VOLUME 34 • NUMBER 35 • DECEMBER 10, 2016

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Management of Obesity
Naji Alamuddin, Zayna Bakizada, and Thomas A. Wadden

All authors: Perelman School of Medicine,

University of Pennsylvania Philadelphia,
PA
Published online ahead of print at
www.jco.org on November 7, 2016.
Corresponding author: Naji Alamuddin,
MD, Perelman School of Medicine,
University of Pennsylvania, Room 3021,
3535 Market Street, Philadelphia, PA
19104; e-mail: naji.alamuddin@
uphs.upenn.edu.
© 2016 by American Society of Clinical
Oncology
0732-183X/16/3435w-4295w/$20.00
DOI: 10.1200/JCO.2016.66.8806
A B S T R A C T
This review examines weight loss and accompanying improvements in obesity-related comor-
bidities produced by intensive lifestyle intervention, pharmacotherapy, and bariatric surgery. Obese
individuals lose approximately 6 to 8 kg (approximately 6% to 8% of initial weight) with 6 months of
participation in a high-intensity lifestyle intervention ($ 14 treatment visits) consisting of diet,
physical activity, and behavior therapy. Such losses reduce progression to type 2 diabetes in at-risk
people and decrease blood pressure and triglyceride levels. All diets, regardless of macronutrient
composition, can produce clinically meaningful weight loss (. 5%) if they induce a deficit $ 500 kcal/d.
Physical activity of 150 to 180 min/wk yields modest short-term weight loss compared with diet but
contributes to improvements in obesity-related conditions. Gradual weight regain is common after
lifestyle intervention but can be prevented by continued participation in monthly weight loss main-
tenance sessions, as well as by high levels of physical activity (ie, 200 to 300 min/wk). Patients unable
to reduce satisfactorily with lifestyle intervention may be candidates for pharmacotherapy, recom-
mended as an adjunct. Five medications have been approved by the US Food and Drug Administration
for chronic weight management, and each has its own risk/benefit profile. The addition of these
medications to lifestyle intervention increases mean weight loss by 2.5 to 8.9 kg compared with
placebo. Patients with severe obesity who are unable to reduce successfully with lifestyle intervention
and pharmacotherapy are eligible for bariatric surgery, including Roux-en-Y gastric bypass, sleeve
gastrectomy, or adjustable gastric banding. The first two procedures yield long-term ($ 3 years)
reductions of $ 20% of initial weight that are associated with decreases in morbidity and potentially
mortality. Greater resources and dissemination efforts are needed to increase the availability of these
three approaches for the millions of Americans who would benefit from them.

J Clin Oncol 34:4295-4305. © 2016 by American Society of Clinical Oncology

Obesity is associated with an enormous
burden of disease, personal suffering, and health
care costs.1-3 Weight loss can improve all of these
outcomes.4,5 Expert panels from the National
Institutes of Health,5 WHO,6 and several pro-
fessional societies have recommended that in-
dividuals with obesity try to lose 5% to 10% of
body weight to improve health and quality of
life.4,7 This can be achieved with a comprehensive
lifestyle intervention that provides instruction in
diet, physical activity, and behavior therapy.4-6
Patients with a body mass index (BMI) $
30 kg/m2 (or $ 27 kg/m2 with a comorbid con-
dition) who cannot reduce adequately with this
approach may be candidates for adjunctive phar-
macotherapy.5-7 Those with severe obesity (ie, BMI
$ 40 kg/m2 or $ 35 kg/m2 with a comorbidity) are
potentially eligible for bariatric surgery.5-7
This review examines the efficacy of these
three approaches in inducing weight loss and
improvements in comorbid conditions in adults.
The accompanying recommendations adhere to
those from the 2013 Guidelines for the Man-
agement of Overweight and Obesity in Adults (ie,
Obesity Guidelines).4 These Guidelines did not
address the pharmacologic treatment of obesity,
which was subsequently examined by expert panels
convened by the Endocrine Society and the American
Association of Clinical Endocrinologists.7,8 We
note that although the interventions that are ex-
amined should be applicable to patients with cancer,
their safety and efficacy, particularly for pharmaco-
therapy and bariatric surgery, have not been studied
in people with cancer. Thus, caution and an in-
dividualized approach to selecting treatment are
recommended.
ASSESSING AND DISCUSSING OBESITY
Calculating BMI and Disease Risk
The Obesity Guidelines recommend that cli-
nicians measure weight and height and calculate

