EJINME-02855; No of Pages 6

European Journal of Internal Medicine xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Drug treatment of obesity: Current status and future prospects

Ashish Kumar Kakkar a,⁎, Neha Dahiya b
a
Dept. of Pharmacology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
b
Dept. of Community Medicine, Lady Hardinge Medical College, New Delhi, India

a r t i c l e i n f o a b s t r a c t

Article history: Obesity is a growing epidemic and a major contributor to the global burden of disease. Obesity strains the
Received 15 December 2014 healthcare systems and has profound economic and psychosocial consequences. Historically, pharmacotherapy
Received in revised form 14 January 2015 for obesity has witnessed the rise and fall of several promising drug candidates that had to be eventually
Accepted 19 January 2015
withdrawn due to unacceptable safety concerns. Currently four drugs are approved for chronic weight
Available online xxxx
management in obese adults: orlistat, lorcaserin, phentermine/topiramate extended release and naltrexone/
Keywords:
bupropion extended release. While lorcaserin and phentermine/topiramate were approved by US Food and
Obesity Drug Administration (FDA) in 2012, after a gap of 13 years following the licensing of orlistat, naltrexone/
Antiobesity agents bupropion has been recently approved in 2014. This review provides a brief overview of these current
Orlistat therapeutic interventions available for management of obesity along with the evidence of their safety and
Lorcaserin efficacy. Additionally, several novel monotherapies as well as combination products are undergoing evaluation
Phentermine/topiramate extended-release in various stages of clinical development. These therapies if proven successful will strengthen the existing
Naltrexone/bupropion extended release armamentarium of antiobesity drugs and will be critical to combat the global public health crisis of obesity and
its associated co-morbidities.
© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Globally, overweight and obesity, most often defined on the basis of
body mass index (BMI) measurements, are the fifth most common risk
factors for death. As per World Health Organization (WHO) estimates,
in 2008, more than 1.4 billion adults aged 20 and older, were
overweight and among them, over 500 million were obese [1]. Recent
prevalence data estimate that more than one-third of adults and 17%
of youth (aged 2–19 years) in the United States are obese [2]. In the
UK, between 1993 and 2011, the proportion of individuals that were
overweight including obese increased from 58% to 65% in men and
from 49% to 58% in women. Among them in 2011, nearly 24% men
and 26% women were estimated to be obese [3]. This prevalence of
obesity has been predicted to increase by 2050 to 60% of adult men,
50% of adult women and 25% of children under 16 years of age [4].
The epidemic of obesity is not limited to the developed countries but
has been documented as a global phenomenon, with the proportion of
obese populations rising in most countries. According to a recent report,
between 1980 and 2008, the number of overweight and obese adults in
developing countries has more than tripled to reach a figure in excess of
900 million adults [5].
⁎ Corresponding author at: Dept. of Pharmacology, Vardhman Mahavir Medical
College and Safdarjung Hospital, New Delhi 110029, India. Tel.: + 91 9868051003.
E-mail addresses: drashishkakkar@gmail.com (A.K. Kakkar), drnehadahiya@gmail.com
(N. Dahiya).
The fundamental drivers of obesity epidemic are the global trade
liberalization, rapid urbanization and economic growth. A dramatic
reduction in the demand for physical activity and global nutritional
transitions have created obesogenic environments. The latter are
primarily driven by large scale decrease in food prices and increase in
consumption of animal products, refined grains and added sugar
resulting in an overall positive energy balance [6]. The chief co-
morbidities associated with obesity include type II diabetes mellitus,
cardiovascular diseases including myocardial infarction, stroke,
hypertension, dyslipidemia, asthma, sleep apnoea, gall bladder disease,
osteoarthritis, chronic neck pain and certain types of cancer [7].
Management of obesity encompasses comprehensive lifestyle
modifications including dietary changes, physical activity and
behaviour modification, pharmacologic therapy and bariatric surgery.
Lifestyle modifications often require multidisciplinary teams to ensure
necessary changes are made as well as maintained but are often
associated with high relapse rates [8]. Bariatric surgery is associated
with risks of peri-operative mortality and operative complications and
is consequently reserved for clinically severe obesity [9]. The surgical
procedures are expensive and operated individuals require lifelong
medical monitoring. Given the current limitations of lifestyle modifica-
tion interventions and bariatric surgery, use of pharmacotherapeutic
agents in management of obesity is critical. Several antiobesity agents
have been approved in the past and were touted as ‘magic pills’ for
addressing the obesity epidemic. However, many of them were
subsequently found to have unacceptable risks leading to their
restricted use/withdrawal from the market (Table 1) [10–13].

