Clinical Chemistry 64:1

118–129 (2018) Reviews

Pharmacotherapy for Patients with Obesity

Kishore M. Gadde,1* John W. Apolzan,1 and Hans-Rudolf Berthoud1

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BACKGROUND: Although pharmacotherapy is not the sis on caloric restriction and increased physical activity, is
cornerstone of obesity treatment, it is a valuable tool that recommended as the first-line therapy for the prevention
could be considered for patients who have not had ade- and treatment of obesity, most patients, especially those
quate benefit from lifestyle interventions or who have with more severe forms of obesity and medical comorbidi-
difficulty maintaining initial weight loss over longer ties, need additional interventions. Furthermore, given
periods. that the most commonly encountered chronic medical
problems in clinical practice—type 2 diabetes (T2D),2
CONTENT: This review focuses on the role of antiobesity hypertension, and dyslipidemia—tend to improve with
drugs, the mechanisms by which the drugs work, poten- weight reduction (2 ), increased emphasis on obesity
tial pharmacological targets in the neural control of food management can reduce the burden of medical manage-
intake and regulation of body weight, the history of an- ment of various comorbidities individually.
tiobesity drugs, a summary of efficacy and safety data Bariatric surgery is a very effective intervention for
from clinical trials, and the clinical application of phar- achieving weight loss and ameliorating obesity-related
macotherapy. Currently, 5 approved drug therapies are comorbidities, but is associated with greater risks and
available in the US for long-term weight management, higher costs relative to nonsurgical interventions, and
with only 2 of these meeting the stronger Food and Drug thus it is not feasible or desirable for millions of individ-
Administration (FDA) criteria of 5% weight loss relative uals with obesity. Bariatric surgery is currently recom-
to a placebo after 1 year and others receiving approval mended for patients with a body mass index (BMI) of
based on the categorical criterion of the proportions of ⱖ40 kg/m2 or ⱖ35 mg/m2 in the presence of weight-
patients achieving 5% weight loss. Interpretation of the related comorbidities (3 ). Pharmacotherapy, with an ef-
results of clinical trials conducted before regulatory ficacy level that falls between that of lifestyle and surgical
agency approval is limited by high dropout rates; thus, interventions, can thus bridge the gap that exists.
the results might not be replicable in clinical practice
settings. Many patients who are suitable candidates for WHO ARE CANDIDATES FOR ANTIOBESITY DRUG THERAPY?
pharmacotherapy are not using the new drugs due to lack Drugs approved for weight management should be con-
of insurance coverage and high out-of-pocket costs. sidered for patients with a BMI of ⱖ30 kg/m2 and those
with a BMI of at least 27 kg/m2 in the presence of weight-
SUMMARY: With the availability of 4 new drugs since related comorbidities when added to lifestyle counseling
2012, clinicians in the US now have more tools for long- (3 ). Pharmacotherapy may be considered for patients
term weight management. The quality of pharmacother- with excess bodyweight who (i) achieve modest benefit
apy clinical investigations needs considerable improve- with lifestyle intervention and need additional weight
ment. Future research should focus on examining the loss; (ii) lose some weight with lifestyle intervention but
mediators and moderators of response. have difficulty maintaining weight loss; (iii) have made
© 2017 American Association for Clinical Chemistry numerous unsuccessful attempts at losing weight with
diet and exercise; and (iv) are unable to comply with
recommended lifestyle changes due to chronic severe
medical conditions.
Contributors to the development and persistence of obesity
in humans include genetic, epigenetic, biological, behav-
WHO RECEIVES ANTIOBESITY DRUG THERAPY?
ioral, psychosocial, environmental, cultural, and dietary fac-
Although nearly half of obesity patients meet BMI eligi-
tors, with the scenario being generally multifactorial (1 ).
bility criteria for antiobesity drugs, it is estimated that
Therefore, although lifestyle modification, with an empha-
ⱕ3.5% receive prescriptions for these drugs in the US
(4 – 6 ). The majority of users of antiobesity drugs are

1
Pennington Biomedical Research Center, Baton Rouge, LA.
* Address correspondence to this author at: Pennington Biomedical Research Center, 6400
2
Perkins Rd, Baton Rouge, LA 70810. E-mail [email protected]. Nonstandard abbreviations: T2D, type 2 diabetes; CNS, central nervous system; RCT,
Received June 13, 2017; accepted September 14, 2017. randomized controlled trial; FDA, Food and Drug Administration; MACE, major ad-
Previously published online at DOI: 10.1373/clinchem.2017.272815 verse cardiovascular events; NDA, new drug application; CVOT, cardiovascular out-
© 2017 American Association for Clinical Chemistry comes trial.

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women (85%), white (86%), and aged ⬍44 years (5, 7 ), including the cortico-limbic systems that make up
with the possible explanation being a higher level of body ⬎80% of the human brain. This expanded system (Fig.
image distress among these groups. 1) is thought to integrate both the classical homeostatic as
well as the hedonic, emotional, and cognitive aspects of
WHO PRESCRIBES ANTIOBESITY DRUGS AND WHICH ARE THE food intake and energy expenditure (10 ). Clearly, with a
MOST PRESCRIBED? larger system comes increased heterogeneity of neu-