© 2016 by American Society of Clinical Oncology 4295

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 Alamuddin et al
BMI at annual visits or more frequently.4 BMI is calculated by
dividing weight (in kilograms) by height (in meters squared). The
WHO defines overweight as a BMI of 25.0 to 29.9 kg/m2, which is
associated with increased risk of cardiovascular disease (CVD)
morbidity.4,5 Obesity begins at a BMI of 30.0 kg/m2 and is divided
into three classes (30.0 to 34.9, 35.0 to 39.9, and $ 40 kg/m2), with
the third class labeled severe obesity. These cut points are based on
findings that, in general, the greater the BMI, the greater the risk of
CVD, type 2 diabetes, and all-cause mortality, although there have
been conflicting findings.4,9,10 Recent evidence also links obesity to
an increased risk of cancer, its recurrence, and poor cancer out-
comes.11 Appendix Table A1 (online only) provides an algorithm
for selecting a weight reduction therapy on the basis of the patient’s
BMI and disease risk status.5
Talking With Patients About Obesity and Weight Loss
Obesity can be a sensitive topic for patients and their prac-
titioners.12 Prejudice against obesity may leave many people with
excess weight feeling stigmatized, including by health care
practitioners.12,13 Patients prefer use of the terms weight or weight
problem rather than obesity.12
Discussing obesity with patients who are already coping with
cancer and its treatment may be particularly challenging. Those
who have completed chemotherapy and other treatments may fear
that weight loss, even if intentional, represents metastases or cancer
progression. Oncologists, who generally may not feel equipped to
provide weight loss counseling, can nonetheless reassure patients
that intentional weight loss is likely to be of benefit, not harm.
Increasing evidence suggests that weight loss may prevent or re-
duce the risk of cancer recurrence, reduce risk of other diseases,
and improve overall quality of life.11
COMPREHENSIVE LIFESTYLE INTERVENTION FOR OBESITY: DIET,
PHYSICAL ACTIVITY, AND BEHAVIOR THERAPY
The Obesity Guidelines advise overweight and obese individuals
who would benefit from weight loss to participate in a compre-
hensive lifestyle intervention for 6 or more months.4 High-
intensity programs are recommended that provide 14 or more
face-to-face, individual, or group sessions (in 6 months), delivered
by a trained interventionist, typically a registered dietitian, exercise
specialist, or health counselor. This approach produces a mean
weight loss of approximately 6% to 8% of initial weight in 6 to
12 months.4 Approximately 60% to 65% of patients lose $ 5% of
initial weight, which is considered clinically meaningful.4
Overview of Lifestyle Modification
The Diabetes Prevention Program (DPP) provides an excel-
lent example of a comprehensive lifestyle intervention.14 More
than 3,200 overweight/obese patients with impaired glucose tol-
erance were assigned to placebo, metformin, or an intensive
lifestyle program designed to produce a 7-kg loss. The program
provided 16 individual counseling sessions during the first
6 months and then at least one visit every other month for up to
4 years. Patients were instructed to consume a low-fat, reduced
4296 © 2016 by American Society of Clinical Oncology
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
calorie diet (ie, 1,200 to 2,000 kcal/d). The physical activity goal
was 150 min/wk of aerobic activity.
At a mean of 2.8 years, lifestyle participants lost a mean of
5.6 kg compared with a significantly smaller 0.1 kg for placebo and
2.1 kg for metformin. The lifestyle intervention, compared with
placebo and metformin, reduced the risk of developing type
2 diabetes by 58% and 31%, respectively. A 10-year follow-up found
that, compared with placebo, the lifestyle intervention maintained
a 34% reduction in the risk of developing type 2 diabetes, even
though the latter patients had regained most of their lost weight.15
Comparable favorable findings were observed in trials conducted in
Finland and China.16,17
Diet
The Obesity Guidelines recommend an energy deficit of 500
to 750 kcal/d, which can usually be achieved by prescribing 1,200 to
1,500 kcal/d for women and 1,500 to 1,800 kcal/d for men.4 This
prescription should yield an average loss of 0.5 to 0.75 kg/wk.
As noted in the Obesity Guidelines, a variety of diets can be
incorporated into lifestyle interventions, including evidence-based
diets that restrict certain types of foods (eg, high carbohydrate,
high-glycemic value).4 All diets, regardless of macronutrient compo-
sition, will produce weight loss if a consistent caloric deficit is achieved.
This was demonstrated by the 2-year POUNDS LOST (Preventing
Overweight Using Novel Dietary Strategies) study, in which all par-
ticipants in four groups were prescribed a 750 kcal/d deficit but were
instructed to consume different percentages of protein, fat, and car-
bohydrate.18 Short- and long-term weight losses did not differ sig-
nificantly at any time among the four diets, all of which were combined
with a lifestyle program. Foster et al19 similarly found no significant
differences in short- or long-term weight loss with low-carbohydrate
versus low-fat diets, each combined with comprehensive lifestyle in-
tervention (Fig 1).
Although the macronutrient composition of reducing diets
does not seem to affect weight loss, it may contribute to im-
provements in cardiometabolic risk factors.20 Table 1 summarizes
select randomized trials (with , 40% attrition) that examined the
effects of macronutrient composition on changes in weight and
health outcomes.18-26 Further research is needed to determine the
0
Low-fat diet group
Change in Weight (kg)
–2 Low-carbohydrate diet group
–4
–6
–8
–10
–12
–14
3 6 12 24
Month
Fig 1. Change in body weight for participants in low-fat and low-carbohydrate
diet groups after 24 months, based on random-effects linear model. Reprinted with
permission.19
JOURNAL OF CLINICAL ONCOLOGY
 Management of Obesity
optimal macronutrient composition of diets for individuals with
specific comorbidities.4
Physical Activity
Lifestyle interventions instruct patients to gradually increase
physical activity to approximately 150 to 180 min/wk over
6 months.4,14,27 Activity usually consists of brisk walking or similar
aerobic exercise. Short-term studies (, 6 months) have shown that
physical activity alone induces minimal weight loss (1 to 2 kg)
compared with losses produced by diet alone or diet plus exercise
(8 to 10 kg).28 However, patients should be encouraged to increase
physical activity in the short term, given findings that cardiore-
spiratory fitness may attenuate CVD mortality.29 Even in the
