the DESI review process was finished
in '69, in the early 1970s the Division of
Neuropharmacology Drug Products at the agency--that
was a division that had the regulatory purview of
these agents--clearly felt the need to develop a
policy whereby they could develop and regulate
obesity drugs. So, flowing from the DESI review
process, three important actions occurred in the
early '70s. These were the Prout Consultant Group,
the Neuropharmacology Drugs Advisory Committee, and
the conduct of the Amphetamine-Anorectic
Project. Let me go through each one of those
The Prout Consultant Group was put
together by folks in the Neuropharmacology Drug
Division at the FDA. It consisted of eight
external consultants and was headed by a physician
named Thaddeus Prout who was an endocrinologist
from Johns Hopkins. This group of eight
individuals met in April of 1071 to discuss
specific issues related to obesity drugs and
regulation and development of these compounds.
They issued these four statements back to
the Neuropharmacology Division: They felt that, in
fact, weight-loss drugs did have some potential
value. They felt that the efficacy trials for
these drugs should be at least 12 weeks in
duration; that the long-term follow-up of patients
was not the responsibility of drug companies; and
that the efficacy of the weight-loss drugs should
be defined as statistical superiority of drug to
placebo. This is an interesting point. This group
was specifically asked to define
significant weight loss. Either they could not do
it or they did not want to do it but, in any event,
they said you should consider this as efficacy. In
other words, if the weight loss on a drug is more
than the weight on the placebo and the difference
is statistically significant, then you have a drug
that works .
About five months after the Prout Group
met and made their recommendations, the
Neuropharmacology Drug Division convened its own
advisory committee, in September of '71, and again
they wanted to get input about how to develop and
regulate the obesity drugs. They were also asked
to provide a definition of clinically significant
weight loss. They did not venture an answer.
Instead, they referred back to Prout's
recommendation that efficacy be defined as
statistical superiority of drug to placebo. This
was another group that could not define clinically
significant weight loss.
So, after two groups deliberated on this
the agency still had no working
clinically significant weight loss. The
Amphetamine-Anorectic Drug Project somewhat
approached this problem in a backward direction.
This was a meta-analysis conducted by members of
the Neuropharmacology Drug Division, along with
agency statisticians. The overall goal was to try
to, once and for all, quantitate the efficacy of
the amphetamine and the amphetamine-like drugs. At
this point there were data available for
fenfluramine and sanorex.
This meta-analysis was quite large. It
included 200 clinical studies. These studies
ranged in duration from one month to six months. I
would say that the average study was six to 8 weeks
in duration. There were about 10,000 patients
involved in the whole analysis. At the end of the
day, when they got done analyzing these data, they
issued two conclusions. The first one doesn't
sound very impressive but this is what they said:
Patients treated with active medication did, in
fact, lose some fraction of a pound a week more
than those on placebo. The second conclusion was
that the data did not suggest that one drug was
superior to another, nor that the amphetamines as a
class were more effective than the amphetamine-like
drugs. This would have major implications, as we
will see in a few minutes.
What were the consequences of this
meta-analysis? In 1973 the agency officially
declared that the amphetamines and the
amphetamine-like drugs were effective for the
treatment of obesity. You will recall that in 1970
they said amphetamines were possibly effective and
they didn't say anything about the amphetamine-like
drugs. So, from doing this meta-analysis, they
felt comfortable in declaring that these two sets
of compounds were both effective for the treatment
The second thing that came out of this
project was class labeling. I mentioned the abuse
problem, the speed epidemic that had continued
through the '60s and into the '70s. So, the abuse
of the amphetamines was still very much on the
minds of the senior leadership at the
people started to reason, well, if you limit the
use of these drugs just for a few weeks you can't
get abuse. So, if we limit their use to only a few
weeks we take care of the abuse problem and that
way we tidy up the risk/benefit profile for these
drugs. So, they made a blanket case and not only
were the amphetamines indicated for short term and
a few weeks actually shows up in the label. People
have often referred to this as a few months but the
label actually says a few weeks.
Instead of just limiting it to the
amphetamines, they threw it over to the
amphetamine-like-like drugs as well so at this
point all these drugs became indicated only for
short-term use, a few weeks use, and I would submit
that was largely driven by concerns about abuse,
The next notable event in this history
came in 1979 when the agency announced its plans to
remove the obesity indication from the
amphetamines. They still hadn't had enough; they
wanted more. They felt that they had good reason
to propose this removal. One of the things that
backed them up, they believed, is that there was
continued evidence of abuse of amphetamines. They
knew it was largely coming from this database
referred to as DAWN, which stands for the Drug
Abuse Warning Network.
The other point has to do with, as I just
mentioned, the risk/benefit profile of the
amphetamines relative to the amphetamine-like
drugs. The FDA had clearly said that they don't
think the efficacy is any different for the
amphetamines than the amphetamine-like drugs but we
do believe that the abuse potential was more of a
problem for the amphetamines than the
amphetamine-like drugs. Therefore, amphetamines
have a less favorable risk/benefit profile versus
the amphetamine-like drugs. If you took the
obesity indication away from the amphetamines
people in this country would not suffer at all;
they had have the amphetamine-like drugs that
worked just as well.
The industry had a chance to respond to
this proposal and they did so. I have listed four
of their rebuttals here. For one thing, industry
felt that the FDA analyses of the DAWN data were
incorrect. They just didn't believe that there was
evidence of continued abuse.
Secondly, they argued that if illicit
production and use of the amphetamines was a real
problem, that was the purview of the state medical
boards and the Department of Justice; it wasn't
something the FDA should get involved in.
Thirdly, they said, wait a minute, abuse
requires use beyond a few weeks and our drugs are
only approved for a few weeks. So, if this is a
problem we are talking about off-label drug use
and, once again, that is not something the FDA gets
Finally, the risk/benefit issue--they felt
that the risk/benefit equation should be made on
its own merits, in other words, relative to
placebo. In this case, the agency was saying that
the risk/benefit profile of the amphetamines was
less favorable than the risk/benefit
the amphetamine-like drugs. According to industry,
they didn't think that was a legitimate or legal or
regulatorily tenable reason to take away the
I have to say that after all this
bickering the industry won out because this planned
action never took place. The agency never removed
the obesity indication from the amphetamines and,
to this day, I know of one amphetamine that still
has in its label its use for short-term treatment
We now enter the 1980s, and I think the
1980s in terms of obesity drug development really
should focus on one particular happening, and that
was the start of the phen-fen studies. In the
early 1980s, a clinical pharmacologist from the
University of Rochester reasoned that the stimulant
effects of phentermine would counter the sedative
effects of fenfluramine such that the two together
would provide a very tolerable combination that
could be used over long-term use. So, he and his
colleagues started these studies in the
In 1992 they published a number of papers
citing the main results of these trials. They
concluded that yes, indeed, the combination was
tolerable and that people could take these drugs
over the course of years, and that it was safe and
Again, these were published in 1992. They
had a major impact on subsequent use of these
drugs, as I have shown here, in this table. These
are the estimated total number of prescriptions for
phentermine in 1992, 2 million. For fenfluarmine
there were about 70,000 prescriptions in
1992--again, the year the papers were published.
Four years later these numbers had gone from 2
million to 11 million and from 69,000 to 7 million.
I am not saying all of this was due to these papers
but a large part of it was.
There was another event that happened
around 1992, and that was the transfer of the
regulatory responsibility of the obesity drugs from
neuropharmacology to the Division of Metabolic and
Endocrine Drugs, where they are now. When the new
drugs arrived in the new division there was fairly
strong feeling that effective drug treatment
required long-term or indefinite treatment.
Therefore, why don't we have long-term pre-approval
trials? There were other thoughts within the
division. There was a strong sense that we need to
get this formulated into a guidance policy. They
convened their advisory committee in a two-day
meeting in 1995 to discuss how to develop and
regulate obesity drugs, with an eye to issuing an
obesity guidance document.
They had a successful meeting. The
obesity draft guidance was issue in 1996. I just
show you two of the more important components of
that guidance document, and these will be issues
that we will be discussing later today.
In terms of efficacy, a 5 percent
benchmark was chosen. At that time, people could
point to the fact that if people lose as little as
5 percent of weight they could get improvements in
lipids, blood pressure and cholesterol and,
therefore, this was a clinically
loss. So, now we finally have a definition for
clinically significant weight loss.
On the other side, in terms of the size
and duration of phase 3 trials, I think most people
felt comfortable that we had agreed that one year
of a placebo-controlled trial would be an adequate
exposure to assess efficacy and some degree of
safety. A lot of people felt though that of these
1500 patients who made it out to a year, 200-500
should be rolled over into an open-label exposure
for a following year, again, to get another sense
of safety. We will be talking about these issues
as well later today.
Just briefly, long-term treatment of
obesity, from FDA's perspective, came about when
dexfenfluramine was approved in 1996. We all know
it was removed from the market the following year
because of valvulopathy. A couple of months after
the removal, sibutramine, or Meridia, was approved.
I have shown you here the actual labeling for the
indication. Meridia is indicated for weight loss
and weight maintenance. Xenical, the most recently
approved drug, in 1999, has the same indications,
weight loss and weight maintenance, but it also has
an additional indication and that is to reduce the
risk for weight regain after prior weight loss.
These are issues that we hope committee members
will engage in a dialogue later this afternoon in
terms of what these terms mean; how they should be
So, if I could provide you with a global
summary, I think it is safe to say that defining or
quantitating the efficacy of weight-loss drugs has
been problematic. It certainly has been a
challenge from a regulatory perspective. It wasn't
until the mid-1990s that we had a workable
definition of clinically significant weight loss,
and that is the 5 percent benchmark. We still
don't have a definition of clinically significant
drug-induced weight loss--that is a different
On the other side of the coin, I also
think it is safe to say that the regulatory history
of the obesity drugs has seen its share
publicized safety problems. Beginning with the
abuse of the amphetamines in the '40s, '50s, '60s
and beyond, primary hypertension became an issue
with a drug called aminorex that was used in Europe
in the '60s. It was never in this country.
But this condition was subsequently linked
to fenfluramine and it was a major issue at the
time that dexfenfluramine was approved. It was
well-known that this drug increased the risk of BPH
in people who took dexfenfluramine. That was
before dexfenfluramine was approved. These
concerns were only later overshadowed by the
cardiac valvulopathy that showed up a year after
their approval. These were all very, very highly
publicized events, basically so many in the
population were exposed to these drugs.
Finally, the approval of Meridia or
sibutramine, back in '97, was accompanied by very
strong warnings, precautions and concerns regarding
the effect of that drug on blood pressure and
Let me close. Since the topic of today's
discussion is the obesity guidance document, I
thought I would just provide a visual reminder of
the goals of not only this guidance document but I
think of all guidance documents, and that is
obviously, on the one hand, to facilitate
industry's development of safe and effective drugs
but, just as importantly, to provide regulators
with the best available evidence upon which to
judge a new drug's risk/benefit profile before the
drug is approved. Obviously, those two things
require a certain amount of compromise and juggling
but I will leave you today with that thought. Keep
that in the back of your mind as we deliberate the
various proposals to change the guidance document.
DR. BRAUNSTEIN: Thank you, Dr. Colman.
Are there any questions from the panel for Dr.
Thank you. We will move on then to Dr.
Katherine Flegal's discussion of the epidemiology
of overweight and obesity.
