REVIEWS

Current pharmacotherapy for obesity

Gitanjali Srivastava and Caroline M. Apovian
Abstract | More than one-third of adults in the USA have obesity, which causes, exacerbates or
adversely impacts numerous medical comorbidities, including diabetes mellitus and
cardiovascular disease. Despite intensive lifestyle modifications, the disease severity warrants
further aggressive intervention, including pharmacotherapy, medical devices and bariatric
surgery. Noninvasive anti-obesity drugs have thus now resurfaced as targeted adjunctive
therapeutic approaches to intensive lifestyle intervention, bridging the gap between lifestyle and
bariatric surgery. In this Review, we discuss FDA-approved anti-obesity drugs in terms of safety
and efficacy. As most of these drugs have a mean percentage weight loss reported in clinical trials
but individual variations in response rates, a future direction of obesity pharmacotherapy
research might include the potential for personalized medicine to target early responders to
these anti-obesity drugs.

Obesity is a chronic, complex, heterogeneous disease
with a disturbing economic burden, and it can cause
more than 200 other medical disorders that affect entire
organ systems1. Since 1980, rates of obesity have doubled
in 73 countries, with a high BMI (>25 kg/m2) account­
ing for ~4 million deaths worldwide and a high cardio­
vascular disease burden2. In the USA, over one-third of
adults (approximately 35% of men and 40% of women)
have obesity; a disproportionate rise in the severity of
obesity has also occurred3. The rapid increase in obesity
prevalence coupled with its devastating health effects
and associated comorbidities highlights the immediate
need for early recognition and treatment of this prob­
lem in the context of the existing available therapeutic
armature.
This Review is thus timely and focuses on current
anti-obesity drugs, as understanding their pharmaco­
logical safety and efficacy is crucial to the clinical care
of patients with obesity who might not have responded
to lifestyle interventions. We also highlight important
clinical insights with regards to the prescription of these
drugs. As obesity is influenced by a myriad of genetic,
Section of Endocrinology,
developmental, biological, environmental, behavioural
Diabetes and Nutrition, and iatrogenic factors (resulting in the diversification
Department of Medicine, of obesity phenotypes with individual variations in
Boston University School of weight-loss response rates) discerning the pattern of
Medicine, 720 Harrison
response to specific anti-obesity drugs will probably
Avenue, 8 th Floor, Suite 801,
Boston, increase their efficacy, which would be an early step
Massachusetts 02118, USA. towards personalized obesity medicine.
Correspondence to C.M.A.  Previously, obesity was regarded solely as a life­
caroline.apovian@bmc.org style or behavioural disorder; however, our current
doi:10.1038/nrendo.2017.122 perspective highlights the complex physiology of the
Published online 13 Oct 2017 disorder 4–6 and its devastating effect on quality of life.
We also now know that the epidemic stems from
changes within the modern microenvironment and
macro­environment, with epi­genetic, genetic, imprint­
ing and early-life events affecting the individual pre­
disposition to weight gain and accrual of fat mass.
Environmental and lifestyle factors such as circadian
rhythm, pala­tability and availability of foods, taste pref­
erences, social habits and resources also signal in a feed­
forward manner to the ‘emotional or cognitive brain’
and central pathways of the ‘metabolic brain’ (REF. 6).
These central nervous system (CNS) pathways within
the arcuate nucleus of the hypothalamus either potenti­
ate or enhance two major opposing pathways that affect
food intake and energy expenditure (FIG. 1): activation
of the orexigenic peptides neuropeptide Y (NPY) and
agouti-related peptide (AgRP) increases food intake
and decreases energy expenditure, whereas activation
of the anorexigenic peptides pro-­opiomelanocortin
(POMC) and cocaine- and amphetamine-regulated
transcript (CART) decreases food intake and increases
energy expenditure7–9. These pathways further receive
humoral, metabolic and neuronal7 afferent and efferent
signals from the gastrointestinal, muscular and adipose
tissue systems, becoming critical integral components
of energy homeostasis10–16.
Currently, there are six major FDA-approved anti-­
obesity medications: phentermine, orlistat, phentermine/
topiramate extended release (ER), lorcaserin, naltrexone
sustained release (SR)/bupropion SR and liraglutide, which
is the only injectable formulation (TABLE 1). Most of these
drugs work through CNS pathways that either reduce
appetite or enhance satiety, with the exception of orlistat,
which decreases the absorption of fat.

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Key points or uncontrolled hypertension. In 1999, owing to safety

• Obesity is a chronic, debilitating disease with devastating overall health effects and
a global burden of disease; weight loss can improve these outcomes
• Anti-obesity drugs should be initiated promptly when appropriate criteria are met if
a patient fails self-directed or professionally directed lifestyle treatment
• Anti-obesity drugs are approved in patients with a BMI ≥27 kg/m2 with at least one
obesity-related comorbidity such as diabetes mellitus, hypertension, hyperlipidaemia
or sleep apnoea or in patients with a BMI ≥30 kg/m2
• Currently, six major FDA-approved anti-obesity medications are available:
phentermine, orlistat, phentermine/topiramate extended release (ER), lorcaserin,
naltrexone sustained release (SR)/bupropion SR and liraglutide (the only injectable
formulation)
• Most of these anti-obesity drugs have an efficacy of 3–7% (estimated net weight loss)
• Identifying the type of obesity on clinical presentation coupled with an understanding
of anti-obesity drug safety, contraindications and adverse effect profiles can
selectively increase weight loss through appropriate use of these drugs
Historical perspective
The development and approval of new anti-obesity drugs
has been particularly challenging owing to an inauspi­
cious history of adverse effects dating back to the 1890s,
when the use of sheep thyroid extract (to induce weight
loss in euthyroid patients) resulted in reports of cardiac
arrhythmias and death17. Subsequently, in the 1930s,
2,4‑dinitrophenol used for weight loss caused fatal hyper­
thermia, agranulocytosis and the development of cata­
racts18–20. In the 1950s, amphetamine use became popular,
especially in combination with other mixed regimens
such as diuretics, laxatives and thyroid hormone, but
resulted in reports of serious myocardial infarction and
sudden deaths21,22. In 1992, a weight-loss trial (n = 121)
involving combination low-dose fenfluramine with
phentermine showed a mean weight loss of 15.9% from
baseline over 34 weeks, with no reported major safety
concerns in patients, which resulted in the popularity of
its usage as a combination drug for weight loss23,24.
In 1996, dexfenfluramine, an isomer of fenfluramine,
was approved by the FDA, although preclinical studies
demonstrated neurotoxicity 25 and epidemiological stud­
ies associated it with pulmonary hypertension26. The drug
was to be discontinued if weight loss of more than 1.8 kg
did not occur within the first month. Shortly afterwards,
associated reports of cardiac valvulopathy and pulmo­
nary hypertension resulted in its immediate withdrawal
from the market, with a published study subsequently
linking dexfenfluramine and fenfluramine to cardiac
valvular disease27. Phentermine was not withdrawn at
that time and has remained on the market since, as the
valvulopathy was linked solely to the serotonin-­releasing
agents fenfluramine and dexfenfluramine.
Sibutramine, a serotonin and noradrenaline reup­
take inhibitor that promotes satiety 28, was the next
agent approved in 1997 in the USA and Canada after
several clinical trials showed this agent promoted 4.2 kg
(range 3.6–4.7 kg) more weight loss than placebo over
12 months29. Safety concerns of the sympathomimetic
drug included elevation of heart rate and blood pres­
sure, and it thus came with a clear contraindication in
patients with cardiovascular disease, stroke, arrhythmia
concerns voiced in Belgium, the drug was allowed to
stay on the market provided that periodic safety moni­
toring updates and the impact on cardiovascular risk
factors were provided. In 2002, sibutramine was sus­
pended in Italy owing to an increase in reported cardio­
vascular adverse events21. In 2005, the 5‑year Sibutramine
Cardiovascular Outcomes (SCOUT; n = 9,804) trial was
initiated to assess the long-term safety of sibutramine by
comparing patients on sibutramine with those on pla­
cebo30. The SCOUT trial specifically enrolled patients
with cardiovascular disease and/or a high risk of cardio­
vascular events (that is, those with type 2 diabetes melli­
tus (T2DM) and cardio­vascular disease, T2DM alone or
cardiovascular disease alone), despite the drug’s contra­
indication in patients with cardio­vascular disease. The
results showed that after 5 years, the overall hazard ratio
(HR) for cardio­vascular events in the sibutramine-treated
group increased (HR 1.16 (95% CI 1.03–1.31; P = 0.02)),
although the HR was similar across individual groups:
T2DM alone, 1.01 (95% CI 0.74–1.38); cardio­vascular
disease alone, 1.28 (95% CI 0.92–1.78); and T2DM with
cardiovascular disease, 1.18 (95% CI 1.02–1.37)30. Before
the study was published, in 2010, following the suspen­
sion of sibutramine from the European market due to
potential risk factors and ongoing safety concerns, the
FDA asked Abbott Laboratories to voluntarily withdraw
sibutramine from the US market22. Despite the withdrawal
of sibutramine, a 2012 re‑analysis of the SCOUT trial
showed that maintained intentional weight loss improved
cardiovascular mortality even in those with pre-existing
cardiovascular disease31. Because of the chequered initial
history of weight-loss medications, anti-obesity drugs
have typically garnered negative publicity over time.
The FDA criteria for a drug to be approved for the
treatment of obesity have been stringent since standard
guidelines were issued in the mid‑1990s32. The new drug
must induce statistically significant placebo-­adjusted
weight loss of >5% at 1 year or >35% of patients should
achieve >5% weight loss (which must be at least twice that
induced by placebo). In addition, the FDA also requires
that the medication show evidence of improvement in
metabolic biomarkers, including blood pressure, lipid
levels and glycaemic control32,33. Current anti-­obesity
medications (FIG. 2; TABLES 1,2) are indicated to be used as
adjuncts to a reduced-calorie diet and increased physical
activity for chronic weight management in adults with
a BMI ≥30 kg/m2 or those with a BMI ≥27 kg/m2 who
have at least one weight-related comorbid condition such
as diabetes mellitus, hypertension, hyperlipidaemia or
sleep apnoea.
Phentermine
Phentermine, which was approved in 1959 for those
aged >16 years, is still the most commonly prescribed
anti-obesity medication in the USA and in other coun­
tries, with the exception of the European Union due to
its potential adverse effects34. Phentermine is a sympa­
thomimetic amine that is believed to suppress appetite
and release insignificant quantities of dopamine com­
pared with amphetamines and thus has a comparatively

