During the past decade, the prevalence of obesity has climbed
dramatically. Data show a 2.4 million increase between 2007 and 2009 in the
number of US adults who are obese, and the epidemic shows no signs of stopping.
The past year was discouraging for weight-loss drugs. Three separate
medications went before the FDA for approval lorcaserin, phentermine
plus topiramate, naltrexone plus bupropion and all three were met with
rejection. In addition, sibutramine, a weight-loss drug approved by the FDA
more than a decade ago, was pulled from the US market because of safety
Caroline M. Apovian, MD, has a positive outlook on
investigational obesity treatments in the pipeline.
Photo by: Mina Dietzius,
courtesy of Bosston
Many physicians who care for obese patients said the field of
weight-loss drug development has been dealt a considerable blow.
As a physician who cares for patients with obesity, it concerns me
globally that once again it looks like we have a barrier toward getting safe
and effective treatments for people with obesity, Steven R. Smith,
MD, scientific director of the Florida Hospital/Sanford-Burnham
Translational Research Institute for Metabolism and Diabetes, said in an
For Endocrine Today Editorial Board member, George A.
Bray, MD, the recent FDA decisions, coupled with the dramatically
increasing obesity epidemic, raise important questions about the future of
pharmacologic treatment for obesity.
There is only one drug approved for long-term use orlistat.
Lifestyle is effective and safe, but preventing weight regain has been
difficult. Surgery is effective, but carries risks, Bray said.
There is a gap for safe and effective medications.
Despite a prevailing sense of frustration, some endocrinologists harbor
hope for the future. Smith said during the past 2 decades, researchers and
physicians have learned an exceptional amount about the science of body weight
regulation while investigating new treatments and, therefore, should not
disregard the potential for other novel therapies.
There is some hope on the horizon, Caroline M. Apovian,
MD, of Boston University School of Medicine, told Endocrine
As obesity statistics skyrocket, the need for medically based obesity
To illustrate this point, Donna Ryan, MD, of the Pennington
Biomedical Research Center in Baton Rouge, La., cited a very
important 2010 study that examined decade trends using National Health
and Nutrition Examination Survey data from 1999 to 2006 compared with 2007 to
2008. Katherine M. Flegal, PhD, and colleagues at the CDC found that the
age-adjusted prevalence of obesity in recent years was 33.8%, and results also
indicated that 6.2% of the US population has a BMI of at least 40.
Katherine M. Flegal
This is a burden of disease that we are going to face in the
future that is going to demand more medical approaches, Ryan said in an
interview. There is no way that we can ignore or deliver surgery to 6.2%
of the population.
Additionally, obesity places a significant burden on the health care
system. Recent CDC estimates of the annual medical costs of obesity are as high
as $147 billion, with averages suggesting that obese Americans have medical
costs that are more than $1,400 than those people of average weight.
More than 50 illnesses are caused by obesity, Louis
Aronne, MD, FACP, clinical professor of medicine at Weill Cornell Medical
College, said in an interview. If we are going to have an impact, we need
to start thinking about obesity in a different way.
Robert Kushner, MD, said it may be important to look at obesity
as an underlying cause of disease as opposed to a separate health problem.
Preventing and treating obesity could considerably cut costs associated with
the disease, as well as potentially replace medications used for other related
illnesses such as diabetes and cardiovascular disease.
The irony is there are medications for every one of these comorbid
conditions of which obesity causes or worsens but there
isnt a single medication thats approved other than phentermine and
over-the-counter orlistat to treat obesity, said Kushner, professor of
medicine at the Feinberg School of Medicine, Northwestern University.
According to most physicians, diet and exercise are the cornerstones of
weight-loss management; however, adherence issues are troublesome.
Nevertheless, currently available medications have not fared much better
for various reasons. Phentermine, which was approved in 1959 for 3-month use,
has not undergone any long-term clinical trials since its approval, and any use
longer than 3 months is considered off-label. Orlistat (Xenical, Hoffmann-La
Roche; Alli, GlaxoSmithKline) is approved for long-term use, but studies only
link the drug to an extra 2.9% loss in body weight when compared with placebo.
Bariatric surgery induces more weight loss but is considered an extreme method
with varying long-term results.
In February, the FDA approved a lower indication for Allergans
adjustable gastric banding system (Lap-Band). Now, adults who have a BMI
between 30 and 40 and at least one obesity-related comorbid condition are
eligible for the procedure. Since its approval in 2001, Allergan estimates that
more than 300,000 people worldwide have the Lap-Band.
