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Current Pharmaceutical Design, 2016, 22, 000-000 1

Approaches for the Development of Drugs for Treatment of Obesity and Metabolic
Syndrome

Maksim L. Maksimov1, Andrey A. Svistunov2, Vadim V. Tarasov1, Vladimir N. Chubarev1, Marco Ávila-
Rodriguez3, George E. Barreto3,4, Olga V. Dralova5 and Gjumrakch Aliev6,7,8

1
Department of Pharmacology of Pharmaceutical Faculty, Sechenov First Moscow State Medical University,
Moscow, Russia; 2Research Institute of Pharmacy of I.M. Sechenov First Moscow State Medical University, Mos-
cow, Russia; 3 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana,
Bogotá D.C., Colombia; 4 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile;
5
Department of Clinical Pharmacology and Propaedeutics of Internal Medicine, Sechenov First Moscow State
Medical University, Moscow, Russia; 6 GALLY International Biomedical Research Consulting LLC., 7733 Louis
Pasteur Drive, #330, San Antonio, TX, 78229, USA; 7 School of Health Science and Healthcare Administration,
University of Atlanta, E. Johns Crossing, #175, Johns Creek, GA, 30097, USA; 8 Institute of Physiologically Ac-
tive Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russia
Maksim L. Maksimov
Abstract: Obesity and metabolic syndrome (MS) are risk factors for diabetes, cancer, some cardiovascular and
musculoskeletal diseases. Pharmacotherapy should be used when the body mass index (BMI) exceeds 30 kg/m
or 27 kg/m
with comor-
bidity. Efficacy and safety of pharmacotherapy depend on the mechanism of action of drugs. In this context, drugs affecting the central
and peripheral mediator systems such as cannabinoid receptor antagonists (Rimonabant), neuronal reuptake inhibitor of NE and 5-HT
(Sibutramine), neuronal reuptake inhibitor of NE 5-HT DA (Tesofensine), agonist of 5-HT 2C receptors (Lorcaserin) have a high risk of
side effects on the central nervous and cardiovascular systems when used for a long period. Apparently, the drugs design targeting
obesity should screen safer drugs that affect fat absorption (Orlistat), activate energy metabolism (Adipokines), inhibit MetAP2
(Beloranib) and other peripheral metabolic processes. The use of synergies of anti-obesity drugs with different mechanisms of action is
an effective approach for developing new combined pharmaceutical compositions (Contrave®, EmpaticTM, Qsymia et al). The purpose of
this article is to review the currently available anti-obesity drugs and some new promising trends in development of anti-obesity therapy.
Keywords: Treatment of obesity and MS, Pharmacotherapy of obesity, Lorcaserin, Tesofensine, Sibutramine, Orlistat, Rimonabant,
Beloranib, Contrave®, EmpaticTM, Qsymia, Adipokines, Liraglutide.

INTRODUCTION MS is a combination of hormonal and metabolic disorders,

The high prevalence of obesity is a serious medical and social
problem caused by various negative factors such as urbanization,
low physical activity and consumption of high-calorie food. For
example, the body mass index (BMI) increased by 0.4-0.5 per dec-
ade all over the world [1-3]. Recent surveys in Russia have shown
that no less than 30 percent of working population is overweight
and 25 percent have obesity. Consequently, the World Health Or-
ganization (WHO) declared obesity as a non-infectious global epi-
demic of XX–XXI centuries [4-8]. Obesity is associated with in-
creased morbidity and disability risk, as well as premature mortality
of cardiovascular disease (CVD), diabetes, cancer, and diseases of
the musculoskeletal system. Life expectancy in patients with obe-
sity and overweight shortens by 4-10 years [9-11].
Numerous recent studies have identified obesity as a leading
cause for the development of type 2 diabetes mellitus (DM 2),
metabolic syndrome (MS) and cardiovascular diseases, which are
among the most important public health problems all over the world
[3, 4, 6, 12]. The CVD morbidity and mortality in people with MS
is significantly higher than in those overt any pathological event.
Patients with MS are subjected to a two-fold risk of CVD and a
five-fold risk of developing DM 2 [12-15]. It is clear that combined
medication and non-drug therapy of metabolic disorders and obe-
sity, as well as overweight correction, is an urgent task for patient
as well as for his/hers physician.
which are pathogenically closely related. It is defined as a set of
risk factors for CVD and DM 2 and characterized by obesity (in-
crease in visceral fat mass), decreased sensitivity of peripheral tis-
sues to insulin. Those factors cause disturbances of carbohydrate,
lipid (high triglycerides and low HDL cholesterol) and purine me-
tabolism, and arterial hypertension (AH). Hypertension observed in
the majority of obese patients (about 80 percent of men and 60
percent of women) is closely correlated with the degree of obesity.
Hypertension significantly increases the risk of apoplexy, heart
attack and peripheral arterial disease. Despite the global agreement
on the need to pay attention to MS, there are some discrepancies in
the criteria for its diagnosis [2, 12, 13, 16-18].
The deterioration of the MS is associated with reduced kidney
filtration function, micro albuminuria [19], increased arterial stiff-
ness [20], diastolic dysfunction, left ventricular hypertrophy (LV),
enlargement of the LV cavity [21], and carotid artery wall thicken-
ing [22], while many of these disorders occur regardless of the
magnitude of blood pressure and the presence of AH [23]. MS is a
reversible state, and appropriate treatment allows to achieve its
disappearance or at least to minimize the severity of its main mani-
festations. The loss of weight, and particularly of the visceral fat,
contributes to the correction of metabolic disorders, improves insu-
lin sensitivity and reduces blood pressure, considerably diminishing
or delaying the risk of complications [24].