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Determinants affecting the Y1R • Forebrain

cognitive or emotional brain • Pituitary gland
PVN • Adrenal gland
Second-order TRH
Biological influences: neurons • GI afferents
• Early-life events CRH
MC3R/
• Imprinting Orexigenic signalling MC4R
• Epigenetics ↑ Food intake Orexin
• Genetics ↓ Satiety LHA
MCH
α-MSH
Higher cortical
Y2R centres
Anorexigenic signalling
Modern macroenvironment: GHSR ↓ Food intake
• Food production, ↑ Satiety
consumption and Limbic system
availability NPY–AgRP
NST
• Social structure and cues POMC–CART
• Weather or outdoor First-order IR Recent
neurons advances:
temperatures influencing LR
physical activity • Brown fat
Third • Microbiome
• Television and technology ventricle
• Cultural norms Vagus • Muscle (irisin)
• Endocrine disruptors nerve
AC
Median eminence
and area postrema
of blood–brain
barrier
Modern microenvironment: PYY Ghrelin Insulin Leptin GLP1
• Nutrition
• Exercise
• Sleep
Endocrine Produced
• Stressors ‘L’ cells primarily
• Circadian rhythm in ileum– in fundus
cecum
Large Stomach Pancreatic Adipose tissue Small intestine
intestine β cells Produced Produced primarily
primarily in in neuroendocrine
white adipose cells; GLP1R on
tissue dorsal vagal complex
(not shown)
PYY

Figure 1 | Neuronal and hormonal pathways influencing food intake
and satiety in the brain. Complex neuro–hormonal pathways, gut
hormones and adiposity signals reciprocally interact between the
hypothalamus, brainstem, higher cortical areas and limbic system to
control appetite regulation. Peripheral signals can also interact via neural
pathways directly. Neuropeptide Y–agouti-related protein (NPY–AgRP;
orexigenic) and pro-opiomelanocortin–cocaine- and amphetamine-­
related transcript (POMC–CART; anorexigenic) neurons reside within the
arcuate nucleus (AC) of the hypothalamus. The cumulative effect of either
inhibition or activation of these orexigenic and anorexigenic neurons
from various signals in the bloodstream through the incomplete blood–
brain barriers (median eminence and area postrema) or neural pathways
influences food intake and satiety. In addition, biological and modern
Nature Reviews | Endocrinology
microenvironmental and macroenvironmental determinants affect the
cognitive or emotional brain with an impact on energy regulatory
pathways that gives rise to clinical heterogeneity (variation) in individuals
with obesity. α‑MSH, α‑melanocyte-stimulating hormone; CRH,
corticotropin-­releasing hormone; GHSR, growth hormone secretagogue
receptor; GI, gastrointestinal; GLP1, glucagon-like peptide 1; GLP1R,
GLP1 receptor; IR, insulin receptor; LHA, lateral hypothalamic area; LR,
leptin receptor; MCH, melanin-concentrating hormone; MC3R,
melanocortin receptor 3; NST, nucleus of the solitary tract; PVN,
paraventricular nucleus; PYY, peptide YY; TRH, thyrotropin-releasing
hormone; Y1R, Y1 receptor; Y2R, Y2 receptor.

lower abuse potential35. Although the exact mechanism
of action is unknown, weight loss might be mediated
through the release of catecholamines in the hypo­
thalamus, which leads to reduced appetite and decreased
food consumption36. Phentermine monotherapy is
approved for 3 months (90 days), as the 1959 labelling has
not been updated despite our understanding of obesity as
a chronic disease.
Efficacy
In a 1968 double-blind, placebo-controlled study evaluat­
ing the efficacy of continuous versus intermittent phenter­
mine in 108 women who were overweight or had obesity,
patients were randomly assigned to three groups37. The
first group was given phentermine continuously for
36 weeks; the second group was given placebo continu­
ously; and the third group was given alternating phen­
termine and placebo every 4 weeks. Mean weight loss
was −12.2 kg and −13.0 kg in the first and third groups,
respectively, compared with −4.8 kg in the placebo group.
The attrition rate was 41%, with no reported statistically
significant differences between groups; the data repre­
sented only those who completed the trial. In a more
recent 2013 clinical trial, which evaluated differences
in phentermine monotherapy compared with combina­
tions, a weight loss of 5.1% was reported at 28 weeks38.