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Primary care physicians account for most prescriptions rotransmitters and modulators as potential targets for
for antiobesity drugs, ranging from 70% to 84%, de- pharmacotherapy. Furthermore, the redundancy and
pending on the period of survey (6, 8 ). Despite the avail- flexibility of the system require treatments that address
ability of 5 medications for chronic weight management ⬎1 pathway. To avoid compensation, treatments ideally
since 1999, phentermine, approved in 1959 for short- impinge on both the energy intake and the energy expen-
term weight loss, remains the most commonly used an- diture arms of the system. This can be achieved by com-
tiobesity drug in the US, accounting for 74%– 89% of all bining drugs with different pharmacodynamic profiles,
prescriptions (6, 7 ). High costs, lack of insurance cover- e.g., a phentermine/topiramate combination. A number
age, and the negative attitudes of prescribers toward phar- of second-generation unimolecular polypharmacy agents
macotherapy and the treatment of obesity in general are under development (11 ).
might be factors contributing to underutilization of
newer antiobesity drugs. Furthermore, removal of some Biological defense mechanisms are a major obstacle to weight
approved antiobesity drugs (fenfluramine, dexfenflu- loss. Another fundamental new insight is the recognition
ramine, sibutramine, rimonabant) because of safety is- that it is the defense of a particular body weight that is at
sues might be a possible explanation for the reluctance of the core of the near-global obesity epidemic. Specifically,
some physicians to prescribe this class of drugs. the powerful counterregulatory and biologically adaptive
mechanisms of increased hunger and decreased metabo-
HOW DOES PHARMACOTHERAPY ASSIST IN WEIGHT LOSS lism that kick into action upon calorie restriction are
AND WEIGHT MANAGEMENT? likely the major obstacles to preventing or reversing obe-
Losing weight requires creation of a negative energy bal- sity (12 ). For any obesity prevention or treatment strat-
ance. With this in mind, patients with obesity are gener- egy, including pharmacotherapy, to be successful, it will
ally counseled to decrease their caloric intake and increase have to be able to suppress these adaptive responses and
physical activity. Antiobesity drugs, via reduction of hun- permanently change the defended level of body weight/
ger and food cravings and enhancement of satiety, help adiposity. Although we can accurately measure these
patients to limit the amount of food they eat, thereby adaptive biological responses, we do not fully understand
increasing their adherence to the prescribed diet plan (9 ). their mechanisms and, more importantly, we neither un-
Although increased energy expenditure is suggested as a derstand the molecular mechanisms that constitute de-
possible additional mechanism for weight loss associated fense of the set point nor how the set point can be
with some antiobesity drugs, reduction in energy intake changed. Bariatric surgeries in patients with obesity and
explains most of the weight loss achieved with all avail- in rodent models strongly suggest that this treatment
able antiobesity drugs. With the exception of orlistat, leads to sustained weight loss because it changes the de-
which reduces the absorption of fat in the gut, currently fended body weight/adiposity level (13 ). Therefore, un-
approved drugs for weight management primarily work derstanding the mechanisms by which bariatric surgeries
via their effects on the central nervous system (CNS). achieve resetting the body weight set point is a major
Therefore, it is important to have a basic understanding research goal as it may lead to nonsurgical interventions
of the CNS pathways involved in the regulation of energy with similar efficacy.
homeostasis.
A powerful basomedial hypothalamus is key to body weight
NEURAL CONTROL OF ENERGY HOMEOSTASIS regulation. A major candidate for body weight set point
regulation is the basomedial hypothalamus, where nutri-
Neural control of energy balance is complex, redundant, and ent availability is sensed and translated into an optimal
flexible. It has become increasingly clear that the neural behavioral and metabolic action pattern (14 ). The baso-
pathways controlling food intake and energy expenditure medial hypothalamus, more than other regions, is exqui-
that lead to the regulation of energy balance, body sitely sensitive to any kind of manipulation, leading to
weight, and fat distribution are complex, redundant, and either extreme obesity or starvation. Agonists and antag-
flexible. The idea of a relatively simple hypothalamic adi- onists to the melanocortin receptors MC4R and MC3R
postat that had emerged about 20 years ago following the are among the most powerful drugs for changing body
discovery of leptin has been replaced with an extensive weight in rodents, but application to humans has not
neural network that encompasses most areas of the brain, been successful because of strong undesirable side effects.

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Fig. 1. Schematic diagram showing potential pharmacological targets in the neural controls of food intake and regulation of body
weight.
A selection of only key neurotransmitters, hormones, and other factors (normal font) and receptors (italic) are shown at their major sites of
action. Abbreviations: AChR, cholinergic acetylcholine receptor; Adipo, adiponectin; AGRP, Agouti-related protein; AMY, amylin; AR␣,
␣-adrenergic receptor; ARß, ß-adrenergic receptor; CART, cocaine- and amphetamine-related transcript; CB1R, cannabinoid receptor-1; CCK,
cholecystokinin; CGRP, calcitonin gene-related peptide; DA, dopamine; DARs, dopamine receptors; ECs, endocannabinoids; FGF19/
20, fibroblast growth factors 19 & 21; FGFRs, fibroblast growth factor receptors; GABA, gamma-aminobutyric acid; GABARs, GABA receptors;
GLUT, glutamate; GUTRs, glutamate receptors; GLP-1, glucagon-like peptide 1; GLP-1R, glucagon-like peptide-1 receptor; IL-6, interleukin-6;
INS, insulin; InsR, insulin receptor; Lep, leptin; LepR, leptin receptor; MCH, melanin-concentrating hormone; NT, neurotensin; NTR, neuro-
tensin receptor; OPIO, opioids; OPIORs, opioid receptors; ORX, orexin/hypocretin; OT, oxytocin; POMC, proopiomelanocortin (␣-MSH); PYY,
polypeptide tyrosine-tyrosine; 5-HT, serotonin; 5-HTR2c, serotonin 2c receptor.