TREATMENT OF OBESITY AND MS

*Address correspondence to this author at the Department of Pharmacology According to international medical practice, it is not possible to
of Pharmaceutical Faculty of I. M. Sechenov First Moscow State Medical reduce body weight for a long time [25] in 90–95 percent of cases,
University, Moscow, Russia (121019, Moscow, Nikitsky Blvd., 13);
Tel/Fax: +74956918739; E-mail: tchoubarov@mail.ru

1381-6128/16 $58.00+.00 © 2016 Bentham Science Publishers

2 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Maksimov et al.

Fig. (1). The obesity pharmacotherapy offers an alternative against the increase of body weight. These pharmacological approaches include central and periph-
eral actions. For example, rimonabant has a central action modulating the cannabinoid system with the consequent activation of the mesolimbic system. Other
drugs such as Sibutramine can inhibit the reuptake of norepinephrine and serotonin causing a strong anorectic action. In parallel, Orlistat might regulate key
metabolic enzymes such as pancreatic lipase and gastric, thus diminishing fat absorption from the food in the gastrointestinal tract. However, many pharmaco-
logical approaches involve detrimental secondary effects.

demonstrating why non-drug treatment should be complemented
with pharmacotherapy.
The expert report of NIH/NHLBI (National Institutes of Health
/ National Heart, Lung, and Blood Institute) finally concluded that
the best results are obtained by using the combined treatment with
drugs, diet, behavioral therapy, and physical activity [25, 26]. There
are six main goals for treatment of patients with MS: i) reduce body
weight; ii) achieve a good metabolic control; iii) achieve optimal
blood pressure; iv) prevent acute and long-term cardiovascular
complications; v) increase life expectancy; vi) improve glycemic
control (in patients with IGT and DM 2); and vii) normalize the
night breathing.
At the initial period of obesity treatment, the purpose is to re-
duce by 5–10 percent of body mass to assess a positive effect of
weight loss on the diseases associated with obesity. Before making
surgery more intensive weight loss may be recommended for pa-
tients with morbid obesity (BMI> 40.0) and obstructive sleep apnea
syndrome. Weight reduction by 1 kg leads to a decrease in systolic
blood pressure by 1.1 mm Hg Art (95% PI 0.7–1.4) and diastolic
blood pressure by 0.9 mm Hg Art (95 % PI 0.6-1.3). Weight loss by
5 kg reduces glucose level in the patients with diabetes by 1 mmol/l
or by 18 mg that is comparable with effect of some hypoglycemic
drugs. The improvement in carbohydrate metabolism is independ-
ent of the way it was achieved [6, 27]. The correction of body
weight should include changes in lifestyle, increased physical activ-
ity, and dietary changes aimed to achieve the balance between in-
take and expenditure of energy. The long-term effect of diets (3 to
14 years) was analyzed in 17 studies involving 3030 patients. The
weight loss of 9–11 kg was observed in 70 percent of patients
(2131) [28].
The most effective and physiological diet, containing reduced
amount of saturated fat and at the same time increased carbohy-
drates, which provides moderate caloric deficit of 500–600 kcal,
should be considered [29]. Nevertheless, it is not clear how differ-
ent diets with different macronutrient composition are comparable
to each other to achieving immediate or "delayed" weight loss. In
Anti-Obesity Drugs Development
randomized trials, the use of the fiber supplements enhances weight
loss, though it does not lead to any long-term beneficial results.
Physical activity is also recommended as a remedy for weight loss,
especially in combination with dietary changes. It is also recom-
mended to diminish risk of CVD, even if there is no weight loss.
The combination of increased physical activity with low calorie diet
leads to a more pronounced effect and changes in body shape
(fat/muscle ratio) in comparison with separate effect of diet or
physical activity alone [29].
The methods of psychotherapy based on principles of operant
stipulation and logical revaluation are used in many weight loss
programs. Such kind of methods provides an average 10 percent
weight loss during six months. In most cases, psychotherapy with-
drawal leads to a restoration of original weight [30].
The medication or even surgical correction of body weight may
be necessary if non-drug therapy turns out to be inefficient, or if
there are some certain indications. In any way pharmacological or
surgical treatment should be done on the background of continuing
non-drug interventions. Indications for drug therapy are BMI
30
kg/m, or BMI
27 kg/m with comorbidity associated with ab-
dominal obesity, family history of DM 2 or another risk factors for
cardiovascular events (dyslipidemia, AH, DM 2) [31].
Upon choosing pharmacological tactics for obesity treatment,
physician should keep in mind the high degree of cardiovascular
risk in patients with obesity as well as serious side effects of phar-
macological therapy, particularly of drugs acting on CNS, such as
Benfluorex, Rimonabant, Sibutramine. Those drugs were named by
medical community "the public health disaster caused by drugs" [2,
32]. Pharmacotherapy should be as safe as possible always. It
should help patients keep compliance, reduce obesity-related health
risks and improve quality of life. The aim of pharmacotherapy is to
help preventing the development of comorbidities associated with
obesity (e.g. atherosclerosis, AH, DM 2 and so on.), and the effi-
ciency of drug therapy should be assessed after 3 months of treat-
ment. If a satisfactory weight loss has been achieved (more than 5