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Table 1 | Currently available anti-obesity medications*,‡,§

Drug (dosage) Mechanism of action Administration Contraindications Warnings Common adverse
effects
Phentermine Sympathomimetic 15 mg or 37.5 mg orally Cardiovascular Rare cases of Increase in HR
(8 mg (short acting), amine once daily; 8 mg orally disease, uncontrolled primary pulmonary and/or BP, dizziness,
15 mg capsule, 2–3 times daily; can hypertension, hypertension or serious dry mouth,
37.5 mg tablet) start with a quarter or a agitated states, regurgitant cardiac constipation,
half of a 37.5 mg tablet history of drug use, valvular disease insomnia and
once daily and titrate hyperthyroidism, irritability
upwards to a maximum glaucoma or MAOI
dosage of 37.5 mg use within 14 days
Orlistat (60 mg OTC, Pancreatic and gastric 120 mg orally three Malabsorption Malabsorption of Flatulence, bloating
120 mg) lipase inhibitor times daily syndrome or fat-soluble vitamins A, and diarrhoea
cholestasis D, E and K
Phentermine/ Combination of Start with 3.75/23 mg Glaucoma, Teratogenicity (risk of Peripheral
topiramate ER|| sympathomimetic orally once daily for hyperthyroidism or cleft palate and/or cleft neuropathy
(3.75/23 mg, amine, anorectic and 14 days; increase to MAOI use within lip), suicidal ideation, (usually transient),
7.5/46 mg, ER antiepileptic drug 7/46 mg once daily 14 days changes in memory dyspepsia, insomnia,
11.25/69 mg and and monthly titration or concentration, constipation and dry
15/92 mg) upwards to achieve metabolic acidosis, mouth
weight loss; discontinue hypokalaemia
if <3% weight loss (especially in patients
on 11.25/69 mg or on potassium-wasting
<5% weight loss diuretics), rise in
on maximum dose creatinine levels,
of 15/92 mg after increase in HR,
12 weeks acute myopia or
acute angle-closure
glaucoma
Lorcaserin|| (10 mg, 5‑HT2c receptor agonist 10 mg orally twice daily Pregnancy Serotonin syndrome Headache, dizziness,
20 mg ER) or 20 mg ER once daily or neuroleptic fatigue, dry mouth,
malignant syndrome; constipation, upper
safety unknown with respiratory tract-like
coadministration symptoms and
of serotonin or hypoglycaemia
antidopaminergic in patients with
agents, cognitive diabetes mellitus
impairment, suicidal
ideation and valvular
heart disease (though
not statistically
significant in clinical
trials)
Naltrexone SR Combination Upwards titration over Uncontrolled Suicidal ideation, Nausea, constipation,
(8 mg)/bupropion opioid antagonist 4 weeks to maximum of hypertension, seizure decrease in seizure headache, vomiting,
SR|| (90 mg) and aminoketone two tablets twice daily disorders, anorexia threshold, acute dizziness, dry mouth
antidepressant nervosa or bulimia, angle glaucoma, and diarrhoea
chronic opioid use, hepatotoxicity to
MAOI use within naltrexone component
14 days, abrupt and increase in HR
discontinuation of and/or BP
alcohol or seizure
medications
Liraglutide|| (3.0 mg) GLP1 receptor agonist Start with 0.6 mg Family or personal Thyroid C‑cell tumours, Nausea,
subcutaneously once history of medullary acute pancreatitis, hypoglycaemia,
daily for 7 days; titrate thyroid cancer or acute gallbladder diarrhoea,
upwards weekly to multiple endocrine disease, increase in HR, constipation,
1.2 mg, 2.4 mg, and then neoplasia type 2 renal impairment and vomiting, headache,
maximum dosage of (MEN2) syndrome hypoglycaemia decreased appetite,
3.0 mg once daily dyspepsia, abdominal
pain, fatigue,
dizziness, increase
in lipase levels and
suicidal behaviour
or ideation
*Approved for BMI ≥30 kg/m2 or ≥27 kg/m2 with at least one comorbid condition such as diabetes mellitus, hypertension, hyperlipidaemia or sleep apnoea.
‡
All contraindicated in pregnancy; medications should not be prescribed with known allergy or hypersensitivity to any drug components.
§
With co‑use of antidiuretic medications, weight loss can cause hypoglycaemia; serum glucose levels should be monitored before and during treatment.
||
Effect on cardiovascular morbidity and mortality has not been established. 5‑HT2c, 5‑hydroxytryptamine receptor 2C; BP, blood pressure; ER, extended release;
GLP1, glucagon-like peptide 1; HR, heart rate; MAOI, monoamine oxidase inhibitor; OTC, over the counter; SR, sustained release.

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abrupt cessation of antihypertensive agents. Medical

Phentermine/topiramate ER
7.5/46 mg for 1 year decision-making regarding off-label, long-term use of
(Gadde et al. 2011)
Phentermine 15 mg daily for 28 weeks
phentermine should be done in concordance with state
(Aronne et al. 2013) medical boards and local laws. Long-term prescription
Naltrexone SR/bupropion SR of phentermine should be limited to patients without
Maximum dose for 56 weeks
(Greenway et al. 2010) evidence of cardiovascular disease or a history of sub­
Liraglutide (Saxenda [liraglutide] stance abuse disorders who have clinical evidence of
3.0 mg for 56 weeks
package insert 2014) drug efficacy and stable baseline heart rate and blood
Lorcaserin pressure readings. Off-label prescribing should also
10 mg twice daily for 1 year
(Smith et al. 2010) include appropriate documentation in medical records
Orlistat 120 mg thrice daily along with a discussion with the patient 8. Case reports of
(Aronne et al. 2013) for 1 year phentermine precipitating atrial fibrillation in patients
0 2 4 6 8 with obesity have been reported in the literature41–43.
% estimated weight loss (drug minus placebo)
Orlistat
Figure 2 | Efficacy of anti-obesity drugs. The percentage estimated weight loss (drug Orlistat is indicated for weight loss in conjunction
minus placebo) for the six currently available anti-obesityNature
drugs isReviews
depicted. ER,
| Endocrinology
with a reduced-calorie diet. It inhibits the activity of
extended release; SR, sustained release. pancreatic and gastric lipases, thereby decreasing fat
absorption by 30%44.

