The New England Journal of Medicine
Review Article
Drug Therapy
Volume 346:591-602
February 21, 2002
Number 8
Obesity
Susan Z. Yanovski, M.D., and Jack A. Yanovski, M.D., Ph.D.
Overweight and obesity are the most common nutritional disorders in the
United States, affecting the majority of adults in the country. Given a
normal body-mass index (defined as the weight in kilograms divided by the
square of the height in meters) ranging from 18.5 to 24.9, 34 percent of the
adult population is overweight (body-mass index, 25 to 29.9), and another 27
percent is obese (body-mass index, >=30). 1
<http://content.nejm.org/cgi/content/short/346/8/#R1> The prevalence of
obesity has increased by more than 75 percent since 1980. 2
<http://content.nejm.org/cgi/content/short/346/8/#R2> The prevalence of
overweight in children and adolescents (defined as a body-mass index in the
95th percentile or higher for age and sex) 3
<http://content.nejm.org/cgi/content/short/346/8/#R3> has more than doubled
since 1976. 4 <http://content.nejm.org/cgi/content/short/346/8/#R4>
Health care professionals should be concerned about overweight and obesity
because of the well-established relations between excess body weight and
such medical conditions as type 2 diabetes, hypertension, and
osteoarthritis. 5 <http://content.nejm.org/cgi/content/short/346/8/#R5>
Evidence-based guidelines issued by the National Institutes of Health call
for weight loss both in obese persons and in overweight persons with two or
more risk factors for obesity-related diseases. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6>
Medications for the treatment of obesity are currently approved for use in
adults who have a body-mass index of 27 or higher plus obesity-related
medical conditions or a body-mass index of 30 or higher in the absence of
such conditions. 7 <http://content.nejm.org/cgi/content/short/346/8/#R7> In
1999, $321 million was spent in the United States on prescription
medications to treat obesity. 8
<http://content.nejm.org/cgi/content/short/346/8/#R8> Between 1996 and
1998, 2.5 percent of the adults in the United States — or about 4.6 million
persons — reported having used such medications. 9
<http://content.nejm.org/cgi/content/short/346/8/#R9> Approximately 10
percent of women and 3 percent of men with a body-mass index of 30 or higher
have reported using weight-loss medications for obesity. 9
<http://content.nejm.org/cgi/content/short/346/8/#R9> In this review we
briefly examine nonpharmacologic approaches to promoting weight loss and
give greater consideration to the use of medications as adjunctive therapy
in the management of obesity.
Nonpharmacologic Approaches to Weight Loss
Although 29 percent of the men in the United States and 44 percent of the
women describe themselves as trying to lose weight, 10
<http://content.nejm.org/cgi/content/short/346/8/#R10> only about 20
percent report restricting caloric intake and increasing physical activity
simultaneously, despite recommendations indicating that this combination is
effective. 6 <http://content.nejm.org/cgi/content/short/346/8/#R6> Many
studies demonstrate that obese adults can lose about 0.5 kg per week by
decreasing their daily intake to 500 to 1000 kcal below the caloric intake
required for the maintenance of their current weight. 11
<http://content.nejm.org/cgi/content/short/346/8/#R11> More severe caloric
restriction, with the use of diets that are very low in calories, increases
the rapidity of weight loss but not the rate of long-term success in
maintaining a reduced weight. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6> Although adding
exercise to caloric restriction minimally increases weight loss during the
acute phase of weight loss, it appears to be the component of treatment that
is most likely to promote long-term maintenance of a reduced weight. 12
<http://content.nejm.org/cgi/content/short/346/8/#R12> Behavioral
treatments help obese persons to develop adaptive thinking, eating, and
exercise habits that enable them to decrease their weight and avoid
regaining weight. 11 <http://content.nejm.org/cgi/content/short/346/8/#R11>
Persons who combine caloric restriction and exercise with behavioral
treatment may expect to lose about 5 to 10 percent of preintervention body
weight over a period of four to six months. 11
<http://content.nejm.org/cgi/content/short/346/8/#R11> Although patients
often perceive this "small" weight loss as insufficient, 13
<http://content.nejm.org/cgi/content/short/346/8/#R13> it suffices to
improve many obesity-related conditions. 14
<http://content.nejm.org/cgi/content/short/346/8/#R14>
Unfortunately, improvements are not sustained if weight is regained; and for
the vast majority of persons, weight loss is followed by a slow, inexorable
climb to the preintervention body weight — or even higher. 15
<http://content.nejm.org/cgi/content/short/346/8/#R15> Bariatric surgical
treatments, such as gastric bypass, can induce long-term weight loss, but
are appropriate only for selected patients with a body-mass index of at
least 40 or a body-mass index of at least 35 along with obesity-related
medical conditions. 6 <http://content.nejm.org/cgi/content/short/346/8/#R6>
Losing weight is difficult for most obese persons, yet long-term maintenance
of a reduced weight is even more challenging.