% in patients without DM or more than 3% in those with it), the
treatment should be continued. Otherwise (no response to treat-
ment) drugs should be cancelled. Also, may be recommended the
changing of therapy or even the surgical treatment [33, 34]. The
weight loss drugs are divided into three groups based on their cen-
tral, peripheral, or combined effect (growth hormone, androgens)
[35, 36].
CANNABINOID RECEPTOR ANTAGONISTS
One of the well-known drugs with central mechanism of action
is Rimonabant, which is a cannabinoid receptor antagonist [37].
Rimonabant was approved in 2006 by the European Medicines
Agency (EMA) for obesity treatment and prevention of CVD [38].
Appetite control by cannabinoids has a dual mechanism of action:
activation of mesolimbic system responsible for emotional state,
and interaction with hypothalamic structures regulating energy
balance [39]. Clinical studies proved the effectiveness of Rimona-
bant for the treatment of not only obesity, but also for therapy of
nicotine dependence. For example, rimonabant facilitates smoking
cessation without rebound weight gain [40, 41]. However, in 2008,
this drug was withdrawn from registration in Europe and some non-
EC countries as a result of serious adverse neuropsychiatric reac-
tions in patients.
SELECTIVE NEURONAL REUPTAKE INHIBITOR OF
NEUROTRANSMITTERS (SEROTONIN AND NOREPI-
NEPHRINE)
Sibutramine is particularly worth mentioning, because it has
been one of the most popular anorectics for a long time [42]. It is a
selective neuronal reuptake inhibitor of neurotransmitters, serotonin
and norepinephrine. Originally, Sibutramine was tested in clinical
trials as an antidepressant [43, 44]. In these studies, the strong an-
Current Pharmaceutical Design, 2016, Vol. 22, No. 00 3
orectic action was found. For example, it promotes normalization of
eating behavior and healthy feeding habits by regulating various
hypothalamic dysfunctions. Sibutramine was first approved for
medical use in Mexico in 1997, and later it was registered in 80
countries. The drug belongs to the category of prescription drugs
and should be administered only under medical supervision.
Belgium was the first country, which in October 1999 raised the
question about safety of Sibutramine, because it increased blood
pressure and heart rate in a number of patients. In Canada, 65 car-
diovascular adverse drug reactions were observed in 2001–2007
during treatment with Sibutramine. It was noted in 13 out of 65
reports that patients had contraindications to its administration. In
Australia, where Sibutramine has been used since 2002, 135 regis-
tered reports of 404 ADRs. Beside the cardiovascular complica-
tions, there were others ADRs identified, including serious, such as:
i) Neurological symptoms, with 62 reports including headache,
dizziness, and serotonin syndrome; ii) Mental, with 50 reports stat-
ing depression, anxiety, aggression, insomnia and agitation; iii)
Gastrointestinal, where 33 reports including nausea, dry mouth and
constipation; iv) Cardiac – 31 reports including cardiac arrhyth-
mias, palpitations and retrosternal pain; v) Vascular – hypertension;
and vi) Respiratory system – dyspnea.
The long-term study SCOUT, which was performed to assess
safety of Sibutramine, involved 10744 patients with obesity or
overweight at the age of 55 years and older. Patients with CVD,
which received sibutramine, showed an increasing risk of nonfatal
MI and nonfatal stroke by 16 %, although the risk of cardiovascular
death or all-cause mortality did not increase. Basing on the SCOUT
research, European Committee for Medicinal Products (CHMP)
concluded in 2010 that the risk associated with the use of medicines
containing Sibutramine, outweighs the benefits, therefore CHMP
recommended to suspend the license for their sale in the European
Union [45-47].
PANCREATIC AND GASTRIC LIPASE INHIBITORS
The strategy of modulating metabolic processes may be di-
rected towards food absorption mechanisms, which influence the
processes of digestion and assimilation of nutrients. Such kind of
mechanism of action underlies the action of Orlistat, which acts
only within the gastrointestinal tract, but not systemically. Orlistat
diminishes fat absorption from the food in the gastrointestinal tract
by inhibiting gastrointestinal lipases (the key enzymes involved in
the hydrolysis of triglycerides of food and release of fatty acids and
monoglycerides) [48]. As a result, about 30 % of food triglycerides
is not digested and absorbed, which causes an additional deficiency
of calories in comparison with using only a hypocaloric diet.
Orlistat is registered and used in more than 140 countries all over
the world. Since 1998, more than 38 million obese patients world-
wide have had therapy with this drug. Evidence-based efficacy of
Orlistat has been proved in the large-scale international clinical
studies, where it is well tolerated, and, unlike drugs suppressing
hunger (such as Sibutramine), it has no significant side effects to
the cardiovascular or central nervous systems.
The results of XENDOS, X-PERT and XXL trials confirmed
the efficacy of Orlistat for body weight reduction used 120 mg three
times a day compared with the starting weight and placebo, both in
clinical trials and during treatment in routine clinical practice. The
prospective, randomized, placebo-controlled XENDOS study for 4
years with 3304 obese patients proved efficacy and safety of long-
term treatment with Orlistat, in which the risk of developing DM 2
decreased by 37 % compared to placebo by the end of fourth year
[49]. Orlistat is the only drug for long-term treatment of obesity
with a proven safety profile for 4 years. In a large-scale XXL study