An 8 mg tablet formulation of phentermine was also
approved as a citizen petition under a new abbreviated
drug application, which was based on earlier studies39.
No current studies have evaluated the efficacy of the
8 mg formulation of phentermine compared with stand­
ard drug dosages of phentermine. Phentermine, like all
sympathomimetic amines, is a Schedule IV controlled
substance.
Safety
All sympathomimetics can cause stimulant-like adverse
effects, which include increases in heart rate and blood
pressure and the provocation of nervousness and/or
insomnia40. The most common treatment-emergent
adverse events (TEAEs) associated with phentermine
include dizziness, dry mouth, difficulty sleeping, irrita­
bility, nausea and/or vomiting, diarrhoea and constipa­
tion33. Phentermine is contraindicated in patients with
cardiovascular disease, hyperthyroidism, glaucoma
or a history of drug abuse and in pregnant women.
Phentermine should not be used while taking, and for
14 days after stopping, a monoamine oxidase (MAO)
inhibitor because of the risk of hypertensive crisis. The
recommended dosage of phentermine is 15–37.5 mg
orally once daily, taken 1–2 h before breakfast; phen­
termine should not be prescribed later in the evening
owing to risk of insomnia. Dosage adjustment should
be individualized to obtain an adequate treatment
response with the lowest effective dose. The 8 mg for­
mulation of phentermine is given orally twice or thrice
daily at least 30 minutes before meals owing to its
short-acting effect.
Clinical insight
Although phentermine is FDA-approved for weight loss,
it is not approved for long-term use. This caveat presents
challenges for providers, as weight regain will probably
occur following prompt discontinuation of the drug due
to the loss of drug-mediated physiologic effects, simi­
lar to patients with rebound hypertension following the
Efficacy
In a 4‑year double-blind, prospective study in which
3,305 patients with obesity were randomly assigned to
lifestyle changes plus either 120 mg orlistat or placebo
three times daily, mean weight loss was statistically
significant with orlistat (5.8 kg versus 3.0 kg with pla­
cebo; P < 0.001)45. Orlistat has been shown to reduce the
incidence of T2DM (6.2% with orlistat compared with
9.0% with placebo), corresponding to a risk reduction of
37.3% (P < 0.0032)45 and to reduced levels of total cho­
lesterol and LDL independent of weight loss46. Pooled
data from randomized, double-blind, placebo-controlled
multicentre clinical trials show a statistically significant
improvement in glucose tolerance, progression to T2DM
in adults with obesity and impaired fasting glucose levels
(3.0% with orlistat compared with 7.5% with placebo)47.
Safety
The most common TEAEs with orlistat (incidence of
5% and at least twice that of placebo) include flatulence,
oily spotting, faecal urgency, fatty/oily stool, oily defeca­
tion, increased defecation and faecal incontinence and
other adverse effects such as nephrotoxicity, hepato­
toxicity, nephrolithiasis and pancreatitis48,49. Due to fat
mal­absorption, the risk of fat-soluble vitamin deficien­
cies is considerably increased, and patients should be
advised to take a multivitamin with the formulation in
conjunction with a diet in which ~30% or less of the
calories come from fat. Orlistat is also available as a non-­
prescription, over-the-counter lower dose of 60 mg com­
pared with the prescription-strength 120 mg formulation;
both formulations are taken orally three times a day.
Clinical insight
Undesirable adverse effects coupled with only a mod­
est average weight loss have decreased the utility and
popularity of this particular medication, although
orlistat might have some benefits in patients with
impaired fasting glucose levels45 and hyperlipidaemia50
and in those who cannot tolerate the centrally acting
appetite-suppressant drugs.

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Table 2 | Major clinical trials of anti-obesity pharmacotherapy

Drug (trial) Study design n Mean Mean % of patients Comments Refs
weight loss weight loss losing ≥5% of
(kg or %)* (kg or %)‡ baseline weight§
Phentermine 36‑week 108 women with overweight –12.2 kg –4.8 kg 56% (all phentermine Data presented for 37
double-blind, or obesity (continuous groups) versus completers; statistically
placebo- dose phen- 20% with ‘dummy’ significant differences
controlled termine); capsules; although were not reported; attrition
study; conti- −13.0 kg participants lost rate 41%
nuous versus (intermittent weight, the study did
intermittent dose phen- not report whether
phentermine termine) ≥5% weight loss
every other from baseline weight
4 weeks was achieved
Orlistat 4‑year 3,305 patients randomly –5.8 kg –3.0 kg 52.8% versus Cumulative diabetes mellitus 45
double-blind assigned to lifestyle changes 37.3% at 4 years for incidence decreased in the
prospective or lifestyle plus orlistat completers orlistat group versus the
study 120 mg three times a day placebo group (6.2% versus
9.0%, with risk reduction
of 37.3%; P < 0.0032)
Phentermine/ Double-blind, 2,487 patients (BMI –9.8 kg –1.2 kg 70% (15/92 mg) and Patients on 15/92 mg 53
topiramate ER placebo- 27–45 kg/m2 with two (15/92 mg 62% (7.5/46 mg) had greater changes in
(CONQUER) controlled or more risk factors) dose); versus 21% (placebo) blood pressure, waist
trial over were randomly assigned −7.8 kg circumference and levels of
1 year (4‑week to placebo (n = 979), (7.5/46 mg lipids, fasting glucose and
titration plus phentermine/topiramate dose) insulin than those on placebo
52 weeks of ER 7.5/46 mg (n = 488) or
treatment) phentermine/topiramate
ER 15/92 mg (n = 981)
once daily
Phentermine/ 2‑year study 227 patients who completed –10.9 kg –2.1 kg 79.3% (15/92 mg) Patients on 15/92 mg had 54
topiramate overall; 1‑year the original blinded (15/92 mg and 75.2% greater changes in levels of
ER (SEQUEL) extension of treatment dose); (7.5/46 mg) versus lipids, triglycerides, fasting
CONQUER −9.6 kg 30.0% (placebo) glucose and insulin and in
(additional (7.5/46 mg waist circumference than
52 weeks of dose) those on placebo
treatment)
Lorcaserin 1‑year 4,008 patients, aged –4.7 kg –2.9 kg 40.2% (once daily) Key exclusion criteria 67
(BLOSSOM) randomized, 18–65 years, BMI 30–45 kg/ (daily dose); and 47.2% (twice included recent cardio-
double-blind, m2 or 27–29.9 kg/m2 with an −5.8 kg daily) versus 25.0% vascular events, diabetes
placebo- obesity-related condition, (twice daily (placebo) mellitus, systolic blood
controlled randomly assigned in a 2:1:2 dose) pressure ≥150 mmHg or
trial ratio to receive lorcaserin diastolic blood pressure
10 mg twice daily, 10 mg ≥95 mmHg; patients on
once daily or placebo lorcaserin lost more weight
than those on placebo
Lorcaserin 2‑year 3,182 adults with overweight –5.8 kg –2.2 kg 47.5% versus 20.3% Weight loss was maintained 68
(BLOOM) randomized, or obesity (mean BMI in a greater proportion of
double-blind, 36.2 kg/m2) randomly patients who continued to
placebo- assigned to receive receive lorcaserin during
controlled lorcaserin 10 mg twice year 2 than those who were
trial daily or placebo; after switched over to placebo
52 weeks, the placebo group
continued placebo, while
those in lorcaserin arm were
reassigned to either placebo
or an additional 52 weeks of
lorcaserin
Lorcaserin 1‑year 604 patients with baseline –5.0 kg –1.6 kg 44.7% (daily) and Significant decreases in heart 69
(BLOOM‑DM) randomized, HbA1c 7–10%, BMI 27–45 kg/ (daily dose); 37.5% (twice daily) rate with both dosages of
double-blind, m2 and treatment with −4.7 kg versus 16.1% lorcaserin compared with
placebo- metformin, sulfonylurea (twice-daily (placebo) placebo (−2.0 bpm twice-daily
controlled or both were randomly dose) dosing and −2.9 bpm daily
trial assigned to treatment dosing versus −0.4 bpm
(lorcaserin 10 mg twice placebo) and in HDL levels
daily or 10 mg once daily) or and waist circumference.
placebo FDA-defined valvulopathy
was not statistically
significant (P = 0.70; 2.3%
placebo versus 2.7%
lorcaserin group at year 1;
2.7% placebo versus 2.6%
lorcaserin at year 2)

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Table 2 (cont.) | Major clinical trials of anti-obesity pharmacotherapy