However, melanocortin-signaling is just one aspect of tion? One possibility for the corruption of hypothalamic
basomedial hypothalamic functions, with a recent study body weight regulatory mechanisms by palatable diets
identifying 50 transcriptionally distinct cell populations rich in saturated fats and sugar is their proinflammatory
in the arcuate nucleus-median eminence alone (15 ). The action mediated by increased numbers of microglia and
effects of the 5-HT2c agonist, lorcaserin, on food intake astrocytes in critical hypothalamic areas. However, cur-
appear to be primarily due to its activation of basomedial rent evidence suggests that the rapid initial hypothalamic
hypothalamic proopiomelanocortin neurons (16 ), al- gliosis is rather a neuroprotective response to cope with
though additional action on the mesolimbic reward cir- neural stress induced by an increased load of saturated
cuit has been suggested (17 ). Thus, targeting basomedial fats and that only long-term overnutrition eventually
hypothalamic signaling mechanisms remains a hot topic changes inflammatory signaling of hypothalamic micro-
in obesity drug development. glia and astrocytes to a more neurotoxic phenotype (19 ).
Importance of manipulating the reward value of food. The This clearly puts the blame for the initial cause of this
literature on nonhuman animals very clearly identifies vicious cycle to overeating of palatable diets high in sat-
palatable food as the major cause of obesity. More than urated fats and sugar. There is considerable evidence for a
40 years ago it was demonstrated that rats become rapidly role of the meso-corticolimbic reward pathways (20 ).
obese on a palatable cafeteria diet, an effect that was mod- Although dopamine is a crucial neurotransmitter in the
erated by access to physical activity and completely re- reward system, it also depends on opioidergic, glutama-
versed by changing the diet back to regular laboratory tergic, ␥-aminobutyric acid (GABA)-ergic, and nicotinic
chow (18 ). How is diet-induced obesity possible in the cholinergic signaling, as well as signaling via orexin and
presence of powerful hypothalamic body weight regula- the melanin-concentrating hormone. Although currently

120 Clinical Chemistry 64:1 (2018)

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Table 1. History of prescription antiobesity drugs.

Year initially
Drug approved Comments

Phentermine 1959 Short-term use; most prescribed drug in the US; withdrawn in Europe in
2000 for unfavorable benefit-to-risk

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Diethylpropion 1959 Short-term use
Phendimetrazine 1959 Short-term use
Benzphetamine 1960 Short-term use
Mazindol 1973 Short-term use; discontinued in 1999
Fenfluramine 1973 Short-term use; withdrawn in 1997 due to increased risk of valvular heart
disease
Dexfenfluramine 1996 Long-term use; withdrawn in 1997 due to increased risk of valvular heart
disease
Sibutramine 1997 Long-term use; withdrawn in 2010 due to increased risk of major adverse
cardiovascular events
Orlistat 1999 Long-term use; Approved in 2003 for pediatric obesitya
Rimonabant 2006 Long-term use; approved in Europe only; withdrawn in 2008 due to
serious psychiatric adverse events
Phentermine + Topiramate 2012 Long-term use; marketed under REMSb to reduce teratogenicity risk
Lorcaserin 2012 Long-term use; marketing delayed by a year due to DEA classification
process
Naltrexone + Bupropion 2014 Long-term use
Liraglutide 3.0 mg 2014 Long-term use; also approved at a lower dose for type 2 diabetes in 2010
a
Alli is lower-dose (60 mg) orlistat approved in 2007 for use without prescription.
b
REMS, Risk Evaluation and Mitigation Strategy.

marketed CNS-acting anorexigenic drugs affect the food thereby enhance associative memories and cognitive
reward system, there are further opportunities for devel- attention.
oping drugs that could selectively manipulate food re-
ward without having undesirable effects on mood, cog- HISTORY OF ANTIOBESITY DRUGS
nition, and executive functions. Drugs approved to treat obesity have been in existence
Fighting obesity through improvement of cognitive func- since the 1950s (Table 1). Until the approval of dexfen-
tions. Several lines of evidence in both rodents and hu- fluramine in 1996 for chronic weight management,
mans have shown strong interactions between obesity weight loss drugs were approved in the US for short-term
and cognitive functions, particularly with learning and use only, about 12 weeks. With the exception of fenflu-
memory (21, 22 ). The rescue of impaired learning and ramine, all drugs approved before 1996 were structurally
memory functions may be an effective strategy to modu- related to amphetamine, although they differed in their
late food intake and reduce body weight in obese subjects effects on enhancing the turnover of norepinephrine and
(23 ). Because habitual and “mindless” behavior routines dopamine, thus differing in their abuse potential. Al-
such as instinctively responding to environmental food though randomized controlled trials (RCTs) of at least 1
cues with eating or automatically taking the elevator in- year were lacking, these sympathomimetic drugs showed
stead of the stairs are less accessible to cognitive modula- a fair amount of efficacy, averaging approximately 3.0 –
tion (24 ), a case can be made for shifting from subcon- 3.6 kg weight loss relative to a placebo (26 ); of these
scious procedural to more conscious, associative forms of drugs, mazindol was discontinued by the manufacturer
memory and more mindful behavior. Because habit for- in 1999. Phentermine, diethylpropion, phendimetra-
mation appears to depend on a shift of activity from zine, and benzphetamine have remained on the US mar-
progressively more ventral to more dorsal striatal loops ket, with phentermine being the most prescribed weight
(25 ), a potential strategy would be to prevent or attenu- loss drug in this class, as well as among all approved
ate this shift. It will thus be important to identify the antiobesity drugs. Fenfluramine, first approved in 1973,
molecular signatures of these different striatal domains to was withdrawn worldwide 24 years later, along with its
ultimately pharmacologically target specific subsets and newly-approved isomer, dexfenfluramine, in 1997 fol-

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Table 2. 1-Year weight loss and secondary efficacy of currently available antiobesity drugs.

