O b e s i t y Ph a r m a c o t h e r a p y

Katherine H. Saunders, MD, DABOM*, Devika Umashanker, MD, MBA,

Leon I. Igel, MD, DABOM, Rekha B. Kumar, MD, MS, DABOM,
Louis J. Aronne, MD, DABOM, FTOS

KEYWORDS
 Obesity  Weight management  Pharmacotherapy  Orlistat
 Phentermine/topiramate  Lorcaserin  Naltrexone/bupropion  Liraglutide

KEY POINTS
 Although diet, physical activity, and behavioral modifications are the cornerstones of
weight management, weight loss achieved by lifestyle modifications alone is often limited
and difficult to maintain.
 Pharmacotherapy for obesity can be considered if patients have a body mass index (BMI)
of 30 kg/m2 or greater or a BMI of 27 kg/m2 or greater with weight-related comorbidities.
 The 6 most commonly used antiobesity medications are phentermine, orlistat, phenter-
mine/topiramate extended release, lorcaserin, naltrexone sustained release (SR)/bupro-
pion SR, and liraglutide 3.0 mg.
 It is important for primary care providers to be familiar with the pharmacotherapy available
to patients who cannot lose weight and sustain weight loss with lifestyle interventions
alone.
 Successful pharmacotherapy for obesity depends on tailoring treatment to patients’ be-
haviors and comorbidities as well as close monitoring of efficacy, safety, and tolerability.

INTRODUCTION

Diet, physical activity, and behavioral modifications are the cornerstones of weight
management.1 However, weight loss achieved by lifestyle modifications alone is often
limited and difficult to maintain. Reduced caloric intake and increased energy

Disclosure Statement: K.H. Saunders, D. Umashanker, and L.I. Igel have no conflicts of interest.
R.B. Kumar is a speaker for Janssen Pharmaceuticals and Novo Nordisk A/S. She is a shareholder
in Zafgen, VIVUS, and MYOS Corporation. L.J. Aronne has received research funding from
Aspire Bariatrics, Eisai, and Takeda Pharmaceuticals. He declares consultant/advisory board
work with Jamieson Labs, Pfizer Inc, Novo Nordisk A/S, Eisai, VIVUS, GI Dynamics, JOVIA Health,
and Gelesis. He is a shareholder of Zafgen, Gelesis, MYOS Corporation, and Jamieson Labs, and
he is on the board of directors of MYOS Corporation and Jamieson Labs.
Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism,
Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065, USA
* Corresponding author.
E-mail address: kph2001@med.cornell.edu

Med Clin N Am 102 (2018) 135–148

https://doi.org/10.1016/j.mcna.2017.08.010 medical.theclinics.com
0025-7125/18/ª 2017 Elsevier Inc. All rights reserved.
136 Saunders et al

expenditure are counteracted by adaptive physiologic responses.2 Not only does

appetite increase but resting metabolic rate slows out of proportion to what would
be expected based on changes in body composition.3 This phenomenon, called adap-
tive thermogenesis or metabolic adaptation, impedes weight loss and contributes to
weight regain.4,5
Antiobesity pharmacotherapy is one strategy to offset the adaptive changes in appe-
tite and energy expenditure that occur with weight loss and to improve adherence to
lifestyle interventions.3 According to the 2013 American College of Cardiology/Amer-
ican Heart Association/The Obesity Society’s guideline for the management of over-
weight and obesity in adults and the Endocrine Society’s clinical practice guidelines
on the pharmacologic management of obesity, pharmacotherapy for obesity can be
considered if patients have a body mass index (BMI) of 30 kg/m2 or greater or a
BMI of 27 kg/m2 or greater with weight-related comorbidities, such as hypertension,
dyslipidemia, type 2 diabetes, and obstructive sleep apnea.1,6
As obesity is a chronic disease, most antiobesity medications are approved for
long-term treatment. Until a few years ago, phentermine (and other sympathomimetic
amines) and orlistat were the only antiobesity medications approved by the Food and
Drug Administration (FDA). In 2012, phentermine/topiramate extended release (ER)
and lorcaserin were approved; in 2014, naltrexone sustained release (SR)/bupropion
SR and liraglutide 3.0 mg were approved.
In this article, the authors review the 6 most widely used antiobesity medications
(Table 1). The authors present efficacy and safety findings, discuss how to best select
agents for each patient, and provide advice on how to manage patients who do not
respond to medications. Although referral to an obesity medicine specialist is an op-
tion for some primary care providers, there are not enough obesity medicine special-
ists to address the obesity epidemic. Therefore, it is important for primary care
providers to be familiar with the pharmacotherapy available to patients who are unable
to lose weight and sustain weight loss with lifestyle interventions alone.