http://dx.doi.org/10.1016/j.ejim.2015.01.005
0953-6205/© 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Kakkar AK, Dahiya N, Drug treatment of obesity: Current status and future prospects, Eur J Intern Med (2015),
http://dx.doi.org/10.1016/j.ejim.2015.01.005
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Table 1
Antiobesity drugs with serious safety concerns leading to withdrawal/restricted use [10–13].

Antiobesity drugs Mechanism of action Regulatory status

Dinitrophenol Uncoupling of mitochondrial oxidative phosphorylation resulting Withdrawn due to risk of cataracts, neuropathy, renal failure,
in increased fat metabolism agranulocytosis and hyperthermia related deaths.
Amphetamines: dexamphetamine, Indirectly acting sympathomimetics; release NA from presynaptic Withdrawn/restricted use due to dependency, abuse
methamphetamine vesicles in the lateral hypothalamus; appetite reduction potential, cardiovascular side effects.
Amphetamine analogues: phentermine, Indirectly acting sympathomimetics; release NA from presynaptic Diethylpropion and phentermine available for short-term use.
phenylpropanolamine, diethylpropion vesicles in the lateral hypothalamus; appetite reduction Phenylpropanolamine withdrawn due to intracranial bleeds
and stroke.
Aminorex Releases norepinephrine; appetite reduction Withdrawn due to pulmonary hypertension.
Mazindol Blocks NA reuptake by presynaptic neurons; appetite reduction Withdrawn due to valvular abnormalities.
Fenfluramine and dexfenfluramine Stimulate the release and inhibit the reuptake of serotonin; Withdrawn due to valvular abnormalities and pulmonary
appetite reduction hypertension.
Sibutramine Blocks the reuptake of serotonin and NA; appetite reduction Withdrawn due to increased cardiovascular events.
Rimonabant Selective cannabinoid receptor subtype 1 (CB1) Withdrawn due to increased risk of psychiatric adverse events
antagonist/inverse agonist; appetite suppression including anxiety, depression and suicidal ideation.