involving 15549 patients with obesity and overweight, 87% of pa-
tients had a reduction of body weight by 5 % or more, and in 51 %
of the patients the body weight decreased by 10 % or more. The
average weight loss was 10.7%. Basing on the data of large-scale
4 Current Pharmaceutical Design, 2016, Vol. 22, No. 00
randomized clinical trials, it is possible to recommend Orlistat not
only as a drug for losing weight, but also for MS treatment, taking
into account the possibility of reducing cardiovascular risk, normal-
izing blood pressure and metabolic parameters [49-51]. The main
side effects of Orlistat are steatorrhea, discomfort and pain in the
abdomen. Its usually significantly regressing during prolonged use.
However, prolonged use of Orlistat might cause a fat-soluble vita-
min deficiency [52].
Other drugs used to correct body weight include antidepres-
sants: Fluoxetine (for patients with obesity, sleep apnea, night
meals and bulimia, depression) [53]; Topiramate (for obese patients
with bipolar disorder) [54]; Bupropion (for patients with obesity
and addiction to smoking) [55]; and Venlafaxine (for patients with
night meals) [56]; Hypoglycemic agents: Metformin – for patients
with obesity and diabetes, obese women with polycystic ovaries, as
well as obese patients receiving antipsychotic drugs leading to insu-
lin resistance [57]; Liraglutide – similar in its action to glucagon-
like peptide (GLP-1) [58]. Mimicking the action of GLP-1, it posi-
tively affects the cells in the pancreas, reduces the level of blood
sugar and slows digestion, causing a sensation of satiety, and con-
tributes to reduction in adipose tissue and weight loss; and Ex-
enatide – a potent incretin mimetic, inducing the increase of glu-
cose-depending excretion of insulin and other hypoglycemic effects
inherent in incretines [59], which allows to improve glycemic con-
trol in patients with DM 2. Finally, exenatide suppresses appetite,
reduces food intake, inhibits gastric motility and slows gastric emp-
tying.
In parallel with research in the field of hypoglycemic drugs
increasingly used for treatment of obesity and MS, previous studies
have assessed the possible impact of thyroid dysfunction on the
development of MS and its components. Thyroid dysfunction is
often associated with changes in body weight and adipose tissue
mass [60]. However, when obese patients with thyroid disease were
treated with a low-energy diet and thyroid hormones, the weight
loss of 14–35 kg was observed along with improving lipid metabo-
lism. The authors point out to the need of examining the function of
thyroid gland in patients with central obesity [61].
PROSPECTIVE DEVELOPMENTS
Currently under development there are peripheral activity drugs
for reducing weight, such as the Y2 receptor agonist, PYY3-36
[62], agonist of glucagon-like peptide (GLP-1receptor) Oxynto-
modulin [63] and Pramlintide [64], analogue of Amylin. Among
drugs acting on CNS, under study are agonists of serotonin 5HT-2C
[65], monoamine reuptake inhibitors (Tezofenadin), and combina-
tions of existing central acting agents such as low-dose opioid re-
ceptor antagonist Naltrexone and dopamine reuptake inhibitor
Bupropion [66].
Tezofenzin (Tesofensine) is a new drug for weight loss, which
is under clinical investigation [67]. Tezofenzin is a serotonin-
norepinephrine-dopamine reuptake inhibitor. It was developed for
the treatment of Parkinson and Alzheimer diseases. In clinical stud-
ies, a low efficacy of Tezofenzin against these diseases has been
noted, however a significant weight loss in patients was shown [68,
69]. At present, the results of using Tezofenzin in 161 volunteers on
the background of their compliance with the diet are obtained. The
6-month clinical trials of Tezofenzin proved that it is more effective
than placebo. Administration of 1 mg of drug reduced body weight
by 12.8 kg or 10.6 % in average; when 0.5 mg was administered,
weight loss was 11.3 kg or 9.2 %; and in the group that used 0.25
mg, weight loss was 6.7 kg or 4.5 %. In the placebo group, weight
loss was of 2.2 kg in average, or about 2 % [70, 71]. These results
recommend Tezofenzin for further study, because even in very low
doses it showed good efficacy, while there were no significant side
effects.
In October 2008, the results of clinical studies on 203 patients
were published. It was shown that Tezofenzin is twice as effective
Maksimov et al.
as Sibutramine and revoked Rimonabant in reducing body weight.
At the same time, Tezofenzin had no tendency to cause depression
and suicide during all period of observation. There were some side
effects such as a dry mouth, constipation, insomnia, diarrhea, dys-
pepsia during trials. The drug had no effect on blood pressure in a
dose of 0.5 mg, and increased heart rate only slightly at this dose
[72, 73].
Lorkaserin is an international non-proprietary name of another
new drug for weight loss. Lorkaserin stimulates 5-HT 2C receptors
of serotonin in the hypothalamus and affects on appetite and me-
tabolism. It has a similar mechanism of action with the famous Fen-
Phen (Fenfluramine and Phentermine), but has a much better
selectivity [74]. Lorkaserin has passed several clinical studies that
showed an average weight loss about 8 % of the original and a ten-
dency to decrease plasma cholesterol. The drug is well tolerated,
but may cause nausea, headache, dry mouth, dizziness, fatigue,
vomiting, with no reported cases of increasing blood pressure, pul-
monary hypertension or cardiovascular events [75]. Clinical trials
had been performed on more than 5,000 patients by 2009. In a
study completed in 2010, 47.5 percent of 3182 patients who were
administered 10 mg of Lorcaserin twice a day for 52 weeks have