The Epidemiology of Overweight and Obesity
DR. FLEGAL: This is the outline. I am
going to give a very brief overview of trends in
obesity and overweight in the United State,; a
history of regulation of weight-loss drugs, a brief
history of definitions of overweight; some
population estimates; prevalence of overweight
categories and comorbidities; and kind of a brief
discussion of some of the aspects of possible
benefits and risks of weight change in mildly
overweight people with comorbid conditions.
Most of the data I am going to present
today come from the series of National Health and
Nutrition examination surveys in the U.S., NHANES.
Many of you are familiar with this but I know some
of you aren't. These are a series of
cross-sectional national representative surveys,
conducted by CDC's National Center for Health
Statistics, in which weight and height are measured
and many other actual measurements are taken. We
have a series of these dating back to the 1960s up
until today. So, we have a little over 40 years of
data on the U.S. population from these surveys.
The most recent one began in 1999 and is
continuous, representing some data from 1999 up to
2002 in that survey.
This slide shows the age-adjusted trends
in obesity, defined as a body mass index of 30 or
above in the United States. Starting back in 1960,
the prevalence was only about 10 percent for men
and today it has gone up to almost 30 percent. As
you see, the prevalence was really fairly constant
from 1960. In '71 to '74 and '76 to '80 there were
not large changes for either men or women. In the
'89 to '94 survey the prevalence went up sharply
and somewhat unexpectedly, and in the most recent
survey it has gone up again so we see this
This is the same setup. This is for
overweight defined as a body mass index of 25 or
above so it includes the obesity data I just showed
you. Again, the prevalence was relatively stable
over the first three surveys and then increased.
One thing to note is that the prevalence
overweight with these definitions has been pretty
high since 1960. Almost 50 percent of men and 40
percent of women were overweight in 1960 according
to this definition.
As you have just seen, the definitions of
overweight and obesity that I am using are based on
body mass index which is calculated as weight in
kilograms divided by height in meters squared.
There are two definitions of overweight in this
system. One is a body mass index of 25 up to 29.9
or a body mass index of 25 or above. Obesity is
then defined as a body mass index of 30 or above
and a healthy weight as a BMI of 18.5 but less than
These definitions have been a long time
getting systematized and standardized. This is a
very brief overview, but basically definitions of
overweight up to the early '80s really were not
systematized and there were very wide international
variations. In the United States there was a lot
of use of weight-height tables like the insurance
company tables that you have probably
is a whole set of issues of skinfolds measurements,
different kinds of prediction equations; a lot of
different kinds of weight-height indices. There is
the Broca index, ponderal index. You can see these
used in different literature and they are used in
different metric systems as well so you never knew
whether it would be kilograms and meters or
centimeters or pounds and inches. So, if you look
at the literature back in the '70s, say, and before
it is very difficult to make any comparisons.
There are a lot of different definitions that were
being used and there were a lot of differences
between countries as well.
I think during the 1980s epidemiologic
consensus began to form around body mass index,
which is also called Quetelet index after the great
Belgian statistician in the 19th century. So, you
can see that this index has been around for a long
time and has been used somewhat, but it began to be
really more the index of choice. An NIH consensus
conference in 1985 recommended the use of body mass
But at that point the cut-off values still
were somewhat varied.
The 1959 Metropolitan Life tables in the
U.S. had a range of desirable weights for a given
height. There was a practice that had grown up of
taking the midpoint of that range as kind of the
ideal weight and then saying if you are at or about
120 percent of that midpoint, then that was the
beginning of the definition of overweight of the
median frame weight range.
At the NIH consensus conference, in '85,
there was data presented from NHANES, as I have
already shown you, about the 85th percentile values
for men and women age 20 to 29. Those were a value
of 27.8 for men, 27.3 for women. The consensus
conference decided to adopt those as some kind of
definition of overweight because they actually
correspond pretty closely to the Met Life, to the
120 percent definition based on Met Life. We, in
fact, used these values as recently as 10 years
ago. We would have been publishing data using
those particular cut-off points.
Meanwhile, BMI cut-points of 25
began to be recommended by expert committees.
These were not suggested originally by these expert
committees. I think the earliest suggestions I am
aware of were by George Bray and George Garrow,
back around 1980 probably or perhaps before. But
these were thought to be more systematized. There
was a 1995 report from an expert committee of the
World Health Organization that suggested these
cut-off points. That was followed in 1998 by the
Clinical Guidelines on the Identification,
Evaluation and Treatment of Overweight and Obesity
in Adults that NHLBI put out, which is really more
or less the basis for our current use of these
Why these values? Here is what it says in
the 1995 expert committee report that they proposed
a classification with cut-off points of 25, 30 and
40. This is based principally on the association
between BMI and mortality.
They go on to say the method used to
establish these kind of points has been largely
arbitrary. In essence, it has been based on visual
inspection of the relationship between BMI and
mortality: the cut-off of 30 is based on the point
of flexion of the curve.
So, in this report and in others there is
not a careful study of the criteria for using
exactly 25 or 30 as opposed to, say, using 30.5 or
27.8. These are kind of general and, as I say,
largely arbitrary. Here is kind of a typical
relation between mortality and BMI curve that would
have been available to that committee. This is
from the American Cancer Society studies.
You see a couple of things here. First of
all, the point of lowest mortality tends to hover
around a BMI of 25. You see this curvolinear,
somewhat U-shaped relationship with much higher
risk out here. Also, body mass index is not a
physiologic measure; it is just an index and you
can kind of intuit that the choice of cut points of
20, 25, 30, 35 and 40 are because these are round
numbers and they vary by 5. These are not really
physiologically based cut points. So, these are
approximations. They are very useful
approximations, by the way. We are very glad to
have internationally standardized definitions that
we can all use. Now you can compare one person's
data with another person's data so these are quite
valuable to have.
The 1998 NHLBI clinical guidelines also
offer the same definitions. Here overweight is 25
to 29.9 and they say the rationale was based on
epidemiological data that show increases in
mortality with BMIs above 25. This increase tends
to be modest until a BMI of 30 is reached. So, you
see that this language also is somewhat imprecise.
I think this is on the following page.
They describe quite a few studies. Very often the
point of minimum mortality is around a BMI of 25.
This is a study of NHANES I where they show the
lowest mortality in the range of 25-30, and they
found, by race and sex, the lowest mortality at
24.5 for white men, 26.5 for white women, and even
higher values for black men and women. There is
other information presented in the same NHLBI
report which also has somewhat similar
So, definitions of overweight have changed
quite a bit over time. We have pretty much settled
down now to using these standard definitions but
that is a little bit of the history.
Getting back to definitions, overweight is
a BMI of 25-29.9. These are slides like the ones I
showed you but now these are really just that
range. There are two things you can see from this.
One is that the prevalence of overweight by these
definitions has really changed very little over
time. It is almost constant. Another thing you
can see is that the prevalence of overweight by
these definitions is quite a bit higher in men than
it is in women, which is less true of the
prevalence of obesity. It is about 38-40 percent
for men and about 25 percent for women.
Just looking at the numbers of people, and
I am going to try to divide this by separate
categories. One is BMI to under 27 and 27 up to 30
because that is one of the cut points used in the
current guidance document. This is just to show
you the number of people in the U.S.
fall into these various categories. I also
included the next lowest category as kind of a
comparison point. In this lowest category of 23 to
less than 25 the numbers of men and women are
approximately equal, about 14 million in each. In
the range of 25 to under 27 there are a few more
men than women. There are about 16 million men and
12 million women. As you go up to the range of 27
to 30 there are more people in this category, which
is actually a broader category, of course, also.
There are 21 million men and about 17 million
Looking at that by age as well, I have
divided this into 4 age groups, 29-29, 40-59, 60-79
and 80 and above. You can see that for a BMI of 25
to 27, men and women both in that BMI range are in
the age groups 20 up to 59. When you get to the
60-79 year-old age range there are fewer people but
you see that in the younger ranges there are more
men than women in these categories. When you get
up to this age range there are actually almost
equal numbers of men and women in the
The same is true for the next category of a BMI of
27-30. So, there is a definite age pattern with
Now I am going to talk about
comorbidities. There are five listed plus "other"
in the guidance document: hypertension,
hyperlipidemia, glucose intolerance, cardiovascular
disease, sleep apnea and other obesity-related
conditions. I don't really have good data to show
you on cardiovascular disease or on sleep apnea or
the other conditions so I am just going to talk
about these three from what we have, hypertension,
high cholesterol and glucose intolerance.
One thing I was asked to do is to consider
the question of the point of inflection of the
curve of the relationship of these comorbidities to
BMI. So, I have presented the data this way and I
have a whole series of slides, all laid out the
The yellow line is men--this is for men,
20-39; the green line, 40-59; the pink line, 60-79;
and then 80 and above. This shows the body mass
index categories along this axis and the
prevalence. There are a couple of things you can
see from this. First of all, you don't see a very
clear point of inflection, for example, between
23-25, 25-27. Here you see a little increase but
in this case it was a decrease here and an increase
there so these bounce around somewhat. So, you see
a gradual increase in the prevalence of these
conditions with the BMI level in all age groups.
You don't visually see an obvious point of
The other thing to notice is that although
we talk about these as obesity-related
comorbidities, this shows you pretty clearly that
they are also age-related comorbidities and, in
fact, the prevalence of any of these conditions in
people with a BMI of 30 who are young is far, far
lower than the prevalence even in people at the
lowest BMI level who are older. So, you need to
keep that in mind. Again, there are other risk
factors for these conditions and age, in
particular, is a very strong risk factor.
This is the same picture now for women.
Again, you see at the old age range a very high
prevalence of hypertension at all BMI levels. You
see in most age groups a slight increase in the
prevalence by BMI level and you don't see a strong
inflection point. By the way, I defined
hypertension as a measure of blood pressure
systolic over 140 or diastolic over 90, or using
medications for hypertension.
This is for high cholesterol, which I
defined for this purpose as total cholesterol of
above 240 mg/dl or using medication. Here you see
a somewhat similar picture. The prevalence is not
as high even in the oldest age group and our data
are somewhat sparse in the older age group. It may
be one of the reasons this curve is not estimated
that well. Again, you see some tendency for
increase in cholesterol with BMI, also a tendency
to increase with age--not a terribly clear
Here is the same information for women.
Again, sort of the same comments would
Finally diabetes--this is just based on
diagnosed diabetes and this is self-report of
diagnosed diabetes so this is not based on
measurements of glucose tolerance or looking at
undiagnosed diabetes. This is people who say that
they have been told that they have diabetes. I
also excluded people who had age at onset below 30
and have used insulin since diagnosis,
approximately since diagnosis, to try to limit this
proximally to type 2 diabetes. Again you see the
increase with BMI. You see the age differential
and you, again, don't really see a strong
inflection point. The same thing for women.
This is just the prevalence of any
comorbidity. I should say any selected comorbidity
because I am only looking at three. This is by age
and body mass index group for men. This has
somewhat smoothed out the lines because there are
more comorbidities involved. Again, there is this
big age differential--you know, fairly smooth
curves; they go up and down some but there is no
obvious inflection point between 25-27
and 27-30 or
This is the same diagram for women.
Again, big age differences; increasing prevalence
of comorbidity with BMI group; fairly smooth lines.
So, how many millions of people are we
talking about? I will show you some other data but
this is when people have 2 or more comorbidities by
BMI categories. For comparison purposes, I put a
lot of BMI levels in here. In this range, which is
the range of interest for this purpose I think,
there are roughly speaking about 4 million people
in the U.S. who have a BMI at that level and have 2
or more comorbidities. That is in contrast to
about 6 million in the 27-30 range who have 2 or
more comorbidities. So, there is a ratio here.