History of Pharmacotherapy for Obesity
For many years, obesity was approached as if it were either a moral failing
or evidence of underlying psychopathology. 16
<http://content.nejm.org/cgi/content/short/346/8/#R16> With the advent of
behavioral treatments for obesity in the 1960s, 17
<http://content.nejm.org/cgi/content/short/346/8/#R17> hope arose that
modification of maladaptive eating and exercise habits would lead to
sustained weight loss, and that time-limited programs would produce
permanent changes in weight. Medications for the treatment of obesity were
proposed as short-term adjuncts for patients, who would presumably then
acquire the skills necessary to continue to lose weight, reach "ideal body
weight," and maintain a reduced weight indefinitely. Unfortunately, such
short-term approaches proved unsuccessful, and the history of many ill-fated
weight-loss regimens is well documented. 18
<http://content.nejm.org/cgi/content/short/346/8/#R18>
The field underwent a paradigm shift in 1992 with the publication of studies
by Weintraub et al. 19
<http://content.nejm.org/cgi/content/short/346/8/#R19> , 20
<http://content.nejm.org/cgi/content/short/346/8/#R20> , 21
<http://content.nejm.org/cgi/content/short/346/8/#R21> , 22
<http://content.nejm.org/cgi/content/short/346/8/#R22> , 23
<http://content.nejm.org/cgi/content/short/346/8/#R23> , 24
<http://content.nejm.org/cgi/content/short/346/8/#R24> , 25
<http://content.nejm.org/cgi/content/short/346/8/#R25> , 26
<http://content.nejm.org/cgi/content/short/346/8/#R26> , 27
<http://content.nejm.org/cgi/content/short/346/8/#R27> concerning the
efficacy of the combination of behavioral treatment and two medications with
different mechanisms of action — fenfluramine and phentermine. Those studies
found that weight loss could be sustained for as long as three and a half
years with continuing pharmacotherapy. Although the number of patients
studied was small, the idea behind the approach — that obesity should be
treated in the same manner as any other chronic disease that might be
ameliorated through the long-term use of medication — differed dramatically
from those of prevailing approaches. The new approach meshed well with the
emerging realization that short-term treatments for obesity generally do not
lead to sustained weight reduction and that patients are generally unwilling
to continue behavioral treatment indefinitely. 11
<http://content.nejm.org/cgi/content/short/346/8/#R11> Long-term use of
weight-loss medications could be seen as a tool to help patients adhere to
the dietary and behavioral changes necessary to maintain a reduced body
weight. 28 <http://content.nejm.org/cgi/content/short/346/8/#R28> , 29
<http://content.nejm.org/cgi/content/short/346/8/#R29> Although the
subsequent withdrawal from the market of fenfluramine (and dexfenfluramine)
because of an association with valvular heart disease 30
<http://content.nejm.org/cgi/content/short/346/8/#R30> had a dampening
effect on the use of medications in the treatment of obesity, an important
lesson remained: obesity could and should be approached as a chronic
condition that requires continuing medical care. For a minority of obese
patients who have substantially increased medical risk and for whom
nonpharmacologic treatments alone prove unsatisfactory, weight-loss
medications may be useful adjuncts to behavioral treatments.
Mechanisms of Action of Weight-Loss Drugs
Medications currently approved for weight loss in the United States ( Table
1 <http://content.nejm.org/cgi/content/short/346/8/#T1> ) fall into two
broad categories: those that decrease food intake by reducing appetite or
increasing satiety (appetite suppressants) and those that decrease nutrient
absorption. A third category, medications that increase energy expenditure,
includes ephedrine, which is not currently approved as a treatment for
obesity in the United States, and other investigational compounds. 31
<http://content.nejm.org/cgi/content/short/346/8/#R31>
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Table 1. Medications Approved for the Treatment of Obesity.
Appetite-Suppressant Medications
Most appetite suppressants work primarily by increasing the availability of
anorexigenic neurotransmitters — notably, norepinephrine, serotonin,
dopamine, or some combination of these neurotransmitters — in the central
nervous system.
Noradrenergic Agents
Noradrenergic drugs available in the United States include phentermine,
diethylpropion, phendimetrazine, and benzphetamine ( Table 1
<http://content.nejm.org/cgi/content/short/346/8/#T1> ). Amphetamines are no
longer recommended (and are not approved for use) for weight loss because of
the potential for their abuse. Benzphetamine and phendimetrazine, which are
classified as Schedule III drugs by the Drug Enforcement Administration
(DEA), are considered by the DEA to have substantially greater potential for
abuse than those on Schedule IV.