Drug Weight loss relative to placebo Glycemic measures Blood pressure Lipids
a
Orlistat Approximately 3.0% +++ ++ ++
Lorcaserin 3.0 to 3.6% +++ + +

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Liraglutide 4.0 to 5.4% ++++ ++ ++
Phentermine/Topiramate 8.6 to 9.3% +++ ++ ++
Naltrexone/Bupropion 3.3 to 4.8% ++ Unfavorable +
a
+ least efficacy; +++++ most efficacy.
When several doses have been studied, data are shown for the most effective dose.

lowing echocardiographic demonstration of increased publication (30 ) that reported a 36-week RCT that com-
risk of mitral and aortic regurgitation among patients pared phentermine 30 mg/day continuously, phenter-
treated with these drugs. It was also in 1997 that sibut- mine 30 mg/day intermittently (1 month on, 1 month
ramine, a serotonin and norepinephrine uptake inhibi- off), and a placebo continuously. All subjects (n ⫽ 108,
tor, was approved for long-term treatment of obesity; women) were instructed to follow an energy-restricted
however, the manufacturer voluntarily withdrew the diet of 1000 kcal/day. Results were reported only for the
drug worldwide at the request of the US Food and Drug 64 women who completed the study. Weight changes
Administration (FDA) in 2010 when results of a long- with continuous phentermine (n ⫽ 17), intermittent
term trial (27 ) in high-risk patients revealed a slightly phentermine (n ⫽ 22), and a placebo (n ⫽ 25) were
increased risk of major adverse cardiovascular events ⫺12.2 kg, ⫺13.0 kg, and ⫺4.8 kg, respectively. A sig-
(MACE) with sibutramine treatment relative to a pla- nificant placebo-subtracted weight loss of 6.4 – 6.7 kg
cebo (hazard ratio, 1.16; 95% confidence interval 1.03– was reported for phentermine 30 –37.5 mg/day in two
1.31; P ⫽ 0.02). There was considerable enthusiasm for 12-week RCTs among Korean obese patients (31, 32 ).
cannabinoid receptor-1 antagonists when rimonabant, In a recently reported 28-week RCT that compared var-
the first drug in that class, was approved in the European ious treatments, phentermine 15 mg/day led to weight
Union in 2006; however, due to increased frequency of loss of 6.1% vs 1.7% for a placebo (33 ). Common side
mood disorders and suicidal behaviors (28 ), it received a effects of phentermine are dry mouth, constipation, and
negative recommendation from an FDA advisory com-
insomnia. There is no scientific evidence that phenter-
mittee, resulting in the manufacturer withdrawing the
mine used alone increases the risk of valvular heart disease
new drug application (NDA). In 2008, the European
(34 ).
Medicines Agency ordered removal of rimonabant from
European markets. Following withdrawal of rimonabant,
CURRENTLY MARKETED DRUGS APPROVED FOR LONG-TERM
further clinical development of at least 3 other cannabi-
WEIGHT MANAGEMENT
noid receptor-1 antagonists—taranabant (Merck), CP-
945 598 (Pfizer), and BMS-646256 (Bristol Myers
Squibb)—was halted without NDA submission. Orlistat. Orlistat, a pancreatic lipase inhibitor that re-
duces intestinal absorption of fat by about one-third, has
CURRENTLY MARKETED ANTIOBESITY DRUGS APPROVED FOR
been available since 1999. Orlistat 120 mg three-times-
SHORT-TERM USE
daily achieves a placebo-subtracted weight loss of approx-
Phentermine, approved in 1959 for short-term use, is a imately 3% (Table 2) and somewhat less in RCTs of
norepinephrine-releasing agent, with possible norepi- longer duration (35, 36 ). Low-dose orlistat (60 mg
nephrine uptake inhibition with lower abuse potential three-times-daily), approved for use without a prescrip-
than amphetamine due to lack of significant dopaminer- tion, achieved a placebo-subtracted weight loss of 1.2 kg
gic effects (29 ). It is the most prescribed weight loss drug (1.6%) after 4 months in the nonprescription NDA
in the US despite the availability of 5 approved drugs for study and 2.3 kg (2.4%) at 6 months in 2 prescription
long-term use in recent years. A 2002 metaanalysis esti- NDA studies (37 ). In December 2003, orlistat was ap-
mated that treatment with phentermine 30 mg/day for proved for weight management of obese adolescents age
8 –24 weeks achieved a mean weight loss of 3.6 kg relative 12 years and above, and to date it remains the only anti-
to a placebo (26 ). Other drugs in this class have fewer obesity drug approved for pediatric patients. In a 1-year
published clinical trials. Although most clinical trials of study of obese adolescents, BMI decreased by 0.55 kg/m2
phentermine were of short duration, there was a 1968 with orlistat treatment compared with an increase of 0.31

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kg/m2 with a placebo; weight increased only 0.5 kg with practice, it would be ideal that a drug prescribed to in-
orlistat but 3.1 kg with a placebo (38 ). duce weight loss is compatible with commonly used an-
tidepressants. However, because the safety of lorcaserin
Lorcaserin. Lorcaserin, a selective serotonin 5-HT2C re- coadministered with selective serotonin reuptake inhibi-
ceptor agonist, was approved in the US in 2012 and tors, serotonin norepinephrine reuptake inhibitors, and
became available almost a year later due to a delay in other drugs that affect serotonergic system has not been