This is about two-thirds of that. I have left out
some comorbidities so presumably these numbers
could be higher so this is just selected
For comparison, even at the next lower
level there are almost 3 million people who would
fall into that category, even the lowest
category. So, these comorbidities, again, are not
limited only to people in these overweight and
obese ranges. At the BMI level of 30-35 the
numbers are really much higher. Also, the numbers
of men and women are pretty equal in these
categories of interest in the overweight range.
There is a difference by age again. This
shows the same slide but now it is just limited to
people in the age range of 20-59. Here there is
about one and a half million people who fall into
this category, which is BMI 25-27 and one or more
comorbidities, and now the numbers of men and women
are no longer equal. There are about twice as many
men as women in this younger category.
This is for ages 60 and above. Remember,
the total here is a little under 4 million so
almost 2.5 million of those people are in the age
range of 60-70 and now we see that there are, not
unexpectedly in this case, more women than men in
this age range in this BMI category with
comorbidities. That is true along the whole
spectrum of BMI levels.
This is sort of changing the design here
but this shows you the number of million of people
with 1 or more, 2 or more or 3 comorbidities. This
is for BMI 25-27 so this is 1 or more, 2 or more or
3, and this shows the total with the different
components of the bar showing the age ranges. So,
what you can see is that, for example, is people
with one or more comorbidity about equal numbers of
people in the 40-59 and 60-70 age ranges and those
make up the majority of people with a smaller
contribution from people 20-39, even though many
people in the population in this 20-39 age range
don't fall into the comorbidity range.
So, we see about 12 million total with one
or more comorbidities as compared to 18 million in
the higher BMI range. When we get down to 2 or
more comorbidities, which is the number I just
showed you, this is approximately 4 million. The
largest group is going to be people in the 60-79
age range and people above 60 make up the majority
of this group, although not everybody in this
That is true also for BMI 27-29.
age structure of these age groups is not the same
as the age structure of the population.
What about weight loss for people with BMI
25-27? I have tried to review the literature. I
have probably not reviewed everything, by a long
shot. As far as I can discern, there is not very
much information about the benefits of weight loss
in this particular BMI range. Most studies of
weight loss don't include that many people in this
level. Again, up to 10 years ago we would not have
considered people in this range to be overweight so
that might be one of the reasons why they were not
really going to be included. Some of them may
actually explicitly exclude people when they study
a BMI of 27 or a BMI or 28.
That is also true of studies of the
benefits of weight loss in the control of
conditions such as hypertension or hyperlipidemia.
They may explicitly exclude people who have BMIs as
low, so to speak, as 25-27 or may include few, if
In kind of a mirror image, I
also read an
article which was complaining that drug trials for
hypertension are conducted in people who are
overweight but not obese so we know very little
about it. So, basically, trials of weight loss and
hypertension are conducted in obese people and in
trials of drug use and hypertension are studied in
overweight people but not the converse. So, we may
have missing information on both sides of that.
The NHLBI clinical guidelines
recommendations for a BMI of 25-29 overweight
recommend treatment only when patients have 2 or
more risk factors or a high waist circumference.
Other than that, weight maintenance is actually
recommended. So, the guidelines here for
overweight treatment do not recommend treatment for
everybody but just for people with other risk
factors. They also mention--I didn't put this on
the slide--that treatment of the other risk factors
is also just as important and should also be
You will see this statement on another
slide, but there are a lot of studies
that short-term weight loss has beneficial effects
on risk factors such as high blood pressure and
cholesterol. That is really very well established.
Most studies suggest that these are monotonic
relations but there is no obvious threshold. So,
you would infer from this that weight loss is very
likely to improve blood pressure and other risk
factors, certainly in the range of BMI of 25-27 as
well and perhaps at any weight level. We don't
really know but there is not that much evidence on
the specific BMI range. This is a fairly
How much benefit would that have? What
would be the net result? That is very hard to
judge in the literature. This is one very
approximate way of looking at it. You have already
seen these data but in a different format. What is
the prevalence of having 2 or more comorbidities by
age group for BMI 23-25 versus 25-27? If you think
that weight loss in the BMI group 25-27 puts you
into this next lower group, which is a very
plausible assumption, roughly speaking
the expected prevalence be?
You can see that effect--this is an
approximation again--by just comparing these 2 bars
which show the prevalence in the 23-25 BMI group
versus the prevalence in the 25-27 for different
age groups. In the youngest age group in which BMI
is probably a stronger risk factor, relative risk
for hypertension associated with BMI stronger are
stronger in the youngest group, you see a pretty
big potential difference of about half the number
of people in this lower BMI group. The number with
2 or more comorbidities is about half. So, that
would suggest that you get a fairly noticeable
prevalence effect by this kind of change in weight.
At the older age ranges the prevalence is high.
So, just looking at these data you would
suspect that if you had people with a BMI of 25-27
and they reduced their weight to 23-25 it is not
likely that they are going to end up down here
where the 20-39 year-olds are. They are more
likely to be approximately where people in their
same age group are. So, the prevalence of having 2
or more comorbidities is likely to be high even
after weight reduction. So, while there is likely
to be a beneficial effect, the net effect on
prevalence may not be that great.
Weight loss is just kind of part of the
therapeutic armamentarium for treatment of various
conditions. There is a whole non-pharmacologic
treatment or therapeutic lifestyle changes which
include weight loss, physical activity and
healthful eating habits, which may mean more fruits
and vegetables, less sodium, less saturated fat, a
whole different range of possible changes. These
are an important part of the treatment of diabetes
and cardiovascular risk factors obviously. Drug
treatment is also often used in managing these
So, you might ask what is the relative
contribution of weight loss in this panoply of
treatments. As far as I can find out, that is not
well established. For example, what would be the
probability that non-pharmacologic treatment alone
versus drug treatment would have on
hypertension? There are review articles and
summary data on this but they tend to start at a
higher BMI level, at BMI of 27 or above or 28 or
above. So, it is somewhat difficult to assess.
Also, for example, there is one paper by
Ed Gregg using the national health interview survey
data that suggests that the intention to lose
weight is associated with improved mortality
regardless of actual weight loss, and the intention
to lose weight may be accompanied by some of these
other changes, such as increased physical activity
and changes in eating habits. So, it is hard to
judge and usually weight loss by itself is not the
only part of it. Therapeutic lifestyle changes
include more, and clinical trials will also look at
lifestyle changes. So, they include more than
weight change and try to assess where weight change
itself falls in the pictures. I couldn't find any
data that really spoke very clearly to this issue.
There are a couple of concerns. This is
from the Look Ahead Action for Health and Diabetes
study, I guess. This is from their website. This
is the sentence I already had on the other slide.
Although we know that weight loss improves risk
factors and clearly improves blood pressure and
glucose tolerance, there are these observational
studies that suggest some association of weight
loss with increased rather than decreased
These studies do not differentiate
intentional from unintentional weight loss so they
definitely have limitations but they can't be
completely ignored either. Because of this, there
is actually a randomized clinical trial of
intentional weight loss going on. There are some
questions we don't really have the answers to about
this possibility of increased mortality with weight
loss so that is one concern, looking at weight loss
in this BMI range.
Another possible concern is, again, that a
lot of the people who are in this BMI range who
have comorbid conditions are elderly and more of
the elderly, not surprisingly, are women rather
than men and there are, you know, some
adverse effects of weight loss in this age range in
the elderly and particularly perhaps for women.
One of these is the possibility that weight loss as
adverse effects on bone health and can result in
lower bone density or greater risk of hip fracture.
This is a report from the study of
osteoporotic fractures where these women were close
to this range and the median and they had an
increased risk of hip fracture with weight loss.
In fact, this study found also an increase in thin
women as well, although the increase was not as
great. They did look at intentionality versus
unintentionality or lack of intention to lose
weight. In this study, and this is not the only
study on this topic but just something to kind of
keep in mind as a possible issue, regardless of
current weight or intention to lose weight there
was an association of weight loss with hip bone
loss and risk of hip fracture. So, they concluded
that even voluntary weight loss in overweight women
increases hip fracture risk.
Just to summarize, definitions
overweight have varied a lot over time, and
epidemiologically useful consensus definitions do
not necessarily represent physiological
The prevalence of selected comorbidities
rises with BMI and doesn't have, at least in my
analysis, clear inflection points. There are about
12 million adults with a BMI 25-27 with at least
one selected comorbidity and about 4 million have
at least 2 selected comorbidities. So, it is a
large group of the population.
Half or more of the adults with BMI 25-27
and selected comorbidities are age 60 and above.
Weight loss, lifestyle changes and drugs are all
used to manage these and other comorbidities. So,
weight loss is part of a whole package of possible
Weight loss is associated with some
possible adverse consequences in observational
studies. So, I would conclude that the benefits
and risks of weight loss for people with BMI 25 to
under 27 have not been clearly
DR. BRAUNSTEIN: Thank you. Are there any
questions from the panel members? Dr. Follmann?
DR. FOLLMANN: I just had a comment. I
hadn't seen the relationship between BMI and
overall mortality before and I was really struck by
the nadir at 25. Many of these documents we have
been reading before this meeting were talking about
a cut point of 25-30 for definition of overweight,
and it just strikes me as maybe curious as to why
you would recommend or why people would consider
having someone who has to be above 25.1, which is
close to optimal, lose weight. So, I was wondering
if you could comment on that.
DR. FLEGAL: Well, I guess I think of this
from an epidemiological perspective. We have
prevalence estimates that use 25 and, you know,
different studies show the nadir at different
points so I don't think you can say that it is
exactly at 25. But the recommendations of NHLBI
are really not to lose weight at a BMI of 25.1
unless you have comorbid conditions. So, avoidance
of weight gain is probably more important in that
DR. BRAUNSTEIN: Yes?
DR. RYDER: Yes, I just have one quick
question. On the two graphs that I you showed
earlier on the age-adjusted trends in obesity, you
used two categorical definitions, one of 25 and one
of 30 with somewhat different patterns.
I have a two-part question. One is if you
use 27 instead of 25 or 30, because I have seen
that put forward, would the display be more like 30
or more like 25?
DR. FLEGAL: I think it would be more like
30 but I haven't actually looked at data.
DR. RYDER: And the second part is the
average weight in the United States over this time
period I believe has been going off in somewhat of
a linear way, or maybe even more than a linear way.
Has the distribution pattern, Poissant
distribution, been maintained or is it just one arm
DR. FLEGAL: That I can't answer.
Basically, the whole distribution of body mass
index is shifting to the right a little bit. But
the distribution is becoming much more skewed so
there are much larger changes at the higher tail of
the distribution. The median has shifted somewhat
but the 90th percentile has shifted a lot. So, the
distribution is both shifting to the right and
becoming much more skewed.
DR. RYDER: Thank you.
DR. CARPENTER: I was struck by the large
impact of age on the comorbidities and, at the same
time, struck by the fact that in your later slides
you demonstrate that the effect on comorbidities
with weight loss is much greater at the young ages.
I wonder if anybody has looked at the duration of
carrying a certain BMI as being more important than
the current BMI as a risk factor for comorbidities.
DR. FLEGAL: There are studies like that.
I don't think they would explain those age
differences. I think basically a lot of people,
even at the lowest BMI in the age range of
60-79--you know, a lot of people have
regardless of BMI. So, any duration or changes
can't affect that. You know, at every BMI level
you have like 70-80 percent of people with
hypertension so, although duration may very well
have an impact, I don't think that can be the
explanation for those prevalence figures.
