Review Article

Metabolic syndrome and related conditions

pISSN: 2287-4208 / eISSN: 2287-4690
World J Mens Health 2021 Apr 39(2): 208-221
https://doi.org/10.5534/wjmh.200010

Anti-Obesity Drugs: Long-Term Efficacy and

Safety: An Updated Review
Young Jin Tak1,2 , Sang Yeoup Lee3,4
1
Department of Family Medicine, Pusan National University School of Medicine, Yangsan, 2Biomedical Research Institute, Pusan National
University Hospital, Busan, 3Family Medicine Clinic and Research Institute of Convergence of Biomedical Science and Technology, Pusan
National University Yangsan Hospital, 4Department of Medical Education, Pusan National University School of Medicine, Yangsan, Korea

As a chronic and relapsing disease, obesity negatiⓇvely impacts the health of men to a greater extent than that of women,
with a higher risk of cardiovascular disease. Since lifestyle modifications alone are often challenging and limited for the main-
tenance of weight reduction, pharmacotherapy should be considered in a timely manner for obese men or overweight pa-
tients with weight-related comorbidities. Recent advances in anti-obesity drugs have enabled the potential of achieving clini-
cally significant weight loss. Increasing evidence has shown that behavior-based interventions with one of these medications
can result in greater weight loss than that elicited by usual care conditions. Data from most recent meta-analyses showed
that the overall placebo-subtracted weight reduction (%) with the use of anti-obesity drugs for at least 12 months ranges from
2.9% to 6.8%; phentermine/topiramate (-6.8%) liraglutide (-5.4%), naltrexone/bupropion (-4.0%), lorcaserin (-3.1%), and
orlistat (-2.9%). However, they have a high cost and may cause adverse outcomes depending on the individual. Very recently,
on February 13, 2020, the US Food and Drug Administration requested withdrawal of lorcaserin from the market because a
safety clinical trial showed an increased occurrence of cancer. Therefore the decision to initiate drug therapy in obese indi-
viduals should be made after the benefits and risks are considered. Thereafter, treatment should be tailored to specific patient
subpopulations depending on their chronic conditions, comorbidities, and preferences. Herein, we provide an overview of
the latest developments in weight loss medications, which may serve as one of the strategies for long-term obesity control.

Keywords: Liraglutide; Lorcaserin; Naltrexone/bupropion; Obesity; Orlistat; Phentermine/topiramate

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

INTRODUCTION men (39%) and women (40%) in 2016 according to the

World Health Organization, recent studies have re-
Recently, the “epidemic of obesity” has emerged as ported more rapid increases in obesity-related indica-
one of the major global health concerns. Between 1975 tors in men than in women [2,3]. This sex disparity can
and 2016, the worldwide prevalence of obesity tripled be explained by genetic, sociocultural, socioeconomic,
and was primarily attributed to the intake of a high and behavioral factors [4]. After starting a career, men
calorie diet and a sedentary lifestyle [1]. Although the might succumb to obesogenic environmental changes—
prevalence of being overweight was similar between frequent dining outside the home, drinking, and stress,

Received: Jan 13, 2020 Revised: Feb 5, 2020 Accepted: Feb 16, 2020 Published online Mar 9, 2020
Correspondence to: Sang Yeoup Lee https://orcid.org/0000-0002-3585-9910
Family Medicine Clinic, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea.
Tel: +82-55-360-1442, Fax: +82-51-510-8125, E-mail: [email protected]

Copyright © 2021 Korean Society for Sexual Medicine and Andrology

 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

which ultimately lead to high calorie intake [3]. Men drugs have been made focusing on not only weight loss
also tend to have lower body image dissatisfaction than efficacy but also cardiovascular safety and lowered
women. Resultantly, they tend to be less interested in risk of cardiovascular disease (CVD). In recent years,
the weight gained over time than women [5]. the US Food and Drug Administration (FDA) has ap-
Excess fat distribution displays different patterns proved newer pharmacological options following more
according to gender; it is concentrated in the centrally cautious studies elucidate their safety and efficacy [17].
located visceral areas in men and subcutaneous ar- As these anti-obesity drugs are approved for long-term
eas in premenopausal women [6]. This difference may management, they provide a better appreciation of the
explain the greater negative impact of obesity on the complex, chronic, and relapsing nature of obesity [18].
cardiovascular health of men than on that of premeno- Importantly, the availability of different medications
pausal women. Unlike subcutaneous fat, visceral fat is offers healthcare providers more options for deriving
related to the worsening of insulin resistance and lipid better patient-tailored treatment plans. In this review,
and fluid metabolism [4]. Additionally, obesity in men we aimed to provide an overview of the latest develop-
predominantly reduces total testosterone due to the ments in weight loss medications, which may serve as
insulin resistance‑associated decrease in sex hormone- one of the strategies for long-term obesity control (Table
binding globulin. Severe obesity is also related to 1).
reductions in free testosterone levels via suppression
of the hypothalamic–pituitary–thyroid axis, whereas ANTI-OBESITY DRUGS FOR LONG-
low testosterone alone results in increases in adipos- TERM USE
ity, thereby establishing a self‑perpetuating cycle of
metabolic impairment [7,8]. Previously, obese men were 1. Orlistat
found to have a greater risk of erectile dysfunction Orlistat (Xenical®) was first approved by the FDA
(ED). In fact, obesity can cause vasculogenic ED, which in 1999. Today, it remains the longest licensed anti-
has common features, including obesity-related meta- obesity drug for long-term use and is available over the
bolic alterations [9]. counter (Alli®). As a non-central nervous system agent,
Timely and appropriate treatment to reduce exces- orlistat 120 mg is prescribed for adults and adolescents
sive body fat is required in men with a body mass in- ≥12 years of age [19].
dex (BMI) ≥30 kg/m2 (25 kg/m2 for some ethnic groups),
≥27 kg/m2 (23 kg/m2 for some ethnic groups) and obe- 1) Mechanism of action
sity-related comorbidities or abdominal obesity (waist Unlike other anti-obesity drugs on the market, or-
circumference [WC] ≥102 cm [90 cm for some ethnic listat does not exert its effect by affecting appetite;
groups]) [10,11]. Although intensive lifestyle modifi- instead, it reduces calorie absorption. The main mecha-
cation, including calorie restriction and engaging in nism of orlistat is the inhibition of gastric and pan-
physical activities, is the first approach to ameliorate creatic lipases, which leads to a ~30% decrease in the
obesity, sustaining these efforts over a long period can absorption of intestinal triglycerides and thus calories
be challenging and often prove insufficient [12]. Cur- [20]. Orlistat is expected to have little effect on weight
rently, most guidelines recommend pharmacotherapy loss with non-fatty food consumption.
as a second-line treatment for weight management
after lifestyle modification [13,14]. In fact, numerous 2) Side effects
medications have been developed for the long-term Common side effects of orlistat include fatty/oily
management of obesity, with different mechanisms stools, increased defecation, fecal urgency, and flatus
targeting various factors and diverse pathways that with discharge. However, by co-prescribing a fiber-
might cause a positive energy balance [15]. During the containing supplement—psyllium, its gastrointestinal
last decades, some anti-obesity drugs have been used side effects can be reduced.
to treat morbid obesity; however, most of these have
been removed from the market owing to serious long- 3) Clinical efficacy
term side effects, particularly cardiovascular-related In the XENDOS (XENDOS (XENical in the preven-
issues [16]. Since then, efforts to develop anti-obesity tion of Diabetes in Obese Subjects) trial, the largest

www.wjmh.org 209
210
Table 1. A summary of anti-obesity drugs for long-term use
Product FDA EMA Korea
Drug Application Mechanism of action Main adverse effect Contraindication
name approval approval approval
Orlistat Xenical®, 60 or 120 mg TID during Gastrointestinal and pan- Oily stools, oily spotting, Pregnancy, cholestasis, mal- Yes Yes Yes

www.wjmh.org
Alli® or within 1 hour of a fat- creatic lipase inhibitor; fecal urgency, fecal absorption 1999 2012 2000
containing meal decrease lipid absorp- incontinence, hyper-
tion defecation, flatus with
discharge, deficiency in
vitamins A, D, E, and K
Phentermine/ Qsymia® 3.75/23 mg QD for 14 days NE agonist/GABA agonist, Paresthesia, dry mouth, Pregnancy, uncontrolled Yes No Yes
topiramate and then 7.5/46 mg QD; glutamate antagonist; constipation, insomnia, HTN, CVD, CKD, glaucoma, 2012 2019
https://doi.org/10.5534/wjmh.200010