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receiving DEA classification for abuse potential. At the established or systematically evaluated, FDA recom-
recommended dose in humans, lorcaserin has minimal mends caution when using lorcaserin in patients taking
affinity for 5-HT2B receptors, stimulation of which is these drugs (45 ). During review of lorcaserin, FDA ad-
suspected to increase the risk of valvular heart disease visory committee members expressed a concern that
(39 ) that led to the withdrawal of fenfluramine and given the minimal efficacy of lorcaserin, physicians might
dexfenfluramine. On reviewing the lorcaserin NDA in combine it with phentermine (46 ). A 12-week study
2010, the FDA noted (40 ) that the mean weight loss (43 ) that compared lorcaserin alone and in combination
associated with lorcaserin was about 3% greater than the with phentermine 15 mg/day or 30 mg/day reported that
mean weight loss associated with a placebo and therefore twice as many patients dropped out due to adverse events
did not satisfy the first (5% difference in weight between in the group that received lorcaserin and phentermine 30
active drug and a placebo) of 2 efficacy criteria set forth in mg/day. Mean weight loss with lorcaserin was 3.3% with
the FDA guidelines; however, lorcaserin 10 mg twice only 28% patients achieving a weight loss of ⱖ5%. The
daily dose satisfied, by a slim margin (47% vs 23%), the study did not have placebo- or phentermine-only arms.
second efficacy criterion (the proportion of patients los-
ing ⱖ5% weight be at least 35% and at least double the Liraglutide 3.0 mg. Liraglutide is an injectable glucagon-
proportion of the placebo-treated group). Concerns were like peptide-1 agonist initially approved in 2010 for
also expressed about the increase in mammary tumors in treatment of T2D at the dose of 1.8 mg daily. Data
preclinical studies in rats. Following rereview in 2012, suggest that liraglutide decreases appetite and enhances
the FDA approved lorcaserin with certain postmarketing satiety via its effects on the CNS (47 ). These findings led
requirements (41 ) that included the conduct of a long- to the development of liraglutide for treatment of obe-
term cardiovascular outcomes trial (CVOT), which be- sity. A 20-week phase-2B trial in patients with obesity
gan in 2014 and completed enrollment of approximately demonstrated that liraglutide treatment led to a dose-
12 000 patients in December 2015; the results are pend- dependent weight loss of ⫺4.8 kg, ⫺5.5 kg, ⫺6.3 kg,
ing. In the largest of the three phase-3 trials of lorcaserin, and ⫺7.2 kg with 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg
patients on lorcaserin had a mean weight loss of 5.8 kg doses, respectively, compared with ⫺2.8 kg with a pla-
during the first year, but they gained 2.5 kg in the second cebo and ⫺4.1 kg with orlistat (48 ). The liraglutide
year, whereas patients who were blindly switched from NDA for obesity included three phase-3 trials of 1 year or
lorcaserin to a placebo gained a mean 4.8 kg (42 ). These more that primarily examined the efficacy of liraglutide
observations suggest that patients continuing on lorca- 3.0 mg/day. One of these trials randomized 3731 over-
serin beyond 1 year regain significant weight and that weight/obese patients in a 2:1 ratio to receive daily lira-
almost all of the lost weight is regained when the drug is glutide 3.0 mg or placebo for 1 year (49 ). The study
discontinued. FDA recommends discontinuation of lor- excluded patients with diabetes but enrolled those with
caserin (Table 3) after 12 weeks if weight loss of at least prediabetes who were followed for an additional 2 years
5% is not achieved (41 ). However, a recently published for a total of 3 years to examine whether liraglutide treat-
RCT showed that only 28% of obese patients treated ment could reduce the risk of developing T2D. The
with lorcaserin 10 mg twice daily achieved 5% weight mean weight change with liraglutide was ⫺8.0% vs
loss after 12 weeks (43 ), thus raising concern about the ⫺2.6% with a placebo at 1 year. For patients with pre-
utility of this drug in clinical practice because only 1 of 4 diabetes at baseline, liraglutide treatment was associated
patients would be suitable for continuing the drug for with a mean weight change of ⫺6.1% vs ⫺1.9% with a
longer than 3 months. placebo (50 ). The time to onset of T2D over 3 years was
The most frequent adverse effects of lorcaserin estimated to be 2.7 times longer with liraglutide than
(Table 4) are headache, dizziness, fatigue, nausea, dry with a placebo (95% CI 1.9 –3.9). In a separate 1-year
mouth, and constipation. The dropout rate due to ad- RCT, weight changes of ⫺6.0% with liraglutide 3.0 mg,
verse events was low (8.4% vs 6.8% with a placebo) for ⫺4.7% with liraglutide 1.8 mg, and ⫺2.0% with a pla-
patients assigned to lorcaserin in phase-3 trials (40 ). The cebo were reported among overweight/obese patients
FDA accepted a relative risk of 1.16 (95% confidence with T2D, confirming that the higher dose is more effec-
interval, 0.81–1.67) for valvular heart disease from expo- tive for weight loss (51 ). In another RCT, overweight/
sure to lorcaserin over 2 years (44 ). Because obesity and obese patients without diabetes were randomized to
depression are both common presentations in clinical liraglutide 3.0 mg or a placebo to examine weight main-

Clinical Chemistry 64:1 (2018) 123

124
Table 3. Dosing of currently available antiobesity drugs.
Reviews

DEA
Drug Trade Name (s) Recommended Dose schedule Comments
a
Phentermine Adipex-P 18.75–37.5 mg QD IV
Fastin 30 mg QD Recommended TID dosing is 30–60 min before meals. QD dosing is in the
Suprenza 15–30 mg QD morning. Avoid dosing close to bedtime.