DR. BRAUNSTEIN: Dr. Follmann?
DR. FOLLMANN: Have there been studies
done that look at the pattern of weight gain over,
say, a 10-year period and how that might affect
mortality? I am thinking of someone who, say,
weighs 200 lbs at 40 and goes up to 250 lbs in a
steady linear fashion as one kind of trajectory,
and the other where they repeatedly diet and their
weight fluctuates a lot over that 10-year period
but they end up at the same weight. So, steady
versus erratic weight velocities--have there been
studies looking at the risk associated with those
two possible trajectories?
DR. FLEGAL: Well, there have been studies
of weight cycling. Sue Yanovski probably knows
more about that than I do. But I believe that a
kind of consensus is that weight cycling probably
doesn't have a large impact on mortality. Is that
DR. S. YANOVSKI: Yes, the difficulty with
these kinds of studies is that they are all
observational studies, and weight cycling in itself
is associated with a lot of psychiatric morbidity,
a lot of other comorbidities and it is really
difficult to tease out cause and effect in those
kinds of studies.
DR. FLEGAL: Again, there are
observational studies that suggest that weight loss
is associated with increased mortality. There are
a lot of questions about intentionality; why do
people change their weight. As Sue was saying,
there are other issues. So, this whole area is a
very tangled and confused area to really sort out.
DR. BRAUNSTEIN: Dr. Hirsch?
DR. HIRSCH: I think you have just about
answered what I was going to ask. The 1997
recommendation concerning the issue that a
randomized clinical trial of intentional
loss is the only way we could prove whether there
are dangers inherent in weight loss--no such trial
that fits any of those issues has been carried out.
Is that true?
DR. FLEGAL: Of intentional weight loss--
DR. HIRSCH: Yes, randomized, prospective
trial. You are saying that is the only way you
could find out what the inherent harms of weight
loss might be.
DR. FLEGAL: Look Ahead is the only one I
am aware of. Is that right, Sue?
DR. S. YANOVSKI: Yes. NIDDK is
sponsoring the Look Ahead clinical trial, which is
5000 individuals with diabetes who are randomized
to intentional weight loss or a controlled
DR. HIRSCH: But no data are available?
DR. S. YANOVSKI: Not yet.
DR. BRAUNSTEIN: Why do you think the
mortality curve is J-shaped? That is, that the
mortality goes up as you start getting to a lower
BMI at a time when all the comorbid risk
seem to be lowest?
DR. FLEGAL: Well, again, there are a lot
of issues that are really unresolved. It could be
that at older ages there is some association--at
all ages there is an association of low BMI with
mortality as well as with high BMI. It may have to
do with issues like not having adequate nutritional
reserves; people going in for surgery at age 65 and
you lose weight in the course of being in a
hospital and deplete your nutritional reserves.
You may be at a higher risk of hip fracture. The
pattern of the causes of mortality may be different
at different BMI levels at different ages. There
are also issues of smoking. Most of these studies
adjust in some way for smoking but smokers tend to
have lower body mass index and be at higher risk.
So, there are a lot of different issues. I don't
think it has really been sorted out very clearly in
DR. BRAUNSTEIN: Thank you. We will move
on to Dr. Frank Greenway's discussion of the
current status of weight-loss drugs.
Current Status of Weight-Loss Drugs
DR. GREENWAY: I was asked to speak on the
safety and efficacy of the drugs that we have for
weight loss at the present time. Obesity, before
the 1985 consensus conference, was felt to be bad
habits rather than a chronic disease, which is the
way we now understand it. At least, it was my
understanding that eating habits can be retrained
over a period of a few weeks and that this at least
was another reason why the older recommendation for
obesity drugs was over a shorter period of time.
The drugs approved before 1985 were,
therefore, approved for periods up to a few weeks,
and tested over that period of time. Mazindol and
fenfluramine are no longer available; phentermine
and diethylpropion are. Dr. Colman already
reviewed the analysis of the FDA information on new
drug applications that were reviewed in the 1970s
that showed that these drugs approximately doubled
the weight loss seen with the placebo groups.
Just a few overview comments about
treating obesity as a chronic disease
medications, first of all, the drugs work only when
they are taken and I will show you a slide to
demonstrate that. The average weight of the
participants in those studies is 100 kg. So, one
can look at these weight loss graphs as percent
weight losses or kilograms of weight loss since it
is 100 kg.
The placebo group in these trials has
always required some type of treatment because IRBs
feel that placebo groups need to get some form of
treatment as well. So, people in these trials are
really getting two different treatments. Weight
loss in these trials usually plateaus at about 6
months. The primary criteria for approving drugs
in Europe is a 10 percent weight loss that is
greater than placebo. A primary criterion in the
United States is a weight loss that is 5 percent
greater than placebo and is statistically
This is a slide of a study done in a
practice situation where patients were given
fenfluramine, a drug no longer
approved. They were
seen monthly for a year. As you can see, the
weight loss plateaus at about 6 months. The
one-year people in this trial had their drug
discontinued but they would continue to be followed
for the following year. When they were followed
off the treatment the weight loss just about went
away by the time they got to the second year.
Another point I wanted to make was about
the ancillary treatment that goes on in these
clinical trials. Back in the early '70s behavior
modification was a new treatment. There was a
trial that was done to approve mazindol and two of
the sites did it in the standard way, which is
demonstrated on this slide. Everybody got a
tear-off diet sheet and the placebo and drug groups
were given pills each week and were weighed each
week. As one can see, the placebo group really
lost no weight over 6 weeks and the mazindol group
lost 6.5 lbs over that period of time.
In another site in that trial behavior
modification was superimposed upon all groups. The
mazindol group in that site lost 8.5 lbs
than 6.5 lbs but the difference between drug and
placebo was reduced considerably, to the point
where, at least in this particular site, the
difference was no longer significant.
To sort of carry that forward, because
this is sort of the difference between the European
and U.S. kinds of criteria, here you can see that
an orlistat trial in Europe had 11 percent weight
loss but only a 2 percent difference from placebo.
This is because there was presumably a larger
ancillary program that was superimposed upon this
weight loss program.
This is a sibutramine trial that was done
in the United States where the difference was to
get a spread between the two groups. You have a 7
percent weight loss with sibutramine and a 2
percent loss with placebo, and there was,
therefore, a 5 percent difference.
In talking about the safety and efficacy
of the drugs that are presently available, the Rand
Corporation was commissioned to prepare an evidence
report on the pharmacologic treatment of
the agency for Health Care Policy and Research of
our federal government. Some new meta-analyses
were done during that process using the studies
that were at least 6 months in duration. Although
this hasn't yet been published, they have given me
permission to present some of that data.
There are several categories that one can
put the drugs available into. One would be
phentermine and diethylpropion which are approved
for obesity but for short-term use. The second
would be orlistat and sibutramine which are
approved for obesity for long-term use. Then there
are drugs that are approved for other indications,
not for obesity, things that are approved for
depression, like fluoxetine and bupropion; things
that are approved for epilepsy such as topiramate
and zonisamide which also give weight loss. Then,
there are 2 drugs that are in phase 3 clinical
trials, Axokine and rimonabant which have some
public information available on them.
The data presented here on efficacy
presents the data in the way the FDA
drugs, that is, the difference between the placebo
group and the drug group. In trials of phentermine
up to 6 months in duration, using 30 mg/day, the
difference between drug and placebo was about 3.5
kg. With diethylpropion, in studies that went up
to about a year, the difference was 3 kg.
One might ask how can one, in this day and
age when we understand obesity to be a chronic
disease, find a use for these medications that are
only approved over a period of a few weeks. This
is a study that was done comparing the green line,
which shows continuous use of phentermine, against
the yellow line, which showed 1 month on 1 month
off; 1 month on, 1 month off.
As you can see, the line is more jagged
but they end up at approximately the same place at
9 months compared to the red line, which is
placebo. So, there are still ways that these drugs
can be useful.
Orlistat, at 120 mg 3 times a day, gave a
2.5 kg difference compared to placebo at 6 months
in the 11 studies in this meta-analysis,
2.75 kg at 1 year in 21 studies.
Orlistat is an inhibitor of pancreatic
lipase. It causes a third of dietary fat to be
lost in the stool. The relative risks for diarrhea
were 3.4, for flatulence 3.1, and dyspepsia 1.5.
So, one can see that these side effects result from
the mechanism of action.
These trials showed a reduction in total
LDL cholesterol and in blood pressure. There was a
slight reduction in glucose and glycohemoglobin in
diabetics, and it was shown that one could prevent
diabetes in those with impaired glucose tolerance.
Sibutramine, in doses of 10-20 mg/day,
showed a 3.5 kg difference from placebo at 6 months
in 12 trials, and about a 4.5 kg difference at 1
year in 5 trials. Sibutramine is a norepinephrine
and serotonin reuptake inhibitor. It had
dose-related dry mouth, insomnia and nausea
associated with it. The heart rate went up 4
beats/minute in these trials, and there was no
consistent effect on blood pressure or lipids.
There was a slight improvement in glucose
glycohemoglobin in diabetics.
One could logically ask, since we have
these two drugs that are approved for long-term use
in obesity and they work by different mechanisms,
could one combine them and get better weight loss.
This is one trial that tried to address that issue.
The yellow line shows sibutramine treatment for a
year. You can see that the weight loss plateau'd
at 6 months and remained stable for the next 6
months. When orlistat was added to sibutramine
there was no further weight loss.
Fluoxetine is a medication that was
approved for depression, not for obesity. It was
studied for obesity, however, and at 60 mg/day, a
higher dose than is typically used for depression,
it caused about a 4.5 kg difference from placebo at
6 months. But, as you probably will notice as
something different compared to the other slides,
there is less difference at 1 year than there was
at 6 months, in this case 3 kg.
Fluoxetine is a reuptake inhibitor of
serotonin. The relative risks of nervousness,
sweating and tremors was 6.6; of nausea and
vomiting 2.7; fatigue and somnolence 2.4; insomnia
2.0; and diarrhea 1.7. There was regain of weight
between 6 months and a year. That is presumably
the reason that it was not approved.
This is a slide to graphically demonstrate
that fact. You can see that the weight loss came
down and plateau'd at around 6 months, but in the
last 6 months of that year there was obvious weight
gain in the fluoxetine group and not in the placebo
Bupropion is a drug that is approved for
depression and smoking cessation. At 200 mg twice
a day in 2 6-month trials there was about a 2 kg
difference from placebo. In one trial at 1 year
there was about a 5 kg difference.
Bupropion is a reuptake inhibitor of
dopamine and norepinephrine. The 6-month studies
were both in depressed patients. The 12-month
study was in obese patients that were not
depressed. So, these may represent 2 different
groups in terms of response. The relative risk for
dry mouth was 3. There was also an increased
incidence in insomnia, and there were no increases
in pulse or blood pressure in those studies.
Topiramate is a drug approved for
epilepsy, not for obesity. At 192 mg/day there was
a trial that showed a 6.5 kg difference between
that drug and placebo. The mechanism or weight
loss with this drug is not clear. The relative
risk of paresthesia was 4.9. Taste perversions was
9.2. There were other central nervous system and
gastrointestinal side effects with this medication.