absence of substantial weight loss, regular aerobic activity may
reduce blood pressure, lipid concentrations, and visceral fat, while
also improving glycemic control.30
Behavior Therapy
Behavior therapy provides a set of strategies for patients to
modify their eating and physical activity. Record keeping is the
most important of these, with patients tracking the type and
amount of foods and beverages consumed, along with their calorie
content.27,31 Monitoring helps patients identify their own eating
patterns, select targets for reducing calorie intake, and track
progress in meeting daily calorie goals. Traditional paper records
and calorie books have largely been replaced by online trackers and
apps. Tracking physical activity by using a paper log or a digital
device is similarly encouraged. Patients are also instructed to weigh
themselves regularly, once a week during weight loss and as often as
daily during weight loss maintenance. Cellular-connected smart
scales measure weight and send the information to a computer,
which provides patients with a graph of their weight change.27
Comprehensive interventions provide a structured weekly
curriculum of behavior change that covers topics such as goal
setting, stimulus control, problem solving, cognitive restructuring,
and coping with dietary lapses.14,27 The DPP treatment protocol
offers an excellent example of a structured lifestyle intervention.14
Patients’ receipt of instruction and feedback from a trained in-
terventionist is critical to weight loss.4
LONG-TERM LIFESTYLE INTERVENTION
Gradual weight regain, as observed in the Foster et al19 study in the
second year, is common after lifestyle intervention. Patients usually
regain 2 to 4 kg in the first year and 1 to 2 kg/y thereafter.19,27 Five
years after treatment, approximately half the patients have returned
to their baseline weight.27 Decreased adherence to diet and activity
prescriptions contribute to weight regain, but these behaviors may
have a metabolic basis.32 Rosenbaum et al33 found that the
maintenance of a 10% reduction in baseline weight was associated
with a decrease in total energy expenditure that was approximately
300 to 500 kcal/d greater than that predicted by changes in weight
and body composition. The decrease in total energy expenditure
was predominantly the result of reduced energy expenditure
during physical activity, reflecting increased work efficiency in
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
skeletal muscle. These compensatory biological responses re-
grettably defend the body against patients’ desired weight loss.32
The most effective behavioral method for preventing weight
regain is continued behavioral counseling on an every-other-week
or monthly basis after initial weight loss. Perri et al34 showed that
participants who attended every-other-week group sessions for
1 year after weight reduction maintained 13 kg of their 13.2 kg end-
of-treatment loss, whereas those with no further care regained
5.1 kg. Wing et al31 demonstrated that the patients who were most
successful at maintaining their lost weight monitored their weight
weekly or more frequently and responded quickly to small in-
creases in weight.
Numerous trials have demonstrated that high levels of
physical activity facilitate the maintenance of lost weight.35,36 The
American College of Sports Medicine recommends that, after
weight loss, patients exercise 60 min/day most days of the week to
reach 200 to 300 min/wk.36 More minutes of activity may be
necessary to compensate for patients’ increased energy efficiency,
described previously.33 Physical activity, such as walking, can be
performed at a moderate intensity and in short bouts as brief as
10 minutes. Multiple short bouts of activity, throughout the day,
are as effective as one long bout in achieving weight control.37
BENEFITS AND LIMITATIONS OF LIFESTYLE INTERVENTION
Numerous reviews have demonstrated that sustained weight loss,
as little as 3% to 5% of initial weight, produces clinically mean-
ingful improvements in blood pressure, triglycerides, high-density
lipoprotein cholesterol, hemoglobin A1c (HbA1c), and the risk of
developing type 2 diabetes.4,5 Larger weight losses induce greater
improvements in these risk factors, as demonstrated by the 1-year
results of the Look AHEAD (Action for Health in Diabetes) study
(Fig 2).38 However, in the Look AHEAD study, improvements in
CVD risk factors (including sleep apnea and depression) were not
sufficient to reduce CVD morbidity and mortality over 10 years.39
Lifestyle interventions in cancer survivors have demonstrated
weight loss,40 improved quality of life, less fatigue, lower incidence
of comorbidity, and favorable changes in biomarkers linked to
cancer risk and prognosis.41-43 For example, a preliminary study
showed a 24% reduced risk of breast cancer recurrence in women
who adhered to a low-fat diet and lost 2.7 kg compared with
a control group.41 A randomized controlled trial (NCT02750826;
Randomized Phase III Trial Evaluating the Role of Weight Loss in
Adjuvant Treatment of Overweight and Obese Women With Early
Breast Cancer) of more than 3,000 women was recently initiated to
further assess the effects of weight loss and increased physical
activity in reducing breast cancer recurrence.
Despite its benefits, intensive lifestyle intervention has a rel-
atively limited reach.27 It is not generally available to patients in
primary care settings, but instead is confined to individuals at
major academic health centers. Efforts to disseminate lifestyle
intervention have increased, as represented by a group version of
the DPP being offered by the local Young Men’s Christian Asso-
ciation.44 Additional studies, including those of patients with
breast cancer,45 have shown that telephone-delivered lifestyle in-
terventions produce clinically meaningful weight loss approxi-
mately equal to that achieved with face-to-face visits.27 In contrast,
© 2016 by American Society of Clinical Oncology 4297
 4298
Table 1. Weight Loss From Randomized Trials That Compared Diets With Various Macronutrient Compositions
No. of Lifestyle
Completed Trial Sessions
First Author No. of Patients F (%) (%) Provided Dietary Intervention Weight Change Months Comment/Other Results
Bazzano21 148 88 80 20 Low-fat 21.8 kg* 12 Fifty-one percent were black. Major exclusion criteria were
Low-carbohydrate 25.3 kg† cardiovascular disease and diabetes. No specific calorie or
energy goals were given. No significant effect on total and
LDL cholesterol. Greater HDL cholesterol increase and
triglyceride decrease in low-carbohydrate group.
Das22‡ 34 Unknown 85 52 Low-glycemic load 27.8%* 12 No differences were observed between groups in change in
High-glycemic load 28.0%* CVD risk factors.
20