Drug (trial) Study design n Mean Mean % of patients Comments Refs
weight loss weight loss losing ≥5% of
(kg or %)* (kg or %)‡ baseline weight§
Naltrexone 1‑year 1,742 patients randomly –5.0% –1.3% 39% (16/360 mg) and Decreases in body weight 74
SR/bupropion randomized, assigned in a 1:1:1 ratio (16/360 mg 48% (32/360 mg) were greater with NB than
SR (COR‑I) double-blind, to receive placebo, NB dose); −6.1% versus 16% (placebo) with placebo
placebo- 16/360 mg or NB 32/360 mg (32/360 mg
controlled trial dose)
Naltrexone 1‑year 1,496 patients randomly –6.4% –1.2% 50.5% versus 17.1% Weight loss was statistically 75
SR/bupropion randomized, assigned in a 2:1 ratio to greater in the NB group versus
SR (COR‑II) double-blind, NB 32/360 mg or placebo; placebo and was maintained
placebo- patients on NB with <5% with continued NB through
controlled trial weight loss between week 56; randomly reassigning
28–44 weeks were randomly those who did not lose
reassigned to continue NB weight to the higher dose (NB
32/360 mg or escalate to NB 48/360 mg) did not change
48/360 mg outcomes
Naltrexone 1‑year 793 patients with obesity –11.5% –7.3% 66.4% versus 42.5% Weight loss was greater in the 76
SR/ randomized, randomly assigned in a 1:3 NB + BMOD group
bupropion SR double-blind, ratio to placebo + BMOD or compared with placebo + 
(COR-BMOD) placebo- BMOD + NB 32/350 mg BMOD; the efficacy of the
controlled trial drug is fixed, and an intensive
lifestyle modification can add
to weight loss
Naltrexone 1‑year 505 patients with overweight –5.0% –1.8% 44.5% versus 18.9% The NB group lost more 77
SR/bupropion randomized, or obesity and T2DM ± oral weight than the placebo
SR (COR- double-blind, anti-hypoglycaemic group, with improved HbA1c
Diabetes) placebo- medication randomly reduction and improvements
controlled trial assigned in a 2:1 ratio to NB in select cardiovascular risk
32/360 mg or placebo factors. NB was associated
with a higher incidence of
nausea, constipation and
vomiting than placebo. There
were no differences in rates of
depression or suicidal ideation
between the groups
Liraglutide 1‑year 3,731 patients with –8.4 kg –2.8 kg 63.2% versus 27.1% Treatment with liraglutide 85,
(3.0 mg; randomized, overweight or obesity 3.0 mg improved weight 88
SCALE- double-blind, without evidence of T2DM loss, glycaemic index,
Obesity and placebo- were randomly assigned blood pressure and waist
Prediabetes) controlled trial to liraglutide 3.0 mg circumference, while
subcutaneously once daily lowering prevalence of
versus placebo; 61.2% had prediabetes. In the 3‑year
prediabetes follow‑up assessment,
patients with obesity and
prediabetes on liraglutide had
reduced risk of progression to
T2DM by 160 weeks
Liraglutide 1‑year 846 adults with T2DM –6.0% –2.0% 54.2% versus 21.4% Among patients with T2DM 86
(3.0 mg; randomized, and overweight or obesity who had overweight or
SCALE- double-blind, were randomly assigned to obesity, weight loss was
Diabetes) placebo- liraglutide versus placebo greater in the liraglutide
controlled trial group. More gastrointestinal
disorders were reported
with liraglutide 3.0 mg
versus liraglutide 1.8 mg and
placebo. No pancreatitis was
reported
Liraglutide 1‑year 422 adults with overweight –6.2% –0.2% 81.4% versus 48.9% Liraglutide, with diet and 87
(3.0 mg; randomized, or obesity who had lost ≥5% exercise, maintained weight
SCALE- double-blind, of initial body weight during loss achieved by calorie
Maintenance) placebo- a calorie-restriction period restriction and induced
controlled trial were randomly assigned to further weight loss over 56
liraglutide versus placebo weeks. Improvements in some
cardiovascular disease risk
factors were also observed
*Treatment from baseline reported. ‡Placebo from baseline reported. §Treatment versus placebo. BLOOM, Behavioural Modification and Lorcaserin for Overweight
and Obesity Management; BLOSSOM, Behavioural Modification and Lorcaserin Second Study Group for Obesity Management; BMOD, behavioural modification;
bpm, beats per minute; CONQUER, Controlled-Release Phentermine plus Topiramate Combination in Overweight and Obese Adults; COR, Contrave Obesity
Research; ER, extended release; NB, naltrexone SR/bupropion SR; SCALE, Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic
Individuals; SEQUEL, 2‑year Sustained Weight Loss and Metabolic Benefits with Controlled-release Phentermine/Topiramate in Obese and Overweight Adults;
SR, sustained release; T2DM, type 2 diabetes mellitus.

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Phentermine/topiramate ER (n = 295)) were entered into an additional 52‑week

Phentermine/topiramate is an extended-release combina­
tion that was approved by the FDA in 2012. Topiramate
is also an antiepileptic drug and is used to treat migraine
headaches. The exact anorexigenic mechanism of
topiramate is not well understood, although it is postu­
lated that the effects are mediated through modulation
of various neurotransmitters, including the inhibition of
voltage-dependent sodium channels, glutamate recep­
tors and carbonic anhydrase and the potentiation of
γ-aminobutyrate activity 51. The combination drug has
shown greater potential weight-loss effects than mono­
therapy alone for each while also reducing adverse effects.
Efficacy
Two large randomized, double-blind, placebo-­
controlled trials over 52 weeks with a 4‑week titration
period (Controlled-Release Phentermine/Topiramate
in Severely Obese Adults (EQUIP)52 and Controlled-
Release Phentermine plus Topiramate Combination
in Overweight and Obese Adults (CONQUER)53), fol­
lowed by a 2‑year extension trial with an additional
52 weeks of treatment (2‑year Sustained Weight Loss and
Metabolic Benefits with Controlled-release Phentermine/
Topiramate in Obese and Overweight Adults (SEQUEL)54
for completers from the CONQUER study) assessed the
efficacy of the combination drug in conjunction with
intensive lifestyle modification and a well-balanced,
reduced-­calorie diet. The EQUIP trial included 1,267
adults with severe obesity (BMI >35 kg/m2) who were
randomly assigned to either phentermine/topiramate
ER 3.75 mg/23  mg or phentermine/topiramate ER
15 mg/92 mg once daily. No statistically significant differ­
ences were observed between baseline groups, and 59.9%
of the participants completed the study regardless of their
assigned treatment.
In the primary efficacy end point analysis, patients
had a statistically significant greater weight loss on the
combination overall than on placebo, with an average
weight loss of −5.1 kg from baseline in the patients who
received 3.75/23 mg compared with −10.9 kg in those
who received 15/92 mg. Approximately 17% of those on
placebo, 45% of those in the 3.75/23 mg group and 67% of
those in the 15/92 mg group lost >5% of baseline weight52.
In CONQUER, a total of 2,487 patients (BMI 27–45 kg/m2
with two or more risk factors) were randomly assigned to
placebo (n = 979), phentermine/topiramate ER 7.5/46 mg
(n = 488) or phentermine/topiramate ER 15/92  mg
(n = 981) once daily with no statistically significant dif­
ferences across groups. The combination drug overall
resulted in significantly greater weight loss than placebo,
with the higher dosage resulting in greater weight loss
than the lower dosage of the medication (−7.8 kg and
−9.8 kg from baseline, respectively, versus −1.2 kg for
placebo). Approximately 21% of patients in the pla­
cebo group, 62% of those in the 7.5/46 mg group and
70% of those in the 15/92 mg group lost >5% of baseline
body weight53.
Participants who completed CONQUER and
who continued their randomly assigned treatments
(placebo (n = 227), 7.5/46 mg (n = 153) and 15/92 mg
(total 108 weeks, approximately 2 years) SEQUEL trial54.
Overall, 84% of the patients completed the SEQUEL study.
Reported mean percentage changes in body weight were
significantly greater on the combination drug (−9.3%
in the 7.5/46 mg group, −10.5% in the 15/92 mg group)
compared with the placebo group (−1.8%; P < 0.0001).
In addition, compared with 56 weeks (CONQUER), at
108 weeks (SEQUEL), a greater percentage of patients lost
>5% of baseline weight (placebo group: 30.0%; 7.5/46 mg
group: 75.2%; and 15/92 mg group: 79.3%)54. In the
secondary end point analysis of all three studies, patients
on the combination drug had statistically significant
improvements in their lipid profile, glycaemic control
and waist circumference52–54.
Safety
Concerns expressed by the FDA included teratogenicity
(specific to both components of the combination drug)
and cardiovascular concerns (specific to the phentermine
component) as well as cognitive, psychiatric and metabolic
acidosis (the last three being specific to the topiramate
component)55. In the EQUIP and CONQUER trials, the
most common adverse events with an incidence of >1%
leading to treatment discontinuation included blurred
vision, headache, irritability, dizziness, paraesthesia,
insomnia, depression and anxiety 52,53. In addition, in the
SEQUEL trial, upper respiratory tract infection, constipa­
tion, paraesthesia and dry mouth were noted54. Rates of
discontinuation at 1 year due to adverse effects were 11.6%
in the 3.75/23 mg group and 7.5/46 mg group, 17.4% in the
15/92 mg group and 8.4% in the placebo group52,53.
In unrelated studies, an increased risk of cleft palate
and/or cleft lip in infants born to mothers on topiramate
therapy during the first trimester (prevalence ratio 5.4
for women on topiramate versus those not exposed to
topiramate (95% CI 2.0–14.5)) was observed56. In addi­
tion, topiramate might decrease the efficacy of oral con­
traceptives, although this is unlikely at doses <200 mg per
day 57. Although topiramate is not a controlled Schedule
IV drug, owing to the phentermine component, the drug
falls under the Schedule IV Controlled Substances Act.
Phentermine/topiramate ER should be taken once daily
in the morning with or without food. Gradual titration
is required, with an initial starting dose of 3.75/23 mg
once daily for 14 days and then an increase to 7.5/46 mg
daily. Further dose escalation to 11.25/69 mg and then
to 15/92 mg is recommended in nonresponders if <3%
weight loss has occurred by 12 weeks on the middle
dose (7.5/46 mg) or <5% weight loss by 12 weeks on
the maximum dose (15/92 mg). Due to the increased
risk of seizures associated with the abrupt withdrawal of
topiramate, graduated downward titration over 3–5 days
is recommended52–54,58.
Clinical insight
Although expensive, the combination drug has robust
weight-loss potential. The individual components of the
drug can be prescribed separately in available mono­therapy
dosages (phentermine 8 mg, 15 mg, 30 mg and 37.5 mg;
topiramate 15 mg, 25 mg, 50 mg, 100 mg and 200 mg).