Zonisamide is another anti-epileptic drug,
not approved for use in obesity. A 16-week trial
showed a 5 kg difference between that drug and
Axokine is a large protein that is
injected subcutaneously and is in development in
phase 3 for the treatment of obesity. There is one
study that is in the public domain that shows a 3.5
kg difference from placebo at 1 year. Axokine
appears to activate the leptin pathway distal to
the place where leptin acts since it acts
animals that don't have leptin. It has injection
site reactions, nausea and a dry cough associated
with its use. Over 30 percent of the people in the
trial that I mentioned developed antibodies to
Axokine. Those patients who developed these
antibodies lost less than 1 percent of their body
weight compared to placebo at a year.
Rimonabant is the other medication on
which there is public information in the phase 3
trials for the treatment of obesity. The one trial
that was reported talked about uncomplicated
obesity. It was a 16-week trial and I took the
liberty of projecting the weight loss consistent
with other weight loss curves of these types of
drugs. If one projects that out to 6 months, one
gets just slightly less than a 5 kg difference,
assuming no weight loss in the placebo group which
was not reported on that website.
There is a second trial that used
rimonabant in dyslipidemic patients. The
difference from placebo was 5 kg at 6 months and
6.5 kg at a year.
Rimonabant is an antagonist of
cannabinoid-1 receptor. In other words, it blocks
the receptor that is thought to be effective in
causing the munchies when people smoke marijuana.
Nausea and diarrhea were greater than 5 percent
above placebo. There was a 10 percent increase in
HDL, a 15 percent reduction in triglycerides and a
reduction in the 2-hour post glucose load insulin,
and no significant effects on pulse or blood
pressure in these dyslipidemic patients.
I put in this slide to put into context
the blue line, which is a typical drug where there
is weight loss of 10 percent, compared with the
gastric bypass which has weight loss of 30 percent
which is durable over 14 years.
In summary, there are short-term weight
loss medications that are approved for treatment of
obesity, such as phentermine and diethylpropion.
There are drugs that are approved for the long-term
use in the treatment of obesity, that is, orlistat
and sibutramine. There are other medications
approved for epilepsy or depression,
bupropion, fluoxetine, topiramate and zonisamide,
which are not approved for use in treating obesity
but which seem to give weight loss. And, there are
two drugs, Axokine and rimonabant, about which
there is public information that are presently in
phase 3 trials for the treatment of obesity.
In conclusion, all these drugs give
between a 2 and 6.5 kg greater weight loss than
placebo in trials that last up to a year, and the
amount of weight loss appears to be medically
significant. The weight loss between these
different drugs is not different statistically and
the choice, therefore, revolves around side
effects. The weight loss and the difference from
placebo are two different things, which I hope I
demonstrated, and data beyond 2 years essentially
does not exist, with a couple of exceptions. Thank
DR. BRAUNSTEIN: Thank you. Questions
from the panel? Yes, Dr. Woolf?
DR. WOOLF: There was a report in "New
York Times" on Monday, I think it
was, of results
of a one-year or a two-year trial in Europe with a
drug that they didn't specify, other than saying it
was a receptor blocker of some sort that had, I
think, 19 lbs weight loss and 3.5 inch reduction in
waist and a 24 percent increase in HDL. Do you
know anything about that?
DR. GREENWAY: That was rimonabant. I saw
that article and that was about rimonabant.
DR. WOOLF: Sorry?
DR. GREENWAY: I read the article and it
was reporting on rimonabant, a new study of
rimonabant, not the one that was reported by Frank.
DR. WOOLF: Thank you.
DR. GREENWAY: Actually, those results
are on the website. I checked it yesterday, 1
year, 52 weeks, 5 and 20 mg.
DR. BRAUNSTEIN: Yes?
DR. ARONNE: Frank, can you talk a little
bit about the problem with dropouts in weight-loss
drug studies, and some of the pros and cons of the
type of analyses used, last observation carried
forward versus completers?
DR. GREENWAY: Well, it seems as though
people in weight-loss studies appear to have a
feeling of being stigmatized when they drop out of
studies because they don't want to come back. It
is very difficult to get final data on people who
drop from weight-loss studies. Weight-loss studies
that go out to a year usually have something like a
30 percent dropout rate.
The traditional way of analyzing these
studies, as Susan suggested, has been the last
observation carried forward, and what that does is
it dilutes the effect of the drug because it
assumes that the reason the people dropped out is
because they didn't lose weight. Actually, what
the physician treating a patient is interested in
is more what happens to the patient that I treat
who stays in treatment, rather than the more public
health perspective of this last observation carried
forward which looks at the entire group. If you
treat everybody, what does the total group gain
from this experience? So, from the way in which
these medications are used, it is much
informative to me, as a clinician, to have the
analysis of completers rather than the last
observation carried forward.
DR. BRAUNSTEIN: Dr. Schambelan?
DR. SCHAMBELAN: Just a quick question
about Axokine. You said it worked distal to
leptin. Do you know if it works distal to the
leptin receptor or just distal to leptin? Is its
actual site of action known?
DR. GREENWAY: The site of action of
Axokine is in the leptin pathway. It is probably
in that signaling pathway but it is distal to the
site where leptin acts.
DR. BRAUNSTEIN: Frank, can you describe,
in the studies that were carried out for one year
with these drugs, what the effect was on the
comorbid states and whether there were any
differences among the drugs? For instance, did
some lead to lowering of blood pressure and others
didn't? Did some lead to lowering of cholesterol
while others didn't? Or were they all fairly
DR. GREENWAY: You are asking me what was
the effect on comorbidities in these studies?
DR. BRAUNSTEIN: Yes.
DR. GREENWAY: Of the two drugs that are
approved for treatment of obesity in the United
States, orlistat seems to have a disproportionate
beneficial effect on lipids, probably because it
enforces a low fat diet. Sibutramine doesn't have
the expected beneficial effect on blood pressure
that one might expect, probably because of its
norepinephrine reuptake mechanism of action.
Otherwise, one gets the expected benefits that one
would expect with weight loss with these drugs.
DR. BRAUNSTEIN: Other questions?
Thank you. Our next speaker will be Dr.
Laura Governale, who is going to speak about
patterns of weight-loss drug use.
Patterns of Weight-Loss Drug Use
DR. GOVERNALE: Good morning. To begin, I
would like to briefly state that the Division of
Surveillance Research and Communications
the Office of Drug Safety is responsible for the
procurement, management and analysis of drug
utilization databases for the FDA's use. The
information contained in these slides has been
approved for this meeting.
The topics I will be discussing today are
the patterns of prescription weight-loss drug use
and the patient demographics associated with
weight-loss drug use. For this presentation
weight-loss drugs are defined as dexfenfluramine,
sibutramine and orlistat and amphetamine congeners
such as phentermine and dimetrazine diethylpropion,
phendimetrazine, diethylpropion, benzphetamine,
mazindol and fenfluramine. We did not include
amphetamines in this analysis. Also not covered in
this analysis are over-the-counter drugs and
nutritional supplements. The analysis is conducted
using proprietary databases at the agency's
Two databases were used in this analysis
from IMS Health. IMS health is a pharmaceutical
marketing usage company that collects
drug use information worldwide. The agency uses
these databases as well in order to obtain drug use
information and trends in the U.S. The two
databases from IMS Health were the National
Prescription Audit Plus and the National Disease
and Therapeutic Index.
NPA, or the National Prescription Audit
Plus, measures the retail outflow of prescriptions
from pharmacies into the hands of consumers by
formal prescriptions. The number of dispensed
prescriptions is obtained from a sample of
approximately 22,000 randomly selected pharmacies
around the country and projected nationally. The
pharmacies in the database account for
approximately 40 percent of all pharmacy stores and
represent approximately 45 percent of prescription
coverage in the U.S. The pharmacies include the
following retail channels such as chain,
independent, mass merchandisers and food stores
with pharmacies, and also include mail-order and
long-term care pharmacies.
The National Disease and
is a survey of roughly 3000 office-based physicians
around the country. The data gathered in NDTI are
designed to provide descriptive information on the
patterns and treatment of disease encountered in
this setting. The data are collected and projected
to provide a national estimate of use. However, in
certain instances the small sample size tend to
make these data unstable and sometimes these
results should be interpreted with caution.
Patterns for prescription weight-loss
drugs dispensed were obtained from NPA Plus. Here
I will present the trends in prescription
weight-loss drug use dispensed from 1966 to 2003
and also the method of payment for these
prescription weight-loss drugs from 1999 to 2003.
This slide, which is based on NPA data,
represents the total number of prescriptions
dispensed for prescription weight-loss products
from 1966 to 2003. The total number of
prescriptions represents new prescriptions as well
as refill prescriptions.
The yellow-shaded area here
total added prescription weight-loss products of
all the individual weight-loss products as shown
here. The individual lines represent individual
active ingredients in some of these weight-loss
drug products. Again, this slide does not include
any amphetamine products.
As you can see, over the last 38 years
there have been fluctuations in prescription
weight-loss products. As you can see, there are
two major spikes in prescription drug use. These
fluctuations in use have been largely due to two or
three prescription drugs at any given time.
The first spike, which occurred during the
early 1970s, around the decade of the '70s, was
most likely due to the enactment of the Controlled
Substances Act in 1970. This was also presented by
Dr. Colman in a previous presentation. This
legislation in essence restricted the production
and distribution of amphetamines which, throughout
the 1960s, were commonly prescribed for weight
loss. When these restrictions were placed on
amphetamines the amphetamine congeners
Also in 1973, the agency declared that
amphetamine and amphetamine-like compounds were
effective for the treatment of obesity. This led
to a large spike in use for diethylpropion and
phentermine products. The number of prescriptions
here peaked at 12.5 million in 1976.
However, we see a decline in use around
1979. In 1979 there was a Federal Register notice
calling for the removal of the obesity indication
in amphetamines. This led to a sharp decline in
use in weight-loss drugs, namely, for phentermine
and diethylpropion. However, the proposal to
remove the obesity indication from the amphetamines
never materialized. Since then, the use of
weight-loss products had steadily declined until
I will focus now on the last 13 years for
prescription drug trends. Looking at the last 13
years, the number of total prescriptions dispensed
for weight-loss drugs reached its lowest point
around the 1990s, early 1990s, with
3.3 million prescriptions dispensed.
Then, in early 1995, 1996, we began to
notice an increase in usage. This was most likely
due to the result of a publication, in 1992, of a
series of papers that concluded that the
combination of phentermine and fenfluramine, or
phen-fen, was safe and effective for long-term
weight loss. In 1996 the FDA approved
dexfenfluramine for the treatment of obesity. The
number of anti-obesity prescription drugs dispensed
reached its peak in 1996 with 21 million
prescriptions. The compounds responsible for this
increase include phentermine, fenfluramine and
Again, dexfenfluramine was marketed under
the name of Vidoxx and fenfluramine was marketed
under the name of Pondimin. During its peak use in
1996 fenfluramine held 33 percent of the market
share with 7 million prescriptions dispensed,
whereas dexfenfluramine held 11 percent of the
market share with 2.3 million prescriptions
dispensed. Phentermine held 52 percent of the
market share with approximately 11 million
This large spike in use was followed by a
market decline over the next two years when, in
1997, the FDA announced a voluntary withdrawal of
fenfluramine and dexfenfluramine following
increased reports of cardiac valvulopathy in
patients treated for obesity. The total number of
prescriptions dispensed went from a peak of 21
million prescriptions down to approximately 7
million prescriptions ion 1998, which represents
approximately a 67 percent decline. Since then the
number of prescriptions dispensed for weight-loss
drugs has declined to approximately 5.8 million
prescriptions in the year 2003.