If <3% weight loss is suppress appetite dysgeusia, anxiety, hyperthyroidism patients

achieved at 12 weeks, depression on MAOIs
increase to 11.25/69 mg
QD for 14 days, followed
by 15/92 mg QD; discon-
tinue gradually if <5%
weight loss is achieved at
12 weeks with the high-
est dose
Naltrexon/ Contrave®, 8/90 mg for 7 days; BID for Opioid receptor antago- Nausea, headache, consti- Pregnancy, uncontrolled HTN, Yes Yes Yes
bupropion Mysimba® 7 days; 2 tablets in the nist/dopamine agonist pation, dizziness, vomit- seizure, anorexia or bulimia 2014 2015 2016
morning and 1 tablet in and NE reuptake inhibi- ing, dry mouth nervosa, abrupt discontinu-
the evening for 7 days; tor; increase satiety, sup- ation of alcohol, benzodi-
and 2 tablets BID there- press appetite azepines, barbiturates or
after antiepileptic drugs, other
bupropion-containing
drugs, opioids or opiate
agonists, MAOIs
Liraglutide Saxenda® 0.6 mg subcutaneous Glucagon-like peptide-1 Nausea, diarrhea, con- Pregnancy, personal or family Yes Yes Yes
injection QD, increase by agonist; slow gastric stipation, vomiting, history of medullary thyroid 2014 2015 2017
0.6 mg weekly to a daily emptying, increase dyspepsia carcinoma or type 2 MEN
target dose of 3 mg satiety, decrease food
reward
Lorcaserin Belviq®, 10 mg BID Serotonin 2C receptor ago- Headache, dizziness, Pregnancy, severe renal dis- Yes No Yes
Belviq XR® 20 mg extended release QD nist; reduce food intake fatigue, nausea, consti- ease 2012 2015
pation, dry mouth Withdrawn from Withdrawn from
the market in the market in
February 2020 February 2020
FDA: Food and Drug Administration, EMA: European Medicines Agency, XR: extended release, TID: three times per day, QD: once daily, BID: twice daily, NE: norepinephrine, GABA: gamma-amino-
butyric acid, HTN: hypertension, CVD: cardiovascular disease, CKD: chronic kidney disease, MAOIs: monoamine oxidase inhibitors, MEN: multiple endocrine neoplasia.
 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

randomized controlled trial (RCT) that evaluated the center, parallel group trial conducted between January
effect of orlistat in 3,305 patients, orlistat was found 2014 and June 2018 in the US, Canada, Mexico, the
to cause a total body weight loss of 2.4% after 4 years. Bahamas, Europe, South America, Australia, and New
More importantly, it significantly lowered the risk Zealand. The study population consisted of 12,000 men
of type 2 diabetes mellitus (T2DM), compared to pla- and women who were overweight or obese. Patients
cebo (6.2% vs. 9.0%), over 4 years [21]. Orlistat also were required to have either established CVD, or to
improved blood pressure (BP), insulin sensitivity, and be at least 50 years old for men or 55 years for women
lipid profiles owing to its primary action of decreas- with T2DM plus at least one additional cardiovascular
ing intestinal fat absorption. However, in this study, risk factor. Eligible patients were assigned randomly to
91% of participants administered orlistat experienced either lorcaserin 10 mg BID or placebo. Approximately
at least one gastrointestinal event and 8% withdrew 96% of patients completed the study, and 62% who
from the study due to adverse events. Further, there completed remained on treatment at the end of study.
are concerns regarding the potential risk of colorectal The median follow-up time was 3 years and 3 months.
cancer due to the presence of excess fat in the colon. The primary safety analysis showed no meaningful
In animal models, orlistat was associated with clusters difference between lorcaserin and placebo in the risk
of apoptosis-resistant, neoplastic, premalignant colonic of major adverse cardiovascular events, demonstrat-
lesions [22]. However, a large retrospective matched ing noninferiority. However, it was found that more
cohort study (n=33,625 on orlistat; 160,374 on placebo) patients taking lorcaserin (n=462; 7.7%) were diagnosed
showed no evidence of an increased risk of colorectal with cancer compared to those taking a placebo, which
cancer after the initiation of orlistat [23]. Meanwhile, a is an inactive treatment (n=423; 7.1%). A range of can-
significant decrease in the absorption of vitamins A, D, cer types was reported, with several different types of
E, and K was observed in participants administered or- cancers occurring more frequently in the lorcaserin
listat [21]. To prevent possible deficiencies in fat-soluble group, including pancreatic, colorectal, and lung. There
vitamins (such as vitamin D), a supplement can be rec- was no apparent difference in the incidence of cancer
ommended. over the initial months of treatment, but the imbal-
ance increased with longer duration on lorcaserin.
2. Lorcaserin On the other hand, lorcaserin has failed to gain ap-
Lorcaserin (Belviq® and Belviq XR®) is a selective proval from the European Medical Agency (EMA) due
agonist of the 5-hydroxytryptamine (5-HT) 2C receptors to preclinical data that revealed the potential of breast
and a Drug Enforcement Administration (DEA) sched- cancer development and concerns regarding psychiatric
ule IV-controlled medication. In 2016, its extended re- issues—the aggravation of depression, suicidal ideation,
leased (XR) form (once daily [QD] 20 mg of lorcaserin) and psychosis and valvulopathy. Moreover, phase III
was approved by the FDA following twice-daily (BID) studies to determine the difference in adverse event in-
10 mg of lorcaserin in 2012. However, on February 13, cidence between groups were deemed underpowered [27].
2020, the FDA requested that the drug manufacturer
voluntarily withdraw lorcaserin from the US market 1) Mechanism of action
because it was determined that potential risk of can- Lorcaserin decreases food intake by increasing sati-
cer associated lorcaserin outweighs the benefits [24]. It ety through its serotonin anorectic effect by stimulat-
was an update to the FDA Drug Safety Communica- ing the proopiomelanocortin (POMC) receptors in the
tion: Safety clinical trial shows possible increased risk arcuate nucleus of the hypothalamus [28]. At least 14
of cancer with weight-loss medicine Belviq, Belviq XR serotonin receptor subtypes that modulate different
(lorcaserin) issued on January 14, 2020 [25]. This with- physiological functions, ranging from hallucinations to
drawal came after the FDA’s reviewing data from the muscle contraction, exist [29]. The side effects caused
Cardiovascular and Metabolic Effects of Lorcaserin by non-specific serotonin agonists (i.e., fenfluramine
in Overweight and Obese Patients – Thrombolysis in and dexfenfluramine) are due to the stimulation of
Myocardial Infarction 61 (CAMELLIA-TIMI 61) clinical the peripheral serotonin 2B receptor. Fenfluramine is
trial to evaluate the risk of CVD problems [26]. It was a predominant 5-HT2b receptor agonist that is believed
a randomized, double-blind, placebo-controlled, multi- to cause adverse CVD effects by stimulating mitotic