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Although topiramate monotherapy is not currently
FDA-approved for the treatment of obesity, it has shown
benefit in patients with emotional eating and binge-­
eating disorder 59 and against weight regain following
bariatric surgery 60. Topiramate is usually prescribed
starting at 25 mg per day for the first 1–2 weeks and is
then increased in increments of 25 mg monthly (to a
maximum of 100–150 mg); dose and titration should be
guided by clinical outcome61. Close follow-up is recom­
mended once monthly for the initial 3 months and then
every 2–3 months thereafter. Transient adverse effects that
resolve quickly (for example, tingling or numbness) are
not usually concerning; however, persistent and worsen­
ing peripheral neuropathy or cognitive impairment such
as personality changes, lethargy, language impairment,
word-finding difficulty and forgetfulness warrant prompt
attention with immediate lowering of the drug dosage or
discontinuation. These adverse effects are reversible62.
Lorcaserin
Lorcaserin, a 5‑hydroxytryptamine receptor 2C (5‑HT2c)
agonist that acts on anorexigenic POMC neurons in the
hypothalamus, was also approved by the FDA in 2012 as
an adjunct to a reduced-calorie diet and increased physi­
cal activity for chronic weight management in adults with
a BMI ≥30 kg/m2 or those with a BMI ≥27 kg/m2 who have
at least one weight-related comorbid condition such as
diabetes mellitus, hypertension, hyperlipidaemia or sleep
apnoea63. Lorcaserin has specific selectivity towards the
5‑HT2c receptor, which alleviates risk associated with
prior agents of this class, such as fenfluramine, which
was found to have affinity for both 5‑HT2A (causing hal­
lucinations) and 5‑HT2B receptors (causing cardiac valve
insufficiency and pulmonary hypertension)64. Serotonin
has been known to modulate food intake and appetite65,66.
Efficacy
The efficacy of lorcaserin was addressed in three major
randomized, double-blind, placebo-controlled trials of
52‑week or 104‑week duration that enrolled patients
with overweight or obesity: Behavioural Modification and
Lorcaserin Second Study Group for Obesity Management
(BLOSSOM)67; Behavioural Modification and Lorcaserin
for Overweight and Obesity Management (BLOOM)68;
and BLOOM-DM69, which evaluated the drug specifically
in adults with T2DM.
The 1-year BLOSSOM trial (n = 4,008 patients with a
BMI ≥27 kg/m2 and more than one obesity-related con­
dition or a BMI of 30–45 kg/m2, aged 18–65 years without
cardiovascular disease or diabetes mellitus, all of whom
received diet and exercise counselling) randomly assigned
patients to three treatment arms: 10 mg lorcaserin twice
daily, 10 mg lorcaserin once daily or placebo; 55.5% of the
participants completed the trial. Both lorcaserin dosage
arms lost significantly more weight than the placebo arm,
with the twice-daily dosing associated with more weight
loss. The mean percentage weight change from baseline
was −2.8%, −5.8% and −4.7% in the placebo, 10 mg twice
daily and 10 mg once daily groups, with 25.0%, 47.2%
and 40.2% of patients losing >5% of baseline weight,
respectively 67.
The BLOOM trial (n = 3,182 patients with an average
BMI of 36.2 kg/m2) evaluated primary outcomes on lor­
caserin (10 mg twice daily versus placebo) at 1 year and
maintenance of weight loss at 2 years. After 1 year,
patients either continued placebo, or those on lorcaserin
were randomly assigned to either placebo or continuation
of the drug for an additional 52 weeks. Mean body weight
was lower in patients treated with lorcaserin for 2 years
compared with the other groups. Mean weight loss in
the lorcaserin group was greater at year 1 (−5.8 kg versus
−2.2 kg for placebo; P < 0.001) and continued into year 2
(−8.1 kg versus −3.3 kg for placebo; P < 0.001), at which
time the weight loss was maintained in a larger portion of
patients who had >5% weight loss at year 1 on lorcaserin
and who continued to receive the drug than in those who
were switched over to placebo in year 2 (67.9% versus
50.5%, respectively; P < 0.001)68. The 10 mg twice-daily
dosing was also associated with greater improvements
in the secondary end points of lipid profile and waist
circumference than placebo.
The BLOOM‑DM study enrolled patients with
T2DM (n = 604) with a baseline HbA1c of 7–10% on met­
formin ± sulfonylurea in patients who were overweight
or had obesity with at least one obesity-related medical
comorbidity. These patients were assigned to lorcaserin
10 mg twice daily (n = 256; 66.6% completion rate), lor­
caserin 10 mg once daily (n = 95; 78.9% completion rate) or
placebo (n = 253; 61.2% completion rate). The lorcaserin
groups had statistically significant reductions in mean
percentage body weight change from baseline (−4.5%
and −5.0% for 10 mg twice daily and 10 mg once daily,
respectively) compared with placebo (−1.5%) and greater
reductions in baseline HbA1c levels (>0.5%, P < 0.001)69.
Safety
The most common adverse effects reported by >2% of
patients on lorcaserin without diabetes mellitus and more
commonly than in those on placebo include headache, diz­
ziness, fatigue, nausea, dry mouth and constipation. The
most common adverse effects reported in patients with
diabetes mellitus on lorcaserin include hypo­glycaemia
(blood glucose levels <65 mg/dl), headache, back pain,
nasopharyngitis, cough and fatigue. Patients in all three
trials had serial echocardiograms due to past cardiac
valvulo­pathy concerns with the older serotonin analogues.
The incidence of new cardiac valvulopathy in lorcaserin
versus placebo groups was not statistically significant
across all three trials; the incidence of worsening valvulo­
pathy in patients who already had existing mitral or aortic
regurgitation was also not statistically significant (12.1%
with lorcaserin twice daily; 11.1% with lorcaserin once
daily; and 30.6% with placebo in BLOSSOM; P = 0.056)67.
In a pooled analysis of all phase III trials, lorcaserin did
not adversely increase FDA-defined cardiac valvulopathy
in patients with pre-existing disease69. Lorcaserin should
be administered at a dose of 10 mg twice daily orally or
20 mg extended-release once daily with or without food.
Lorcaserin should be discontinued if <5% weight loss is
achieved at 12 weeks and should not be coadministered
with another drug of the serotonin class, which might lead
to neuroleptic malignant-like syndrome63.