© 2016 by American Society of Clinical Oncology

Fabricatore 79 80 63 30 Low-glycemic load 24.5%* 9 All participants had type 2 diabetes. Larger reductions in
Low-fat 26.4%* HbA1c in the low-glycemic load group.
Foster19 307 68 63 38 Low-carbohydrate 26.3 kg* 24 Greater increase in HDL cholesterol and greater decrease in
Low-fat 27.4 kg* triglycerides at 3 and 6 months in the low-carbohydrate
group. Greater decrease in LDL at 3 and 6 months in the
low-fat group.
Gardner23 311 100 80 8 Atkins (low-carbohydrate) 24.7 kg* 12 Greater increase in HDL cholesterol in Atkins than in Ornish
Zone (even distribution) 21.6 kg† group; greater decrease in triglycerides in Atkins than in
LEARN (calorie-restricted) 22.2 kg*† Zone group. Systolic blood pressure decreased more in
Ornish (low-fat) 22.6 kg*† Atkins than in all other groups; diastolic blood pressure
decreased more in Atkins than in Ornish group.
Sacks18 811 64 80 66 Low-fat, average protein 22.9 kg* 24 LDL cholesterol decreased significantly more in lowest-fat/
(highest carbohydrate) highest-carbohydrate than in highest-fat/lowest-
Low-fat, high-protein 23.8 kg* carbohydrate groups. HDL cholesterol increased more with
High-fat, average-protein 23.1 kg* lowest-carbohydrate than with highest-carbohydrate diet.
High-fat, high-protein (lowest 23.5 kg* All diets similarly decreased triglyceride levels. All diets
Alamuddin et al

carbohydrate) except highest carbohydrate decreased fasting insulin

(greater decrease in the high-protein v average-protein
diets).
Shai24 322 14 85 24 Low-fat 22.9 kg* 24 HDL cholesterol increased in all groups, significantly more in
Mediterranean 24.4 kg† the low-carbohydrate than low-fat group. Triglyceride
Low-carbohydrate 24.7 kg† levels decreased more in the low-carbohydrate than in the
low-fat group. In diabetic participants, only the
Mediterranean diet group had a decrease in fasting
glucose.
Stern25 132 17 66 15 Low-carbohydrate 25.1 kg* 12 Triglyceride levels decreased more in the low-carbohydrate
Conventional (low-fat) 23.1 kg* group than in the low-fat group. HDL cholesterol decreased
less in the low-carbohydrate group than in the low-fat

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

group. In patients with type 2 diabetes, greater
improvements in HbA1C s in the low-carbohydrate group.
Yancy26 120 76 66 9 Low-fat 26.5%* 6 Low-carbohydrate group showed greater decreases in

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Low-carbohydrate, ketogenic 212.0%† triglycerides and greater increases in HDL.
diet with nutritional
supplements

NOTE. All studies were analyzed by use of an intention-to-treat population; exceptions are indicated by ‡. Results reported as greater, larger, or increased more represent statistically significant differences between
treatment conditions.
Abbreviations: CVD, cardiovascular disease; F, female; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Within each study, different symbols (*, †) indicate statistically significant differences in weight loss between groups.