Clinical Chemistry 64:1 (2018)

Lomaira 8 mg TID
Diethylpropion Tenuate 25 mg TID IV As above
Tenuate Dospan 75 mg QD
Phendimetrazine Bontril 35 mg TID III As above
Prelu-2 105 mg QD
Benzphetamine Didrex 25–50 mg TID III Recommended TID dosing is 30–60 min before meals.
Orlistat Xenical 120 mg TID None Recommended to take at mealtime. Dosing is same for adults and adolescents.
Alli 60 mg TID
Phentermine/Topiramate Qsymia 7.5/46 mg QD IV Start at 3.75/23 mg QD. Increase to 7.5/46 mg after 2 weeks. If weight loss is
<3% after 3 months, discontinue or increase dose to 15/92 mg QD. Consider
15/92 mg QD
using a transition dosing of 11.25/69 mg while moving to 15/92 mg.
Discontinue if weight loss is <5% after 3 months on the 15/92 mg dose.
Lorcaserin Belviq 10 mg BID IV Discontinue if weight loss is <5% after 3 months.
Belviq XR 20 mg QD
Naltrexone/Bupropion Contrave 16/180 mg BID None Available as 8/90 mg tablets only. Start 1 tablet every morning. Increase to 1
tablet BID during second week. Increase to 2 in the morning and 1 in the
evening during third week. From Week 4, dose 2 tablets BID.
Liraglutide 3.0 mg Saxenda 3 mg QD None Available as a pre-filled, multi-dose injector pen that delivers solution in selected
doses. Start 0.6 mg QD. At weekly intervals, increase the dose by 0.6 mg until
3.0 mg QD dose is reached. Inject subcutaneously in the abdomen, thigh or
upper arm. Discontinue if weight loss is <4% after 4 months.
a
QD, once daily; BID, two times daily; TID, three times daily.

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 Table 4. Most frequent adverse events and limitations of use of currently available antiobesity drugs.

Drug Adverse events Limitations of use and precautions

Phentermine Dry mouth, constipation, insomnia

Obesity Pharmacotherapy

Diethylpropion Contraindicated in patients with advanced cardiovascular disease, moderate to severe

hypertension, hyperthyroidism, glaucoma, and agitate states. Small increases in
Phendimetrazine heart rate and blood pressure may be observed. Mild to moderate abuse potential.
Benzphetamine
Orlistat Fecal urgency, fecal incontinence, flatus Contraindicated in chronic malabsorption syndrome, and cholestasis. Must take a
with discharge, oily spotting multivitamin supplement containing fat-soluble vitamins. Rare cases of liver injury.
Lorcaserin Headache, dizziness, fatigue, nausea, dry Safety of coadministration with antidepressants has not been established. Monitor for
mouth, constipation, cough, symptoms of toxicity related to serotonin excess. Potential for serotonin syndrome, a
hypoglycemia in patients with diabetes rare but serious condition. Monitor for signs and symptoms of valvular heart
disease.
Liraglutide 3.0 mg Nausea, vomiting, diarrhea, constipation, Contraindicated in patients with personal or family history of medullary thyroid
dyspepsia, abdominal pain, headache, carcinoma or Multiple Endocrine Neoplasia syndrome type 2. Should not be used
fatigue, hypoglycemia, increased with insulin. Do not use with other GLP-1 agonists. Causes thyroid C-cell tumors in
lipase rats and mice. Discontinue if pancreatitis is suspected.
Phentermine/Topiramate Paresthesia, dizziness, insomnia, Contraindicated in patients with glaucoma, hyperthyroidism, and during and within 2
dysguesia, constipation, dry mouth weeks of taking monoamine oxidase inhibitors.
Available under a Risk Evaluation and Mitigation Strategy (REMS) that requires
negative pregnancy test before treatment and monthly thereafter to reduce the risk
of teratogenicity. Small increase in heart rate. Monitor electrolytes to detect
metabolic acidosis and elevated creatinine. Monitor closely for depression, anxiety,
and memory problems.
Naltrexone/Bupropion Nausea, vomiting, headache, dizziness, Contraindicated in patients with uncontrolled hypertension, chronic opioid use,
insomnia, dry mouth, diarrhea seizure disorders, anorexia nervosa or bulimia, during withdrawal from alcohol,
barbiturates, benzodiazepines, and antiepileptic drugs. Should not use with other
bupropion-containing products and during or within 2 weeks of taking monoamine
oxidase inhibitors. Monitor for suicidal ideation and behavior. Monitor for increases
in heart rate and blood pressure. Rare cases of hepatotoxicity.

All antiobesity drugs are contraindicated in pregnancy.

Clinical Chemistry 64:1 (2018) 125

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Reviews

tenance after they had achieved an average 6.0% weight weight loss (⫺10.7%) that was significantly superior to
loss with a low-calorie diet (52 ). During the maintenance the weight loss achieved by each of the other 3 compari-
phase, mean weight changes were ⫺6.2% for liraglutide sons (placebo ⫺2.1%, phentermine ⫺4.6%, topiramate
vs ⫺0.2% for a placebo. Although liraglutide is associ- ⫺6.3%). Subsequently, a once-daily formulation was
ated with an increase in resting heart rate of 2–3 bpm tested in a 28-week RCT in which 2 doses of combina-
compared to a placebo, a long-term CVOT of 9340 pa- tion therapy (phentermine/topiramate 7.5/46 mg or