Among the currently approved antiobesity agents for chronic weight
management, orlistat was approved in 1999 and subsequently after a
long gap of more than a decade, two new therapies, lorcaserin and
phentermine/topiramate were approved in 2012. In 2014, FDA finally
approved the combination of bupropion/naltrexone as a treatment
option for the management of obesity.
2. Current pharmacotherapeutic options for the management
of obesity
2.1. Orlistat
Orlistat, a synthetic hydrogenated derivative of a endogenous lipase
inhibitor — lipstatin, is a potent, long acting reversible inhibitor of
pancreatic and gastric lipases, which are required for the hydrolysis of
dietary fat into free fatty acids and monoacylglycerols. Thus its principal
mechanism involves interference with lipase catalysed breakdown and
subsequent systemic absorption of about 30% of dietary ingested fats.
Orlistat was approved by FDA for prescription sale in 1999 and over
the counter sale in 2007 and remains the only approved therapy in
Europe for long-term management of obesity. While orlistat 120 mg
formulation is available on prescription only, a dose of 60 mg is ap-
proved for over-the-counter sales.
A meta-analysis of 16 double blind, placebo controlled, random-
ized controlled trials (RCTs) involving 10,631 patients, where
orlistat therapy was used in conjunction with a weight loss diet
for a period of 1 to 4 years, found 2.9 kg (95% CI: 2.5 to 3.2 kg) or
2.9% (95% CI: 2.5 to 3.4%) greater weight loss in the orlistat group
as compared to placebo.
Pooled analysis further demonstrated that 21% more orlistat
recipients (95% CI: 18% to 24%) achieved 5% weight loss and 12% more
participants (95% CI: 9% to 14%) in the active treatment group achieved
10% weight loss. Orlistat treated patients also demonstrated significantly
greater reduction in waist circumference (2.1 cm, 95% CI: 1.3 to 2.9 cm)
as well as BMI (1.1 kg/m2, 95% CI: 0.7 to 1.4 kg/m2). However, long-term
treatment resulted in similar amounts of weight regain between orlistat
and placebo treated patients but the initially observed weight differen-
tials were preserved [14].
In 2003, orlistat was approved for the management of obesity in
adolescent age group. The largest study of orlistat in adolescents was a
54 week multicentre, placebo controlled trial that enrolled 539 obese
participants aged 12–16 years. The study subjects also underwent
dietary modifications, exercise and behavioural therapy. At the end of
study period, body mass index decreased by 0.55 kg/m2 in orlistat
treatment group and increased by 0.31 kg/m2 in those receiving placebo
(p = 0.001). Also a greater proportion of adolescents treated with
orlistat had a 5% or higher (26.5% vs. 15.7%, p = 0.005) and 10% or
higher decrease in BMI (13.3% vs. 4.5%, p = .002) [15]. A recent
systematic review of clinical efficacy of orlistat in achieving weight
loss in obese adolescents concluded orlistat in combination with a
hypocaloric diet plus lifestyle modifications resulted in a short-term
weight loss greater than that achieved by diet and behavioural therapy
alone [16].
As evident from its mechanism of action, the principal adverse
effects of orlistat include faecal incontinence, flatus with discharge,
oily faecal spotting, faecal urgency, oily evacuation, and soft stools
[17]. Pooled analysis of orlistat studies revealed that nearly 5% of
orlistat-treated patients discontinued therapy due to GI adverse effects,
which was 2% greater than patients in the placebo group. Also levels of
vitamins A, D, E and beta carotene were lowered with orlistat treatment
with the greatest effects on vitamin D levels [14]. Patients on orlistat are
routinely advised supplementation with a multivitamin pill containing
fat soluble vitamins. In 2010, FDA approved a revised label for orlistat
to include new information about cases of severe liver injury with
hepatocellular necrosis or acute hepatic failure that have been reported
with the use of orlistat. This labelling revision was based on FDA's
review of 13 postmarketing cases of severe liver injury involving the
use of orlistat [18]. Orlistat is also known to interfere with absorption
of several drugs resulting in their sub-therapeutic levels and diminished
clinical effectiveness. The most prominent examples include fat soluble
vitamins, warfarin, amiodarone, ciclosporin, lamotrigine, valproic acid,
vigabatrin, gabapentin and thyroxine [19].
2.2. Lorcaserin
Lorcaserin is indicated as an adjunctive therapy to a reduced calorie
diet and exercise in the long-term weight management of adults who
are either obese or are overweight and have at least one concomitant
weight related condition, for e.g. dyslipidaemia, hypertension, and
type 2 diabetes. Lorcaserin is a highly selective and potent 5-HT2C
agonist with ~ 15 fold and ~100 fold higher affinities for the serotonin
2C receptors vs. 5-HT2A and 5-HT2B receptors respectively [20]. Role of
serotonin in energy homeostasis is well known and clinically
exemplified by the efficacy of weight loss agents fenfluramine and
sibutramine both of which increased the synaptic availability of
serotonin. Lorcaserin differs from the previous non-selective serotonin
agonists in that it exerts minimal activity on 5-HT2A and 5-HT2B
receptors, which mediate hallucinations and cardiovascular side effects
including valvulopathy and pulmonary hypertension respectively [20].
This selectivity underlies the potential promise of lorcaserin in retaining
the antiobesity efficacy minus the safety concerns that plagued and led
to the withdrawal of earlier serotonergic drugs.
Safety and efficacy of lorcaserin has been assessed in three random-
ized, double blind placebo controlled Phase III clinical trials having
acronyms: BLOOM, BLOSSOM and BLOOM-DM (Table 2) (21–23).
Most common adverse events reported in lorcaserin treated patients in-
clude headache (16.8%), upper respiratory tract infections (13.7%),
nasopharyngitis (13%), dizziness (8.5%), nausea (8.3%), fatigue (7.2%),