Orlistat was released into the market
around 1997, and sibutramine in 1999. Currently,
or in year 2003, they hold second and third place
in the market with 1.3 million prescriptions
dispensed for orlistat or 22 percent of the market
share, and 760,000 prescriptions dispensed for
sibutramine, which represents 13 percent
Phentermine continues to predominate the
market with approximately 3 million prescriptions
dispensed, which represents over 50 percent of the
market share. Other products, such as the
amphetamine congeners, have steadily declined in
use since the mid-1990s and collectively account
for less than a million prescriptions per year.
This slide, in contrast to the previous
slides, represents only new prescriptions
dispensed. Furthermore, this analysis excludes the
mail-order and long-term care channels. Therefore,
the numbers of prescriptions reported in this
analysis are smaller than in the previous slides.
This graph is an analysis of method of
payment for prescription weight-loss drugs. As you
can see, the number of new prescriptions paid by
cash has declined steadily over the past 5 years,
from approximately 5 million in year 1999 to 2.6
million in year 2003. However, the number of
third-party payment for new prescriptions has
remained steady at approximately 1.1 to
prescriptions over the 5-year period surveyed. The
drop in cash payment, in effect, has increased the
proportion of third-party payment for these drugs
from 20 percent in year 1999 to approximately 30
percent in year 2003. So, the main message from
this slide is that cash payment remains an
important mechanism for the payment of these
weight-loss prescription drugs.
Next I will discuss the patient
demographics associated with prescription
weight-loss drugs. The data are based on IMS
Health, National Diseases and Therapeutic Index.
Again, the data are projected nationally. However,
it does not represent disease burden, nor is it
representative of all disease states in the nation.
Rather, the data reflect a population of ambulatory
patients, visiting physicians and office-based
practice settings during which a weight-loss drug
is mentioned during the visit. Again, due to the
limitations in data sampling in this database, any
perceived trends must be interpreted with caution.
The topics I will be discussing
patient demographics include the principal
diagnoses associated with prescription weight-loss
drugs, the gender distribution, age distribution
and race distribution.
This table represents the principal
diagnoses associated with prescription weight-loss
products for ambulatory patients. Not
surprisingly, obesity is the diagnosis most often
mentioned with weight-loss drug products, with
approximately 89 percent or 1.8 million projected
This slide represents the number of
mentions associated with the use of weight-loss
drugs as reported by office-based physician
practice settings. This is a measure of drug
mentions again and is not reflective of disease
burden in the nation.
As you can see, females account for a
clear majority in use for prescriptions of
weight-loss products, with an average of 2.3
million drug appearances or 85 percent over the
time period surveyed.
Taking a closer look at the most recent
calendar year, we see that the adult age group,
18-44, accounts for the largest majority of drug
use for prescription weight-loss products, with
approximately 1.2 million or 62 percent of total
drug appearances. This is followed next by age
45-64 category, with 624,000 mentions or 32.6
percent of total drug appearances in the year 2003.
In conclusion, the majority of weight-loss drug
products is in the young, female, adult and middle
This graph represents the race
distribution of patients associated with the use of
prescription weight-loss drugs as reported by
office-based physician practice settings. Again,
the reporting in this database, NDTI, is reported
by the physician and not is not self-reported by
the patient. The key take-away from this graph is
that a proportion represented by each race group
has remained constant over the time period
surveyed. Approximately three-quarters of use is
from Caucasian patients.
Now that I have represented the data, I
will present the limitations on each of these
databases. The NDA Plus data provide only limited
demographic information on prescription use.
Therefore, we did not use this database for this
analysis. Instead, we used NDTI to obtain
demographic information which has these
limitations: As you can see, the small sample size
makes some projections unstable. Again, the data
are not generalizable to all of these patients.
And, due to the limitations, any perceived trends
must be interpreted with caution.
In conclusion, over the last 38 years
there has been a fluctuation in the total number of
prescriptions dispensed for prescription
weight-loss products. These fluctuations have been
largely due to two or three drugs at any given
The second point is that cash payment
remains an important mechanism for payment for
these products. Also the primary users of these
products are Caucasian women between the
ages of 18
and 44. That is the end of the presentation.
DR. BRAUNSTEIN: Thank you. Any questions
from members of the panel? Yes?
MS. COFFIN: On your slide that talks
about the race distribution of the patients you can
see huge differences and, of course, the Caucasian
patients are shown as the largest amount. How does
that normalize to the population as a whole? Is
the population as a whole from '98 to 2003 more
greatly Caucasian than it is Asian American or
DR. GOVERNALE: Again, this database is
not supposed to represent any epidemiology of
obesity. It represents patients visiting
office-based physicians and it could reflect just
that there are more Caucasian patients visiting
DR. BRAUNSTEIN: Dr. Woolf?
DR. WOOLF: Do you know if the heavy use
of cash for these drugs is because they are being
excluded by drug plans that the patients have? Are
they being excluded from the formularies
patients are covered on? Is that why cash is so
DR. GOVERNALE: I think if I heard your
question, it is why are most of these products not
DR. WOOLF: Yes, is the reason that cash
accounts for three-quarters of the method of
payment because they are being excluded from drug
DR. GOVERNALE: Yes, that is the
limitation with these products. Most of these
products are not covered by third-party payers and,
therefore, that is why they are being paid for by
DR. BRAUNSTEIN: Dr. Watts?
DR. WATTS: I was interested in your
demographics. I may be making wrong inferences but
it seems to me if the largest use of these drugs in
the real world is by younger white women, that may
be more for cosmetic benefits of weight loss. This
is a question then for Dr. Greenway. I didn't get
from your presentation the demographics
subjects that are studied in the typical weight
loss trial. Are they different from the people who
are using these drugs as we heard from this
DR. GREENWAY: The patients in the regular
weight-loss trials primarily have a BMI between 30
and 40. So, they aren't in the trials because they
have just cosmetic concerns, but I think that what
you have observed is correct, that obesity is
stigmatized in our society, particularly
stigmatized in regards to women, and that is
probably the reason that we have 80 percent of
these obesity trials that are composed of women.
Clearly, 80 percent of the population isn't women.
DR. WATTS: To extend that though, is
there a particular age of the subjects in the
studies that you showed? Were they different,
older, from the use of these drugs in the real
DR. GREENWAY: The average age of the
people in the trials is usually around 40. So,
they may be slightly older than this
group but I
think they are probably fairly representative.
DR. BRAUNSTEIN: Dr. Yanovski?
DR. S. YANOVSKI: These data did not
report out BMI. They might have the physician
diagnosis for obesity correct but you couldn't tell
how many of the patients in these studies had BMIs
above a certain range. Is that correct?
DR. GOVERNALE: Correct. There is no
linkage of BMIs to the diagnosis of obesity.
DR. S. YANOVSKI: So, in preparation for
this I pulled an article by Laura Kettle Conning
and colleagues at CDC that looked at use of
prescription weight-loss pills in U.S. adults from
1996-98 that I think addresses your question. They
used the behavioral risk factors surveillance
survey and they looked at all patients who reported
use of prescription weight-loss drugs. They then
looked at the proportion of patients who reported
using prescription weight-loss drugs who had a BMI
of less than 27, which was the lower limit for
indication with comorbidities. What they found was
that 5 million U.S. adults had used
weight-loss drugs in that 2-year period. Of that
group, 25 percent reported that they had a BMI of
less than 25. So, it looks like there is
substantial use of these medications for cosmetic
DR. BRAUNSTEIN: Dr. Schambelan?
DR. SCHAMBELAN: I just want to pursue Dr.
Woolf's question about the reason that the cash
payment is decreased. Do we know that there has
been a systematic change in policy of third-party
payers as to what they will approve for weight-loss
drugs? Perhaps you don't know but other panelists
DR. BRAUNSTEIN: What will the effect of
the recent change in coverage of the drugs by
Medicare have on all this? I guess that is part of
DR. SCHAMBELAN: Well, Medicare or other
DR. GOVERNALE: We did not look into the
reasons for why some of these prescription drug
products are being covered or not covered
third-parties, but that could be a very interesting
question to look into for future analyses.
DR. BRAUNSTEIN: Dr. Aronne?
DR. ARONNE: While there hasn't been a
systematic change in the number of plans which are
covering drugs, what we have seen is that
practitioners of obesity medicine where we focus on
obesity to treat someone's diabetes, sleep apnea or
other complications, is a steady increase in the
willingness of insurance companies to pay for drug
therapy in an appropriate setting. So, with prior
approval, if the patient is in a medically
supervised program, the insurance companies will
pay for the drugs. Right now in the New York area
it is more than 40 percent. The last number I
heard was that 44 percent of patients who have
insurance get coverage for these types of drugs.
DR. BRAUNSTEIN: Any further questions?
We will take a 15-minute break. Thank
DR. BRAUNSTEIN: We are changing the order
a bit. We are going to ask Dr. Richard Atkinson,
who is director of Obetech Obesity Research Center,
to speak on the role of drugs in the treatment of
obesity: current and future. Following that, we
will then move to the open public hearing, followed
by Dr. Orloff's talk.
Role of Drugs in the Treatment of Obesity:
Current and Future
DR. ATKINSON: Thank you, Dr. Braunstein.
Thank you, Dr. Orloff and Dr. Colman for inviting
me to speak. I am coming today wearing two hats.
One is the president of the American Obesity
Association and the second is a physician/clinician
who has literally treated thousands of obese people
over the years.
From that perspective, I have looked into
the eyes of these people and seen the pain and
heard their pain as they talk, and I have failed
them and I think we have all failed them. The
physicians and scientists have failed them. The
drug companies have failed them and the
has failed them. That sounds like a negative
message and I am going to spend a little time
talking about why I think we have all failed. But
I think the promise of the future is really very
bright and I will try to end up on that.
I always like to start off with something
that is not unique to me; I probably stole it from
someone, but obesity is a chronic disease of
multiple etiologies characterized by the presence
of excess adipose tissue. Everybody has excess
adipose tissue but the critical word I think here
is "disease." I think we have heard in this
discussion this morning even some questioning of
the idea of obesity as a disease. But I believe
obesity is a chronic disease and if you think of
other chronic diseases, try to think of one that is
not treated with drugs.
If obesity is a chronic disease and most
other chronic diseases are treated with drugs, why
not obesity? We know that the biochemistry of
obese individuals is different from that of lean
That is very well known. Bob
others have some data that when obese people lose
weight their biochemistry does not become the same
as lean people's. For example, lipoprotein lipase,
the major clearer of triglycerides out of the
bloodstream, in adipose tissue lipoprotein lipase
goes up; in muscle it goes down. So, people who
were formerly obese are poised to regain their fat.
What do we do with drugs? We change the
biochemistry. So, the rationale for using drugs is
to change the biochemistry of the bodies of obese
There have been, as you have heard, a
number of barriers to the use of drugs. The first
one I am going to put up here is discrimination
against obesity. I am going to spend several
slides talking about this.
When Dr. Orloff asked me to talk, we
talked about the fact that we were going to have a
very nice bunch of scientific presentations and I
am going to come with a more emotional part with
this presentation. But as president of an
organization that is advocating for these
want to point out some of the discrimination
against obesity. The fact of physician and
clinician ignorance of obesity, an particularly of
obesity drugs; economic factors; policy and
political barriers, and I have come much more to
appreciate that. We have had several meetings with
people from the FDA, NIH and others and I have come
to appreciate more some of the barriers. There is
a lack of advocacy about obese people and, finally,
currently there is a modest effectiveness of
obesity drugs, as we have heard.