www.wjmh.org 211
 https://doi.org/10.5534/wjmh.200010

activity and subsequent cell overgrowth within the after 1 year. Based on the findings, 14.6% of subjects in
valve leaflets [30]. Owing to its high selectivity for the lorcaserin group had lost >10% weight compared to
5-HT2c receptor (15-fold and 100-fold selectivity over the 4.8% of subjects in the placebo group who had a similar
5-HT2A and 5-HT2B receptors, respectively), lorcaserin CVD risk at the 3.3-year median follow-up [34]. Lorcase-
can suppress appetite and hunger without triggering rin resulted in a weight loss of ~3.3% from the baseline
pulmonary hypertension or valvular heart defects [31]. total body weight and improved fasting glucose, fasting
Many studies suggest that lorcaserin has multiple psy- insulin, and hemoglobin A1c (HbA1c) levels. In a small-
chological effects—reducing craving and impulsivity er cohort of the BLOOM-DM (Behavioral Modification
and elevating satiety), which contribute to weight loss. and Lorcaserin for Overweight and Obesity Manage-
ment in Diabetes Mellitus) trial, which comprised 603
2) Side effects overweight or obese patients with T2DM and HbA1c
The common side effects of lorcaserin include nau- 7.0% to 10.0%, a mean reduction in HbA1c was found
sea, headache, dizziness, fatigue, dry mouth, cough, in the lorcaserin group compared to the placebo group
constipation, hypoglycemia, and back pain. (0.9% vs. 0.4%) [35]. Due to the concerns regarding the
potential effect of lorcaserin on other types of 5-HT
3) Clinical efficacy receptors, which could thus affect valvular competency,
Lorcaserin was evaluated in the BLOOM (Behav- patients were monitored with serial echocardiograms
ioral Modification and Lorcaserin for Obesity and during these phase III trials. A pooled risk of 1.15 (95%
Overweight Management) and BLOSSOM (Behavioral confidential interval=0.81–1.67) was found for the FDA-
Modification and Lorcaserin Second Study for Obesity defined valvulopathy, suggesting that an unacceptable
Management), randomized, double-blind, placebo-con- increase in the risk of valvulopathy was not present
trolled phase III trials, which sought to investigate the with the use of lorcaserin [36]. Although many long-
efficacy and safety of different doses of lorcaserin. In term trials demonstrated beneficial effects of lorcase-
the BLOOM study, 3,182 participants aged 18–65 with rin in T2DM and its substantial CVD safety profiles,
a BMI ranging from 30–45 kg/m2 received either 10 mg weight loss efficacy of lorcaserin is only modest.
lorcaserin BID or placebo for 52 weeks [32]. At the end
of the trial, participants in the lorcaserin group contin- 3. Phentermine/topiramate
ued the intake of lorcaserin at the same dose or placebo Phentermine/topiramate ER (Qysmia®) was approved
for an additional 52 weeks. All patients were given diet by the FDA in 2012 as the first combination agent
and exercise counseling. At the conclusion of the trial, for the long-term management of obesity. However,
a weight loss greater than 10% was achieved in 22.6% the EMA has not approved this medication due to its
of participants in the lorcaserin group vs. 7.7% in the abuse potential, the lack of long-term data on the car-
placebo group. Of the participants administered lorca- diovascular effects of phentermine, and the cognitive
serin for an additional 52 weeks, 67.9% of those who side effects of topiramate—attention, language, and
had an initial weight reduction >5% maintained this memory impairment [27]. As this drug combination
loss compared to the 50.3% patients re-randomized to contains phentermine, it is a controlled DEA schedule
receive placebo. In the BLOSSOM study, 4,008 patients IV substance.
between 18–65 years of age with a BMI from 30–45
kg/m2 received either 10 mg QD or 10 mg BID of lor- 1) Mechanism of action
caserin or placebo. After 52 weeks, significantly more This drug combination mainly suppresses appetite
participants administered either 10 mg QD or 10 mg through mechanisms that remain unclear. The central
BID of lorcaserin lost >10% of body weight (22.6% and sympathetic action of phentermine, a noradrenergic
17.4%, respectively), compared to 9.7% in the placebo agonist, is to enhance the release of norepinephrine,
group [33]. In a more recent RCT, 12,000 patients with dopamine, and serotonin [37]. Topiramate, a gamma-
a BMI >27 kg/m2 and confirmed CVD in men >50 or aminobutyric acid agonist, glutamate antagonist, and
women >55 years of age were administered 10 mg BID carbonic anhydrase inhibitor, was approved for the
lorcaserin vs. placebo. This study primarily assessed the treatment of epilepsy and prophylaxis of migraines
cardiovascular safety and efficacy of this medication [38]. However, significant weight loss was observed

212 www.wjmh.org
 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

among epileptic patients treated with topiramate, mg group was 10.9%, compared to 1.6% in the placebo
thereby leading to its evaluation in clinical studies for group. Similarly, in the CONQUER trial, participants
the treatment of obesity. Although the actions of topi- administered the same dose of phentermine/topiramate
ramate on the central nervous system have not been ER for 1 year achieved a 9.8% reduction in weight from
completely understood, rodent studies have suggested baseline, compared to 1.2% in the placebo group. In the
that it acts as a neurostabilizer and may boost thermo- CONQUER trial, patients administered phentermine/
genesis [39,40]. topiramate ER 7.5/46 mg for 1 year had a total body
weight loss of 7.8%. Notably, both studies demonstrated
2) Dose escalation and side effects an improvement in the cardiovascular risk factors. The
Phentermine/topiramate is prescribed for QD use. SEQUEL study, a 2-year extension trial, was performed
To prevent insomnia, its known side effect, it is recom- to assess the sustained weight loss of participants after
mended that this medication is taken in the morning. completion of the CONQUER trial [43]. The study find-
According to the package insert, the dose of phenter- ings reinforced previous findings that phentermine/
mine/topiramate should be gradually escalated. After topiramate ER intake can result in meaningful weight
a starting dose of 3.75/23 mg QD is administered for loss and significant improvements in BP, lipid profiles,
2 weeks, 7.5/46 mg is administered; this dose was best fasting glucose, fasting insulin, and WC.
tolerated by the participants in the study. The dose
should be administered for a minimum of 3 months be- 4. Naltrexone/bupropion
fore a further increase to the highest dose of 15/92 mg. Naltrexone/bupropion (Contrave®) is a drug combina-
Additionally, the dose is only increased if the patient tion for the long-term management of weight loss. In
fails to achieve a total body weight loss of 3% after 3 2014, this combination was approved the FDA (Mysim-
months. If the patient tolerates the medication poorly, ba® approved by the EMA). Each component of this
a slow titration down or off (ideally over 3–5 days) medication has been used in other medical conditions
is warranted to reduce the risk of seizure; this result since the 1980s [18]. As there is no potential of abuse
was found in a study where patients with a history of with this medication, it is not a controlled substance.
seizures abruptly discontinued topiramate intake [18].
Common side effects of phentermine/topiramate ER 1) Mechanism of action
include insomnia, paresthesia, dizziness, dry mouth, As an antidepressant, bupropion is used as a smoking
dysgeusia, and constipation [38]. A fetal safety issue cessation aide. Its anorectic mechanism of action in-
also exists with this medication: it increases the risk volves the inhibition of dopamine and norepinephrine
of oral clefts. Thus, advice on contraceptive planning reuptake. Naltrexone was approved for the treatment
is imperative before this medication is prescribed to of opioid and alcohol addiction and antagonizes an
women of child-bearing age. opioid‐dependent feedback loop that limits the effects
of bupropion on the POMC neurons; hence, this drug
3) Clinical efficacy combination works synergistically [44].
Regarding weight loss efficacy, adequate assessments
of phentermine/topiramate ER have been conducted 2) Dose escalation and side effects
via long-term studies. EQUIP and CONQUER were A slow dose escalation of naltrexone/bupropion is rec-
each one-year, randomized, double-blind, placebo-con- ommended to minimize the side effect of nausea, with
trolled studies comprising 1,267 and 2,487 participants, a starting dose of 8/90 mg (a single combination tablet)
respectively [41,42]. The EQUIP trial included non- QD for 1 week (at week 2; 1 tablet BID in the morning
diabetic patients with a BMI ≥35 kg/m2 whereas the and evening, at week 3; 2 tablets in the morning and
CONQUER study included patients with a BMI rang- 1 tablet in the evening, at week two tablets BID (the
ing from 27–45 kg/m2 and more than two obesity-relat- maximum dose). Typical side effects include headache,
ed comorbid conditions. The study findings enabled the dizziness, dry mouth, and gastrointestinal discomfort
approval of phentermine/topiramate ER by the FDA. (i.e., nausea, vomiting, constipation, or diarrhea). Al-
In the EQUIP study, the mean weight loss at 1 year for though naltrexone/bupropion results in significant
participants in the phentermine/topiramate ER 15/92 weight reduction and long-term evidence to support its