It is interesting to me that another surgical device was approved
for a lower BMI indication before we have another weight-loss drug out
there, Apovian said.
Aronne likened it to an era where people are going to be going
from Weight Watchers to the operating room. He said surgery is clearly
effective, but most patients would prefer trying medical options first.
Physicians are not the only ones feeling the pressure, according to
Patients are literally dying for some kind of therapy. The
treatment gap in between [the currently available options] is huge, and
patients recognize it, he said.
The overarching question is: Could a new weight-loss pill curb the
growing obesity epidemic? The answer remains complex, but physicians said
having one more tool in the toolbox will help them make a dent by allowing them
to tailor treatment to the individual.
Obesity is not one condition; its like cancer. There are
multiple cancers, there are multiple drugs for cancer, and the type of cancer a
patient has dictates the course of treatment you embark upon, Kushner
said. Obesity is very similar.
Why would a pill succeed where diet and exercise have failed? A drug can
help increase adherence by mitigating some of the biological and genetic
factors contributing to obesity in certain patients, according to Aronne. For
instance, a pill can alleviate cravings, aid patients in exercising greater
control over their eating habits and, in some cases, boost the amount of
calories burned off through the sympathetic system.
Evidence indicates that obesity is a disorder of neuroendocrine
regulation, Aronne said. Leptin resistance is probably one of the
central mechanisms, and even though we cant get at that yet, we can work
Additionally, initial weight loss prompted by a pill may make exercising
easier for some obese patients by relieving stress on their knees, hips and
back, according to Smith.
They actually have a greater capacity for physical activity after
losing weight. They feel better and are more capable, he said.
Moreover, most obese patients who have struggled with adherence to
lifestyle changes because of frustration for not seeing results may find
motivation in actually experiencing the benefits of weight loss for the first
The strongest motivation for behavior change is success. If a
patient does not see success, he or she is not likely to follow the
recommendations, Kushner said. If the medication is going to
augment or amplify the success rate, including how much weight a patient loses,
he or she is more likely to be incentivized to continue with diet and exercise
Nevertheless, as with all treatments, medications have shortcomings.
Obvious downsides are potential adverse effects. This problem, however, is not
unique to weight-loss drugs and is easily addressed by judicious use and
comprehensive patient and physician education, Kushner said. Careful
observation of patient response is essential.
Emphasizing that a pill is a supplement to lifestyle modifications, not
a panacea, is also important, Aronne said, noting that, in the past, physicians
prescribing weight-loss medications were not always responsible, and these
drugs were viewed as a magic solution rather than an ancillary
treatment. Yet, endocrinologists are positioned to prevent this problem from
Endocrinologists, in my opinion, are a perfect group of people who
can play an important role in a team managing weight problems, he said.
Endocrinologists need to play a leading role in the same way that
infectious disease doctors played leading roles when HIV first appeared.
Concerns about adverse events associated with the investigational drugs
up for approval in 2001 and 2010 took center stage at the FDA meetings.
The panels discussed data that linked lorcaserin (Lorqess, Arena
Pharmaceuticals) to mammary tumors, mammary adenocarcinoma and brain
astrocytoma. Combination phentermine plus topiramate (Qnexa, Vivus) met similar
resistance because of links to psychiatric and cognitive events,
teratogenicity, metabolic acidosis and major CV events. Although naltrexone
plus bupropion (Contrave, Orexigen) received recommendation for approval from
an FDA advisory committee, the agency ultimately viewed the risks for elevated
blood pressure as outweighing the drugs benefits. Finally, sibutramine
(Meridia, Abbott Laboratories) was removed after 10 years of market
availability after data from the Sibutramine Cardiovascular Outcomes (SCOUT)
trial linked the drug to major CV events, including nonfatal myocardial
infarction and stroke.
The amount of weight loss associated with obesity medications has been
scrutinized as well. For example, the investigational naltrexone/bupropion
combination reportedly induced a modest 5% body-weight reduction a
number that has increased to 8% in later trials as compared with
Some said, however, that these data do not denote a significant benefit
in terms of weight loss.
These are averages, Kushner said. An average is a
statistical analysis, but patients dont respond as an average; they
respond as individuals.
Therefore, he said efficacy data should be interpreted in terms of
responders and nonresponders. With each medication, clinical trials
demonstrated that certain populations lost at least 10% of their body weight,
and those are the ones for which treatment would be appropriate.
Most experts agree that one drug will not work for everyone, a reason
why approval of more treatments in the weight-loss toolbox is important.