I am going to talk a little bit about
discrimination. Obesity is the last bastion of
socially acceptable bigotry. If you are a radio
announcer or a TV announcer and you tell a joke, a
race joke or an ethnic joke, or a joke directed
against homosexuals, you will get fired. Fat jokes
are told all the time. Look in your comic pages
and virtually every day there is some slam against
fat people and nothing is done.
This discrimination against obesity is in
the people who are in our field. Stan Heshka and
David Allison are two very good friends, two very
bright people, good scientists, but "labeling
obesity a disease may be expedient but it is not a
necessary step in a campaign to combat obesity and
it may be interpreted as a self-serving advocacy
without a sound scientific basis." Well, those are
pretty strong words for somebody who is in the
There is a lack of medicalization of
obesity. Think about obesity compared with some
other chronic diseases. For example, newly
diagnosed type 2 diabetes, newly diagnosed
hypertension--a very high percentage of those
patients will respond very well to diet and
exercise. it goes away. I did a study about 20
years ago and it goes away in 80 percent of the
people. But the first words our of the mouth of a
primary care physician are not "I'm going to put
you on a diet and exercise program;" it is "I'm
going to put you on drugs."
The primary treatment for obesity is diet
and exercise and drugs are an
adjunct. As we have
heard from Colman's talk, that has been true for
many, many years. Many patients must demonstrate
that they have failed diet and exercise before they
can get either drugs or surgery. There is no other
disease where that happens.
Physician and clinician
ignorance--obesity, obviously, is not thought to be
a real disease. As many of you know, we have been
doing some work on viruses that cause obesity and I
have gotten up and had people shake their fist at
me and say, "you're trying to give these fat people
an excuse." Wow! Physicians are uncomfortable
about counseling overweight or obese patients. I
have a talk on discrimination against obesity to
document many papers in the literature where this
has been shown.
Physicians and clinicians are not
knowledgeable about nutrition, physical activity,
and particularly about obesity drugs. This is a
disease that is killing 400,000 people per year
according to the CDC. At the University of
Wisconsin I was able to get a clinical
course on the curriculum and we had exactly three
lectures on obesity. Since I left, that has now
been cut to one. That is pretty much all they get
about obesity in the whole curriculum.
Physicians are unaware of referral
information. If you have a fat person, what do you
do? They feel helpless and there is a feeling that
if you refer a patient to an obesity physician you
are sort of sending them to a charlatan. There is
a bias. We have heard a little bit about that
today, that drug treatments are dangerous,
ineffective and somehow not worthy.
There are economic factors that are
barriers to obesity drugs. I was flabbergasted to
hear Lou Aronne's comment that in New York 40
percent of third-party payers are starting to pay
for drugs. That is super. We looked in Wisconsin
and in our population it was between 10-15 percent.
They had a very high percentage of HMOs and these
HMOs simply didn't cover obesity or obesity drugs.
Some of the reasons for that are that the
treatment is fairly expensive. This, after all, is
a chronic disease. The insurance companies and
employers are worried about breaking the bank.
There are a large number of overweight and obese
people. We heard Katherine Flegal's talk. Over 30
percent of the entire adult population is obese,
has a BMI of 30 or above. So, one, there is a
large population that might want to use those drugs
or use that treatment and, secondly, given a
choice, they will.
We heard from Susan Yanovski about maybe
as many as 25 percent of people that are using
these drugs are using them for cosmetic purposes.
That is a little bit of a discrimination in itself.
There is a whole industry that makes drugs for
cosmetic purposes, like skin rashes and so forth
and so on. So, what is so bad about somebody
wanting to lose some weight when, if you are
overweight, you have a harder time getting a job,
getting promoted in a job, finding a spouse. If
you are a small kid other kids don't want to play
with you. It is not just a cosmetic problem; this
is a socioeconomic huge discrimination
against obese people.
For many of the insurance companies and
insurance plans and HMOs savings in the future
costs are too remote compared to current expenses.
Their bottom line is a year or less. If it doesn't
pay for itself in a year, let's don't pay for it.
Turning to the government, honest to God,
at a Harvard CME course put on by George Blackburn,
I am happy to say a former member of the FDA, he
made the statement, "gaining weight doesn't hurt
you and losing weight doesn't help you." I am
embarrassed to say I got into a shouting match with
him in front of 400 people.
Obesity drugs I think have been held to a
different standard in the past than drugs for other
diseases. I will just bring up the phen-fen
debacle versus troglitazone. Within two months of
the first unconfirmed, uncontrolled case series
that was prematurely reported by The New England
Journal--it wasn't even published yet but what was
released as a press release--within two months of
that fenfluramine and dexfenfluramine
off the market. It was not really sure that anyone
had died from fenfluramine or dexfenfluramine.
Sixty people had died from troglitazone and it
stayed on the market two more years.
Now, the cynic in me says that is because
diabetes is a real disease and obesity is not.
That may not be fair and there are other factors,
but from my side, coming from an advocacy
organization, it looks like that is discrimination
against obesity. I am not saying that fenfluramine
and dexfenfluramine should not have been taken off
the market, but the timing was interesting.
The recent experience of obesity
drugs--dexfenfluramine had quite a hard time
getting approved. Sibutramine was initially turned
down and only upon appeal was approved. Orlistat
had what apparently was a spurious association with
cancer so they had to go back and do a great many
more trials to look at the patients to show that
there was not a correlation with cancer.
As many of you know, and as many of you
here have participated in, the American
Association has sponsored a series of meetings with
people from the FDA, the NIH, other government
agencies, scientists and many representatives of
the pharmaceutical industry who have obesity drugs
or are interested in obesity drugs. And, one of
the things I have been impressed with is that the
people at FDA have a huge load on their shoulders
because if anything goes wrong, it is their
problem. We have, you know, 100 million people who
might be wanting to take these drugs and if even a
few of them start to have problems, it is the FDA's
fault for having not been more careful.
Fenfluramine had been on the market since
1973. It was not until 1997 that it was found to
have cardiac valve problems. The problem with
pulmonary hypertension, as Eric noted, was there
but it was really pretty rare. So, I have a much
better understanding of the pressures, both
political and from media and from scientists, on
the FDA and why they simply have to be cautious.
From the Medicare/Medicaid perspective, we
have already heard today that until just
a month or
so ago the language in the Medicare and Medicaid
regulations was "obesity is not a disease" despite
the fact that it was called a disease in 1985 by an
NIH consensus development conference. Apparently,
efficacy standards, in contrast to drugs and
treatments for most other chronic diseases, will
have to have some sort of proving that this
treatment works. Now, as I said earlier, we
have failed these people but obese people fail
themselves. The expectations and the behavior of
obese people contribute to the problem because many
do not believe they are worthy or respect. Obese
people discriminate against obese people actually
more than thin people discriminate against obese
people. They do not bind together for action.
Trying to get people to join this advocacy group
has been absolutely amazing. I thought everybody
in the world who was obese would sign up. They
don't. They are ashamed to be associated with the
world of obesity. They simply do not act as
Other barriers to obesity drugs
limited choices and poor efficacy. There are only
two drugs still on patent. Why haven't the drug
companies done more in the past? They are
certainly doing it now. There are really only
three categories of drugs, as you have heard, the
adrenergic agents, sibutramine which is in a
category by itself and orlistat which is in a
category by itself. We still have an infantile
understanding of the etiology of obesity and
mechanisms of action of drugs. We heard about
topiramate. We don't have a clue as to how it
works. It causes weight loss but we don't know how
As we have heard, typical weight-loss
agents, single agents at least, cause only about a
10 percent loss from initial body weight, and there
has been very limited use of combinations of drugs.
I will come back to that.
This is the data on dexfenfluramine, the
index study from Europe, the best study that
dexfenfluramine had, and there was about a 10
percent weight loss at a year.
Sibutramine, about an 8 percent or 9
percent weight loss at a year with 15 mg.
Sibutramine out over 2 years, again over in
Europe--again, this is about a 13 percent weight
loss. This is the Storm trial.
With orlistat, about a 10 percent weight
loss at one year. This is a 2-year trial. The
2-year data was about 8 percent.
If you are a 220 lb woman and you lose 22
lbs, your physician can tell you all he or she
wishes, "oh, you're healthy; your blood pressure's
better; your blood sugar's better, your lipids are
better." That woman or that man who is obese is
still suffering the slings and arrows of
discrimination by society. As a matter of fact,
when we showed the data from 2000, John Monroe's
group in BMJ and in Practitioner back a long time
ago, these were 36-week trials and the percent
weight loss was about 13 percent in each. That is
pretty much all there is with phentermine which is
the most commonly used drug.
That is sort of, if not the bad
least the mediocre news. Let's look at what is
going on for the future. I apologize, I am sure
some of the companies out there have some areas
that I have left out here. But we know gut
peptides are a very fierce focus of action with CCK
analogues and enterostatin and so on; opioid
antagonists, the ones in phase 3 trials; various
neurotransmitter agonists and antagonists;
thermogenic agents, the Holy Grail--increase your
metabolic rate, keep eating and increase your
muscle mass and reduce your fat mass. Growth
hormone and growth factors have been disappointing
to date but maybe there is something there. Things
that enhance lipid oxidation I think will be of
particular interest; and nutrient partitioning
agents will be very interesting agents for the
future. I am sure this isn't all. There are many
more areas in which we may be able to affect food
intake, body weight or body composition.
These are just some of the potential
agents. Again, several people and particularly
Frank have talked about bupropion,
zonisamide which are already out there. There are
several in clinical trials, and then there are a
number of others here. From my understanding,
there are about 350 different drugs in the
This is the data on bupropion. Frank
already showed this, about a 10 percent weight loss
at a year.
Topiramate--I put this slide up because it
shows 5-year data in epilepsy patients. As Frank
showed you, it has a pretty reasonable comparison
against placebo at 6 months.
This is the data from Gadde on zonisamide,
again showing a 32-week weight loss of about 9
However, single drugs are not likely to be
very effective or much better than about 10 percent
or 15 percent because there are so many redundant
systems regulating food intake and body weight,
something so critical to life as that. So, I think
I am not sure we are even born yet with our use of
drug combinations. I talked about the infancy of
drubs. Obesity is a chronic disease. Most chronic
diseases are treated with drugs. Most chronic
diseases require more than one drug. How many
chronic diseases can you think of that are treated
with just one drug?
You heard about phentermine and
fenfluramine. Combinations of drugs may have
additive or synergistic effects. As Weintraub
showed with phen-fen, some of the side effects may
even be offset.
Here is the original Weintraub data
showing about a 15 percent weight loss at a year.
As you know, he took those data out to 4 years. He
had a pretty good dropout rate but still had
Here is another combination of ephedrine
and caffeine. Either one alone is not terribly
effective but the combination causes about a 16
percent weight loss that persisted out to a year.
That is, of course, not on the market anymore.
Here is some data that we did at the
University of Wisconsin comparing
phentermine and fluoxetine and the slope is about
the same. These are 6-month data. Again, we had a
pretty good dropout. We did not have a control
This meeting is all about the guidances
and what is going to happen to the guidances. So,
let me put on my helmet, get my lance out and tilt
at this windmill for a while to talk about some of
the things that I think would be very useful to
have from an obesity advocacy point of view.
Obesity is a major public health problem.
We have an epidemic here. There have been 10 times
more people dying of obesity-related causes than
are dying of AIDS in this country alone. Why
shouldn't obesity drugs be fast track as they are
for many other drugs? As Dr. Greenway pointed out,
in virtually all the drugs that we see the weight
loss plateaus certainly by 6 months.