JOURNAL OF CLINICAL ONCOLOGY

 Management of Obesity

A 0 B 0

Change in Fasting Glucose (mg/dL)

−0.2 −10
Change in HbA1c (%)

−0.4 −20

−0.6 −30
P < .001 P < .001

−0.8 −40

−1 −50
Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15% Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15%
Lost < 2% Lost < 5% Lost < 10% Lost < 15% Lost < 2% Lost < 5% Lost < 10% Lost < 15%

C D 20

Change in Triglycerides (mg/dL)

0
0
−2
Change in BP (mmHg)

−20
−4

−6 −40

−8
−60
−10 P < .001
SBP: P < .001 SBP
DBP: P < .001 DBP −80
−12

−14 −100
Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15% Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15%
Lost < 2% Lost < 5% Lost < 10% Lost < 15% Lost < 2% Lost < 5% Lost < 10% Lost < 15%

E F 8
8
HDL: P < .001 HDL
HDL: P < .001 HDL LDL: P = .2915 LDL
LDL: P = .3614 LDL
Change in HDL and LDL (mg/dL)
Change in HDL and LDL (mg/dL)

4
4

0
0

−4
−4

−8 −8

−12 −12
Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15% Gained > 2% Gained ≤ 2% ~ Lost ≥ 2% ~ Lost ≥ 5% ~ Lost ≥ 10% ~ Lost ≥ 15%
Lost < 2% Lost < 5% Lost < 10% Lost < 15% Lost < 2% Lost < 5% Lost < 10% Lost < 15%

Fig 2. Change in risk factors by weight loss categories for the Look AHEAD cohort. Data in all figures are presented as least square means and 95% CIs adjusted for
clinical sites, age, sex, race/ethnicity, baseline weight, baseline measurement of the outcome variable, and treatment group assignment. (A) Change in hemoglobin A1c
(HbA1c), (B) in fasting glucose, (C) in blood pressure (BP), (D) in triglycerides, and (E) in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) by weight loss
category. (F) Change in HDL and LDL by weight loss category for the subset of patients who were not receiving lipid-lowering medication. DBP, diastolic blood pressure;
SBP, systolic blood pressure. Adapted and reprinted with permission.38