All of the above medications are approved by the Food and Drug
Administration (FDA) for use of "a few weeks" only (generally presumed to be
12 weeks or less) for the treatment of obesity. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> Few studies of their
safety and efficacy have extended to six months or beyond. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Such studies show a
consistent but moderate difference in weight loss (a difference of 2 to 10
kg) in comparisons with placebo. 32
<http://content.nejm.org/cgi/content/short/346/8/#R32> , 33
<http://content.nejm.org/cgi/content/short/346/8/#R33> , 34
<http://content.nejm.org/cgi/content/short/346/8/#R34> , 35
<http://content.nejm.org/cgi/content/short/346/8/#R35> , 36
<http://content.nejm.org/cgi/content/short/346/8/#R36> , 37
<http://content.nejm.org/cgi/content/short/346/8/#R37> Side effects of
noradrenergic medications include insomnia, dry mouth, constipation,
euphoria, palpitations, and hypertension. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> Although the most
widely used of these compounds, phentermine, was used in combination with
fenfluramine, it has not been independently associated with valvular heart
disease. 38 <http://content.nejm.org/cgi/content/short/346/8/#R38> The only
over-the-counter appetite-suppressant medication approved for the treatment
of obesity, phenylpropanolamine, was recently withdrawn from the market
because of concern about an association with hemorrhagic stroke in women. 39
<http://content.nejm.org/cgi/content/short/346/8/#R39>
Serotonergic Agents
Serotonergic agents act by increasing the release of serotonin, inhibiting
its reuptake, or both. Fenfluramine (Pondimin) and dexfenfluramine (Redux),
medications that both stimulated serotonin release and inhibited its
reuptake, were withdrawn from the market in the United States in 1997
because of associations with valvular heart disease and pulmonary
hypertension. Their efficacy in controlled studies appeared similar to that
of the noradrenergic agents. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> , 40
<http://content.nejm.org/cgi/content/short/346/8/#R40>
Selective serotonin-reuptake inhibitors are currently approved for a number
of indications that are not related to obesity, including depression and
obsessive–compulsive disorder. Some selective serotonin-reuptake inhibitors
have induced weight loss in short-term studies, and fluoxetine (Prozac) (at
a dose of 60 mg) has undergone considerable evaluation to determine its
efficacy for weight loss. 41
<http://content.nejm.org/cgi/content/short/346/8/#R41> , 42
<http://content.nejm.org/cgi/content/short/346/8/#R42> Unfortunately,
although patients who received fluoxetine for six months lost more weight
than those who received placebo, steady regain occurred during the next six
months despite the continuation of medication, eroding any difference
between the treatment groups. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Sertraline (Zoloft),
evaluated as an adjunct for weight maintenance after a very-low-calorie
diet, showed a similar lack of long-term efficacy. 43
<http://content.nejm.org/cgi/content/short/346/8/#R43>
Mixed Noradrenergic–Serotonergic Agents
Sibutramine (Meridia), an inhibitor of both norepinephrine reuptake and
serotonin reuptake that also weakly inhibits dopamine reuptake ( Figure 1
<http://content.nejm.org/cgi/content/short/346/8/#F1> ), is approved by the
FDA for weight loss and weight maintenance in conjunction with a
reduced-calorie diet. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> Sibutramine is given
in a dose of 10 to 15 mg once daily and may be given in a 5-mg dose to
patients who do not tolerate the 10-mg dose. Unlike fenfluramine and
dexfenfluramine, it does not induce serotonin release, and has not been
implicated in the development of valvular heart disease. 44
<http://content.nejm.org/cgi/content/short/346/8/#R44> , 45
<http://content.nejm.org/cgi/content/short/346/8/#R45> Over a six-month
period, subjects who follow a reduced-calorie diet and receive sibutramine
typically lose 5 to 8 percent of their preintervention body weight, as
compared with 1 to 4 percent among subjects who receive placebo. 46
<http://content.nejm.org/cgi/content/short/346/8/#R46> , 47
<http://content.nejm.org/cgi/content/short/346/8/#R47> , 48
<http://content.nejm.org/cgi/content/short/346/8/#R48> , 49
<http://content.nejm.org/cgi/content/short/346/8/#R49> Sibutramine-induced
reductions in weight appear to be largely maintained for periods of up to
one year and remain significantly greater than those observed in patients
who receive placebo. 50
<http://content.nejm.org/cgi/content/short/346/8/#R50> Published studies
with up to two years of data are now available. The Sibutramine Trial of
Obesity Reduction and Maintenance followed 605 European adults who took 10
mg of sibutramine daily for 6 months, after which 467 participants who had
lost more than 5 percent of their preintervention body weight were randomly
assigned to continue to receive sibutramine or to receive placebo for 18
months. 51 <http://content.nejm.org/cgi/content/short/346/8/#R51> Although
weight was regained in both groups during the second year of follow-up,
weight losses were significantly greater among those who received
sibutramine for the full two years of the trial. More than 25 percent of
those who continued to take sibutramine maintained their reduced weight for
the entire observation period. As in most studies of weight-loss
medications, the large numbers of dropouts in both the study-drug group and
the placebo group limit the generalizability of the findings. 51
<http://content.nejm.org/cgi/content/short/346/8/#R51> By the end of the
study, the dose of sibutramine had been increased to 20 mg, a dose higher
than is approved in the United States, in 52 percent of the subjects taking
the medication. However, 86 percent of the subjects who did not regain any
of the weight they had lost were taking no more than 15 mg of sibutramine
daily. Sibutramine may also increase weight loss and improve maintenance of
reduced weight in subjects who have previously lost weight with a
very-low-calorie diet. 52
<http://content.nejm.org/cgi/content/short/346/8/#R52>
<http://content.nejm.org/cgi/content/full/346/8/591/F1>
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Figure 1. Mechanisms of Action of Sibutramine.