Why should we need to show efficacy? Why
should the trials go out past that? Why not have
safety? You know, safety is what is really
important. If you show efficacy, and almost all
the drugs show a 5 percent weight loss in 6 months
or better, virtually all the safety issues have
been seen by then, and when we have a drug on the
market--fenfluramine--for 20-some years and we
don't pick up that it has a problem, it is just a
crap shoot. Why not go ahead and allow the drug
companies to cut those massive costs of research to
get the drugs on the market earlier, and then have
a much more rigorous long-term safety evaluation as
the drugs are on the market and they can begin to
recover some of their costs?
This extended run-in period--I see very
little usefulness for the run-in period. I am
raising some of the questions that were brought up
at the discussions that we have had, four
discussions so far. One of the things that most
people feel is really pretty useless is a run-in
period. In one of the original guidances people
were supposed to show weight loss and only those
people who showed weight loss would then be allowed
to go on to the clinical trial. That makes no
sense at all. We know that long-term diet and
exercise don't work. The question is do drugs work
long term? Trying to get people to change their
behavior is very, very difficult. If you can
change their biochemistry maybe we can get
Frank Greenway showed a trial on mazindol
with and without behavior modification, and when
you throw in behavior modification you reduce the
apparent efficacy of the drug but you can only lose
weight so fast. If you starve yourself you can
only lose weight so fast. So, as you have a better
diet and exercise program you wash out the effect
of the drug. Why have a run-in period at all?
Another thing that I think would be
useful--I was quite interested in Eric's comments
about what used to be the acceptable standard, any
statistically significant difference from placebo.
Drugs almost certainly will have to be used in
combination. Unfortunately, sibutramine and
orlistat don't work in combination but phentermine
and fenfluramine did. I, and I know others in this
room, have used phentermine and
and appear to get a little better weight loss than
with either one alone. That has not been studied
in any organized fashion. So, if safe, these drugs
not only cause modest weight loss, many hold
promise that they could be used in combination with
other drugs and I would love to see that in the
guidances somehow. Varied indications for use are
justified. Others have shown that rapid weight
loss initially is associated with better response
of blood pressure, blood sugar. Jim Anderson has
done two meta-analyses showing that rapid weight
loss early, no matter what the time period, no
matter what the outcome measure--the people who
have lost a lot initially have at least as good or
better outcome variables. So, maybe drugs that
only cause a short-term weight loss might be useful
and then you switch to something else.
So, I think there are many varied
indications for use. Some for short term; some for
long term; some for use after a very low calory
diet, and perhaps the committee could consider some
of those indications.
One of the things that David Orloff and I
spent some time talking about on the phone is how
desperate the American public for drugs to treat
obesity. So, I think rational expectations for the
media and for patients--current drugs are only
modestly effective. Drugs in the pipeline appear
to be similar in terms of efficacy. The maximum
weight loss that I have heard is about 17 percent.
When companies over-hype the weight loss
or try to convince people that a 5 percent or 10
percent weight loss is wonderful, it is not. So, I
think over-hyping is bad on the part of the drug
companies. On the other hand, over-caution by the
FDA and scientists is detrimental. Hundreds of
thousands of people are dying of obesity-related
causes. Some drugs cause some problems. We have
to be safe but there is that tradeoff and Eric's
balance at the end I thought was particularly
appropriate. The media has not always been
responsible. In fact, I would say the media has
been predominantly irresponsible. I still remember
the Redux revolution--the cover on Time magazine,
this is going to solve all your problems, America.
The general public is desperate. They need
perspective and understanding of obesity as a
disease. Physicians have not really given them
that perspective. Unfortunately, I think long-term
lifestyle changes are needed. Trying to change
behavior is very difficult but that is what we are
stuck we right now.
For the future, I believe drugs of the
future of obesity treatment has the offer of
virtually every other chronic disease. Obesity is
due to biochemical differences. Drugs change
biochemistry. And, why am I so optimistic? Frank
Greenway showed you the data on obesity surgery is
somewhere between 25-40 percent of anethole body
weight. Surgery doesn't work because it makes a
little gastric pouch. It works because it changes
the biochemistry of the body. There are starting
to be lots of papers on changes in metabolic rate
and multiple different hormones. And, if surgery
can do it I have no doubt that the smart people at
the drug companies are going to figure
out how they
can reproduce that kind of weight loss with one
drug or combinations of drugs. The surgery changes
At least 350 drugs are in the pipeline, I
understand, and I think that bodes very well for
the future. Combination treatment I think is going
to be necessary, and I think the future is
So, I will just end up by showing the
slide for the American Obesity Association. It is
a lay advocacy group. Its mission is to improve
the quality of life of obese people. I guess you
got copies of these slides but this is my contact
information, here. Thank you very much.
DR. BRAUNSTEIN: Thank you, Richard.
Questions from the panel? Let me start off with
one. You mentioned that fenfluramine had been on
the market for some time before the valvulopathy
was uncovered. If we look at the previous
speaker's slides on the use of fenfluramine, it
really didn't pick up greatly until the Weintraub
papers had come out. So, I wonder if what we are
talking about in terms of safety is a numbers game;
if you really do need a large number of patients to
pick up some of these potentially disastrous
complications. I would like your thoughts on that.
DR. ATKINSON: Yes, I notice there was
something like 70,000 prescriptions of fenfluramine
per year over a long period of time. That went up
to several million later. But Weintraub's paper
came out in 1992. By 1993 those numbers were going
up dramatically and it still took until 1997 before
it was identified, and there were millions of
people taking it obviously, and fenfluramine and
dexfenfluramine had been used in Europe.
Obviously, dexfenfluramine had been approved 10
years earlier. So, it is not just here. It was
all over the world that it was being used and it
wasn't picked up.
So, you know, I think drugs are going to
have consequences and obviously we need to look
very carefully at the drugs and study them, but I
would argue for shorter initial trials and more
intensive longer-term trials. I noticed in one
slide that the FDA was not charged with showing the
safety of drugs after they have been approved.
That probably ought to change.
DR. S. YANOVSKI: I would just like to
comment on your excellent question about
dexfenfluramine and why it hadn't been picked up
earlier with the fenfluramine. Before the
Weintraub papers came out these drugs were used
only exclusively short term, often 30 days or less
and it was never more than 90 days. It was only
after the Weintraub paper came out that they
started getting used for months and months and, in
some cases, even years. Since there was a length
of treatment response relationship with the
valvulopathy, that is likely why it wasn't seen
DR. ATKINSON: Yes, that is an interesting
point, however, there were a number of people that
were reported that had valvulopathy who used it for
a relatively short period of time. It is probably
an idiosyncratic reaction.
DR. BRAUNSTEIN: Dr. Woolf?
DR. WOOLF: I am unclear. Are you
proposing that drugs for the treatment of obesity
be held to a different standard in terms of
evaluation of efficacy and safety than drugs in
general? At least the drugs that we discussed in
this committee before have had trials longer than 6
months, and certainly the clinical trials that I
participated in have been longer than 6 months.
So, are you proposing a different standard for
obesity drugs, or that the FDA change its modus
DR. ATKINSON: I couldn't hear that very
well, but what I heard is am I proposing different
standards for obesity drugs? I think there are
different standards for different drugs. For
example, drugs for Alzheimer's disease, drugs for
AIDS, after relatively limited safety and efficacy
evaluations, are allowed to go on the market. The
point I am making is we have an epidemic of obesity
and a third of the population is affected. I think
it is not unreasonable to say how can we improve
the delivery of drugs, new and better
more drugs so we can try some of those
combinations? No, I don't want to have different
standards but I think there are different standards
for drugs and I would like to put obesity with sort
of the ones that get handled expediently.
DR. BRAUNSTEIN: Dr. Schade?
DR. SCHADE: I have a question about
weight loss. If one assumes that the drugs overall
result in, let's say--I am going to be
optimistic--10 percent weight loss, if you look at
the mortality or morbidity curve, if somebody has a
BMI of 35 and they lose 10 percent of the weight so
they drop to a BMI of 32, is their mortality then
exactly the same as a group that doesn't lose
weight but has a BMI of 32?
DR. ATKINSON: Yes, that is a very good
question. I don't know the answer to that.
Katherine Flegal's data were mainly focused on the
lower BMI groups. As you start up, when you start
getting to 30 and above, those curves start going
up fairly dramatically I think, if that is right,
Katherine. But I can't tell you that if you have
lost 2, 3 or 5 BMI units, do you then assume the
mortality and the morbidity of people who have
never been above that. I just don't know that.
DR. SCHADE: Well, the reason I ask that
is when we treat diabetes we treat hemoglobin A1C
and we assume, through our treatment, that we then
reduce the hemoglobin A1C and we can plot on the
curve the benefit. I just wondered whether the
curve for obesity is similar.
DR. ATKINSON: Yes, and I think that is
good. As you heard, there are some trials that are
ongoing to try to look at these sorts of things.
Again, this is a disease that
affects--what?--100-some million people in the U.S.
and we know almost nothing about it.
DR. BRAUNSTEIN: Dr. Aronne?
DR. ARONNE: Can I comment on the last
question? I think that the benefit from small
amounts of weight loss is disproportionate to the
amount of weight lost because of the initial loss
of visceral fat. When you look at the composition
of weight that is initially lost, it is
riskiest fat that is lost first so small amounts of
weight loss appear to have disproportionate
benefit, out of proportion of what you would expect
from that small amount. What some people have
suggested is following something like the
C-reactive protein and that in the future that
could turn out to be our version of the hemoglobin
A1C because it is a measure of the inflammatory
burden of fat, and a lot of people believe that
visceral fat is where a lot of the C-reactive
protein is coming from.
DR. BRAUNSTEIN: Dr. Orloff?
DR. ORLOFF: Can you reiterate your
position on the run-in aspect of trial designs, and
specifically address whether you are proposing that
all run-ins of any duration, of any type, be
DR. ATKINSON: No, certainly not. I think
a run-in period in the trials that I have designed
and gone out and done, investigator initiated type
clinical trials, we have put in a 2-week run-in
period that was not a treatment period but
stretched out the initial evaluation. What that
does is get out the people who are not serious, who
don't want to come or it is too difficult to come,
or whatever. But in terms of requiring a weight
loss or requiring people to show that they can
adhere to a diet before they are allowed to go on
drugs, that is not true for other kinds of
diseases, for example, diabetes and hypertension,
and there may be companies that would want to do
that and would want to have a run-in, or that would
be what they think their drug is going to be useful
for--in other words, get the weight off and then
this is going to be their weight maintenance drug.
Fine, they can have a run-in. But I think the
mandate that all companies have to have an extended
run-in I don't agree with.
DR. ORLOFF: Again, a bit more
clarification. Do you still advocate diet and
exercise and continued reinforcement of those
lifestyle aspects for treatment of obesity in the
context of the trial?
DR. ATKINSON: Yes, I guess it was fairly
dramatically shown here. Dr. Greenway showed the
difference in weight losses that are achieved in
the United States versus over in Europe. The
companies design the trial to get well over
whatever the standards are. So, I think that can
I make the statement often that everybody,
whether they are skinny or fat, needs to have a
good diet and lifestyle. I think as people come in
they need to be informed of what is a healthy
lifestyle and the exercise and the vegetables, and
all those things. Again, I am speaking for myself
not for anybody else, but I think the idea of
allowing the drug companies individually to figure
out where in the spectrum they want to put that is
not unreasonable, but at least some lip service
ought to be given, if for no other reason, because
people will do things very differently. I mean,