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Clinical insight of initial body weight on the NB + BMOD regimen

Although lorcaserin is recommended as a 10 mg twice- versus BMOD alone (P < 0.001)76. In COR-Diabetes,
daily dose, in clinical trials, the 10 mg once-daily participants had diagnosed T2DM ± antidiabetic med­
dose produced similar weight-loss outcomes as the ication. The NB 32/360 mg group lost on average −5.1%
twice-daily dosing 67,69. In addition, a 20 mg once-daily of baseline weight compared with the placebo group
extended-­release formulation of lorcaserin is now avail­ (−1.8%; P < 0.001), with 44.5% of the patients losing
able. In patients with cardiovascular disease, where sym­ >5% of baseline weight compared with those on pla­
pathomimetics should be avoided, lorcaserin might be a cebo (18.9%; P < 0.001), and had significantly greater
good option. Lorcaserin has a lower potential for increas­ reductions in HbA1c and improved cardiovascular risk
ing heart rate and blood pressure than phentermine and factors, including lipid profile77.
phentermine/topiramate ER68.
Safety
Naltrexone SR/bupropion SR The combination, NB, did not increase rates of depres­
The naltrexone SR/bupropion SR (NB) combination sion and suicidal ideation more than placebo in the
was demonstrated in preclinical animal models to func­ clinical trials74–77. Transient nausea, most frequently
tion in a synergistic manner, augmenting POMC activ­ occurring during the 3‑week dose-escalation period, was
ity to cumulatively reduce food intake and satiety 70,71. the most common adverse effect in approximately one-
Naltrexone blocks opioid receptor-mediated POMC third of patients. Other more common adverse events
auto-inhibition, and bupropion selectively inhibits reup­ reported with an incidence of at least 2% among patients
take of dopamine and noradrenaline. Monotherapy of treated with NB compared with placebo included nau­
these two drugs has also been used to treat addiction to sea, constipation, headaches, vomiting, dizziness and dry
nicotine (bupropion) and alcohol (naltrexone), and thus mouth78. The current NB formulation is available in 8 mg
the combination has an effect on CNS reward pathways, naltrexone SR and 90 mg bupropion combined dosing,
food intake and satiety through antagonistic feedback which is upwards titrated over a 4‑week period for a total
inhibition33,72. Bupropion monotherapy (300 mg per day) dosage of two tablets twice daily: one tablet once daily in
in patients with obesity and depressive symptoms has the morning during week 1, one tablet twice daily during
also been shown to facilitate weight loss (−4.6% versus week 2, two tablets in the morning and one tablet in the
−1.8% with placebo (n = 191); P < 0.001)73. evening during week 3, and finally two tablets twice daily
during week 4. The drug should be discontinued if <5%
Efficacy weight loss is achieved over 12 weeks and should not be
Four major 56‑week phase III randomized, placebo-­ used in patients with a history of seizures, drug addic­
controlled trials have evaluated the efficacy of combina­ tion and bulimia and/or anorexia nervosa. Patients
tion NB (variable dosages) versus placebo — Contrave should be advised to avoid the medication before a
Obesity Research  I (COR-I; n = 1,742) 74, COR-II procedure such as dental work, in which opiates might
(n = 1,496)75, COR-Behavioural Modification (COR- be administered.
BMOD; n = 793)76 and COR-Diabetes (n = 505)77 — in
patients with either a BMI of 30–45 kg/m2 or a BMI Clinical insight
>27–29.9 kg/m2 with evidence of dyslipidaemia and/or Adverse effects such as nausea are particularly com­
hypertension. mon in patients prescribed NB. During the initial drug-­
In COR‑I, the percentage weight loss from base­ dosage titration stage, if a patient experiences significant
line on NB 16/360 mg, NB 32/360 mg or placebo was nausea or other adverse effects, the dose should not be
−5.0%, −6.1% and −1.3%, respectively (P < 0.000), further escalated until the adverse effects have subsided
with 39% (16/360 mg) and 48% (32/360 mg) of the or the patient has demonstrated better tolerability.
patients on NB losing >5% of initial body weight Persistent or lingering adverse effects might warrant dis­
compared with those on placebo (16%; P < 0.0001; continuation of the drug. If no more than 5% of initial
P < 0.0099 for NB 16/360 mg versus NB 32/360 mg)74. body weight is lost within 12 weeks, NB should be dis­
COR‑II evaluated patients on NB 32/360 mg versus continued. In patients with food addiction and obesity,
placebo; the 16/360 mg dosing was not included in NB is advantageous74,78. A particular efficacy in patients
this trial. Patients on NB 32/360 mg lost significantly with binge-eating disorder and concomitant alcohol
more weight from baseline (−6.4% versus −1.2% with abuse has been anecdotally observed with NB, but this
placebo; P < 0.001), with 50.5% of the patients losing observation requires further study 79–82.
>5% of initial body weight (compared with 17.1% of
those on placebo; P < 0.001)75. COR-BMOD compared Liraglutide
the obesity drug NB 32/360 mg added to an intensive Liraglutide is a glucagon-like peptide 1 (GLP1) receptor
behavioural modification intervention (NB + BMOD) agonist of an incretin-derived hormone that acts through
versus the intervention alone (BMOD) in conjunction both peripheral and central receptor pathways affecting
with a reduced-calorie diet. At week 56, the average glucose homeostasis, food intake and satiety. Because of
changes in body weight were significantly greater for its incretin properties, this compound is an attractive
the NB + BMOD group versus BMOD alone (−11.5% drug for patients with T2DM and obesity. Currently, lira­
versus −7.3%; P < 0.001), with more patients losing >5% glutide is the only injectable anti-obesity drug; all others
(66.4% versus 42.5%) and >10% (41.5% versus 20.2%) are taken orally.