Sibutramine and its active metabolites inhibit the reuptake of serotonin and
norepinephrine, thereby prolonging the actions of these neurotransmitters at
their postsynaptic receptors.
Side effects of sibutramine include increases in blood pressure and pulse;
although these are usually mild, they lead to the discontinuation of
sibutramine in up to 5 percent of patients. 47
<http://content.nejm.org/cgi/content/short/346/8/#R47> , 48
<http://content.nejm.org/cgi/content/short/346/8/#R48> , 50
<http://content.nejm.org/cgi/content/short/346/8/#R50> , 51
<http://content.nejm.org/cgi/content/short/346/8/#R51> In general,
reductions in blood pressure in those who lose weight with sibutramine are
less than the reductions in blood pressure seen with similar weight loss
obtained with other treatments. 47
<http://content.nejm.org/cgi/content/short/346/8/#R47> Adverse reactions
also include dry mouth, headache, insomnia, and constipation. 45
<http://content.nejm.org/cgi/content/short/346/8/#R45> Commensurate with
weight loss, other metabolic risk factors improve; these include
hyperlipidemia and hyperuricemia, as well as glycemic control and plasma
insulin levels in patients with type 2 diabetes. 46
<http://content.nejm.org/cgi/content/short/346/8/#R46> , 48
<http://content.nejm.org/cgi/content/short/346/8/#R48> , 50
<http://content.nejm.org/cgi/content/short/346/8/#R50> , 51
<http://content.nejm.org/cgi/content/short/346/8/#R51> , 53
<http://content.nejm.org/cgi/content/short/346/8/#R53>
Medications That Reduce Nutrient Absorption
The only FDA-approved medication for obesity that reduces nutrient
absorption is orlistat (Xenical), which acts by binding to gastrointestinal
lipases in the lumen of the gut, preventing hydrolysis of dietary fat
(triglycerides) into absorbable free fatty acids and monoacylglycerols (
Figure 2 <http://content.nejm.org/cgi/content/short/346/8/#F2> ). Patients
who take 120 mg of orlistat with or up to one hour after meals excrete in
the stool approximately one third of the dietary fat they ingest, thereby
reducing calorie and fat intake. In double-blind, placebo-controlled trials,
orlistat had moderate efficacy for weight loss in adults. Orlistat-treated
subjects who completed trials lasting one year lost approximately 9 percent
of their preintervention body weight, as compared with 5.8 percent among
those who took placebo. 54
<http://content.nejm.org/cgi/content/short/346/8/#R54>
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Figure 2. Inhibition of Fat Absorption by Orlistat.
Orlistat has also been found to slow the rate of regain of weight during a
second year of use; orlistat-treated subjects regained less weight during
the second year than placebo-treated subjects did (a regain of 35.2 percent
vs. 62.4 percent, a difference of about 2.5 kg). 55
<http://content.nejm.org/cgi/content/short/346/8/#R55> , 56
<http://content.nejm.org/cgi/content/short/346/8/#R56> , 57
<http://content.nejm.org/cgi/content/short/346/8/#R57> In these long-term
studies, orlistat-treated patients also had moderate decreases in diastolic
blood pressure, insulin levels while fasting, and total cholesterol and
low-density lipoprotein cholesterol, with a small cholesterol-lowering
effect that was independent of weight loss. Orlistat induced small
reductions in body weight in patients with type 2 diabetes that were
nevertheless significantly greater than those that occurred in such patients
who received placebo (losses of 6.2 kg vs. 4.3 kg); orlistat also led to
improvement in glycosylated hemoglobin values and a decreased requirement
for sulfonylurea drugs. 58
<http://content.nejm.org/cgi/content/short/346/8/#R58> Orlistat appears to
have similar efficacy regardless of whether it is prescribed in a primary
care or a specialized treatment setting. 59
<http://content.nejm.org/cgi/content/short/346/8/#R59>
Side effects of orlistat include flatulence with discharge, fecal urgency,
fecal incontinence, steatorrhea, oily spotting, and increased frequency of
defecation. These side effects are usually mild to moderate, and generally
decrease in frequency with ongoing treatment. However, such side effects
lead to discontinuation in nearly 9 percent of patients, as compared with a
rate of discontinuation of 5 percent among patients treated with placebo. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> , 54
<http://content.nejm.org/cgi/content/short/346/8/#R54> Orlistat also
decreases absorption of fat-soluble vitamins, primarily vitamin D, an effect
that can be counteracted by daily administration of a multivitamin at least
two hours before or after a dose of orlistat. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7>
Dietary Supplements and Herbal Preparations
Unlike prescription and over-the-counter medications, dietary supplements
are not prospectively reviewed for safety or efficacy by the FDA, which
takes action only if a dietary supplement is shown to present "a significant
or unreasonable risk." 60
<http://content.nejm.org/cgi/content/short/346/8/#R60> Producers of a
dietary supplement cannot claim that it treats a disease (including obesity)
but may claim that it reduces the risk of a disease in a population. 60
<http://content.nejm.org/cgi/content/short/346/8/#R60>
Allison and colleagues 61
<http://content.nejm.org/cgi/content/short/346/8/#R61> critically reviewed
the published literature on herbal and dietary supplements for which claims
have been made about the promotion of weight loss: chitosan, chromium
picolinate, conjugated linoleic acid, ephedra alkaloids (ma huang), and
garcinia cambogia. They found that most such reports were based on poorly
designed trials that lacked randomization, blinding, or control groups.