PHENTERMINE

Phentermine was approved by the FDA in 1959 and has been the most commonly pre-
scribed medication for obesity in the United States. It is an adrenergic agonist that in-
creases resting energy expenditure and suppresses appetite. Phentermine is
indicated for short-term use (3 months), as there are no long-term safety trials of phen-
termine monotherapy; but it was approved in combination with topiramate ER for
long-term therapy. Many practitioners prescribe phentermine for greater than
3 months as off-label therapy for ongoing weight management.
Two other sympathomimetic amines, diethylpropion and phendimetrazine, are also
available in the United States; but data on these agents are minimal, and they are pre-
scribed much less frequently.
Until recently, the available doses of phentermine were 15.0, 30.0, and 37.5 mg.7–9
As prescribing practices should be individualized to determine the lowest effective
dose, many practitioners recommend using quarter or half tablets of these formula-
tions. In 2016, the FDA approved an 8-mg formulation, which can be prescribed up
to 3 times daily.10 Administration of the last dose late in the day should be avoided
to prevent insomnia. Phentermine is a schedule IV controlled substance.
In a 28-week randomized controlled trial comparing phentermine, topiramate ER,
and the combination of the two agents, phentermine 15 mg daily produced an average
6.0-kg weight loss compared with a 1.5-kg weight loss with placebo.11 Forty-six
percent of participants assigned to phentermine lost at least 5% of initial body weight
Table 1
Antiobesity medications

Mechanism,
Dosage, and Consider This
Available Trial and Weight Loss Most Common Medication in These Avoid This Medication
Medication Formulations Duration Trial Arms (%) Adverse Events Patients in These Patients
Phentermine7–10 Adrenergic Aronne LJ, et al11 15 mg daily 6.06a Dry mouth, Younger patients who Patients with
Schedule IV agonist 28 wk 7.5 mg daily 5.45a insomnia, need assistance with uncontrolled
controlled 8.0 mg–37.5 mg Placebo 1.71 dizziness, appetite suppression hypertension,
substance daily (8-mg (topiramate irritability active or unstable
NOTE: approved dose can be ER and coronary disease,
for short-term prescribed up phentermine/ hyperthyroidism,
use to TID) topiramate ER glaucoma, anxiety,
Capsule, tablet arms excluded) insomnia, or patients
who are generally
sensitive to
stimulants; patients
with a history of drug
abuse or recent
MAOI use; patients
who are pregnant
Orlistat14,15 Lipase inhibitor XENDOS16 120 mg TID 9.6 (wk 52)a Fecal urgency, oily Patients with Patients with
60–120 mg TID 208 wk 5.25 (wk 208)a stool, flatus with hypercholesterolemia malabsorption
with meals Placebo 5.61 (wk 52) discharge, fecal and/or constipation syndromes or other

Obesity Pharmacotherapy
Capsule 2.71 (wk 208) incontinence who can limit their GI conditions that
intake of dietary fat predispose to GI
upset/diarrhea;
patients who cannot
modify the fat
content of their
diets; patients who
are pregnant