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Efficacy unknown in humans and no incidence of medullary thy­

In dose–response studies, liraglutide at all dosages was roid cancer on liraglutide has been reported to date92,93.
found to cause a greater mean weight loss than placebo; Liraglutide is administered subcutaneously once daily
the weight-loss response was also dose-dependent. in a 5‑week upwards dose titration to 3.0 mg. Moreover,
Liraglutide 3.0 mg caused significantly greater weight loss liraglutide is of particular benefit in patients with T2DM
than placebo or orlistat83,84. The efficacy of 3.0 mg liraglu­ or those with severe insulin resistance.
tide subcutaneously once weekly versus placebo in combi­
nation with a reduced-calorie diet and increased physical Clinical insight
activity was further assessed in four 56‑week studies: Liraglutide is initiated at 0.6 mg subcutaneously once
Satiety and Clinical Adiposity — Liraglutide Evidence in daily for the first week; the dose is escalated by 0.6 mg
Nondiabetic and diabetic individuals (SCALE)-Obesity increments every week, up to a maximum of 3.0 mg. If a
and Prediabetes85 (n = 3,731 individuals without diabetes patient experiences adverse effects such as nausea dur­
with a BMI >30 kg/m2 and overweight individuals with­ ing dose escalation, dose increases should be aborted
out diabetes with a BMI >27 kg/m2 plus more than one until better tolerability or cessation of adverse effects is
comorbidity); SCALE-Diabetes86 (n = 846 adults with achieved84. In patients with T2DM and overweight or
T2DM); SCALE-Maintenance87 (n = 422 patients who obesity, efforts to tailor pharmacological therapy for
had already lost >5% of initial body weight by calorie diabetes mellitus to promote weight loss, such as the
restriction); and follow-up 3‑year assessment 88 of the addition of GLP1 receptor agonists to the first-line agent
SCALE-Obesity and Prediabetes trial (n = 2,254 patients metformin, are recommended8.
with prediabetes who completed SCALE-Obesity and
Prediabetes re‑randomized 2:1 to either liraglutide Future directions — personalized therapy
3.0 mg subcutaneously once daily for 2 years versus pla­ The field of obesity pharmacotherapy has evolved over
cebo with a 12‑week, off-treatment follow‑up period with time. We now know that this complex and regulated
the primary outcome defined as time to diabetes onset by human energy system yields biological heterogeneity
160 weeks). In all three primary trials, patients on lira­ that translates into clinical heterogeneity and, in turn,
glutide lost significantly more weight from baseline than innumerable different obesity phenotypes and varia­
those on placebo (8% versus 2.6%, respectively, in SCALE- tions in treatment response. We have only just begun
Obesity and Prediabetes; 6.0% versus 2.0%, respectively, to recognize clinical obesity phenotypes and have not
in SCALE-Diabetes; additional 6.2% versus 0.2%, yet progressed to pharmacometabonomics research
respectively, in SCALE-Maintenance; P < 0.0001)85–87. that could identify therapeutic gene clusters involved in
A higher percentage of patients lost statistically more distinguishing early responders from nonresponders to
weight (>5% from baseline weight) on liraglutide than weight-loss medications94.
those in the placebo arm, with significant improvements Delineation, elucidation and translation of these
in glycaemic control, lipid profile and cardio­vascular clinical phenotypes into identifiable genotypes for
markers, including waist circumference 85–87. In the therapeutic purposes is not new to personalized med­
3‑year follow‑up to SCALE-Obesity and Prediabetes, icine; in fact, metabolic and genetic profiling in order
66% of patients in the liraglutide group (970/1,472) had to target responders is a novel approach to personalized
regressed from prediabetes to normoglycaemia by week drug therapy and can positively affect patient care and
160, compared with 36% of patients in the placebo group outcomes95. Psychiatric medicine, where only a subset
(268/738; odds ratio 3.6, 95% CI 3.0–4.4, P < 0.001). of patients respond to pharmacotherapy and ineffec­
Liraglutide induced greater weight loss than placebo at tive treatment results in unnecessary adverse effects of
week 160 (−6.1% (s.d. 7.3) for liraglutide versus −1.9% drug exposure, has utilized pharmacogenetic genom­
for placebo, P < 0.0001)88. ics to predict underlying treatment failure or success
response rates96. For example, a recent psychiatric study
Safety suggested that genetic variation in ERBB4 might dif­
The most common TEAEs across all four trials were ferentially affect schizophrenia treatment response to a
mostly gastrointestinal (nausea, diarrhoea, constipa­ specific drug 97. Similarly, tamoxifen therapy in oncologic
tion, vomiting, dyspepsia and abdominal pain), tran­ treatment of patients with breast cancer is influenced
sient and of mild to moderate intensity 85–88. In past years, by genetic variants and drug interaction of cytochrome
lira­glutide, an incretin-based agent, has been reported P450 2D6 inhibitors, which influence plasma concentra­
to cause pancreatitis on the basis of spontaneous post-­ tions of active drug metabolites and hence outcomes of
marketing reports, although the association has not been patients treated with tamoxifen98–101.
found to be statistically significant or clearly evident for Recognizing and targeting phenotypes early in the
pancreatitis or pancreatic cancer 89,90. If pancreatitis is treatment algorithm can result in successful clinical
suspected, the medication should be discontinued with response rates. Over the past decade, metformin has
appropriate management. Liraglutide is contraindicated demonstrated efficacy in the prevention of weight gain
in patients with a family or personal history of medul­ and, in some cases, in the promotion of weight loss in
lary thyroid carcinoma or patients with multiple endo­ both adults and children on antipsychotic medications
crine neoplasia type 2 (MEN2) syndrome91. Malignant (a distinct phenotype)102–104. Our paradigm approach
thyroid C‑cell carcinomas were detected in rats and for patients meeting criteria for anti-obesity pharmaco­
mice exposed to liraglutide, although this correlation is therapy (that is, a BMI >27 kg/m2 with comorbidity or

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a BMI >30 kg/m2) most commonly recommends the
addition of FDA-approved medications to lifestyle mod­
ification, provided the patient does not have a specific
contraindication or adverse effect on the medication8.
However, there are currently no recommendations for
which type or class of patients the drugs will be supra-­
therapeutic for, and this art is left to the skilled obesity
specialist with expertise and experience in recognizing
and appreciating these phenotypes.
Again, variation in individual treatment response is
evident, and thus successful patient phenotyping, as a
first step, would provide more accurate therapy selection
and an improved therapeutic algorithm. We also know
individual variation in weight occurs in response to
diet 105 despite dietary adherence, obesity drugs67,68,75 and
even bariatric surgery 106. Whereas some patients lose a
significant portion of weight as expected (>5% of initial
body weight), others actually gain weight, and a subset
might have treatment failures (losing <5% of initial body
weight), which results in an average weight loss being
most commonly reported in clinical trials through linear
regression models. This point is particularly important
to note when evaluating the efficacy of an anti-obesity
drug in an individual patient. Although current obesity
pharmaco­therapy research has not yet progressed to pre­
dictive biological markers of successful clinical response,
the future holds promise given the recent availability of
newly FDA-approved anti-obesity drugs.
Conclusions
Weight-loss intervention requires a multimodal com­
prehensive approach that utilizes both lifestyle and
behavioural interventions. In addition, pharmacological
therapy as an adjunct therapy can now be used for those
patients who fail to respond to lifestyle modification
alone. However, pharmacological application of these
anti-obesity drugs continues to be an art, given varia­
tion between individuals in their response to the drugs
despite a statistically significant >5% average weight loss
reported in clinical trials.

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Acknowledgements
The authors thank A. McCarthy for editorial and administra-
tive assistance.
Author contributions
G.S. and C.M.A. researched data for the article, made sub-
stantial contributions to discussions of the content, wrote the
article and reviewed and/or edited the article before
submission.
Competing interests statement
G.S. declares no competing interests. C.M.A. has received
personal fees from Gelesis, GI Dynamics, Johnson and
Johnson, Merck, NovoNordisk, Nutrisystem, Orexigen,
Sanofi-Aventis, Scientific Intake, Takeda and Zafgen; grants
from Aspire Bariatrics, the Robert C. and Veronica Atkins
Foundation, Coherence Lab, Energesis, Gelesis, GI Dynamics,
Myos, Orexigen, PCORI, Takeda and Vela Foundation; and
other forms of support from Science-Smart. No grant support
or external funding was provided to G.S. or C.M.A. for the
drafting of this manuscript.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

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