shown at least 5% weight reduction compared to placebo (20.3 %)
[76]. It should be noted that patients had no signs of valvular heart
disease, despite the increased risk of tumor formation in rats [77,
78].
Clinical trials are performed with a new combination drug Con-
trave®. Contrave® contains two drugs: antidepressant Bupropion,
which is also used as a smoking cessation drug, and Naltrexone
used for the treatment of drug dependence. Bupropion monotherapy
also causes weight loss in some patients, but it is insignificant, and
therefore FDA has not approved bupropion for the treatment of
obesity [79, 80]. Contrave® affects the center of hunger in hypo-
thalamus. However, compliance to therapy by Contrave® is rela-
tively low, and only half of the patients were able to complete the
study, because 34.1 % of patients had nausea (compared to 10.5 %
in the placebo group). There was no significant increase in blood
pressure [81, 82]. Orexigen Theraupetics Inc. performed a study on
9000 patients to demonstrate that the drug does not increase the risk
of cardiovascular events.
Clinical trials were performed with Empatic™. Empatic™ is a
combination of 2 drugs consisting of Zonisamide SR and
Bupropion SR. While zonisamide is an anticonvulsant drug for the
treatment of epilepsy seizures, bupropion is a well-known antide-
pressant. Empatic™ considerably speeds up metabolism in hypo-
thalamus. Clinical trails performed in May 2006 to determine the
optimal dosing regimen were assessed on 620 patients at 14 clinical
centers. The results discovered a dose-dependent effect of Empa-
tic™: There was a weight loss from 10.1 % to 12.1 % after treat-
ment with Zonisamide SR 120 mg and Bupropion SR 280 mg. The
weight loss from 14.0 % to 15.1 % was observed with SR Zoni-
samide 360 mg and Bupropion SR 360 mg. During treatment of
729 patients with Empatic™ for 24 weeks, almost three-quarters of
patients had lost at least 5 % of body weight, and almost half of
them had lost at least 10 % of weight. There were identified no
serious adverse events (sometimes observed insomnia, nausea and
headache) which proves that this combination is safe enough, dem-
onstrating that Empatic™ might be safe for the treatment of obe-
sity.
In 2012, the FDA approved the first of two new drugs for
weight loss in the last 13 years: Qsymia (Previous name: Qnexa)
manufactured by VIVUS Pharmaceuticals and Belviq manufactured
by Arena Pharmaceuticals. Qsymia is a mixture of two separate
registered drugs: Phentermine and a slow-release form of Topi-
ramate. Phentermine is approved by FDA and has been used for
many years to reduce weight [83]. At the same time, Topiramate
has been approved by FDA as an anticonvulsant for the treatment of
epilepsy and may be also used for treating migraine or as antide-
Anti-Obesity Drugs Development
pressant [84, 85]. Nevertheless, it is expected that combination of
Topiramate and Phentermine will be more efficient for appetite
suppression and weight loss [86] in comparison with separate use of
Phentermine or Topiramate in the highest doses. The recently per-
formed clinical 1- year study on 1267 patients with a BMI > 35
kg/m2 have shown that high doses of Qsymia allow achieve more
weight loss compared to placebo [87, 88]. Another 1-year study
also examined the efficacy and safety of the drug on 2487 patients
with obesity and additional risk factors. After 56 weeks of using
drugs in medium and high doses a weight loss of 7.8 % and 9.8 %
respectively was achieved in comparison with 1.2 % in the placebo
group [89]. In the long term, the 675 patients treated with high
doses of Qsymia for 2 years showed a weight loss of 11.4 % (10.4
% after one year) compared to 2.5 % in the placebo group. The
results of the two-year safety study of Qsymia showed no side ef-
fects on heart or memory, and there were no sleep disturbance,
depression, and suicidal thoughts. However, it was observed that
women who used Topiramate during the first trimester of preg-
nancy had twice the probability of having a baby with a cleft palate,
i. e. 0.36 % compared to 0.16 % in the control group [90, 91].
At present, the adipose tissue is considered as paracrine and
endocrine organ, wherein the visceral fat is much more active in
terms of endocrinology than subcutaneous one. It is well known
that obesity leads not only to proliferation and hypertrophy of adi-
pocytes, but also to some changes in metabolic activity of adipose
tissue. The well-known adipokines (leptin, adiponectin, dipeptidyl
peptidase-4 (DPP-4) and others) are actively involved in the regula-
tion of energy balance by regulating food intake, fat distribution,
sensitivity to insulin and energy consumption [92].
Adipokines are considered as potential biomarkers and pharma-
cological targets for the treatment of obesity. Some adipokines such
as leptin, adiponectin, DPP-4, fibroblast growth factor-21 (FGF-
21), nesfatin-1, bone morphogenetic protein-7 or osteogenic pro-
tein-1 (BMP-7), tumor necrosis factor alpha (TNF-
), apelin and
vaspin are being investigated as potential candidates for the devel-
opment of drugs against obesity [93]. Most of these adipokines act
in brain, thus increasing energy consumption and causing weight
loss [94]. Thus, the concept of relationship between the CNS and
adipose tissue promotes the search for new adipokines, which influ-
ence obesity and might be potential targets for pharmacological
strategy in discovering new drugs. Among the well-known adipoki-
nes, only leptin has reached late stages of clinical studies, and the
other adipokines are still in preclinical studies.
Secretion of leptin in the adipose tissue was discovered in 1994,
and it was proposed for treatment of obesity because of its anorexi-