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137
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Saunders et al
Table 1
(continued )
Mechanism,
Dosage, and Consider This
Available Trial and Weight Loss Most Common Medication in These Avoid This Medication
Medication Formulations Duration Trial Arms (%) Adverse Events Patients in These Patients
Phentermine/ Adrenergic EQUIP21 15/92 mg daily 10.9a Paresthesias, Younger patients who Patients with
topiramate ER19 agonist/neuro- 56 wk 3.75/23 mg daily 5.1a dizziness, need assistance with uncontrolled
Schedule IV stabilizer Placebo 1.6 dysgeusia, appetite suppression hypertension,
controlled 3.75/23–15/92 mg CONQUER22 15/92 mg daily 9.8a insomnia, active or unstable
substance daily (dose 56 wk 7.5/46 mg daily 7.8a constipation, coronary disease,
titration) Placebo 1.2 dry mouth hyperthyroidism,
Capsule SEQUEL23 15/92 mg daily 10.5a glaucoma, anxiety,
108 wk 7.5/46 mg daily 9.3a insomnia, or patients
(52-wk Placebo 1.8 (wk 0–108) who are generally
extension of sensitive to
CONQUER stimulants; patients
trial) with a history of drug
abuse or recent
MAOI use; patients
with a history of
nephrolithiasis;
patients who are
pregnant or trying to
conceive
Lorcaserin25 Serotonin (5HT-2C) BLOOM27 10 mg BID 5.8a Headache, Patients who would Patients on other
Schedule IV receptor agonist 52 wk Placebo 2.2 dizziness, benefit from appetite serotonin-modulating
controlled 10 mg BID or BLOSSOM29 10 mg BID 5.8a fatigue, nausea, suppression medications and
substance 20 mg XR daily 52 wk 10 mg daily 4.7a dry mouth, patients with known
Tablet Placebo 2.8 constipation cardiac valvular
BLOOM-DM28 10 mg BID 4.5a disease; patients who
52 wk 10 mg daily 5.0a are pregnant
Placebo 1.5
Naltrexone/ Opioid receptor COR-I32 16/180 mg BID 6.1a Nausea, vomiting, Patients who describe Patients with
bupropion SR43 antagonist/ 56 wk 8/180 mg BID 5.0a constipation, cravings for food and/ uncontrolled
dopamine and Placebo 1.3 headache, or addictive behaviors hypertension,
norepinephrine COR-II33 16/180 mg BID 6.4a dizziness, related to food; uncontrolled pain,
reuptake 56 wk Placebo 1.2 insomnia, dry patients who are recent MAOI use,
inhibitor COR-BMOD34 16/180 mg BID 9.3a mouth trying to quit history of seizures, or
8/90 mg daily to 56 wk Placebo 5.1 smoking, reduce any condition that
16/180 mg BID COR-Diabetes35 16/180 mg BID 5.0a alcohol intake, and/or predisposes to
Tablet 56 wk Placebo 1.8 have concomitant seizure, such as
depression anorexia/bulimia
nervosa, abrupt
discontinuation of
alcohol,
benzodiazepines,
barbiturates, or
antiepileptic drugs;
patients who are

Obesity Pharmacotherapy
pregnant

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139
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Saunders et al
Table 1
(continued )
Mechanism,
Dosage, and Consider This
Available Trial and Weight Loss Most Common Medication in These Avoid This Medication
Medication Formulations Duration Trial Arms (%) Adverse Events Patients in These Patients
Liraglutide GLP-1 receptor SCALE Obesity 3.0 mg daily 8.0a Nausea, vomiting, Patients who report Patients with a history
3.0 mg44 agonist and Placebo 2.6 diarrhea, inadequate meal of pancreatitis,
0.6–3.0 mg daily Prediabetes38 constipation, satiety and/or have personal/family
Prefilled pen for 56 wk dyspepsia, type 2 diabetes, history of MTC or
subcutaneous SCALE Diabetes37 3.0 mg daily 6.0a abdominal pain prediabetes, or MEN2; patients with
injection 56 wk 1.8 mg daily 4.7a impaired glucose an aversion to
Placebo 2.0 tolerance; patients needles; patients
SCALE 3.0 mg daily 6.2a requiring use of who are pregnant
Maintenance39 Placebo 0.2 concomitant
56 wk (after psychiatric
initial 5% medications
weight loss
with LCD)