www.wjmh.org 213
 https://doi.org/10.5534/wjmh.200010

efficacy exists [18], its side effects of elevation of BP and food consumption by acting on the hypothalamus,
and heart rate make it challenging to prescribe to pa- limbic/reward system, and cortex [54]. Unlike human
tients with significant CVD. GLP-1, liraglutide is more stable in plasma and binds
strongly to plasma proteins, thereby enabling a much
3) Clinical efficacy longer half-life (13 hours) than the human endogenous
Naltrexone/bupropion was assessed in four phase III GLP-1 (a few minutes) [55].
multicenter, long-term, double-blind placebo-controlled
trials. The COR (Contrave Obesity Research)-I (n=1,742), 2) Dose escalation and side effects
COR-II (n=1,496), and COR-BMOD (Behavior MODifi- The optimal dose of liraglutide for weight loss is 3
cation) (n=793) trials included patients with a BMI ≥27 mg daily; however, to prevent the side effects of nau-
kg/m2, at least one weight-related comorbid condition sea and vomiting, treatment should be initiated with 0.6
(i.e., hypertension [HTN]), and COR-DM (Diabetes Mel- mg QD and gradually escalated each week by 0.6 mg
litus) [45-48]. The percent weight loss observed in COR- up to 3 mg [38]. Previously, a meta-analysis revealed
I, COR-II, and COR-BMOD in patients administered that among all FDA-approved anti-obesity medications,
naltrexone/bupropion 32/360 mg for 56 weeks compared liraglutide had the highest discontinuation rate due to
to placebo was 6.1% vs. 1.3%, 6.4% vs. 1.2%, and 9.3% its side effects (13% of patients) [56]. The most frequent
vs. 5.1%, respectively [49]. The final study, the COR- placebo-subtracted side effects were nausea (25.0%),
DM trial, evaluated weight loss in 505 patients with vomiting (12.2%), diarrhea (11.6%), constipation (11.0%),
T2DM who were either overweight or obese [48]. Here, and dyspepsia (6.4%), which were tolerated by most pa-
patients administered naltrexone/bupropion 32/360 mg tients over time [57-59].
for 56 weeks vs. placebo lost 5.0% vs. 1.8%. Moreover,
their HbA1c was reduced relative to the baseline value 3) Clinical efficacy
(0.6% vs. 0.1%) [50]. These trials revealed improvements Liraglutide was approved base on the results of
in high-density lipoprotein cholesterol and triglycerides three main RCTs; The SCALE Obesity and Prediabe-
in naltrexone/bupropion-treated patients. However, im- tes, the SCALE Diabetes and the SCALE Maintenance
provements in WC, fasting insulin, and insulin resis- [58,60,61]. In the SCALE Obesity and Prediabetes, obese
tance index (homeostasis model assessment of insulin participants (n=2,487), including 61.2% of the predia-
resistance, HOMA-IR) were only identified in partici- betic cohort, received liraglutide 3 mg QD or placebo.
pants in the COR-I, COR-II, and COR-BMOD studies After 56 weeks, a weight loss of 8.0% was achieved in
[51]. the liraglutide group (vs. 2.6% of placebo) and 63.2%
and 33.1% of the participants in the liraglutide group
5. Liraglutide achieved ≥5% and ≥10% weight reduction, respectively
Liraglutide (Saxenda®) is an injectable glucagon-like [58] (vs. 27.1% and 10.6% in the placebo group, respec-
peptide 1 (GLP-1) derivative that was approved by the tively). Moreover, cardiovascular indicators, includ-
FDA in 2014 for weight management (dose, 3.0 mg sub- ing BP and lipid profiles, were better improved in the
cutaneous [SC] daily). This approval followed that of a treatment group. Particularly, HbA1c (-0.30%±0.28%)
lower dose (1.8 mg daily [Victoza®]) in 2010 for T2DM and fasting glucose levels (-7.1±0.8 mg/dL) were signifi-
management [52]. cantly reduced in subjects administered liraglutide 3.0
mg compared to placebo. The SCALE Diabetes assigned
1) Mechanism of action overweight or obese patients with T2DM (n=846) to
After meals, GLP-1 is secreted from the distal ileum, receive liraglutide 3 mg QD or 1.8 mg QD or placebo
proximal colon, and the vagal nucleus of the solitary for 56 weeks and reported a decrease in the weight of
tract and exhibits multiple effects as an incretin hor- the patients (6.0%, 4.7%, and 2.0%, respectively) [58].
mone [53]. GLP-1 mainly regulates blood glucose by en- Early achievement of weight loss ≥4% with liraglutide
hancing insulin secretion from the pancreatic beta-cells 3 mg (at 16 weeks) was associated with greater weight
and inhibits glucagon secretion in a glucose-dependent reduction at the study’s termination [62]. Compared to
manner. GLP-1 also induces postprandial satiety and the 1.8 mg SC daily group, the liraglutide 3.0 mg SC
fullness, slows gastric emptying, and decreases appetite daily group had a greater improvement in the T2DM