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diarrhoea (6.5%), urinary tract infection (6.5%), back pain (6.3%), consti-

Reference
pation (5.8%) and dry mouth (5.3%) [24]. It is pertinent to note that

[21]

[22]

[23]
lorcaserin is not approved for use in Europe. The sponsor was forced
to withdraw lorcaserin's marketing authorization application following

more frequent in the lorcaserin groups than

dizziness. Valvulopathy was documented in
2% of patients each in the lorcaserin BD and

infection. Symptomatic hypoglycaemia was

were headache, back pain, nasopharyngitis,
EMA's concern regarding carcinogenicity based on laboratory data, psy-

nausea, fatigue, dizziness and urinary tract

the rates of cardiac valvulopathy were not

Most commonly seen adverse events with

were headache, dizziness and nausea and
Most commonly reported adverse events

Most frequently reported adverse events

chiatric disorders and valvulopathy reported during clinical trials [25].

lorcaserin were. headache, nausea, and

increased with the use of lorcaserin
2.3. Phentermine/topiramate extended-release formulation

Combination of phentermine and topiramate extended-release was

approved by FDA in July 2012. Phentermine, chemically related to

in the placebo group

amphetamines, is an anorexiant drug approved for short-term treat-
placebo groups
ment (≤12 weeks) of obesity. It exerts its therapeutic effects primarily
by increasing the adrenergic tone that reduces food intake as well as
increases resting energy expenditure [26,27]. Topiramate has been ap-
Safety

proved since 1996 for the treatment of seizure disorders and later on
in 2004, for migraine prophylaxis. The exact mechanism by which
patients and 20.3% placebo recipients had lost ≥5% of

Lorcaserin QD: 801 groups respectively lost ≥5% of baseline body weight
67.9% patients who continued lorcaserin maintained

(50.4%) and lorcaserin QD group (52.2%) achieved

QD patients lost ≥5% body weight as compared to
Lorcaserin BD: 256 16.1% with placebo (p b 0.001). Weight loss ≥10%
37.5% lorcaserin BD patients and 44.7% lorcaserin
their body weight (p b 0.001). At the end of year 2,

topiramate effects weight loss is unclear, but it induces appetite

their weight loss compared with 50.3% of placebo

as compared to 25% in placebo group (p b 0.001).

47.2% and 40.2% patients in lorcaserin BD and QD

placebo group (p b 0.001). Significantly greater

was achieved in 16.3% (BD) and 18.1% (QD) of
At the end of 1 year, 47.5% of lorcaserin treated

suppression and satiety via a combination of neurotransmitter

proportion of patients in lorcaserin BD group
Weight loss ≥10% was seen in 22.6% (BD) and

HbA1c ≤7% as compared to placebo (26.3%).

lorcaserin recipients and 4.4% of those in the
17.4%(QD) of lorcaserin recipients and 9.7% of

gamma-aminobutyric acid (GABA) mediated inhibitory activity,

modulation of voltage-gated calcium and sodium channels, inhibition
of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate
participants in the placebo group.

glutamate receptors, and inhibition of carbonic anhydrase leading to

receiving patients (p b 0.001)

taste alterations [28,29].