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tients with T2D revealed that those assigned to liraglu- 15/92 mg) were compared against individual compo-
tide 1.8 mg had a lower MACE incidence compared to a nents (topiramate 46 mg or 92 mg; or, phentermine 7.5
placebo group after a median follow-up of 3.8 years (53 ). mg or 15 mg) and a placebo (33 ). Weight changes
Nausea, vomiting, and diarrhea are common adverse (intention-to-treat analysis) were ⫺1.7% for a placebo,
effects of liraglutide, especially nausea, which has an in- ⫺5.5% for phentermine 7.5 mg, ⫺6.1% for phenter-
cidence of almost 40%. Liraglutide caused thyroid C-cell mine 15 mg, ⫺5.1% for topiramate 46 mg, ⫺6.4% for
tumors in rats and mice. It is contraindicated in patients topiramate 92 mg, ⫺8.5% for phentermine/topiramate
with a personal or family history of medullary thyroid 7.5/46 mg, and ⫺9.2% for phentermine/topiramate
cancer or in patients with type 2 Multiple Endocrine 15/92 mg. Although both doses of combination therapy
Neoplasia Syndrome. led to robust weight loss, the 7.5/46 mg dose had better
tolerability than the 15/92 mg dose. Unfortunately, the
Phentermine/Topiramate. As discussed above, phentermine addition of phentermine did not lower the incidence of
has been in use for nearly 6 decades in the US. The combi- neuropsychiatric adverse events as hoped.
nation of phentermine and topiramate has been well inves- The long-term safety and efficacy of phentermine/topi-
tigated for treatment of obesity, and it received FDA ap- ramate was examined in 2 large phase-3 trials, one that en-
proval in 2012. Topiramate, an unusual drug with several rolled patients with moderate to severe obesity (57 ) and
pharmacological actions, including blockade of sodium and another that enrolled overweight/obese patients with
L-type calcium channels, antagonism of glutamate ␣-amino- weight-related comorbidities (58 ). Both RCTs demon-
3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate re- strated robust efficacy with phentermine/topiramate
ceptors, facilitation of GABA-mediated chloride fluxes, with placebo-subtracted weight losses of ⫺6.6% for the
and inhibition of carbonic anhydrase activity, is ap- 7.5/46 mg and ⫺8.6% to ⫺9.3% for the 15/92 mg dose.
proved for treatment of epilepsy and migraine prophy- In addition to weight loss, there were clinically significant
laxis. Weight loss has been a frequent finding among improvements in blood pressure, triglycerides, and glyce-
patients treated with topiramate, although it is not pre- mic measures with phentermine/topiramate treatment.
cisely known which mechanism of topiramate contrib- The most frequent adverse effects of phentermine/
utes to its effects on weight (54 ). A 2011 metaanalysis of topiramate in phase-3 trials were paresthesia, dry mouth,
10 RCTs of 16 – 60 weeks duration revealed that topira- constipation, insomnia, dizziness, and dysguesia (59 ).
mate treatment led to robust weight loss, relative to a Cognitive and psychiatric adverse events occurred 2–3
placebo, of 5.3 kg in overweight/obese adults (55 ). In times more frequently with phentermine/topiramate rel-
addition to weight loss, topiramate treatment led to a ative to a placebo, leading to twice (18% vs 9%) as many
reduction in blood pressure and significant improvement patients dropping out due to tolerability issues. Topira-
of glycemia in studies of overweight/obese patients with mate increases the risk of oral clefts among babies born to
T2D and hypertension (55 ). Although topiramate dem- mothers who were exposed to topiramate during the first
onstrated consistent and clinically meaningful benefits trimester of pregnancy (60 ); therefore, to minimize the
for obese patients, the risk associated with it at the doses risk, a negative pregnancy test is required before starting
that resulted in weight loss, especially cognitive and psy- phentermine/topiramate and monthly thereafter (61 ).
chiatric adverse effects, hindered further development of At the time of approval in 2012, based on the observation
this drug for weight management. Therefore, efforts fo- of a slight increase in heart rate, especially in the first two
cused on combining low-dose topiramate with a low dose months of treatment with phentermine/topiramate, the
of another weight loss drug. In this context, phentermine FDA required (62 ) that a postmarketing CVOT be con-
appeared to be suitable candidate to combine with topi- ducted and completed by 2017; a review of clinical trials
ramate due to their varied pharmacological mechanisms registry in June 2017 revealed that such a study has not
and dissimilar adverse effect profiles. been conducted.
Gadde et al. (56 ) examined the efficacy and safety of
combining topiramate 100 mg/day with phentermine 15 Naltrexone/Bupropion. Bupropion, a marketed antide-
mg/day in comparison with individual components in a pressant that is also approved for smoking cessation, has
24-week RCT in 200 obese adults. Generic phentermine been shown to promote clinically significant weight loss
was administered in the morning and topiramate was in 3 RCTs in obese patients (63 ). Naltrexone, an opioid-
given in the evening. Combination therapy led to robust receptor antagonist, decreases food intake in animals and

126 Clinical Chemistry 64:1 (2018)

Obesity Pharmacotherapy
Reviews

decreases food cravings in obese humans, with weight loss the pharmacological actions of the various drugs. For
reported for female subjects (64, 65 ). A 16-week proof- example, for patients who report intense food cravings,
of-concept trial (66 ) revealed no difference in weight loss phentermine/topiramate and naltrexone/bupropion may
achieved with bupropion alone (⫺3.6%) vs a naltrexone/ be good options based on published studies of topiramate
bupropion combination (⫺4.0%). In a subsequent RCT and naltrexone (64, 74 ), lorcaserin for patients who struggle
of 24-weeks duration, in which study dropout rates were with impulse control (75 ), phentermine/topiramate for eat-