Abbreviations: BID, twice daily; 5HT, 5-hydroxytryptamine; GI, gastrointestinal; GLP-1, glucagonlike peptide-1; LCD, low-calorie diet; MAOI, monoamine oxidase inhib-
itor; MEN2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; TID, 3 times daily; XR, extended release.
a
P <.001 versus placebo.
Adapted from Igel LI, Kumar RB, Saunders KH, et al. Practical use of pharmacotherapy for obesity. Gastroenterology 2017;152(7):1765–79; and Saunders KH, Kumar RB,
Igel LI, et al. Pharmacologic approaches to weight management: recent gains and shortfalls in combating obesity. Curr Atheroscler Rep 2016;18(7):36; with permission.
 Obesity Pharmacotherapy 141

and 20.8% lost at least 10% of initial body weight, whereas 15.5% and 6.8% of sub-
jects assigned to placebo achieved at least 5% and 10% weight loss, respectively.
Interestingly, there seems to be no advantage of continuous compared with inter-
mittent phentermine treatment, at least on a short-term basis. A 36-week, double-
blind, placebo-controlled trial compared continuous phentermine, continuous
placebo, and alternating phentermine/placebo every 4 weeks.12 The mean weight
loss was 12.2 kg and 13.0 kg in patients who received phentermine continuously
and intermittently, respectively, compared with 4.8-kg weight loss in the placebo
group. The weight loss in this study was higher than expected, as data were presented
for completers only.
The most common treatment-emergent adverse events (TEAEs) include headache,
dry mouth, insomnia, dizziness, irritability, nausea/vomiting, diarrhea, and constipa-
tion. Phentermine should not be prescribed in combination with other sympathomi-
metic amines or with monoamine oxidase inhibitors (MAOIs). Contraindications
include pregnancy/nursing, history of cardiovascular disease or drug abuse, hyperthy-
roidism, glaucoma, and agitated states.

ORLISTAT

Before 2012, the only antiobesity medicine approved for long-term use was orlistat,
which was approved by the FDA in 1999. Orlistat is indicated for obesity management
including weight loss and weight maintenance when used in conjunction with a
reduced-calorie diet. It is also indicated to reduce the risk of weight regain after prior
weight loss.
Orlistat promotes weight loss by inhibiting pancreatic and gastric lipases, thereby
decreasing the absorption of fat from the gastrointestinal tract. On average, 120 mg
of orlistat taken 3 times per day with meals decreases fat absorption by 30%.13
The recommended dosage of orlistat is one 120-mg capsule or one 60-mg capsule
3 times per day with each meal containing fat.14,15 The medication can be taken during
a meal or up to 1 hour after food consumption. Patients on orlistat should be advised
to follow a nutritionally balanced, reduced-calorie diet with approximately 30% of cal-
ories from fat. The daily intake of fat, carbohydrate, and protein should be distributed
over 3 meals. Patients should take a multivitamin (separately from the medication)
while on orlistat, as it can decrease the absorption of fat-soluble vitamins (A, D, E, K).
In a double-blind prospective study that randomized 3305 patients with a BMI of
30 kg/m2 or greater to lifestyle changes with either orlistat 120 mg or placebo 3 times
daily, the mean weight loss was significantly greater with orlistat (5.8 kg) than with pla-
cebo (3.0 kg) after 4 years.16 Fifty-three percent of the patients assigned to orlistat
lost 5% or greater of their initial body weight, and 26.2% lost 10% or greater of their
initial body weight.
In addition to promoting weight loss, orlistat lowers serum glucose levels and im-
proves insulin sensitivity. The cumulative incidence of diabetes in the XENical in the
Prevention of Diabetes in Obese Subjects (XENDOS) trial was 6.2% with orlistat and
9.0% with placebo, which corresponds to a risk reduction of 37.3%. Orlistat has
also been found to improve blood pressure, total cholesterol, and low-density lipopro-
tein cholesterol.17
Orlistat is not commonly used for obesity management because of the side effects
of fecal urgency, oily stool, and fecal incontinence; but it may have a role as an addi-
tional medicine for patients who are constipated on other antiobesity pharmaco-
therapy. A slow dose titration or the addition of a psyllium fiber supplement can
reduce side effects.
142 Saunders et al