Although some dietary supplements have mechanisms of action that could
plausibly lead to weight loss or have shown promising results in small-scale
studies in humans or animals, Allison et al. found that there were
insufficient data to provide evidence of either the safety or the efficacy
of any of these compounds as agents promoting weight loss. Herbal compounds
containing ephedra alkaloids and caffeine are the only types for which there
are data from randomized, double-blind, placebo-controlled trials indicating
efficacy in promoting weight loss. 61
<http://content.nejm.org/cgi/content/short/346/8/#R61> , 62
<http://content.nejm.org/cgi/content/short/346/8/#R62> , 63
<http://content.nejm.org/cgi/content/short/346/8/#R63> However, all such
studies have been short-term (six months or less).
Ephedrine is an adrenergic agent with thermogenic and appetite-suppressant
properties. 49 <http://content.nejm.org/cgi/content/short/346/8/#R49> In
the United States, ephedrine is approved for nonprescription use for mild
asthma and upper respiratory symptoms. Ephedrine in combination with
caffeine, aspirin, or both, has been found in controlled trials to produce
greater weight losses than placebo for periods of up to one year, although
most studies have been short-term. 31
<http://content.nejm.org/cgi/content/short/346/8/#R31> , 64
<http://content.nejm.org/cgi/content/short/346/8/#R64> , 65
<http://content.nejm.org/cgi/content/short/346/8/#R65> , 66
<http://content.nejm.org/cgi/content/short/346/8/#R66> , 67
<http://content.nejm.org/cgi/content/short/346/8/#R67> Ma huang (Ephedra
sinica) is a botanical source of ephedra alkaloids often included in dietary
supplements sold for the purpose of promoting weight loss. Dietary
supplements containing ephedra alkaloids frequently contain a dosage that
differs substantially from that indicated on the product label. 68
<http://content.nejm.org/cgi/content/short/346/8/#R68> Case reports
concerning ephedra alkaloids (often in combination with caffeine) have noted
serious cardiovascular and central nervous system events, including
hypertension, cardiac arrhythmia, stroke, seizure, myocardial infarction,
and sudden death. 69 <http://content.nejm.org/cgi/content/short/346/8/#R69>
However, the incidence of such events among persons who take ephedra
alkaloids at the recommended doses has not been established. 70
<http://content.nejm.org/cgi/content/short/346/8/#R70> Because of the
unpredictable amounts of active ingredients and the potential for harmful
effects, the National Institutes of Health guidelines state that herbal
preparations are not recommended as part of a weight-loss program. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6>
Weight-Loss Medications Currently in Clinical Trials
Medications Approved by the FDA for Indications Other Than Obesity
A number of medications with different mechanisms of action are currently in
clinical trials to evaluate their safety and efficacy in obese patients.
Bupropion (Wellbutrin) is an atypical antidepressant that is chemically
unrelated to tricyclic agents or selective serotonin-reuptake inhibitors. It
is a relatively weak inhibitor of the reuptake of norepinephrine, serotonin,
and dopamine and has structural similarities to diethylpropion. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> After it was noted in
studies concerning depression that bupropion was associated with small
weight losses, trials evaluating the use of sustained-release bupropion in
the treatment of obesity were initiated and are currently being conducted.