This is how we manage hypertension; we need to start doing this
with obesity. One drug isnt going to do it. There are multiple pathways
going to the brain. The desire to eat is linked to survival; we cant just
knock out one path; another path is going to come in and take over,
Aronne said if 10 drugs were available for weight loss, such as with
hypertension, patients would most likely be able to eat better and maintain
their overall weight loss.
If a patient is taking BP medicine and their BP is not going
down, then you switch to a different category [of medication], Aronne
said. But with BP medicine, there are a hundred drugs in nine different
categories. Unfortunately, we are not in that situation.
Part of the problem with getting new drugs approved is that
investigational weight-loss drugs are not positioned for medical intervention,
according to Ryan.
The FDA panelists who reviewed the drug tended to view obesity as
a cosmetic problem. One panelist even compared obesity drugs to Latisse
(bimatoprost, Allergan), a treatment designed to make eyelashes grow, she
said. Weight loss needs to be taken more seriously.
Click here to view a timeline on the brief history of weight-loss
drugs in the US.
Until the medical gap between diet and exercise and surgery is filled,
physicians are becoming more resourceful with weight-loss management.
We have to be creative and think out of the box, Apovian
said. In some cases, this means using medications off-label, even drugs that
are not currently indicated for weight-loss management.
At my clinic, the patients come to us because they know we will
try whatever we can to help them lose weight, including topiramate,
phentermine, naltrexone, bupropion, pramlintide (Symlin, Amylin), exenatide
(Byetta, Amylin) and metformin.
Smith said he too started looking at diabetes drugs in a way that allows
him to initiate therapy for prediabetes and hyperglycemia in a way that is
weight-centric as opposed to glycemic-centric.
Aronne said physicians should be aware of managing other medications
that may be linked to additional weight gain for obese patients.
The typical patient I see is taking seven or eight medicines.
Often, theyll be taking a medicine that may cause them to gain weight. If
we get rid of one or two of those medications, that may help them to lose more
weight through diet and exercise, Aronne said.
Some diabetes drugs are entering clinical trials that will examine
effects on weight loss. Two primary examples are liraglutide (Victoza, Novo
Nordisk) and exenatide. According to a 2009 study published in The
Lancet, varying doses of liraglutide were associated with mean weight
losses of 1.2 kg to 7.2 kg, and 76% of thecohort lost more than 5% of their
body weight with 3 mg of liraglutide compared with placebo (30%) and orlistat
(44%). Similarly, a 2010 study, also published in The Lancet,
indicated that weight loss with exenatide was significantly greater than weight
loss with sitagliptin (Januvia, Merck) or pioglitazone (Actos, Takeda).
Certainly, many endocrinologists are probably using this
preliminary pilot data to use these drugs for weight loss, Kushner said.
In light of the recent FDA decisions, many are uneasy about the future
of obesity drugs. However, the outlook is not completely bleak.
These drugs are still in the running, Ryan said. They
are down, but they are not out.
She said combination phentermine plus topiramate seems to be the most
promising obesity drug. However, the future for other drugs in the current
pipeline seems less positive. The FDA requested a large-scale, multicenter,
randomized, CV-endpoint trial for Contrave, which will cost Orexigen millions
of dollars. Because of this, and other similar instances, some question the
ability of the company to proceed financially.
Nevertheless, there is hope as other approaches populate the pipeline.
There is continuing emphasis on trying to identify targets for
developing drugs that could treat obesity through nontraditional
approaches, Smith said, noting that they differ from most of the current
efforts, which have targeted neural receptors and pathways to reduce food
Ryan said there have been great advances in understanding the biology
and energy balance that underlie obesity.
Even surgery has reinforced the importance of gut peptides in
appetite regulation and weight loss. There are many avenues to pursue: gut
peptides; leptin; renewed interest in brown fat, she said.
Additionally, other research has focused on naturally occurring hormonal
systems, shifting the focus way from the central nervous system as the target
organ for obesity treatment, according to Smith.
Apovian said she remains positive about investigational injectable
compounds. She and colleagues are conducting early trials on the roles of
leptin and pramlintide in obesity. Although final results are still a few years
away, it appears that weight loss may exceed 12%. Because leptin is an
adipocyte hormone and pramlintide a pancreatic hormone, the adverse effect
profile is excellent and without CV issues, she added.
I think of the treatment gap like this: Were going to fill
it, Smith said. It may take a long time, but we have to stay the
course and recognize that we can be smarter about it.
He said hypertension drugs are an example of why he remains so
optimistic, despite the present climate.