genic effect. Leptin acts on nuclei of hypothalamus, which regulates
the appetite and body weight [95]. It is interesting to note that in
obese patients there is an increase in serum levels of this adipokine,
and injection of exogenous leptin gives no weight loss effect, what
may be explained by the development of resistance to leptin [96,
97]. Thus, the recombinant leptin is not used for clinical treatment,
but it may be considered a remedy for a small number of patients
with congenital leptin deficiency. Metreleptin is an analog of hu-
man leptin, and has been recently approved for the treatment of
lipodystrophy in Japan [98]. Some studies have been recently per-
formed on the combined use of leptin with other peptides, such as
amylin, exendin-4 and FGF-21, for the treatment of obesity [99].
Thus, the combination of an agonist of amylin and analogue of
leptin (pramlintide/metreleptin) in clinical studies proved to be
effective in reducing body weight. Phase II of clinical trials was
suspended due to generation of antibodies and significant side ef-
fects [100]. In the future, the use of leptin’s analogues for the
treatment of obesity will require an increase in the activity of the
drug and a more prolonged action, with a more stable weight loss,
as well as safety and minimization of side effects.
Adiponectin is another promising adipokine for the treatment of
obesity with central and peripheral effects, which causes the in-
Current Pharmaceutical Design, 2016, Vol. 22, No. 00 5
crease in sensitivity to insulin, weight loss and an increase in en-
ergy consumption [101]. Previous studies were performed with
recombinant adiponectin and adiponectin analogs, and showed that
adiponectin affects the sensitivity to insulin and body weight [102].
The most promising strategy appears to develop agonists of adi-
ponectin. For example, adipoRon became a drug with such mecha-
nism of action, with positive effects on insulin resistance in mice
that get diet with a high fat content [103]. At present, there is still
no data about clinical trials in humans.
Recently, a special attention is paid to adipokine DPP-4, which
was originally studied as incretin inhibitor disrupting the body's
natural incretins. With inhibiting DPP-4, the activity of incretins is
prolonged, which in its turn increases the level of active incretins in
blood.
Several inhibitors of DPP-4 are used in clinics as antidiabetic drugs
(Sitagliptin, Vildagliptin, Saxagliptin) [104]. These drugs, in con-
trast to insulin and sulfonylurea derivatives, do not contribute to a
further weight increase in patients with DM 2.
In the search for new therapeutic alternatives, investigators
have considered other adipokines such as nesfatin-1, vaspin and
amylin. Nesfatin-1, which is secreted in the stomach, adipose tissue
and brain, directly affects the metabolism of glucose and can be
considered as a new molecule of saturation [105]. Similarly, vaspin
increases insulin resistance, although finally mechanism of its ac-
tion is still not clear [106]. These promising drugs must ensure a
stable and sustainable weight loss in conjunction with improvement
in other obesity-related pathologies. Nevertheless, the mechanisms
of action of adipokine candidates in regulating the homeostasis
have not been studied.
There is a new direction in the treatment of obesity, which
should manage to change energy consumption. New strategies are
focused on the fact that the amount of brown adipose tissue, which
actively dissipates energy as heat, is in inverse correlation with
BMI [107]. The main function of brown adipose tissue is ther-
mogenesis. It has been shown that the brown adipose tissue is acti-
vated at a low ambient temperature, while at higher ambient tem-
peratures it ceases to work actively. Adipokines produced by brown
adipose tissue have a positive effect on metabolism and may con-
tribute to the “browning” of white adipose tissue, thereby reducing
the body fat and reducing the weight.
LY2405319 is an analog of FGF-21 with effects on body
weight loss and fasting level of insulin. Its use also led to improve-
ment in lipid profile in patients with obesity and DM 2 [108], sug-
gesting FGF-21 as an effective target for the treatment of obesity.
Unfortunately, there is currently no clinical data on the effects of
BMP-7 on the development of obesity and metabolic diseases, but
this adipokine can also be considered a new therapeutic target.
Despite the initial expectations of using irizin as a drug against
obesity, in vivo and in vitro studies were not reproducible in hu-
mans. Thus, the direct use of irizin for "browning" of adipose tissue
appears to be unpromising. Although some studies have reported an
increase of irizin after physical work, recent studies in humans indi-
cate that neither rapid nor long-lasting physical exercises do not
increase the concentration of endogenous FNDC5/irizin [109, 110].
The main problem for developing drugs aimed at browning and
thermogenesis is tissue safety. The main risk is that the activation
of thermogenesis increases the adrenergic activity and may cause
cardiovascular side effects.
Recently, Danish pharmaceutical company Novo Nordisk
(Novo Nordisk A/S) announced that FDA had approved its applica-
tion for registration of a new drug Saxenda (Liraglutide) for the
treatment of obesity [58]. Liraglutide is the first approved analogue
of glucagon-like peptide 1 (GLP-1) for obesity treatment. GLP-1 is
a hormone released in response to food intake. It was earlier ap-
proved and widely used for the treatment of diabetes. Both endoge-
nous GLP-1 and Liraglutide regulate appetite and food consump-
6 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Maksimov et al.