214 www.wjmh.org
 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

measures, including HbA1c, fasting plasma glucose, COMBINATION OF ANTI-OBESITY

HOMA-IR, and number of hypoglycemic agents. The DRUGS IN CLINICAL DEVELOPMENT
SCALE Maintenance aimed to evaluate weight main-
tenance in non-diabetic participants who underwent As obesity occurs via multifactorial pathways, a
a ≥4-week run-in with a low-calorie diet. Subjects who single drug might exhibit limited efficacy. Thus, a
lost ≥5% of their body weight (n=422) were randomized high dose might be required, which often causes unac-
to receive liraglutide 3.0 mg SC daily or placebo for 56 ceptable side effects. Combination therapy comprising
weeks. The liraglutide 3.0 mg SC daily group achieved multiple anti-obesity drugs with complementary modes
an additional weight loss of 6.2% (0.2%, placebo) [61]. of action is warranted to broaden the target energy
One of the main benefits of liraglutide, besides weight regulatory systems via actions on distinct mechanisms,
loss, is its favorable effects on CVD outcomes in obese which could maximize the effect on weight manage-
patients with T2DM. ment while maintaining safety and tolerability [72]. To
Despite initial considerations of the risk of acute date, however, there has been no approved combination
pancreatitis, long-term trials suggest that the risk agent for obesity management, besides phentermine/
of this disease does not significantly increase with topiramate and naltrexone/bupropion. Other co-admin-
liraglutide [63,64]. Particularly, biomarkers of acute istered medications have been investigated to elucidate
pancreatitis—amylase and mainly lipase—increase their long-term efficacy and adverse events [15,16]. Most
in a non-dose dependent manner during treatment combinations primarily focus on both controlling hun-
with GLP-1 receptor analogs. However, their increase ger/appetite/satiety and inhibiting peripheral calorie
was not accompanied by symptoms; moreover, when absorption (i.e., phentermine/sodium glucose co-trans-
monitored, acute pancreatitis could not be predicted porter 2 [SGLT-2] inhibitor, a GLP-1 agonist/other gut
[65]. Based on rodent studies that demonstrated the hormones, or an SGLT-2 inhibitor). SGLT-2 inhibitors,
proliferative effect of liraglutide on thyroid C-cells, such as dapagliflozin, empagliflozin, and canagliflozin,
contraindications for liraglutide include patients with block glucose reabsorption from the renal tubules and
(or a family history of) medullary thyroid carcinoma result in glycosuria. Therefore, they are primarily
or type 2 multiple endocrine neoplasia [27]. In rodents used by diabetic patients for blood sugar control [73].
administered incretin-based medications, pancreatic, Interestingly, these drugs are effective, to some extent,
intestinal, and breast neoplasms were found to develop in individuals without diabetes [74]. Theoretically, the
more frequently; however, these results were not found amount of glucose loss in urine is approximately 75
in human studies [66-68]. A phase IIIb RCT reported g/d (300 kcal energy deficit). Resultantly, 7–8 kg of
no difference in calcitonin levels and medullary thy- weight loss owing to these medications can be expected
roid carcinoma rates between liraglutide (≤1.8 mg) and in patients with diabetes over 6–12 months. However,
placebo during a follow-up of 3.5–5 years [69]. Addition- in previous clinical studies with diabetic patients, only
ally, the total risk of malignant and benign neoplasms, 2–3 kg weight loss was achieved with such agents; this
including pancreatic cancer, was not found to increase was attributed to compensatory hyperphagia/increased
in the liraglutide vs. placebo group [63,64,70]. However, appetite [75]. Thus, combining an appetite suppressor,
these results should be interpreted cautiously and an such as phentermine, with a SGLT-2 inhibitor can
intensive post-marketing surveillance of liraglutide serve as a good option for weight management. In a re-
should be performed as the studies were not designed cent clinical trial that examined canagliflozin in com-
to assess cancer risk and the incidence of medullary bination with phentermine, additional weight loss was
thyroid carcinoma was too low for detection in the tri- achieved (6.9%, canagliflozin 300 mg+phentermine 15
als. As no concern regarding neuropsychiatric safety mg vs. 1.3%, canagliflozin 300 mg vs. 3.5%, phentermine
was reported, this medication can serve as a good op- 15 mg) [76]. Similarly, SGLT-2 inhibitors combined with
tion for obese patients with mental disorders [71] if a GLP-1 agonist caused a greater weight reduction
they can afford this costly medication (liraglutide 3.0 than individual administration of each agent [77].
mg) and agree to a daily injection.

www.wjmh.org 215
 https://doi.org/10.5534/wjmh.200010

INITIATING AND TERMINATING Treatment response to most of these drugs should be

PHARMACOTHERAPY FOR OBESITY evaluated at around 12 weeks using the maintenance
dose. A trial period of 3 to 4 months is essential for
Despite the marked availability, anti-obesity drugs predicting whether a patient might achieve a clinically
are reported to be underused by healthcare providers significant weight loss at 1 year (classified as respond-
[3,78]. Only 2% of obese adults who are eligible for obe- ers or non-responders); this is supported by data that
sity pharmacotherapy receive prescriptions for these early weight loss with any medical intervention is a
agents from their doctor [79]. As a highly stigmatized good indicator of long-term outcomes [62,81-83]. Recently
disease, there remains a misconception that obesity is approved anti-obesity drugs have “stopping rules” that
mainly due to a lack of willpower and representative of are suggested by the FDA and EMA to help clinicians
laziness; thus, these patients are considered undeserv- identify patients that might achieve a weight reduction
ing of proper treatment with medications or surgery >5% within 1 year. Stopping rules can avoid unneces-
[80]. The high cost of these medications also prevents sary exposure and enhance the risk–benefit ratio [27].
adequate prescription for long periods. Weight loss is If <5% weight loss is achieved after 12 weeks of treat-
extremely challenging to achieve and sustain, and long- ment with a full dose (<4% weight loss at 16 weeks for
term management of obesity often requires adjunctive liraglutide), the medication should be discontinued and
pharmacological interventions. Today, practitioners other drugs should be considered. However, it can be
have access to several FDA-approved options. More- difficult for practitioners to determine whether to con-
over, as there is growing evidence that these drugs can tinue the use of a given anti-obesity drug at the twelfth
delay the onset of obesity-related complications and week, if the full dose has not been administered. Ad-
improve metabolic and cardiovascular parameters, they ditionally, stopping rules are based on the results of the
should be considered in a timely manner. trials that conducted combined interventions involving
The decision to initiate drug therapy in an obese in- an anti-obesity drug and intensive lifestyle modifica-
dividual should be made after the risks and benefits tions not medication only. Thus, the decision regarding
are considered. Importantly, health providers should the further continuation of a given medication should
determine the risk-benefit profile of a given anti-obesity be made according to its effectiveness at reducing
drug on a patient-by-patient basis. Further, the treat- weight when diet, exercise, and behavioral modifica-
ment goals should be clear. Patient preferences based tions are adopted. Without a low-calorie diet and an
on tolerability markedly affect adherence and can increase in physical activity, the application of a medi-
cause poor adherence or discontinuation, thereby negat- cation alone could lead to failure to achieve weight re-
ing the treatment effects [13,14]. At every visit, physi- duction of 5% even after 12 weeks of treatment.
cians should discuss the adverse events that accompany
a given drug and evaluate the drug’s effect on weight CONCLUSION
loss. The goal of treatment with anti-obesity drugs in
obese individuals should be long-term maintenance of As the morbidity and mortality of obesity have sig-
weight reduction and improvement in overall health. nificantly increased, most current guidelines recom-
In most clinical trials that evaluated pharmacologic mend pharmacotherapy as the second line of treatment
interventions for more than 12 months, a weight loss for this disorder following lifestyle modifications. Phar-
of 4% to 8% was typical [56]; however, this is rather macological treatment should be considered as part of
disappointing considering the high prices of these a comprehensive strategy for the treatment of patients
drugs. Therefore, upon initiation of an anti-obesity with a BMI ≥30 or ≥27 kg/m2 and an obesity-related co-
medication, health providers must communicate sev- morbidity—HTN, T2DM, dyslipidemia, and sleep apnea.
eral important messages to their patients. First, not ev- Additionally, the efficacy of medical treatment should
ery drug will produce effective results in patients and be evaluated after the first 3 months of drug use. Sub-
individual responses will vary widely. Second, when stantial research has been dedicated to the development
the maximal therapeutic effect of a drug is achieved, a of a newer generation of anti-obesity drugs. In recent
plateau will be reached. Lastly, when drug therapy is years, many novel agents have undergone phase III
discontinued, weight regain is normally expected. clinical trials. Compared to placebo, these drugs cause