To me, there is a pro-research and dig-deep-into-the-biology
message here because the knee-jerk is to say, We failed, lets
stop, Smith said. If you told somebody that about
hypertension in 1975, they would have maybe felt the same way, but look where
we are now. Its a more hopeful message based upon the reality of the
history that we have with hypertension, with oncology, with a variety of other
endocrine areas where weve made great strides based on science.
by Melissa Foster and Katie Kalvaitis
For more information:
- Astrup A. Lancet. 2009;374:1606-1616.
- Bergenstal RM. Lancet. 2010;376:431-439.
- CDC. MMWR. 2010;59:1-5.
- Flegal KM. JAMA. 2010;303:235-241.
Do you consider obesity a
Genetic causes, adverse outcomes characterize obesity as disease
Obesity has defining elements of a disease: a genetic component, morbid
consequences and, at one time, it was an adaptive feature.
The best analogy would be sickle cell anemia. Here is a disease of the
red blood cell that is genetic, has morbid outcomes and used to be protective
against malaria infections. This adaptation, however, is no longer needed in
areas where malaria is not a public health threat, such as North America.
Therefore, in an area without malaria, the disease has no adaptive function and
instead causes severe problems.
Obesity works in the same way. Biologically, obesity has a clear pathway
related to genetics. For example, if both parents are obese, then their child
has an 80% to 90% chance of being obese, whereas if neither parent is obese,
the childs odds of being obese are substantially lower. Environmental,
social and behavioral factors, however, remain contributors in some cases,
regardless of genetics.
The morbid consequences of obesity include health problems, such as
diabetes, hypertension and CVD. One thing that physicians might want to
remember is that it has clearly been shown that if you resolve these other
health issues, such as high blood pressure and cholesterol, obese patients are
still at a higher risk for heart disease.
Whats more is that obesity began as an adaptive feature.
Currently, we are in a classic genetic mismatch where our genetics were set up
to survive times of famine. However, we no longer have that problem in the
United States and other more developed countries that are doing well and have a
constant food supply. Therefore, genetics are now working against us. People
who are already predisposed to obesity now gain weight more easily when
compared with others whose genetics make it more difficult.
Ken Fujioka, MD, is director of the Nutrition and Metabolic Research
Center and the Center for Weight Management at Scripps Clinic in La Jolla,
No strong association between obesity, other health conditions yet
Is obesity a disease? It is a question of how you ask the question. A
disease, from the point of view of clinicians and health care providers, is an
entity that generally causes signs or symptoms. Many obese patients have
diabetes or hypertension, or signs of disease, but then there are some people
with a lot of adiposity who are seen in clinics and have no complaints or
Additionally, obesity may not always be present at or near the onset of
other diseases, such as diabetes and hypertension. A person may have been obese
at one point in his or her life, but may have lost the weight by the time he or
she develops these other conditions. Furthermore, obesity may not need to be
tremendous to contribute to the development of other diseases. Therefore, these
issues make it difficult to determine a strong association between obesity and
subsequent health problems.
Another problem with finding a robust relationship between obesity and
other diseases is a lack of aggressive interventions for treatment of obesity.
If there were aggressive interventions that show that reducing adiposity in
adult years lowers risk of these adverse outcomes, then evidence that obesity
is a disease would be more compelling. Obesity may in fact be soundly linked to
conditions such as CVD, but without a potent treatment strategy involving a
combination of lifestyle changes and pharmacology some clinicians will believe
that evidence that adiposity is related to these outcomes is not overwhelmingly
However, obesity may still be considered a disease, even if not at this
point in time. Some physicians and researchers make the point that with chronic
conditions such as obesity, clinicians should be examining the long-term
factors as well as the short-term causes contributing to related health
conditions, such as CVD. Moreover, once more potent interventions for obesity
are established, we will be able to learn more about it as a disease.
Peter W.F. Wilson, MD, is a professor of medicine in the cardiology
division at Emory University School of Medicine. He is also an Endocrine
Today Editorial Board member.
Disclosures: Dr. Apovian is a paid consultant for Arena
Pharmaceuticals, Orexigen and Vivus. Dr. Aronne is a paid consultant for
Amylin, Allergan, GlaxoSmithKline, Novo Nordisk, Orexigen and Vivus. Dr.
Fujioka is a paid consultant for Abbott, Orexigen and Vivus. Dr. Kushner is on
the advisory board for Orexigen and Vivus. Dr. Ryan reports no relevant
financial disclosures. Dr. Smith is a consultant for Amylin and Arena
Pharmaceuticals, and has received research support from Orexigen. Dr. Wilson
reports no relevant financial disclosures.