Orlistat should not be used in patients who are pregnant or who have chronic
malabsorption syndromes or cholestasis. Orlistat can decrease the absorption of
medications, such as cyclosporine, levothyroxine, warfarin, amiodarone, antiepileptic
agents, and antiretroviral drugs.

PHENTERMINE/TOPIRAMATE EXTENDED RELEASE

In 2012, the FDA approved phentermine/topiramate ER for chronic weight manage-

ment as an adjunct to a reduced-calorie diet and increased physical activity. The ratio-
nale for a combination medication is that appetite regulation involves multiple
pathways, so targeting different mechanisms simultaneously can have an additive
effect on body weight. Another benefit is that the smaller dose of each medication
reduces the risk of TEAEs.
Topiramate was approved for epilepsy in 1996 and migraine prophylaxis in 2004.
The medication’s effect on caloric intake is thought to be mediated through modula-
tion of gamma-aminobutyric acid receptors, inhibition of carbonic anhydrase, and
antagonism of glutamate.18
Phentermine/topiramate ER is available in 4 doses (3.75/23 mg, 7.5/46 mg, 11.25/
69 mg, and 15.0/92 mg), which are lower than the maximum doses of the individual
agents.19 The medication should be taken once daily in the morning with or without
food. After 14 days of 3.75/23 mg daily, patients can progress to 7.5/46 mg daily.
Phentermine/topiramate ER should be discontinued or the dose should be escalated
if 3% weight loss is not achieved after 12 weeks. For escalation, a titration dose of
11.25/69 mg is taken daily for 2 weeks and then increased to 15/92 mg daily for main-
tenance. The medication should also be discontinued if 5% weight loss is not
achieved after 12 additional weeks on 15/92 mg daily.
Phentermine/topiramate ER is a schedule IV controlled substance. The FDA re-
quires a Risk Evaluation and Mitigation Strategy to inform prescribers and women
of reproductive potential about the possible increased risk of orofacial clefts in
infants exposed to phentermine/topiramate ER during the first trimester of
pregnancy.20
Two randomized, double-blind, placebo-controlled trials, EQUIP and CONQUER,
evaluated the efficacy of phentermine/topiramate ER over 56 weeks.21,22 The
CONQUER trial randomized 2487 patients with a BMI of 27 to 45 kg/m2 and 2 or
more comorbidities (hypertension, dyslipidemia, diabetes or prediabetes, or abdom-
inal obesity) to phentermine/topiramate ER 15/92 mg, phentermine/topiramate ER
7.5/46 mg, or placebo. Compared with placebo, both doses resulted in significantly
greater weight loss (9.8 kg with 15/92 mg, 7.8 kg with 7.5/46 mg, and 1.2 kg with pla-
cebo). Seventy percent of patients achieved at least 5% weight loss with 15/92 mg
compared with 62% with 7.5/46 mg and 21% with placebo.
The SEQUEL trial evaluated ongoing weight loss with phentermine/topiramate ER
for 52 weeks after completion of the CONQUER study.23 The mean percentage reduc-
tion in body weight was found to be significantly greater in the treatment groups
compared with placebo (10.5%, 9.3%, and 1.8% with 15/92 mg, 7.5/46 mg, and
placebo, respectively). The study also reported a 76% reduction in the progression
to diabetes in subjects receiving 15/92 mg and a 54% reduction in subjects receiving
7.5/46 mg compared with placebo.
The most common TEAEs with phentermine/topiramate ER include paresthesias,
dizziness, dysgeusia, insomnia, constipation, and dry mouth. Contraindications
include pregnancy (a pregnancy test is recommended before starting followed by
monthly tests in appropriate patients), glaucoma, hyperthyroidism, and MAOI use.
 Obesity Pharmacotherapy 143