71 <http://content.nejm.org/cgi/content/short/346/8/#R71> , 72
<http://content.nejm.org/cgi/content/short/346/8/#R72> Bupropion is
contraindicated in patients with seizure disorders. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7>
In several clinical trials studying the safety and efficacy of topiramate
(Topamax), a novel antiepileptic agent, for seizure control 73
<http://content.nejm.org/cgi/content/short/346/8/#R73> or affective
disorders, 74 <http://content.nejm.org/cgi/content/short/346/8/#R74>
reduced food intake and weight loss were noted. Trials of the safety and
efficacy of topiramate in obese patients who do not have seizures, including
patients with binge eating disorder 75
<http://content.nejm.org/cgi/content/short/346/8/#R75> or hypothalamic
obesity, 76 <http://content.nejm.org/cgi/content/short/346/8/#R76> are
ongoing. Adverse effects of topiramate include kidney stones and central
nervous system symptoms, such as paresthesias, dizziness, fatigue, and
somnolence. 77 <http://content.nejm.org/cgi/content/short/346/8/#R77>
Metformin (Glucophage), a medication that inhibits hepatic glucose
production and improves sensitivity to insulin, is approved by the FDA for
the treatment of type 2 diabetes. Metformin not only reduces hyperglycemia
but has also been noted to prevent weight gain or even to induce small
weight losses in adults. 78
<http://content.nejm.org/cgi/content/short/346/8/#R78> , 79
<http://content.nejm.org/cgi/content/short/346/8/#R79> Metformin is being
studied in overweight, nondiabetic adults and children to determine its
effects on body weight, insulin resistance, and related medical conditions.
80 <http://content.nejm.org/cgi/content/short/346/8/#R80> , 81
<http://content.nejm.org/cgi/content/short/346/8/#R81> , 82
<http://content.nejm.org/cgi/content/short/346/8/#R82> Metformin may cause
nausea, flatulence, bloating, and diarrhea at the beginning of treatment,
and approximately 5 percent of adults cannot take the drug at any dose
because of such side effects. 83
<http://content.nejm.org/cgi/content/short/346/8/#R83> The most serious
side effect of metformin is lactic acidosis, which is estimated to occur at
a rate of 3 cases per 100,000 patient-years of exposure, primarily in
patients with renal insufficiency, congestive heart failure, pulmonary
disease, or liver disease, which are contraindications to its use. 84
<http://content.nejm.org/cgi/content/short/346/8/#R84>
Investigational Medications
Levels of leptin, a hormone secreted by adipocytes, reflect the lipid
content of the total body of a nonfasting person. 85
<http://content.nejm.org/cgi/content/short/346/8/#R85> In a few children,
severe, early-onset obesity has been associated with an inability to produce
functional leptin protein. 86
<http://content.nejm.org/cgi/content/short/346/8/#R86> Treatment of a
leptin-deficient girl with recombinant human leptin induced a dramatic
reduction in body weight (a loss of 16.4 kg) and changes in body
composition. 87 <http://content.nejm.org/cgi/content/short/346/8/#R87> Less
dramatic changes have been observed in adults with sufficient leptin levels
who are treated with recombinant human leptin. A dose-dependent decrease in
body weight and fat was observed, and the greatest weight loss (a mean [±SD]
loss of 7.1±8.5 kg) occurred in eight persons who took leptin in a daily
dose of 0.3 mg per kilogram of body weight for 24 weeks. 88
<http://content.nejm.org/cgi/content/short/346/8/#R88> Pain and induration
at the injection site, especially at higher doses, led to discontinuation in
some patients. Ongoing studies are evaluating both different formulations of
leptin 89 <http://content.nejm.org/cgi/content/short/346/8/#R89> and
leptin-replacement therapy during low-calorie dieting. 90
<http://content.nejm.org/cgi/content/short/346/8/#R90> It remains unknown
whether treatment with leptin will be beneficial in persons without
mutations in the leptin gene.
Other medications that are currently in clinical trials to determine their
ability to induce weight loss include ciliary neurotrophic factor, 91
<http://content.nejm.org/cgi/content/short/346/8/#R91> a neuroactive
cytokine that exerts its effects through a receptor whose mode of signal
transduction is similar to that of the leptin receptor; a peptide analogue
of the human growth hormone fragment 177-191 92
<http://content.nejm.org/cgi/content/short/346/8/#R92> ; and agonists of the
{beta}3-adrenergic and cholecystokinin-A receptors. 93
<http://content.nejm.org/cgi/content/short/346/8/#R93>
Strategies for Use of Medications in the Treatment of Obesity
Because obesity is a chronic condition, pharmacotherapy should be initiated
with the expectation that long-term use will most likely be needed. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Numerous studies
indicate that, just as blood pressure may increase when antihypertensive
drugs are discontinued, regaining of weight is extremely likely when
weight-loss medications are discontinued. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> , 52
<http://content.nejm.org/cgi/content/short/346/8/#R52> Therefore, careful
consideration of the known (and possible) risks of long-term medical therapy
must be weighed against potential improvements in the patient's risk of
obesity-related disease. National Institutes of Health guidelines recommend
that pharmacotherapy should be initiated only in patients with a body-mass
index of at least 30 in the absence of obesity-related medical conditions or
a body-mass index of at least 27 in the presence of such conditions. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6>
Approved prescription medications for weight loss appear to have similar
efficacy in controlled studies. Other than weight loss during the first few
weeks of drug treatment, no predictors of responsiveness in an individual
patient or class of patients have been established. Therefore, an empirical
choice of a specific medication should be based on consideration of
underlying medical conditions or contraindications to particular drugs,
concurrent medications, need for monitoring, approval for long-term use,
cost, and the preference of the patient. National Institutes of Health
guidelines suggest that nonpharmacologic therapies should be attempted for
six months and that weight-loss drugs should be considered if weight loss is
unsatisfactory (e.g., less than 0.45 kg per month). 94
<http://content.nejm.org/cgi/content/short/346/8/#R94> In addition,
behavioral treatment combined with pharmacotherapy may result in better
outcome than drug treatment alone. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6> , 95
<http://content.nejm.org/cgi/content/short/346/8/#R95> An evidence-based
algorithm representing an overall approach to the treatment of obesity is
shown in Figure 3 <http://content.nejm.org/cgi/content/short/346/8/#F3> . A
practical guide designed to assist physicians in treating obese patients in
the primary care setting is available. 94
<http://content.nejm.org/cgi/content/short/346/8/#R94>
<http://content.nejm.org/cgi/content/full/346/8/591/F3>
View larger version (59K):
[in this window] <http://content.nejm.org/cgi/content/full/346/8/591/F3>
[in a new window] <http://content.nejm.org/cgi/content-nw/full/346/8/591/F3>
Figure 3. Evidenced-Based Algorithm for the Treatment of Obesity.