216 www.wjmh.org
 Table 2. Data from meta-analyses of the anti-obesity drugs approved for long-term use for weight loss
Odds ratio Odds ratio
Weighted mean difference % of patients with % of patients with
Study (95% CrI) for (95% CrI) for
Subject Lifestyle intervention (kg) (95% CI) for the % weight loss ≥5% weight ≥10% weight
Drug (duration achieving discontinuation
(drug/placebo) (diet/exercise/behavior) drug-to-placebo (drug/placebo) loss at 1 year loss at 1 year
≥1 year) ≥5% weight due to adverse
comparison at 1 year (drug/placebo) (drug/placebo)
loss event
Orlistat 17 trials 5,572/5,572 Reduced fat intake or 2.60 4.6/1.7 2.70 48.8/22.6 17.9/8.8 1.84
500–800 kcal deficit/ (2.16–3.04) (2.34–3.09) (1.53–2.21)
non-specific increase or
30 minutes of moderate
exercise per day/yes or
no
Phentermine/ 3 trials 1,802/1,735 500 kcal deficit/non- 8.80 8.5/1.7 9.22 72.0/22.8 49.7/8.6 2.29
topiramate specific increase/yes (7.42–10.2) (6.63–12.85) (1.71–3.06)
Naltrexone/ 5 trials 6,963/5,897 500 kcal deficit/non- 4.95 6.1/2.1 3.96 52.4/28.3 28.3/9.7 2.64
bupropion specific increase or (3.96–5.94) (3.03–5.11) (2.10–3.35)
30 minutes of moderate
exercise per day/yes
Liraglutide 4 trials 3,096/1,649 500 kcal deficit/minimum 5.27 7.1/1.7 5.54 60.3/24.6 30.4/8.4 2.95
150 minutes of brisk (4.52–6.06) (4.16–7.78) (2.11–4.23)
walking per week/yes
Lorcaserina 4 trials 9,453/9,440 600 kcal deficit/30 3.22 5.1/2.0 3.10 42.7/19.7 19.0/6.7 1.34
minutes of moderate (2.46–3.97) (2.38–4.05) (1.05–1.76)
exercise per day/yes
CI: confidence interval, CrI: credible interval.
a
Withdrawn from the market for safety issue related to an increased cancer incidence in February 2020.

www.wjmh.org
Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

217
 https://doi.org/10.5534/wjmh.200010

a significant weight reduction, including meaningful havior in overweight and obese adults: Is there a sex differ-
improvements in cardiometabolic profiles, while dem- ence? J Korean Med Sci 2015;30:1017-24.
onstrating good tolerability and safety in patients with 6. White UA, Tchoukalova YD. Sex dimorphism and depot dif-
obesity. Data from most recent meta-analyses showed ferences in adipose tissue function. Biochim Biophys Acta
that the overall placebo-subtracted weight reduction (%) 2014;1842:377‐92.
with the use of anti-obesity drugs for at least 12 months 7. Fui MN, Dupuis P, Grossmann M. Lowered testosterone
ranges from 2.9% to 6.8%; phentermine/topiramate (3 in male obesity: mechanisms, morbidity and management.
trials, -6.8%) liraglutide (4 trials, -5.4%), naltrexone/bu- Asian J Androl 2014;16:223-31.
propion (5 trials; -4.0%), lorcaserin (4 trials; -3.1%), and 8. Masterson JM, Soodana-Prakash N, Patel AS, Kargi AY,
orlistat (17 trials, -2.9%) (Table 2) [56,84-88]. Ramasamy R. Elevated body mass index is associated with
Most prior trials conducted on these medications secondary hypogonadism among men presenting to a tertiary
also performed an intensive consultation on diet and academic medical center. World J Mens Health 2019;37:93-8.
exercise in not only the placebo but also the treatment 9. Moon KH, Park SY, Kim YW. Obesity and erectile dysfunc-
groups. Thus, these medications were proposed for tion: from bench to clinical implication. World J Mens Health
use as pharmacotherapy in conjunction with healthy 2019;37:138-47.
eating, physical activity, and behavior modification. 10. Clinical guidelines on the identification, evaluation, and
Further, prior findings demonstrated that anti-obesity treatment of overweight and obesity in adults--the evidence
drugs cannot be used as a panacea for the treatment report. National Institutes of Health. Obes Res 1998;6 Suppl
of obesity; instead, they should be used to facilitate 2:51S-209S.
weight control. 11. Lee SY, Park HS, Kim DJ, Han JH, Kim SM, Cho GJ, et al. Ap-
propriate waist circumference cutoff points for central obesity
Conflict of Interest in Korean adults. Diabetes Res Clin Pract 2007;75:72-80.
12. Curioni CC, Lourenço PM. Long-term weight loss after
The authors have nothing to disclose. diet and exercise: a systematic review. Int J Obes (Lond)
2005;29:1168-74.
Author Contribution 13. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG,
Donato KA, et al. 2013 AHA/ACC/TOS guideline for the
Conceptualization: SYL. Investigation: SYL, YJT. Writing – management of overweight and obesity in adults: a report
original draft: YJT. Writing – review & editing: SYL, YJT. of the American College of Cardiology/American Heart As-
sociation Task Force on Practice Guidelines and The Obesity

REFERENCES Society. Circulation 2014;129:S102-38.

14. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley
1. World Health Organization. Obesity and overweight. Fact DL, Jastreboff AM, et al. American Association of Clinical
sheet [Internet]. Geneva: World Health Organization; c2018 Endocrinologists and American College of Endocrinology
[cited 2020 Jan 12]. Available from: http://www.who.int/me- comprehensive clinical practice guidelines for medical care of
diacentre/factsheets/fs311/en/. patients with obesity. Endocr Pract 2016;22 Suppl 3:1-203.
2. Chen Y, Peng Q, Yang Y, Zheng S, Wang Y, Lu W. The preva- 15. Bhat SP, Sharma A. Current drug targets in obesity pharma-
lence and increasing trends of overweight, general obesity, cotherapy - a review. Curr Drug Targets 2017;18:983-93.
and abdominal obesity among Chinese adults: a repeated 16. Coulter AA, Rebello CJ, Greenway FL. Centrally acting agents
cross-sectional study. BMC Public Health 2019;19:1293. for obesity: past, present, and future. Drugs 2018;78:1113-32.
3. Park YW, Choi KB, Kim SK, Lee DG, Lee JH. Obesity in 17. Daneschvar HL, Aronson MD, Smetana GW. FDA-ap-
Korean men: results from the fourth through sixth Ko- proved anti-obesity drugs in the United States. Am J Med
rean National Health and Nutrition Examination Surveys 2016;129:879.e1-6.
(2007~2014). World J Mens Health 2016;34:129-36. 18. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME,
4. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Murad MH, Pagotto U, et al. Pharmacological management
Cell Endocrinol 2015;402:113‐9. of obesity: an endocrine Society clinical practice guideline. J
5. Hwang JH, Ryu DH, Park SW. Interaction effect between Clin Endocrinol Metab 2015;100:342-62.
weight perception and comorbidities on weight control be- 19. Xenical (orlistat) patient information [Internet]. South San