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Alamuddin et al
Internet- or smart-phone-delivered interventions alone typically
produce losses that are one third to one half smaller than those
produced by in-person counseling.27,46 Commercial programs
provide another option for dissemination, provided there is peer-
reviewed published evidence of their safety and efficacy.4,27
PHARMACOLOGIC TREATMENT OF OBESITY
Weight loss medications are indicated for adults with a BMI $
30 kg/m2 (or a BMI $ 27 kg/m2 with at least one weight-related
comorbidity) who are unable to reduce successfully with lifestyle
intervention alone.4-7 Pharmacotherapy facilitates adherence to
dietary recommendations by reducing hunger or increasing sati-
ation4-7; it may also counteract compensatory hormonal changes
precipitated by caloric restriction and weight loss.32 Medication is
recommended only as an adjunct to comprehensive lifestyle
modification.4-7 Combining the two approaches generally pro-
duces additive weight loss, greater than either approach alone.47
Pharmacotherapy is approved by the US Food and Drug
Administration (FDA) for chronic weight management, with the
recognition that patients may need to continue receiving obesity
medications indefinitely in the same manner as drugs for other
chronic conditions (eg, hypertension).7 Weight loss medications
should not be expected to cure obesity in 6 months, any more than
antihypertensive agents would be anticipated to have lasting
benefits if withdrawn after the same amount of time. Obesity, for
most persons, is a chronic condition requiring long-term care.4-7
Medication Approved for Short-Term Weight
Management
Phentermine, approved by the FDA in 1959 for short-term use
(# 3 months), is the most widely prescribed weight loss medi-
cation in the United States because of its efficacy and low cost.48,49
It is frequently used off-label for chronic weight management. The
mechanism of action for phentermine includes inhibiting nor-
adrenaline reuptake, which is associated with reports of decreased
hunger and food intake.7,49 Common adverse effects include in-
somnia and dry mouth, and the medication is contraindicated with
anxiety disorders, a history of cardiovascular disease, and
seizures.7,49 Little is known about the long-term safety or efficacy of
phentermine as a monotherapy. A 1968 double-blind, 36-week
trial observed a mean loss of 12.2 to 13.0 kg compared with 4.8 kg
for placebo.48
Medications Approved for Chronic Weight Management
Medications described in this section, beginning with orlistat,
are all FDA approved for chronic weight management on the basis
of at least 1 year of safety and efficacy data. For medications
approved after orlistat, approval was contingent upon satisfactory
completion of a postmarketing trial that demonstrated that the
drug did not increase CVD events.49
Orlistat is a gastrointestinal lipase inhibitor that blocks the
absorption of approximately 30% of the fat contained in a meal,
thus reducing net calorie intake.7,49 As detailed in Table 2, orlistat is
available as either a prescription or over-the-counter drug.7 It is
contraindicated with cyclosporine, chronic malabsorption
4300 © 2016 by American Society of Clinical Oncology
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
syndrome, and other conditions listed in Table 2. Adverse effects
include oily spotting and fecal urgency, which often leads patients
to terminate the drug. Randomized controlled trials (RCTs) ob-
served a mean absolute loss of 5 to 10 kg (at $ 1 year) in patients
who received orlistat with lifestyle modification compared with
3 to 6 kg for placebo with lifestyle counseling.7,49 Figure 3 shows that,
averaged across studies, the addition of orlistat 360 mg/d to lifestyle
counseling increased mean weight loss by 3.6 kg compared with
placebo (ie, placebo-subtracted loss).7,49 Additional trials showed
that patients who continued use of orlistat in year 2 had significantly
reduced weight regain compared with patients who had lost weight
with orlistat in year 1 but were thereafter randomly assigned to
placebo.50 The latter finding indicates that patients are at risk for
regaining weight when medication is terminated.
Lorcaserin seems to reduce food intake by selectively stim-
ulating serotonin 2C receptors in the brain.7 Its most common
adverse effects include headache, nausea, and dry mouth. The
medication is contraindicated with other serotonergic agents,
including selective serotonin reuptake inhibitors.7,49 In a 1-year
RCT of 3,182 patients, lorcaserin (plus lifestyle intervention)
produced a mean loss of 5.8 kg compared with 2.2 kg for placebo;
47.5% of lorcaserin- versus 20.3% of placebo-treated patients
lost $ 5% of initial weight.51 Continued used of lorcaserin for
a second year significantly reduced weight regain compared with
placebo.
Phentermine/topiramate extended-release (ER) combines the
previously discussed phentermine with topiramate, which is FDA
approved for seizure prophylaxis but also induces weight loss (by
mechanisms not fully understood).7 Common adverse effects
include dry mouth, paresthesia, and insomnia.7,49 In the 56-week
CONQUER (Effects of Low-Dose, Controlled-Release, Phenter-
mine Plus Topiramate Combination on Weight and Associated
Comorbidities in Overweight and Obese Adults) study,52 patients
treated with phentermine 7.5 mg/topiramate 46.0 mg and phen-
termine 15.0 mg/topiramate 92.0 mg lost 8.1 kg and 10.2 kg,
respectively, compared with 1.4 kg for placebo, giving the top dose
the largest placebo-subtracted difference of all current medica-
tions.49 In addition, 62% and 70% of patients in the two medi-
cation groups, respectively, lost $ 5% of weight versus 21% for
placebo. Pregnant women must avoid topiramate because it in-
creases the risk of oral cleft lip and/or cleft palate in infants.7,49
Naltrexone/bupropion ER combines naltrexone, an FDA-
approved opioid receptor antagonist for the treatment of alco-
hol and opioid dependence, with bupropion, a dopamine and
norepinephrine reuptake inhibitor approved for depression and
smoking cessation.7,53 The combination seems to reduce food
intake by increasing the firing of pro-opiomelanocortin neurons
that contribute to satiation.7,53 Common adverse effects include
nausea, constipation, and dizziness; contraindications include
uncontrolled hypertension, seizure disorders, and anorexia nerv-
osa or bulimia. A 1-year RCT revealed mean absolute losses of
6.1 kg in medication-treated patients and 1.4 kg in placebo-treated
patients54; 48% and 16% of patients, respectively, lost $ 5% of
initial weight.
Liraglutide 3.0 mg/d is an injectable glucagon-like peptide-1
(GLP-1) receptor agonist that increases insulin release, while also
slowing gastric emptying and stimulating GLP-1 receptors in the
brain involved with appetite and energy regulation.7,55 Common
JOURNAL OF CLINICAL ONCOLOGY
 www.jco.org
Generic Drug
Orlistat, prescription
(120 mg)
Orlistat, OTC (60 mg)
Lorcaserin
Phentermine/topiramate
Naltrexone/bupropion
Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
Liraglutide
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NOTE. Adapted and reprinted with permission.7
Abbreviations: GABA, g-aminobutyric acid; GLP-1, glucagon-like peptide-1; MAOI, monoamine oxidase inhibitor; OTC, over the counter; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin
reuptake inhibitor.
*Mean weight loss in excess of placebo as percentage of initial body weight or mean kilogram weight loss over placebo.
© 2016 by American Society of Clinical Oncology
4301
Dose
120 mg three times a day
60-120 mg three times
a day
10 mg twice a day
Starting dose: 3.75 mg
phentermine/23 mg
topiramate ER once a day
Recommended dose:
7.5 mg phentermine/
46 mg topiramate ER
once a day, High dose:
15 mg phentermine/
92 mg topiramate ER
once a day
32 mg naltrexone/360 mg
bupropion twice a day
3.0 mg injectable
Table 2. Pharmacotherapy Currently Approved for Chronic Weight Loss
Mean Placebo-Subtracted Weight
Loss
Mechanism of Duration of
Action kg* % Trial (years) Common Side Effects Contraindications
Pancreatic and gastric 2.9-3.4 2.9-3.4 1 Decreased absorption of Cyclosporine (taken 2 hours
lipase inhibitor fat-soluble vitamins, before or after orlistat
steatorrhrea, oily dose), chronic
spotting, flatulence with malabsorption syndrome,
discharge, fecal urgency, pregnancy and
oily evacuation, breastfeeding, cholestasis,
increased defecation, levothyroxine, warfarin,
fecal incontinence antiepileptic drugs
Pancreatic and gastric 2.9-3.4 2.9-3.4 1 Same as orlistat, Same as orlistat, prescription
lipase inhibitor prescription
5-HT2C receptor agonist 3.6 3.6 1 Headache, nausea, dry Pregnancy and
mouth, dizziness, breastfeeding; use with
fatigue, constipation caution: SSRIs, SNRIs,
MAOIs, St John’s wort,
triptans, bupropion,
dextromethorphan
GABA receptor Recommended 6.6 1 Insomnia, dry mouth, Pregnancy and
modulation dose, 6.6 constipation, breastfeeding,
(topiramate) plus High dose, 8.6 8.6 paresthesia, dizziness, hyperthyroidism,
norepinephrine- dysgeusia glaucoma, MAOIs,
releasing agent sympathomimetic amines
(phentermine)
Management of Obesity
Reuptake inhibitor of 4.8 1 Nausea, constipation, Uncontrolled hypertension,
dopamine and headache, vomiting, seizure disorders,
norepinephrine dizziness anorexia, nervosa or
(bupropion) and bulimia, drug or alcohol
opioid antagonist withdrawal, MAOIs
(naltrexone)
GLP-1 agonist 5.8 1 Nausea, vomiting, Medullary thyroid cancer
pancreatitis history, multiple endocrine,
neoplasia type 2 history
 Alamuddin et al