Adapted from the National Institutes of Health. 94
<http://content.nejm.org/cgi/content/short/346/8/#R94> BMI denotes
body-mass index.
Identification of Patients with a Response to Treatment
Although the mean weight loss attributable to medications for obesity is
less than 5 percent, individual patients do have more robust responses. As
compared with placebo, pharmacotherapy more than doubles the percentage of
patients in whom a weight loss of 5 or 10 percent is achieved. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6> , 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Identification of
patients with a response would enable the risks and costs of drug treatment
to be concentrated among those who are most likely to benefit. In addition
to preintervention body weight, 51
<http://content.nejm.org/cgi/content/short/346/8/#R51> success during the
first month of therapy usually predicts ultimate weight loss. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6> , 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Therefore, in
patients without a weight loss of at least 2.0 kg during the first four
weeks of treatment, adherence to the medication, diet, and exercise
recommendations should be reassessed and the possible need for an adjustment
in the dosage should be considered. If there continues to be minimal
response to the medication, the clinician should consider discontinuing it
or substituting another medication. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> For none of the
currently available medications does the dose need to be tapered before
treatment is stopped. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6>
Pharmacotherapy for the Prevention of Weight Regain
A major area of promise for pharmacotherapy is in enhancing weight
maintenance in those who have lost weight by a variety of methods. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28> Because almost all
nonsurgical obesity treatments lead to weight loss for the first four to six
months followed by regain, pharmacotherapy can be instituted either to
enhance weight loss during the active weight-loss phase or to prevent later
regain. Although longer-term studies suggest that weight-loss medications
can decrease the rate of regain, 51
<http://content.nejm.org/cgi/content/short/346/8/#R51> , 52
<http://content.nejm.org/cgi/content/short/346/8/#R52> , 56
<http://content.nejm.org/cgi/content/short/346/8/#R56> , 57
<http://content.nejm.org/cgi/content/short/346/8/#R57> it is important to
note that data on the safety and effectiveness of use for more than two
years are not available for any FDA-approved weight-loss medication.
Off-Label Use of FDA-Approved Medications
Use of FDA-approved medications in a manner inconsistent with labeling is
considered off-label use, a common practice in medicine. Prudent physicians
should inform patients whenever they prescribe medications to be used in a
manner that is not consistent with FDA labeling and should discuss the
paucity of data on safety and efficacy and obtain the patient's consent for
such use. Whenever possible, patients who wish to use medications in such a
manner should be encouraged to participate in clinical trials. 28
<http://content.nejm.org/cgi/content/short/346/8/#R28>
Intermittent Use
Several small, short-term studies have described good results with the
intermittent use (e.g., in alternating months) of appetite-suppressant
weight-loss drugs. 18 <http://content.nejm.org/cgi/content/short/346/8/#R18>
One fairly large study found that the safety and efficacy of intermittent
use of sibutramine (12 weeks of the drug alternating with 12 weeks of
placebo) were similar to those of continuous sibutramine treatment. 96
<http://content.nejm.org/cgi/content/short/346/8/#R96> An increase in the
rate of side effects just after drugs are stopped or restarted has been
noted in other studies. 25
<http://content.nejm.org/cgi/content/short/346/8/#R25> , 34
<http://content.nejm.org/cgi/content/short/346/8/#R34> Further studies of
the intermittent use of such medications would help to answer questions
about the effectiveness of this approach.