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extremely high (63% withdrew early in one of the ing disorders (76 ), naltrexone/bupropion for patients who
groups), additional weight loss was shown with bupro- struggle with addiction (77 ) and/or depression, liraglutide
pion combined with 2/3 doses of naltrexone (67 ). or lorcaserin to induce weight loss in overweight/obese pa-
In phase-3 RCTs, bupropion 360 mg/day combined tients with prediabetes or T2D, and orlistat for obese indi-
with naltrexone 32 mg/day or 16 mg/day achieved viduals who need to reduce their fat intake.
placebo-subtracted weight losses of 4.2% and 3.7%, re-
spectively (68 ). However, FDA reviewers expressed con- How effective are antiobesity drugs beyond 1 year? As is the
cern about heart rate and systolic and diastolic blood case with all nonsurgical interventions for treating obe-
pressure increases relative to a placebo, which were 2.4 sity, some weight is regained when antiobesity drugs are
bpm, 2.4 mmHg, and 2.0 mmHg, respectively, in the continued beyond 1 year (42, 50, 69, 70, 78 ), resulting
first 8 weeks. Heart rate and blood pressure remained in a net placebo-subtracted mean weight loss of 2%– 4%
somewhat increased even at 1 year. Further concern was after 2– 4 years, with liraglutide demonstrating the most
that naltrexone/bupropion treatment was associated with efficacy and lorcaserin and naltrexone/bupropion being
mean daytime systolic blood pressure and diastolic blood less effective.
pressure increases of 3.3 mmHg and 3.1 mmHg, respec-
tively, relative to a placebo (68 ). The FDA required a What happens when an antiobesity drug is stopped? Similar
preapproval CVOT but granted approval for naltrexone/ to the observations made with lifestyle interventions, lost
bupropion in 2014 following review of interim data from weight is regained when drug therapy for weight manage-
that trial. However, after the sponsor made an inappropriate ment is stopped, although there is some net weight loss
public release of confidential interim data, the study’s steer- when followed for few months (42, 79, 80 ). Thus, for
ing committee recommended its termination (69 ). End-of- patients who are tolerating the drug well and continuing
study data showed there was no difference in MACE inci- to benefit, further continuation of the drug therapy
dence between patients assigned to naltrexone/bupropion should be considered.
or a placebo (2.8% and 2.7% events). Notably, the authors
of the study expressed concern that only 17.3% of placebo Conclusions
patients and 27% of naltrexone/bupropion patients were
still taking the study drug at 2 years. Study discontinuation Currently, marketed drug therapies for chronic weight
rates attributed to adverse events were significantly higher management achieve 3% to 9% weight loss, relative to a
among patients assigned to naltrexone/bupropion vs a pla- placebo, after 1 year among patients with obesity when all
cebo (28.1% vs 8.7%). participants are provided some level of lifestyle counsel-
Naltrexone/bupropion is associated with a high inci- ing. Weight loss achieved with lorcaserin, orlistat, and
dence of gastrointestinal (nausea, vomiting, constipation, naltrexone/bupropion is at the lower end of the range and
dry mouth) adverse effects in addition to headache, dizzi- phentermine/topiramate at the upper end, with liraglu-
ness, insomnia, and anxiety. Naltrexone/bupropion is con- tide falling in between. Despite much enthusiasm for the
traindicated in patients with uncontrolled hypertension, sei- newer drugs at the time of approval, only a small propor-
zure disorders, and anorexia nervosa or bulimia, and it tion of eligible patients are using them due to their high
should be avoided in patients receiving chronic treatment cost. Thus, it is not surprising that phentermine, which
with opioids and in those abruptly stopping alcohol, benzo- has been available in the US for well over 5 decades,
diazepines, barbiturates, or antiepileptic drugs. remains the most prescribed drug for weight manage-
ment, although it has never been studied in a randomized
ISSUES OF INTEREST TO CLINICIANS WHEN USING
controlled trial of at least 1 year. Weight loss achieved
ANTIOBESITY DRUGS
with drug therapy generally seems to improve glycemic
control, but improvements of blood pressure and lipids
What factors predict weight loss with antiobesity drugs? are smaller and inconsistent.
Weight loss in the first 3– 6 months appears to be the best
predictor of weight loss after 1 year (70 –73 ). Although
we do not have substantial information from research Author Contributions: All authors confirmed they have contributed to
studies to guide us with regard to treatment selection, the intellectual content of this paper and have met the following 3
there are a few factors clinicians could consider based on requirements: (a) significant contributions to the conception and design,

Clinical Chemistry 64:1 (2018) 127

Reviews

acquisition of data, or analysis and interpretation of data; (b) drafting Stock Ownership: None declared.
or revising the article for intellectual content; and (c) final approval of Honoraria: None declared.
the published article. Research Funding: K.M. Gadde, NIH, AstraZeneca; J.W. Apolzan,
NIH, USDA; H.-R. Berthoud, NIH.
Authors’ Disclosures or Potential Conflicts of Interest: Upon man- Expert Testimony: None declared.
uscript submission, all authors completed the author disclosure form. Dis- Patents: K.M. Gadde, awarded several patents related to obesity and
closures and/or potential conflicts of interest: body weight. The inventions disclosed in Gadde’s patents have not

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been discussed in this manuscript.
Employment or Leadership: None declared.
Consultant or Advisory Role: K.M. Gadde, AstraZeneca for a diabetes Acknowledgment: The authors thank Katelyn Daigle for editorial as-
study with all payments made to his academic institution. sistance in preparing and revising this manuscript.

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