218 www.wjmh.org
 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

Francisco (CA): Genentech USA, Inc.; c2016 [cited 2020 Jan lation 2000;102:2836-41.
1]. Available from: https://www.aace.com/files/obesity/tool- 31. Meltzer HY, Roth BL. Lorcaserin and pimavanserin: emerg-
kit/xenical_patient_info.pdf. ing selectivity of serotonin receptor subtype-targeted drugs. J
20. Yanovski SZ, Yanovski JA. Long-term drug treatment for obe- Clin Invest 2013;123:4986‐91.
sity: a systematic and clinical review. JAMA 2014;311:74-86. 32. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E,
21. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical Stubbe S, et al. Multicenter, placebo-controlled trial of lorca-
in the prevention of diabetes in obese subjects (XENDOS) serin for weight management. N Engl J Med 2010;363:245-56.
study: a randomized study of orlistat as an adjunct to lifestyle 33. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR,
changes for the prevention of type 2 diabetes in obese pa- Shanahan WR, et al. A one-year randomized trial of lorcase-
tients. Diabetes Care 2004;27:155-61. rin for weight loss in obese and overweight adults: the BLOS-
22. Garcia SB, Barros LT, Turatti A, Martinello F, Modiano P, Ri- SOM trial. J Clin Endocrinol Metab 2011;96:3067-77.
beiro-Silva A, et al. The anti-obesity agent Orlistat is associat- 34. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J,
ed to increase in colonic preneoplastic markers in rats treated Im K, et al. Cardiovascular safety of lorcaserin in overweight
with a chemical carcinogen. Cancer Lett 2006;240:221-4. or obese patients. N Engl J Med 2018;379:1107-17.
23. Hong JL, Meier CR, Sandler RS, Jick SS, Stürmer T. Risk of 35. O’Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M,
colorectal cancer after initiation of orlistat: matched cohort Zhang J, et al. Randomized placebo-controlled clinical trial
study. BMJ 2013;347:f5039. of lorcaserin for weight loss in type 2 diabetes mellitus: the
24. The US Food and Drug Administration. 2-13-2020 FDA drug BLOOM-DM study. Obesity (Silver Spring) 2012;20:1426-36.
safety communication [Internet]. Silver Spring (MD): The 36. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan
US Food and Drug Administration; c2020 [cited 2020 Feb WR, Anderson CM. Echocardiographic assessment of cardiac
16]. Available from: https://www.fda.gov/drugs/drug-safety- valvular regurgitation with lorcaserin from analysis of 3 phase
and-availability/fda-requests-withdrawal-weight-loss-drug- 3 clinical trials. Circ Cardiovasc Imaging 2013;6:560-7.
belviq-belviq-xr-lorcaserin-market. 37. Rothman RB, Baumann MH. Appetite suppressants, cardiac
25. The US Food and Drug Administration. 01-14-2020 FDA valve disease and combination pharmacotherapy. Am J Ther
drug safety communication [Internet]. Silver Spring (MD): 2009;16:354-64.
U.S. Food and Drug Administration; c2020 [cited 2020 38. Velazquez A, Apovian CM. Updates on obesity pharmaco-
Jan 16]. Available from: https://www.fda.gov/drugs/drug- therapy. Ann N Y Acad Sci 2018;1411:106-19.
safety-and-availability/safety-clinical-trial-shows-possible- 39. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D. Topira-
increased-risk-cancer-weight-loss-medicine-belviq-belviq-xr. mate reduces energy and fat gains in lean (Fa/?) and obese (fa/
26. Bohula EA, Scirica BM, Inzucchi SE, McGuire DK, Keech fa) Zucker rats. Obes Res 2000;8:656-63.
AC, Smith SR, et al. Effect of lorcaserin on prevention and 40. Richard D, Picard F, Lemieux C, Lalonde J, Samson P, Des-
remission of type 2 diabetes in overweight and obese patients haies Y. The effects of topiramate and sex hormones on en-
(CAMELLIA-TIMI 61): a randomised, placebo-controlled ergy balance of male and female rats. Int J Obes Relat Metab
trial. Lancet 2018;392:2269-79. Disord 2002;26:344-53.
27. Patel DK, Stanford FC. Safety and tolerability of new-gener- 41. Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers
ation anti-obesity medications: a narrative review. Postgrad ML, Najarian T, et al. Controlled-release phentermine/topi-
Med 2018;130:173-82. ramate in severely obese adults: a randomized controlled trial
28. Gustafson A, King C, Rey JA. Lorcaserin (Belviq): a selective (EQUIP). Obesity (Silver Spring) 2012;20:330-42.
serotonin 5-HT2C agonist in the treatment of obesity. P T 42. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B,
2013;38:525-34. Schwiers ML, et al. Effects of low-dose, controlled-release,
29. Roth BL, Willins DL, Kristiansen K, Kroeze WK. 5-Hydroxy- phentermine plus topiramate combination on weight and as-
tryptamine2-family receptors (5-hydroxytryptamine2A, sociated comorbidities in overweight and obese adults (CON-
5-hydroxytryptamine2B, 5-hydroxytryptamine2C): where QUER): a randomised, placebo-controlled, phase 3 trial.
structure meets function. Pharmacol Ther 1998;79:231-57. Lancet 2011;377:1341-52.
30. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride 43. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Pe-
A, Hufeisen SJ, et al. Evidence for possible involvement of terson CA, et al. Two-year sustained weight loss and metabol-
5-HT(2B) receptors in the cardiac valvulopathy associated ic benefits with controlled-release phentermine/topiramate
with fenfluramine and other serotonergic medications. Circu- in obese and overweight adults (SEQUEL): a randomized,

www.wjmh.org 219
 https://doi.org/10.5534/wjmh.200010

placebo-controlled, phase 3 extension study. Am J Clin Nutr liraglutide decreases circulating leptin and increases GIP lev-
2012;95:297-308. els and these changes are associated with alterations in CNS
44. Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, responses to food cues: a randomized, placebo-controlled,
Atkinson RL, Fujioka K, et al. Rational design of a combina- crossover study. Metabolism 2016;65:945-53.
tion medication for the treatment of obesity. Obesity (Silver 56. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Pro-
Spring) 2009;17:30-9. kop LJ, et al. Association of pharmacological treatments for
45. Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Gut- obesity with weight loss and adverse events: a systematic re-
tadauria M, Erickson J, et al. Effect of naltrexone plus bupro- view and meta-analysis. JAMA 2016;315:2424-34.
pion on weight loss in overweight and obese adults (COR-I): 57. Lean ME, Carraro R, Finer N, Hartvig H, Lindegaard ML,
a multicentre, randomised, double-blind, placebo-controlled, Rössner S, et al. Tolerability of nausea and vomiting and asso-
phase 3 trial. Lancet 2010;376:595-605. ciations with weight loss in a randomized trial of liraglutide in
46. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, obese, non-diabetic adults. Int J Obes (Lond) 2014;38:689-97.
et al. A randomized, phase 3 trial of naltrexone SR/bupropion 58. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A,
SR on weight and obesity-related risk factors (COR-II). Obe- Krempf M, et al. A randomized, controlled trial of 3.0 mg of
sity (Silver Spring) 2013;21:935-43. liraglutide in weight management. N Engl J Med 2015;373:11-
47. Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O’Neil 22.
PM, et al. Weight loss with naltrexone SR/bupropion SR com- 59. Farr OM, Sofopoulos M, Tsoukas MA, Dincer F, Thakkar
bination therapy as an adjunct to behavior modification: the B, Sahin-Efe A, et al. GLP-1 receptors exist in the parietal
COR-BMOD trial. Obesity (Silver Spring) 2011;19:110-20. cortex, hypothalamus and medulla of human brains and
48. Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, the GLP-1 analogue liraglutide alters brain activity related
Burns C, et al. Effects of naltrexone sustained-release/bupro- to highly desirable food cues in individuals with diabetes: a
pion sustained-release combination therapy on body weight crossover, randomised, placebo-controlled trial. Diabetologia
and glycemic parameters in overweight and obese patients 2016;59:954-65.
with type 2 diabetes. Diabetes Care 2013;36:4022-9. 60. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A,
49. Fujioka K, Braverman-Panza J. Answers to clinical questions Skjøth TV, et al. Efficacy of liraglutide for weight loss among
in the primary care management of people with obesity: patients with type 2 diabetes: the SCALE diabetes random-
pharmacologic management. J Fam Pract 2016;65:S16-23. ized clinical trial. JAMA 2015;314:687-99.
50. Jeon WS, Park CY. Antiobesity pharmacotherapy for patients 61. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale
with type 2 diabetes: focus on long-term management. Endo- PM, et al. Weight maintenance and additional weight loss
crinol Metab (Seoul) 2014;29:410-7. with liraglutide after low-calorie-diet-induced weight loss:
51. Apovian CM, Istfan NW. Obesity: guidelines, best practices, the SCALE Maintenance randomized study. Int J Obes (Lond)
new research. Endocrinol Metab Clin North Am 2016;45:xvii- 2013;37:1443-51.
xviii. 62. Fujioka K, O’Neil PM, Davies M, Greenway F, C W Lau D,
52. Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou Claudius B, et al. Early weight loss with liraglutide 3.0 mg pre-
SA, Katsiki N, et al. Pharmacotherapy of type 2 diabetes: an dicts 1-year weight loss and is associated with improvements
update. Metabolism 2018;78:13-42. in clinical markers. Obesity (Silver Spring) 2016;24:2278-88.
53. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. 63. Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti
Effects of the once-daily GLP-1 analog liraglutide on gastric G, et al. Safety issues with glucagon-like peptide-1 receptor
emptying, glycemic parameters, appetite and energy me- agonists (pancreatitis, pancreatic cancer and cholelithiasis):
tabolism in obese, non-diabetic adults. Int J Obes (Lond) data from randomized controlled trials. Diabetes Obes Metab
2014;38:784-93. 2017;19:1233-41.
54. Ten Kulve JS, Veltman DJ, van Bloemendaal L, Barkhof F, 64. Bahtiyar G, Pujals-Kury J, Sacerdote A. Cardiovascular effects
Drent ML, Diamant M, et al. Liraglutide reduces CNS acti- of different GLP-1 receptor agonists in patients with type 2
vation in response to visual food cues only after short-term diabetes. Curr Diab Rep 2018;18:92.
treatment in patients with type 2 diabetes. Diabetes Care 65. Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jen-
2016;39:214-21. sen CB, DeVries JH. Impact of liraglutide on amylase, lipase,
55. Farr OM, Tsoukas MA, Triantafyllou G, Dincer F, Filippaios A, and acute pancreatitis in participants with overweight/obesity
Ko BJ, et al. Short-term administration of the GLP-1 analog and normoglycemia, prediabetes, or type 2 diabetes: second-