Table 1. Mechanism of action of some anti obesity drugs. Abbreviations: CNS, Central Nervous System; GLPR-1, Glucagon-like
peptide receptor; DPP-4, dipeptidyl peptidase-4; MetAP2, methionine amino peptidase 2.

Drug Pharmacological group Mechanism of action Target

Phentermine Anorectics Norepinephrine releasing agent CNS

Sibutramine Anorectics Serotonin-norepinephrine reuptake inhibitor CNS

Rimonabant. Anorectics Selective bloker of the cannabinoid CB 1 receptors CNS

Lorcaserin Anorectics 5-HT 2c receptor agonist CNS

Venlafaxine Antidepressant Selective serotonin reuptake inhibitor CNS

Fluoxetine Antidepressant Selective serotonin reuptake inhibitor CNS

Bupropion Antidepressant Dopamine-norepinephrine reuptake inhibitor CNS

Topiramate Anticonvulsant Involves GABA-A receptors voltage-gated sodium channels, high- CNS
voltage activated calcium channels, , AMPA/kainite receptors, carbonic
anhydrase isoenzymes

Naltrexone Opioid antagonist Block of all types of opioid receptors CNS

Exenatide Hypoglycemic agents A potent incretin mimetic Endocrine system

Liraglutide Hypoglycemic agents GLPR-1 agonist Endocrine system

Metformin Oral antidiabetic drug (bigua- Suppressing hepatic glucose production Endocrine system
nide group)

Sitagliptin Antidiabetic drugs Inhibitors of DPP-4 Adipokines

Metreleptin Treatment of lipodystrophy Analog of human leptin Adipokines

Beloranib Anti obesiy drugs Inhibition of MetAP2 Metabolism

Orlistat Anti obesity drugs Pancreatic and gastric lipase inhibitor Break down try-
glicerides in intestine

Qsymia Combined anti obesity drug Synergism of ingredients CNS

containing Phentermine and a
slow-release form of Topi-
ramate.

EmpaticTM Combined anti obesity drug EmpaticTM considerably speeds up metabolism in hypothalamus Hypothalamus
containing Zonisamide and
Bupropion