Efficacy and safety of phentermine/topiramate (PHEN/TPM)
extended release combination is supported by three Phase III trials
namely CONQUER, EQUIP, and SEQUEL studies. All these studies were
randomized, double blind placebo controlled trials comprising of three
study groups: low dose PHEN/TPM, high dose PHEN/TPM and placebo.
Efficacy

The 56-week EQUIP study randomized 1267 obese patients to receive

either low-dose (3.75/23 mg), or high-dose (15/92 mg) PHEN/TPM or
placebo in conjunction with a reduced energy diet. Patients in the
Lorcaserin QD: 95
Lorcaserin: 1587

three study groups lost 5.1%, 10.9% and 1.6% of baseline body weight re-
Lorcaserin BD:
Placebo: 1595

Placebo: 1601

spectively (p b 0.0001). At 56 weeks, significantly greater proportion of

Placebo: 253

patients on phentermine/topiramate ER achieved ≥ 5% weight loss as

patients
No. of

compared to placebo: 66.7% on high dose, 44.9% on the low dose and
1602

17.3% for placebo respectively (p b 0.0001). The most frequently report-

ed adverse events occurring more often with PHEN/TPM (15/92 mg)
were treated with metformin, a sulfonylurea or
patients were randomly assigned in a 1:1 ratio.

continue with lorcaserin or to placebo group.

treatment than placebo were paresthesias (18.8%), dry mouth (17%),

Placebo, lorcaserin 10 mg once daily (QD) or
randomly reassigned, in a 2:1 ratio, to either
For year 2, patients in lorcaserin group were

Lorcaserin 10 mg twice daily (BD). Patients

Placebo, lorcaserin 10 mg twice daily (BD),
Placebo, lorcaserin 10 mg/day; for year 1,

constipation (14.1%), dysgeusia (8.4%), and insomnia (7.8%) [30].

CONQUER study represents the largest trial that randomized 2487
overweight or obese adults having a BMI of 27–45 kg/m2 and ≥2 co-
lorcaserin 10 mg once daily (QD)

morbidities (hypertension, dyslipidaemia, diabetes mellitus or prediabe-

tes, or abdominal obesity) to placebo, once-daily low dose PHEN/TPM
(7.5/46 mg), or once-daily high dose PHEN/TPM (15/92 mg) in a 2:1:2
ratio. At 56 weeks, significantly more participants on phentermine/
topiramate ER achieved ≥5% and ≥10% weight loss compared to placebo:
Intervention

70% and 48% in the 15/92 mg dose group, 62% and 37% in the 7.5/46 mg
Phase III clinical studies assessing safety and efficacy of lorcaserin.

dose group, versus 21% and 7% for placebo respectively. Most common
adverse events reported in high dose PHEN/TPM group were dry
both

mouth (21%), paraesthesia (21%), constipation (17%), insomnia (10%),

dizziness (10%) and dysgeusia (10%) [31]. SEQUEL study was an exten-
Two year, multicentre,

One year, multicentre,

One year, multicentre,

double-blind, placebo

double-blind, placebo

double-blind, placebo

sion study that enrolled 676 participants who had participated in the
CONQUER trial for an additional 52 weeks (making a total of 108
controlled study

controlled study

controlled study

weeks), maintaining their original treatment assignment. At 108

randomized,

randomized,

randomized,

weeks, significantly more patients at both dose levels of PHEN/TPM dem-

Design

onstrated ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared to placebo
(p b 0.001). The active treatment was associated with an improvement of
cardiovascular and metabolic parameters and decreased rates of incident
BLOOM-DM (Behavioral
obesity management)

lorcaserin for obesity

BLOSSOM (Behavioral

diabetes as compared to placebo [32]. The adverse event rates between

BLOOM (Behavioural

diabetes mellitus)
lorcaserin second
modification and

modification and

modification and
study for obesity

week 56 and week 108 were less as compared to those between week
overweight and

management in
and overweight
management)
lorcaserin for

0 and week 56.