220 www.wjmh.org
 Young Jin Tak and Sang Yeoup Lee: An Updated Review on Anti-Obesity Drugs

ary analyses of pooled data from the SCALE clinical develop- exenatide or dapagliflozin alone in patients with type 2 dia-
ment program. Diabetes Care 2017;40:839-48. betes inadequately controlled with metformin monotherapy
66. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, (DURATION-8): a 28 week, multicentre, double-blind, phase
Atkinson M, Butler PC. Marked expansion of exocrine and 3, randomised controlled trial. Lancet Diabetes Endocrinol
endocrine pancreas with incretin therapy in humans with 2016;4:1004-16.
increased exocrine pancreas dysplasia and the potential 78. Thomas CE, Mauer EA, Shukla AP, Rathi S, Aronne LJ.
for glucagon-producing neuroendocrine tumors. Diabetes Low adoption of weight loss medications: a comparison of
2013;62:2595-604. prescribing patterns of antiobesity pharmacotherapies and
67. Koehler JA, Baggio LL, Yusta B, Longuet C, Rowland KJ, Cao SGLT2s. Obesity (Silver Spring) 2016;24:1955-61.
X, et al. GLP-1R agonists promote normal and neoplastic 79. Xia Y, Kelton CM, Guo JJ, Bian B, Heaton PC. Treatment of
intestinal growth through mechanisms requiring Fgf7. Cell obesity: pharmacotherapy trends in the United States from
Metab 2015;21:379-91. 1999 to 2010. Obesity (Silver Spring) 2015;23:1721-8.
68. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. 80. Colbert JA, Jangi S. Training physicians to manage obesity-
Pancreatitis, pancreatic, and thyroid cancer with glucagon-like -back to the drawing board. N Engl J Med 2013;369:1389-91.
peptide-1-based therapies. Gastroenterology 2011;141:150-6. 81. Handjieva-Darlenska T, Handjiev S, Larsen TM, van Baak
69. Hegedüs L, Sherman SI, Tuttle RM, von Scholten BJ, Rasmus- MA, Jebb S, Papadaki A, et al. Initial weight loss on an 800-
sen S, Karsbøl JD, et al. No evidence of increase in calcitonin kcal diet as a predictor of weight loss success after 8 weeks:
concentrations or development of C-cell malignancy in re- the Diogenes study. Eur J Clin Nutr 2010;64:994-9.
sponse to liraglutide for up to 5 years in the LEADER trial. 82. Rissanen A, Lean M, Rössner S, Segal KR, Sjöström L. Predic-
Diabetes Care 2018;41:620-2. tive value of early weight loss in obesity management with or-
70. Nauck MA, Jensen TJ, Rosenkilde C, Calanna S, Buse JB; listat: an evidence-based assessment of prescribing guidelines.
LEADER Publication Committee on behalf of the LEADER Int J Obes Relat Metab Disord 2003;27:103-9.
Trial Investigators. Neoplasms reported with liraglutide 83. Fujioka K, Plodkowski R, O’Neil PM, Gilder K, Walsh B,
or placebo in people with type 2 diabetes: results from the Greenway FL. The relationship between early weight loss and
LEADER randomized trial. Diabetes Care 2018;41:1663-71. weight loss at 1 year with naltrexone ER/bupropion ER com-
71. O’Neil PM, Aroda VR, Astrup A, Kushner R, Lau DCW, Wad- bination therapy. Int J Obes (Lond) 2016;40:1369-75.
den TA, et al. Neuropsychiatric safety with liraglutide 3.0 mg 84. Singh AK, Singh R. Pharmacotherapy in obesity: a systematic
for weight management: results from randomized controlled review and meta-analysis of randomized controlled trials of
phase 2 and 3a trials. Diabetes Obes Metab 2017;19:1529-36. anti-obesity drugs. Expert Rev Clin Pharmacol 2020;13:53-
72. Wilding JP. Combination therapy for obesity. J Psychophar- 64.
macol 2017;31:1503-8. 85. Kuo HH, Wang KT, Lee YH, Lin PL, Liu ME, Lin CY, et al.
73. Lupsa BC, Inzucchi SE. Use of SGLT2 inhibitors in type Effects of lorcaserin on cardiometabolic risk factors in over-
2 diabetes: weighing the risks and benefits. Diabetologia weight and obese patients: a systematic review and meta-
2018;61:2118-25. analysis. J Clin Pharm Ther 2020;45:35-44.
74. Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: 86. Singh AK, Singh R. Efficacy and safety of lorcaserin in
effects in overweight and obese subjects without diabetes obesity: a systematic review and meta-analysis of random-
mellitus. Obesity (Silver Spring) 2014;22:1042-9. ized controlled trials. Expert Rev Clin Pharmacol 2020. doi:
75. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise 10.1080/17512433.2020.1703109 [Epub].
T, et al. Metabolic response to sodium-glucose cotrans- 87. O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Ped-
porter 2 inhibition in type 2 diabetic patients. J Clin Invest ersen SD, Wharton S, et al. Efficacy and safety of semaglutide
2014;124:499-508. compared with liraglutide and placebo for weight loss in
76. Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, patients with obesity: a randomised, double-blind, placebo
Vercruysse F, et al. Coadministration of canagliflozin and and active controlled, dose-ranging, phase 2 trial. Lancet
phentermine for weight management in overweight and obese 2018;392:637-49.
individuals without diabetes: a randomized clinical trial. Dia- 88. Dong Z, Xu L, Liu H, Lv Y, Zheng Q, Li L. Comparative ef-
betes Care 2017;40:632-9. ficacy of five long-term weight loss drugs: quantitative infor-
77. Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, et al. mation for medication guidelines. Obes Rev 2017;18:1377-85.
Exenatide once weekly plus dapagliflozin once daily versus

www.wjmh.org 221