Contrave® Combined anti obesity drug Contrave® affects to the center of hunger in hypothalamus Hypothalamus
containing Bupropion and
Naltrexone

tion thus diminishing sense of hunger and increasing satiety [111].
Liraglutide causes glucose-dependant stimulation of insulin secre-
tion and improves functioning of beta cells in the pancreas. At the
same time, Liraglutide inhibits unnecessarily high glucose-glucagon
secretion. Double effect of Liraglutide on the food intake and blood
glucose level is important not only for patients with obesity, but
also for patients with diabetes. Liraglutide is used in injections once
a day starting from the dose of 0.6 mg and increasing its weekly by
0.6 mg up to recommended 3 mg.
Safety and efficacy of Saxenda were estimated in 3 clinical
studies involving about 4,800 patients with obesity and overweight,
suffering from obesity-related comorbidities. The clinical studies
demonstrated after the first year that average weight loss of patients
without diabetes was 4.5 % compared with placebo. In this study,
62.3 % of participants, who received Saxenda, lost at least 5 % of
body weight compared with 34.4 % of patients receiving placebo.
The results of another clinical trial, in which the patients with DM 2
were involved, indicated that average weight loss after 1year was
3.7 % compared with placebo. In this study, 49 % of patients,
which were administered Saxenda, had lost at least 5% of body
weight compared to 16 % of those who got placebo, and in 22.4 %
of patients the body weight decreased by more than 10 % in com-
parison with 5.5 % in placebo group. The most common adverse
reactions of Saxenda were nausea (2.9 %), vomiting (1.7 %) and
diarrhea (1.4 %), and also an increased risk of hypoglycemia. The
instruction to this drug contains a warning that Liraglutide tests on
rodents caused tumors of the thyroid. However, it was not proved
that Liraglutide causes C-cell tumors in humans [112].
Agents affecting metabolism are in early stages of develop-
ment. Beloranib, which was originally developed for treating can-
cer, is investigated much better than other anti-obesity drugs. The
mechanism of action of Beloranib is realized through inhibition of
Anti-Obesity Drugs Development
methionine amino peptidase 2 (MetAP2) that triggers fat oxidation
and reduces appetite [113]. The study of Beloranib included 147
patients with hypothalamic injury, 122 of them had good
compliance and completed the study. Patients were mostly repre-
sented by obese women with 100.9 kg of body weight and body
mass index of 37.6 kg/m2, who were randomized into three groups.
The first group had 0.6 mg of beloranib, the second group – 1.2 mg
and the third group – 2.4 mg . The results of this study showed that
after 12 weeks of treatment, patients administered 0.6 mg, 1.2 mg
or 2.4 mg beloranib lost an average of 5.5, 6.9 and 10.9 kg, respec-
tively, against 0.4 kg in placebo group (all p <0.0001). The study
also showed that weight loss in patients, which administrated be-
loranib, was progressive and continued until the 12th week of the
trial [114]. The Zafgen company recently announced the start of
Phase 3 of investigation of Beloranib.
The mechanisms of action of drugs used for the treatment of
obesity at the different levels of biological organization of organism
are summarized in Table 1. The analysis of this table shows that the
new promising trend in drug design of anti-obesity drugs may be a
combination of drugs acting at the different mechanisms of hunger,
food consumption and utilization. The successful example of using
synergism are Qsymia, containing Phentermine and a slow-release
form of Topiramate, EmpaticTM, containing Zonisamide and
Bupropion, Contrave® ,containing Bupropion and Naltrexone. The
advantage of combined drugs is a greater pharmacological activity
in comparison with activity of each of its ingredients. The target of
those combined medicines are mainly CNS and hypothalamus, with
important central side effects. However, orlistat does not affect
CNS and endocrine system with good safety. In combination with
other drugs (Phentermine, Rimonabant, Sibutramine antidepres-
sants), Orlistat have no important drug interactions in the brain. In
this context, we assume that combination of orlistat with the above
mentioned drugs should be more effective as the result of syner-
getic effect of ingredients. We also hypothesize that synergetic
action should allow reducing dose of CNS acting drugs and safety.
No publications have been found so far about the combination adi-
pokines and hypoglycemic agents (glucagon-like peptide receptor
(GLPR-1) agonist, a potent incretin mimetic etc). Drug interaction
approach at the different levels of biological organization also gives
us powerful tool to predict dangerous combination. We assume that
norepinephrine releasing agents are incompatible in one dosage
form with dopamine-norepinephrine reuptake inhibitor
(Bupropion), serotonin-norepinephrine reuptake inhibitor (Sibutra-
mine) and another anorectics, which influence the release and reup-
take of biogenic amines.
CONCLUSION
Obesity is not only an excessive amount of adipose tissue re-
sulting from malnutrition and low level of physical activity, but also
a complex set of hemodynamic and metabolic dysfunctions. In the
pharmacotherapy of obesity and metabolic syndrome, the correction
of weight is an important approach aimed at reducing the risk of
cardiovascular complications, improving quality of life and progno-
sis. T HE Study and application of various approaches in the phar-
macotherapy of obesity is extremely relevant to the health care
system and society. It is possible to highlight that the arsenal of
endocrinologists and other practitioners will be replenished by suf-
ficiently effective and, what is most important, safe drugs for treat-
ing obesity and metabolic syndrome in coming years. The use of
combined anti-obesity drugs with different mechanisms of action is
a promising trend for the development of more effective medicines.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
Current Pharmaceutical Design, 2016, Vol. 22, No. 00 7
ACNKOWLEDGMENTS
GEB is supported by Pontificia Universidad Javeriana.
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Received: October 26, 2015 Accepted: December 8, 2015
Current Pharmaceutical Design, 2016, Vol. 22, No. 00 9
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