Due to its potential for foetal harm, phentermine/topiramate ER was
approved with a Risk Evaluation and Mitigation Strategy (REMS) that
Study
Table 2

aims to inform prescribers and female patients of reproductive age

group regarding the increased risk of congenital defects especially

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4 A.K. Kakkar, N. Dahiya / European Journal of Internal Medicine xxx (2015) xxx–xxx

Study included obese patients with uncomplicated obesity (no presence of hypertension, dyslipidemia, or type 2 diabetes mellitus) with a BMI ≥30 and ≤45 kg/m2 or obese and overweight patients with controlled hypertension and/or dys-
Reference orofacial clefts associated with first trimester exposure to drug, the im-
portance of pregnancy prevention, and the need to discontinue therapy
[44]

[45]

[46]

[47]
if pregnancy occurs [33]. Post approval requirements include a long-
term trial to assess the effects of new drug on the risk for major adverse
Most frequent adverse event in NB groups was

cardiovascular events in subjects with confirmed cardiovascular dis-

reports of nausea were recorded than placebo

Most commonly seen adverse events with NB

nausea (42.3 vs. 7.1%), constipation (17.7 vs.

NB was associated with greater incidence of
ease, safety and efficacy in obese paediatric and adolescent patients,
nausea. Headache, constipation, dizziness,

NB 32 was generally well tolerated, more

vomiting, and dry mouth were also more

were nausea, headache, and constipation

drug utilization and pregnancy exposure, study to assess renal function,
frequently seen in NB treated subjects.

as well as other animal and in vitro studies [34]. Meanwhile, European

7.1%), and vomiting (18.3 vs. 3.6%).

Medicines Agency (EMA) has rejected the marketing application for
phentermine/topiramate extended release twice on grounds of poten-
tial cardiovascular, psychiatric and cognitive effects associated with its
long-term use, teratogenicity, and its potential misuse by patients for
whom it is not intended [35].

2.4. Naltrexone/bupropion extended release

Safety

Study included obese and overweight patients with type 2 diabetes mellitus and with or without controlled hypertension and/or dyslipidemia with a BMI ≥27 and ≤45 kg/m2.
Bupropion is an aminoketone antidepressant that enhances both
patients was −5%; proportion of NB32-treated patients who
Mean weight loss from baseline to week 56 in NB32 treated

Mean weight loss from baseline to week 56 in NB32 treated

Mean weight loss from baseline to week 56 in NB32 treated

Mean weight loss from baseline to week 56 in NB32 treated

noradrenergic and dopaminergic neurotransmission via reuptake inhi-

patients was −6.1%; proportion of NB32-treated patients

patients was −6.4%; proportion of NB32-treated patients

patients was −9.3%; proportion of NB32-treated patients

achieved a clinically meaningful weight loss of ≥5% from

who achieved a clinically meaningful weight loss of ≥5%

who achieved a clinically meaningful weight loss of ≥5%

who achieved a clinically meaningful weight loss of ≥5%

bition. It is indicated for the treatment of depression, prevention of sea-

sonal depressive disorder, and for smoking cessation. Naltrexone is a
pure opioid antagonist indicated for the treatment of alcohol depen-
dence and for prevention of relapse to opioid dependence [36]. The
combination of naltrexone and bupropion has been recently approved
as an extended release formulation under the brand name, Contrave
from baseline at week 56 was 50.5%
from baseline at week 56 was 48%

from baseline at week 56 was 66%

for the treatment of obesity [37].

baseline at week 56 was 44.5%

The precise mechanisms of action of naltrexone/bupropion as an

antiobesity agent are poorly understood. Animal studies indicate
that naltrexone and bupropion have effects on two separate areas
of the brain involved in the regulation of energy balance: hypotha-
lamic melanocortin system and the mesolimbic dopamine reward
system. Bupropion has been shown to stimulate hypothalamic
proopiomelanocortin (POMC) neurons that release alpha-
Efficacy

melanocyte stimulating hormone (α-MSH) and β-endorphin. α-

MSH binds to MC3 and MC4 receptors inhibiting food intake and in-
Placebo: 581

Placebo: 495

Placebo: 202

Placebo: 170

ducing satiety, as well as increasing resting energy expenditure. On

NB32: 1001
NB16: 578
NB32: 583

NB32: 591

NB32: 335

the contrary, binding of β-endorphin to μ-opioid receptors on POMC

Patients
No. of

neurons mediates an autoinhibitory feedback loop leading to a de-

crease in the release of α-MSH. Naltrexone can antagonize the ef-
fects of β-endorphins and thereby interrupting the negative
bupropion SR 360 mg/day (NB32) plus
Placebo, naltrexone SR 16 mg/day and