LORCASERIN

Lorcaserin, a selective serotonin (5-hydroxytryptamine [5HT])-2C receptor agonist,

was approved by the FDA in 2012 as a long-term treatment of obesity. Lorcaserin
reduces appetite and increases satiety by binding to the 5HT-2C receptors on
anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus. Because
of its selective agonism of the serotonin 2C receptor, lorcaserin was designed to
avoid cardiac valvular effects mediated through the 5HT-2B receptor. The develop-
ment program has not observed an increased incidence of valvulopathy over
2 years, and long-term data are being collected in a 5-year cardiovascular outcome
study.24
The recommended dosage of lorcaserin is 10 mg twice daily with or without food.25
There is also a new 20-mg extended release tablet, which can be taken once daily.26
The medication should be discontinued if 5% or less weight loss is achieved after
12 weeks. Lorcaserin is a schedule IV controlled substance.
The phase III double-blind placebo-controlled Behavioral Modification and Lorca-
serin for Overweight and Obesity Management (BLOOM) trial included 3182 adults
who were overweight or obese and received lorcaserin 10 mg twice daily or placebo
for 52 weeks, in conjunction with diet and exercise.27 At week 52, all subjects treated
with lorcaserin were rerandomized to either placebo or lorcaserin for an additional
year. At 1 year, the average placebo-subtracted weight loss was 3.6%, and 47% of
the subjects taking lorcaserin lost at least 5.0% as compared with 20.5% in the control
group. Subjects who showed a weight loss of at least 5% in year 1 and were main-
tained on lorcaserin treatment in year 2 were able to maintain their weight loss better
than those who had been switched to placebo.
The Behavioral Modification and Lorcaserin for Obesity and Overweight Manage-
ment in Diabetes Mellitus (BLOOM-DM) study was conducted in subjects with obesity
and type 2 diabetes.28 At 52 weeks, 37.5% of patients treated with lorcaserin 10 mg
twice daily showed a weight loss of at least 5%, which was more than twice the per-
centage in the placebo group. There was a reduction of hemoglobin A1c (HbA1c) of
0.9% in those on lorcaserin as compared with a 0.4% reduction in the placebo group.
The most common TEAEs include headache, dizziness, fatigue, nausea, dry mouth,
and constipation.27–29 There is a theoretic interaction with other serotonergic drugs, as
coadministration may lead to the development of serotonin syndrome or neuroleptic
malignant syndromelike reactions.

NALTREXONE SUSTAINED RELEASE/BUPROPION

Naltrexone/bupropion was approved for the treatment of obesity in 2014. Bupropion is

a dopamine and norepinephrine reuptake inhibitor that was FDA approved as an an-
tidepressant in 1989 and as a smoking cessation aide in 1997. Naltrexone is an opioid
antagonist that was FDA approved for the treatment of opioid dependence in 1984
and alcohol use disorder in 1994.
Together, naltrexone/bupropion has effects in 2 separate areas of the brain involved
in the regulation of food intake. One region is the arcuate nucleus of the hypothalamus,
which is integral to appetite regulation. The second region is the mesolimbic dopamine
reward circuit. By increasing the firing rate of hypothalamic POMC neurons while
simultaneously modulating the dopamine reward circuit, both appetite and food crav-
ings are reduced.30,31
Each tablet of naltrexone/bupropion contains 8 mg of ER naltrexone and 90 mg of
ER bupropion. The initial prescription should be for one tablet daily in the morning with
instructions to increase by one tablet weekly to a therapeutic dosage of 2 tablets twice
144 Saunders et al