Drug Combinations
Treatment in which drugs of different therapeutic classes are combined in
order to enhance efficacy or reduce adverse effects is common in the
treatment of chronic diseases. It is possible that combination drug
treatments for obesity will eventually be developed that are both safe and
effective. However, in the absence of data from large trials, clinicians
must exercise great caution in recommending unproven therapeutic
combinations. For the most part, only case series 97
<http://content.nejm.org/cgi/content/short/346/8/#R97> , 98
<http://content.nejm.org/cgi/content/short/346/8/#R98> , 99
<http://content.nejm.org/cgi/content/short/346/8/#R99> and preliminary
studies 100 <http://content.nejm.org/cgi/content/short/346/8/#R100> , 101
<http://content.nejm.org/cgi/content/short/346/8/#R101> , 102
<http://content.nejm.org/cgi/content/short/346/8/#R102> have examined the
use of combinations of medications to enhance weight loss. A study in which
orlistat was added to sibutramine treatment after one year of sibutramine
alone found no enhancement of weight loss. 103
<http://content.nejm.org/cgi/content/short/346/8/#R103> At present, using
more than one drug in combination for the treatment of obesity cannot be
recommended outside clinical trials. 6
<http://content.nejm.org/cgi/content/short/346/8/#R6>
Treatment of Children and Adolescents
In general, the only children and adolescents who should be considered for
pharmacotherapy are those with a body-mass index in the 95th percentile or
higher for their age and sex plus an obesity-related medical condition that
may be remediable by a reduction of weight. In selected populations of
children 6 to 12 years old, intensive, family-based behavioral treatment
programs have been found to have a favorable effect on children's weight for
as long as 10 years. 104
<http://content.nejm.org/cgi/content/short/346/8/#R104> In contrast, there
have been no long-term (i.e., at least one year), randomized, double-blind,
placebo-controlled trials involving children (defined, for FDA regulatory
purposes, as persons less than 16 years of age) that have demonstrated the
safety and effectiveness of weight-loss medications. The safety and
effectiveness of orlistat and sibutramine for children and adolescents have
not been established. 7
<http://content.nejm.org/cgi/content/short/346/8/#R7> Medications that are
currently in clinical trials involving children include orlistat, 105
<http://content.nejm.org/cgi/content/short/346/8/#R105> sibutramine, 106
<http://content.nejm.org/cgi/content/short/346/8/#R106> ephedrine–caffeine,
107 <http://content.nejm.org/cgi/content/short/346/8/#R107> and metformin.
82 <http://content.nejm.org/cgi/content/short/346/8/#R82> In addition,
octreotide (a somatostatin agonist) is being evaluated in children and
adolescents with the hypothalamic obesity syndrome. 108
<http://content.nejm.org/cgi/content/short/346/8/#R108> Further studies are
needed before pharmacotherapy outside clinical trials can be recommended for
younger patients.
Summary
Obesity is a serious and prevalent disorder whose effective management
requires ongoing care. Currently approved prescription medications for
weight loss, although moderate in their efficacy, can help carefully
selected obese patients lose weight and can reduce the rate of regain.
Behavioral interventions to improve diet and increase physical activity are
considered the primary means to promote and maintain weight loss.
Weight-loss medications should be considered as an adjunct only for patients
who are at substantial medical risk because of their obesity and in whom
nonpharmacologic treatments have not resulted in sufficient weight loss to
improve health or to prevent regain. The safety and efficacy of weight-loss
medications beyond two years of use have not been established. In addition,
although some risk factors for obesity-related disease are improved with the
use of weight-loss medications, the long-term effect of such medications on
morbidity and mortality has not been determined.
In many ways, the current state of treatment for obesity is similar to the
state of the treatment of hypertension several decades ago. 18
<http://content.nejm.org/cgi/content/short/346/8/#R18> Few medications were
available, their efficacy was limited, and predictors of response were
lacking. Just as research into the underlying causes and consequences of
hypertension has led to dramatic improvements in its treatment, advances in
our understanding of energy balance will most likely lead to more effective
treatments for obesity in the future. With such understanding, we can hope
not only to develop safe and effective ways to help obese persons to achieve
and maintain a healthy weight but also to understand how to prevent the
development of obesity in those who are at risk.
Supported by a grant (ZO1 HD-00641) from the National Institute of Child
Health and Human Development (to Dr. Jack A. Yanovski). The opinions
expressed herein are those of the authors and do not necessarily reflect the
views of the National Institutes of Health, the Public Health Service, or
the Department of Health and Human Services.
Source Information
From the Division of Digestive Diseases and Nutrition, National Institute of
Diabetes and Digestive and Kidney Diseases (S.Z.Y.) and the Unit on Growth
and Obesity, Developmental Endocrinology Branch, National Institute of Child
Health and Human Development (J.A.Y.), National Institutes of Health,
Bethesda, Md.
Address reprint requests to Dr. Susan Yanovski at the Obesity and Eating
Disorders Program, NIDDK, 6707 Democracy Blvd., Bethesda, MD 20892-5450, or
at [log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.