Placebo, naltrexone SR 32 mg/day and

Placebo, naltrexone SR 32 mg/day and

Placebo, naltrexone SR 32 mg/day and

feedback loop. The co-administration of the two compounds thus

bupropion SR 360 mg/day (NB16),

bupropion SR 360 mg/day (NB32)

bupropion SR 360 mg/day (NB32)

bupropion SR 360 mg/day (NB32)

leads to a more potent and prolonged stimulation of POMC neurons

Phase III clinical studies of naltrexone plus bupropion as anti-obesity combination therapy.

intensive lifestyle modification

naltrexone SR 32 mg/day and

leading to synergistic effects on energy balance [38]. Naltrexone/

bupropion is also believed to modulate the mesolimbic reward
pathways contributing to further antiobesity effects by regulating
goal-oriented behaviours [39].
Although bupropion monotherapy has been shown to be beneficial
Intervention

counselling

in treating patients with obesity [40–42], the magnitude of observed

clinical effects have remained modest and inadequate as per FDA
criteria for approval of a drug as antiobesity agent. Similarly for naltrex-
one, several animal and human studies supported its potential as a
weight loss agent. However, minimal weight loss induced by the mono-
56 week, multicentre, randomized,

56 week, multicentre, randomized,

COR-BMODa 56 week, multicentre, randomized,

56 week, multicentre, randomized,

double-blind, placebo controlled

double-blind, placebo controlled

double-blind, placebo controlled

double-blind, placebo controlled

therapy further lead to exploration of its combination with POMC acti-

vator bupropion for the treatment of obesity [43].
The Phase III development program of naltrexone/bupropion
lipidemia with a BMI ≥27 and ≤45 kg/m2.

consisted of 4 multicentre, randomized, double-blind, and placebo con-

trolled studies of 56 week duration each (Table 3) [44–47]. Treatment
with naltrexone SR/bupropion SR resulted in early, sustained and statis-
tically significant weight loss as evaluated by primary trial endpoints of
percent change in body weight and the proportion of patients who
Design

study

study

study

study

achieved a ≥5% weight loss from baseline values.

Favourable effects were observed on weight related cardio-
metabolic parameters such as waist circumference, triglycerides, high
COR-DM b

density lipoproteins and high-sensitivity C-reactive protein. Patient re-

COR-IIa
COR-Ia
Study
Table 3

ported outcomes such as quality of life and control of eating were also
b
a

improved in these clinical studies [48].