daily (32/360 mg). The medication should be discontinued if patients have achieved
5% or less weight loss at 16 weeks (after 12 weeks at the maintenance dose).
Four 56-week randomized double-blind placebo-controlled trials (COR-I, COR-II,
Contrave Obesity Research Behavior Modification [COR-BMOD], and COR-Dia-
betes) were conducted to evaluate the effect of naltrexone/bupropion plus lifestyle
modification in 4536 patients with overweight or obesity.32–35 The COR-I, COR-II,
and COR-BMOD trials enrolled patients with a BMI of 30 kg/m2 or greater or a
BMI of 27 kg/m2 or greater and at least one weight-related comorbidity. The COR-
Diabetes trial enrolled patients with a BMI of 27 kg/m2 or greater with type 2 diabetes
with or without hypertension and/or dyslipidemia.
In the COR-I trial, the mean weight loss of 6.1% was observed in patients receiving
naltrexone/bupropion 360/32 mg compared with 1.3% in patients receiving placebo;
48% of naltrexone/bupropion patients lost greater than 5% body weight from baseline
as compared with 16% of placebo patients. In the COR-Diabetes trial, 44.5% of pa-
tients receiving naltrexone/bupropion lost 5% or greater of their body weight after
56 weeks compared with 18.9% of patients receiving placebo. Patients receiving
naltrexone/bupropion demonstrated a 0.6% reduction in HbA1c from baseline
compared with a 0.1% reduction in patients receiving placebo.
The most common side effects of naltrexone/bupropion include nausea/vomiting,
constipation, headache, dizziness, insomnia, and dry mouth. Administration of
naltrexone/bupropion with high-fat meals should be avoided, as this significantly in-
creases the systemic levels of both bupropion and naltrexone. Naltrexone/bupropion
is contraindicated in patients taking MAOIs or chronic opioids and in patients with un-
controlled hypertension, history of seizures, or conditions that predispose to seizure,
such as anorexia or bulimia nervosa, or abrupt discontinuation of alcohol, benzodiaz-
epines, barbiturates, or antiepileptic drugs. Bupropion carries a black box warning (as
do all antidepressants) related to a potential increase in suicidality in patients younger
than 24 years during the early phase of treatment, so patients should be monitored
closely for mood changes when initiating naltrexone/bupropion.

LIRAGLUTIDE 3.0 MG

Liraglutide 3.0 mg was the second agent approved by the FDA in 2014 for chronic
weight management. Liraglutide mimics the gastrointestinal incretin hormone, gluca-
gonlike peptide-1, which is released in response to food intake. It is also FDA
approved for the treatment of type 2 diabetes in doses up to 1.8 mg. Among patients
with obesity and without diabetes, liraglutide 3.0 mg daily was found to reduce hunger,
decrease food intake, and delay gastric emptying.36
Liraglutide is administered as a subcutaneous injection once daily. The starting
dosage is 0.6 mg daily for 1 week with instructions to increase by 0.6 mg weekly to
a therapeutic dosage of 3.0 mg daily. Slower dose titration can reduce gastrointestinal
side effects. The medication should be discontinued if patients have not achieved at
least 4% weight loss at 16 weeks.
Two phase III trials, SCALE Diabetes and SCALE Obesity and Prediabetes, evalu-
ated the effect of liraglutide 3.0 mg on subjects who were overweight or obese with
and without diabetes, respectively.37,38 Both 56-week, randomized, placebo-
controlled, double-blind trials illustrated significantly greater mean weight loss than
placebo. In SCALE Diabetes, the mean weight loss was 6.0% with 3.0 mg daily,
4.7% with 1.8 mg daily, and 2.0% with placebo. In SCALE Obesity and Prediabetes,
participants assigned to 3.0 mg daily lost a mean of 8.0% body weight compared with
2.6% in the placebo group.
 Obesity Pharmacotherapy 145