obesity medications and the lack of insurance coverage. For these

Phentermine 15 mg/d /
reasons, phentermine remains the most widely prescribed weight
Topiramate ER 92 mg/d
loss medication, despite the availability of newer, better-studied
Phentermine 7.5 mg/d /
Topiramate ER 46 mg/d medications that may be more efficacious.7,59
Naltrexone ER 32 mg/d /
Bupropion ER 360 mg/d

Liraglutide 3 mg/d
SURGICAL TREATMENT OF OBESITY

Lorcaserin 20 mg/d Patients with severe obesity who are motivated to lose weight but
Orlistat 360 mg/d
have been unsuccessful with the previously described approaches,
should be advised about bariatric surgery.4 This section provides an
Orlistat 180 mg/d overview of the most frequently used operations (all of which are
usually performed laparoscopically), along with their mechanisms
0 -2 -4 -6 -8 -10
of action, efficacy, benefits, and complications.
Placebo-Subtracted
Weight Reduction at 12 Months (kg)
Roux-en-Y Gastric Bypass
Fig 3. Efficacy of weight loss medications approved by the US Food and Drug Roux-en-Y gastric bypass (RYGB) is considered the gold
Administration for chronic weight management. ER, extended-release. Data standard for weight loss surgery. It involves dividing the stomach to
adapted with courtesy of Yanovski SZ and Yanovski JA.49,53 create a small gastric pouch in the upper fundus, which is anas-
tomosed to a Roux limb of jejunum that bypasses 75 to 150 cm of
small bowel, resulting in bypass of the majority of the stomach, the
adverse effects of liraglutide 3.0 mg/d include nausea and
entire duodenum, and most of the jejunum, thereby restricting
vomiting.7,55 The medication is contraindicated if there is a family
food and limiting absorption (Fig 4).60 The procedure combines
history of medullary thyroid cancer or multiple endocrine neo-
restrictive and malabsorptive mechanisms and produces a median
plasia type 2. The FDA has required postmarketing studies to
loss of 31.5% of initial weight at 3 years.62 The Swedish Obese
evaluate the potential risk of breast cancer with liraglutide, given an
Subjects (SOS) study revealed a sustained approximately 25%
imbalance in the number of breast cancer cases in patients re-
reduction at 10 years.63 Complications of RYGB include anasto-
ceiving the drug compared with placebo. In a representative RCT,
motic leakage, acute gastric dilatation, ulceration, nutritional
liraglutide 3.0 mg produced a mean loss of 8.4 kg compared with
deficiencies, and the dumping syndrome.4,61 Thirty-day mortality
2.8 kg for placebo; 63.2% versus 27.1% of patients, respectively,
rates are approximately 0.2%, with other serious complication
lost $ 5% of initial weight.55 In a 56-week trial, liraglutide was
rates of approximately 5%.4,64
shown to significantly improve the maintenance of weight loss
compared with placebo.56
Sleeve Gastrectomy
Sleeve gastrectomy (SG) was introduced in the United States
in 2007 but is now the nation’s most commonly performed
BENEFITS AND LIMITATIONS OF PHARMACOTHERAPY
FOR OBESITY bariatric surgery. It involves removing approximately 75% of the
stomach, thus bypassing the gastric fundus and body.62 In addition
Studies of weight loss medications approved for chronic use have to its restrictive properties, SG accelerates gastric emptying and
demonstrated reductions in the risk of developing type 2 diabetes dramatically reduces ghrelin levels.65 SG produces weight losses
and other CVD risk factors. The 4-year XENDOS (XENical in the
Prevention of Diabetes in Obese Subjects) trial, for example,
demonstrated a 37.3% decrease in progression to diabetes in
patients treated with orlistat compared with placebo.57 A meta-
analysis similarly showed greater placebo-subtracted reductions in
systolic and diastolic blood pressure (of 1.8 and 1.5 mm Hg, re-
spectively) in patients receiving orlistat versus placebo,58 both
combined with lifestyle modification. Similar reductions in HbA1C
and blood pressure have been observed with phentermine/
topiramate, lorcaserin, and liraglutide.51,52,55 However, CVD
outcomes studies remain to be completed on newly approved drugs
to show, at a minimum, that they do not increase CVD risk.
Despite the high prevalence of obesity, there is limited use of
weight loss medications. Patients and practitioners may be dis-
appointed by the modest size of the weight losses produced by most
Roux-en-Y Vertical Sleeve Adjustable
drugs and by weight regain after their termination. They also may Gastric Bypass Gastrectomy Gastric Band
have lingering concerns about the long-term safety of obesity
pharmacotherapy.49 Other obstacles include stigmatization of Fig 4. Types of metabolic and bariatric surgery. Adapted from Pories W.60