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 A.K. Kakkar, N. Dahiya / European Journal of Internal Medicine xxx (2015) xxx–xxx
Table 4
Key emerging antiobesity drugs in the pipeline [10,52,53].
Drug Mechanism of action
Liraglutide Long acting glucagon-like peptide 1 (GLP-1) analogue
Exenatide GLP-1 analogue
Cetilistat Gastrointestinal and pancreatic lipase inhibitor
Velneperit Neuropeptide Y5 receptor inhibitor, appetite suppression
Tesofensine Inhibition of serotonin, dopamine, and noradrenaline reuptake Phase III
Metreleptin Leptin receptor agonist
Bupropion SR + Dopamine and norepinephrine reuptake inhibitor +
zonisamide SR antiepileptic causing enhancement of dopamine and serotonin
(Empatic) neurotransmission
Obinepitide Dual neuropeptide Y2/Y4 receptor agonist
The most common treatment related adverse events seen in naltrex-
one/bupropion treated patients were nausea (32.5%), constipation
(19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia
(9.2%), dry mouth (8.1%), and diarrhoea (7.1%) [49]. Due to the presence
of bupropion in the combination, the extended release formulation
carries a black box warning indicating increased risk of suicidal behav-
iour and ideation as well as risk of neuropsychiatric symptoms in indi-
viduals taking bupropion for smoking cessation. The sponsor had
initially applied for approval of combination therapy in 2010. However,
FDA failed to approve Contrave in February 2011 citing concerns about
its cardiovascular safety profile. However, the sponsor reapplied for
FDA approval with encouraging data related to cardiovascular safety of
combination therapy in 2014 and finally got the marketing authorization
[50]. This marketing permission of naltrexone/bupropion comes with
rider requiring several post marketing studies including a cardiovascular
outcomes study to evaluate the cardiovascular risk; two clinical pharma-
cology studies assessing safety and efficacy in children; a animal juvenile
toxicity study focussing on growth and development as well as learning,
behaviour and memory; a study investigating effects on cardiac conduc-
tion; clinical trials to evaluate dosing in patients with hepatic or renal in-
sufficiency and a clinical trial to assess potential drug interactions
involving the combination product [37].
3. Antiobesity drugs: what's in the pipeline?
Currently available pharmacotherapy for obesity has limitations in
the form of few approved drugs, limited drug efficacy and significant ad-
verse effects. Orlistat remains the sole agent licensed for use in the man-
agement of obesity in the UK. FDA approved the above mentioned two
new therapies after a long gap of 13 years and naltrexone/bupropion is
a recently introduced treatment option still undergoing evaluation
through mandatory post marketing studies. Conventional therapies
aimed at treating obesity are either unable to achieve the benchmark
of clinical efficacy as set by FDA or possess adverse effects that limit
the duration of their use. The diverse range of side effects seen with
these medications indicates that the neural pathways targeted by cur-
rently available as well as withdrawn therapies are not just implicated
in energy homeostasis and appetite regulation but also play critical
role in several tissues [51]. Given the significant unmet need for safe,
efficacious and tolerable antiobesity medications, a large number of po-
tential new therapies are currently being evaluated and are at various
stages of development. The most promising of these therapies are sum-
marized in Table 4 [10,52,53]. Besides monotherapies, several combina-
tion therapies are also being investigated. Polytherapy appears to be
especially suited for the management of obesity since such combinations
can overcome counter-regulatory responses, allow lower doses to be
Please cite this article as: Kakkar AK, Dahiya N, Drug treatment of obesity: Current status and future prospects, Eur J Intern Med (2015),
http://dx.doi.org/10.1016/j.ejim.2015.01.005
5
Status Comments
Phase III completed Injectable formulation; currently approved for the treatment of type
2 diabetes
Phase III Injectable formulation; currently approved for the treatment of type
2 diabetes
Phase III completed Orally active; recently approved in Japan for the treatment of obesity
with complications
Phase II Orally active
Orally active; originally investigated for the treatment of Alzheimer's
disease and Parkinson's disease.
Phase III Injectable formulation; FDA approved orphan drug indicated as an
adjunct to diet as replacement therapy for treating the complications
of leptin deficiency in patients with congenital or acquired
generalized lipodystrophy.
Phase II completed Orally active
Phase II Injectable formulation
used with possible synergy and minimize the adverse effects [54–56].
Given the projected market size of USD 2.4 billion by 2021 for clinical
effective and safe antiobesity drugs [57], such enthusiasm towards de-
velopment of novel weight loss therapies is not surprising.
4. Conclusions
History of drug treatment of obesity has seen the rise and fall of
several therapeutic agents that despite showing promising efficacy in
body weight reduction, had to be withdrawn from the market, due to
serious adverse effects. As of now, four drugs are approved by FDA for
long-term weight management in obese adults and only one of them
is available in Europe. Significant unmet need and the robust projected
growth rates of antiobesity drug market have fuelled the clinical devel-
opment of several promising weight loss therapies. These future phar-
macological agents have the potential of either superseding the
existing therapies or being used in combination with available
medications. As is true for other chronic conditions, sustained efficacy
of weight loss therapies will require polytherapeutic as well as long-
term treatment strategies.
Conflict of interest
We have no conflicts of interest to declare.
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