The efficacy of liraglutide for weight maintenance was investigated in the SCALE
Maintenance study.39 Four hundred twenty-two subjects who were overweight or
obese and had lost at least 5% of their initial body weight on a low-calorie diet
were randomly assigned to liraglutide 3.0 mg daily or placebo for 56 weeks. The
mean weight loss on the initial diet was 6.0%. By the end of the study, participants
in the liraglutide group lost an additional 6.2% compared with 0.2% with placebo.
The most common TEAEs include nausea, vomiting, diarrhea, constipation,
dyspepsia, and abdominal pain. Liraglutide is contraindicated in patients who are
pregnant or those with personal or family history of medullary thyroid carcinoma or
multiple endocrine neoplasia syndrome type 2. Thyroid C-cell tumors were found in
rodents given supratherapeutic doses of liraglutide; however, there is no evidence
of liraglutide causing C-cell tumors in humans. Concomitant use of liraglutide with in-
sulin or insulin secretagogues can increase the risk of hypoglycemia.

PRACTICAL TIPS FOR TREATMENT

Since 2012, 4 new antiobesity medications have been approved. When patients are
unable to lose and maintain weight loss with lifestyle interventions alone, providers
should consider the use of pharmacotherapy to counteract metabolic adaptation
and improve adherence to diet and exercise.1,6
There are 2 important questions to ask when prescribing an antiobesity medication
to patients. The first question is whether there are undesirable side effects, contrain-
dications, or drug-drug interactions. For example, avoid orlistat if patients have a con-
dition predisposing to malabsorption and avoid phentermine and phentermine/
topiramate ER if patients have unstable coronary disease.
The second question is whether any of the medications could improve another
symptom or condition. For example, consider phentermine/topiramate ER if patients
have migraines or naltrexone SR/bupropion SR if patients also would like assistance
with smoking cessation. Table 1 provides examples of ideal and poor candidates for
each medication.
Pharmacotherapy should not be prescribed in the absence of behavioral counseling
focusing on diet, physical activity, and lifestyle modifications, which are the corner-
stones of weight management. Patients should be monitored at least monthly for
the first 3 months of treatment and then at least once every 3 months.6 Efficacy and
safety should be assessed and behavioral interventions should be reinforced at
each visit.
If a medication is determined to be ineffective or if there are safety or tolerability con-
cerns at any time, the medication should be discontinued and alternative medications
or treatment approaches should be pursued.6 Another agent with a different mecha-
nism of action can be considered.
Obesity pharmacotherapy is intended for long-term use, as obesity is a chronic dis-
ease. Continued use of medication promotes sustained weight maintenance by offset-
ting increased appetite and reduced energy expenditure secondary to the metabolic
adaptation that occurs with weight loss. Once a desired weight has been achieved,
reducing the dose or frequency of medication is a possible strategy that requires
further study.

FUTURE CONSIDERATIONS

Many patients require more than one medication to achieve clinically significant weight
loss. By targeting multiple pathways simultaneously, combination therapy can have an
additive or synergistic effect on body weight. In addition to phentermine/topiramate ER
146 Saunders et al

and naltrexone SR/bupropion SR, other combinations are under investigation,

including phentermine/lorcaserin and phentermine/canagliflozin.40,41 Instead of initi-
ating 2 medications simultaneously, an alternative strategy is a stepwise approach in
which an additional agent is added when patients reach a weight plateau.
Pharmacotherapy can be combined with bariatric surgery, both before and after the
procedure. As weight regain after bariatric surgery is common, the addition of an an-
tiobesity medication can be an effective tool to counteract recidivism and enhance
weight maintenance.42 Although data are limited, the optimal time to initiate antiobe-
sity pharmacotherapy seems to be when patients reach a nadir weight instead of after
weight regain has occurred. Finally, the combination of antiobesity pharmacotherapy
with endoscopic procedures and devices is another area that requires further
investigation.

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