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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Management of Obesity

similar to or slightly smaller than RYGB.4,65,66 In a 3-year RCT,
Schauer et al66 observed mean losses of 24.5% and 21.1% in
patients who underwent RYGB versus SG, respectively, compared
with 4.2% for patients who received medical therapy and lifestyle
modification. Postoperative complications (ie, leakage and vom-
iting as a result of overeating) are lower with SG than RYGB;
however, mortality rates are difficult to compare because of their
relatively low prevalence (, 1%).4,61
Adjustable Gastric Banding
Adjustable gastric banding (AGB) is the least invasive surgical
procedure and involves placing an inflatable silicone band around
the fundus of the stomach creating a small pouch.4,610 Saline can be
added or removed through a subcutaneous port to adjust the
diameter of the band. This is a restrictive procedure, with no
changes in gut anatomy or hormones. AGB results in median
weight loss of approximately 15.9% of initial weight at 3 years.62
Complications include band erosions, slippage, port problems,
wound infections, and acid reflux, often requiring a revision or
repeat surgery. The mortality rate for surgery is close to zero.64
Small weight losses and the need to eventually revise 40% or more
of AGB procedures have led to a marked decrease in the use of this
approach in the United States.61
BENEFITS AND LIMITATIONS OF BARIATRIC SURGERY
RYGB and SG are associated with dramatic and durable im-
provements in obesity-related complications, which may include
reduced mortality. The prospective SOS study observed a 29%
reduction in total mortality in surgically treated patients compared
with matched controls who received medical management.63 A
case-control study of 15,850 patients similarly revealed a 40%
reduction in all-cause mortality as a result of reductions in death
from CVD, type 2 diabetes, and obesity-related cancers.67 In ad-
dition to improving hypertension, hyperlipidemia, and obstructive
sleep apnea, bariatric surgery is particularly effective in amelio-
rating type 2 diabetes.66
The SOS study revealed that bariatric surgery was associated
with a significant reduction of cancer in women, but not in men, in
whom there was a statistically nonsignificant reduction.68 Simi-
larly, in a retrospective analysis study, obese women who un-
derwent bariatric surgery had a 71% lower risk of developing
uterine cancer compared with obese women who did not have
surgery.69 However, another retrospective cohort study found that
participants who received bariatric surgery had a higher incidence
of colorectal cancer compared with obese controls who did not
have bariatric surgery.70 Of note, the number of women enrolled in
studies of bariatric surgery is much larger than that of men, which
may be one reason for the statistical difference observed between
women and men.
Limitations of bariatric surgery include its high initial costs,
risks of significant short- and long-term complications, and sig-
nificant weight regain after 1 year in approximately 20% to 25% of
patients.4,62 Despite these limitations, bariatric surgery is by far the
most effective intervention for managing weight and comorbidities
in people with severe obesity. However, fewer than 200,000 people
per year receive surgery.
CONCLUSION
This review has shown that intensive lifestyle intervention,
pharmacotherapy, and bariatric surgery can produce clinically
meaningful weight loss associated with improvements in obesity-
related comorbidities. Greater resources and treatment dissemi-
nation efforts are needed to help the millions of Americans who
would benefit from these approaches. As important, innovative
public policy and public health approaches are needed to prevent
the development of obesity and, thus, to reduce the number of
persons who require weight management.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors

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n n n

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 Alamuddin et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Management of Obesity
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Naji Alamuddin Thomas A. Wadden
No relationship to disclose Honoraria: Novo Nordisk, Nutrisystem, Weight Watchers, Orexigen
Therapeutics
Zayna Bakizada Consulting or Advisory Role: Novo Nordisk, Orexigen Therapeutics,
No relationship to disclose Nutrisystem, Weight Watchers
Research Funding: Eisai, Novo Nordisk

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 Management of Obesity

Appendix

Table A1. Guide to Selecting Treatment

BMI Category
Treatment 25-26.9 27-29.9 30-34.9 35-39.9 $ 40
Diet, physical activity, and behavior therapy With comorbidities With comorbidities + + +
Pharmacotherapy With comorbidities + + +
Surgery With comorbidities With comorbidities With comorbidities

NOTE. (+) Indicates treatment was used regardless of comorbidities. Prevention of weight gain with lifestyle therapy is indicated in any patient with a body mass index
(BMI) $ 25 kg/m2, even without comorbidities, whereas weight loss is not necessarily recommended for those with a BMI of 25-29.9 kg/m2 or a high waist cir-
cumference, unless they have two or more comorbidities. Combined therapy with a low-calorie diet, increased physical activity, and behavior therapy provide the most
successful intervention for weight loss and weight maintenance. Consider pharmacotherapy only if a patient has not lost 1 pound per week after 6 months of combined
lifestyle therapy. Reprinted with permission.5

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