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Current Medicinal Chemistry, 2019, 26, 1-12 1

REVIEW ARTICLE

Obesity Therapy: How and Why?

S. Paccosi1, B. Cresci2, L. Pala2, C.M. Rotella2,3 and A. Parenti1,*

1
Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Flor-
ence Italy; 2Diabetology, Careggi University Hospital, Florence, Italy; 3Department of Biomedical Clinical
and Experimental Sciences, Endocrine Unit, University of Florence, Florence Italy

ARTICLE HISTORY
Received: February 13, 2018
Revised: May 11, 2018
Accepted: December 24, 2018
DOI:
10.2174/0929867326666190124121725
Abstract: Background: Obesity represents the second preventable mortality cause world-
wide, and is very often associated with type 2 diabetes mellitus (T2DM). The first line treat-
ment is lifestyle modification to weight-loss, but for those who fail to achieve the goal or have
difficulty in maintaining achieved results, pharmacological treatment is needed. Few drugs are
available today, because of their side effects.
Objective: We aim to review actual pharmacological management of obese patients, high-
lighting differences between Food and Drug Administration – and European Medicine
Agency-approved molecules, and pointing out self-medications readily obtainable and widely
distributed.
Method: Papers on obesity, weight loss, pharmacotherapy, self- medication, and diet-aid
products were selected using Medline. Research articles, systematic reviews, clinical trials
and meta-analyses were screened.
Results: Anti-obesity drugs with central mechanisms, such as phentermine and lorcaserin, are
available in USA, but not in Europe. Phentermine/topiramate and naltrexone/bupropion com-
binations are now available, even though the former is still under investigation from EMA.
Orlistat, with peripheral mechanisms, represents the only drug approved for weight reduction
in adolescents. Liraglutide has been approved at higher dose for obesity. Anti-obesity drugs,
readily obtainable from the internet, include crude-drug products and supplements for which
there is often a lack of compliance to national regulatory standards.
Conclusions: Mechanisms of weight loss drugs include the reduction of energy intake or the
increase in energy expenditure and sense of satiety as well as the decrease of hunger or the
reduction in calories absorption. Few drugs are approved, and differences exist between USA
and Europe. Moreover, herbal medicines and supplements often sold on the internet and
widely used by obese patients, present a risk of adverse effects.

Keywords: Obesity, type-2 diabetes, pharmacology, action-mechanism, self-medication, dietary supplements.

1. INTRODUCTION amplify adherence to weight loss programs in the early

2 phases, where the use of approved weight loss medica-
Treatment of overweight (BMI ≥ 25 kg/m ) is based
tion is proposed to improve additional comorbidities,
on a comprehensive lifestyle modification that pertains
thus ameliorating patient’s physical functioning, and
to diet flanked by physical exercise and behavioral
compliance to behavior modifications. In addition,
changes. According to most guidelines including Ital-
pharmacotherapy could also be helpful in promoting
ian Recommendations [1], other tools, such as pharma-
long-term weight maintenance. Anti-obesity drugs have
cotherapy, should be considered for BMI ≥ 27 kg/m2
had, and continue to have, a troubled story for many
with comorbidities or BMI over 30 kg/m2. Drugs might
reasons [2], especially when a safety vs efficacy ratio is
considered. This undoubtedly represents an obstacle to
*Address correspondence to this author at the Department of Health fast development of safe and effective molecules. Re-
Sciences, Clinical Pharmacology and Oncology Section, V. le G.
Pieraccini, 6, 50139 Florence Italy; E-mail: astrid.parenti@unifi.it cently, the regulatory control organs (Food and Drug

0929-8673/19 $58.00+.00 © 2019 Bentham Science Publishers

2 Current Medicinal Chemistry, 2019, Vol. 26, No. 00 Paccosi et al.

Administration -FDA and European Medicines as well as by long-term imbalance between hunger and
Agency-EMA) have demonstrated greater strictness satiety signals [12].
before approving the use of safe compounds, especially
with respect to possible cardiovascular (CV) adverse 2. ANTI-OBESITY DRUGS: CENTRAL MECHA-
effects [3]. Currently, available medications for the NISMS
treatment of the patient with obesity work either on the A drug to be used in obesity therapy should promote
brain or gut. Several homeostatic brain circuits regulate weight loss basically through the management of food
feeding behavior by promoting food intake or suppress- intake, obtained through orexigenic signal reduction, in
ing appetite [4]. Regulation of energy and food intake order to reinforce the concept of eating less by reduc-
mainly occurs in the central nervous system (CNS), ing the sense of hunger and increasing satiety [13].
where hypothalamus, brainstem, and reward system
processes respond to peripheral signals [5]. Many hy- 3. PHENTERMINE
pothalamus nuclei are involved in energy homoeostasis
In the USA, phentermine is an FDA approved drug
regulation, among them agouti-related protein
since 1959, and has been the most frequently pre-
(AgRP)/neuropeptide Y (NPY) and pro-
scribed anti-obesity drug under various trade names. In
opiomelanocortin (POMC) neurons in the arcuate nu-
Europe is forbidden to manufacture, import or market
cleus (ARC) are principally involved in hunger and
preparations containing phentermine. Diethylpropion
satiety stimulation, respectively [6]. Moreover the 'Gut-
and phendimetrazine are other sympathomimetic
Brain- Axis' allows to transfer information from gastro-
amines available in USA, with poor data regarding
intestinal tract to the CNS through gut hormones [7, 8].
their effects and seldom prescribed. Phentermine is a
Orexin and ghrelin stimulate people to eat, while leptin,
sympathomimetic drug with pharmacological activity
insulin and brain-gut peptides induce satiety [9].
similar to amphetamine: it increases the release of
Monoaminergic circuits of the brain stem and the
catecholamines, in particular norepinephrine, acting as
mesolimbic reward system are involved in energy bal-
an inhibitor of appetite. Given the absence of long-term
ance with mechanisms only partially understood [10].
safety trials of phentermine monotherapy, it is indi-
In the brain stem and hypothalamus, particularly in ar-
cated for short-term use (3 months) even if practitio-
cuate nucleus, paraventricular nucleus (PVN) and lat-
ners are used to prescribe phentermine for longer times
eral hypothalamic area (LHA), serotoninergic mecha-
as off-label therapy for ongoing weight management.
nism of satiety is located [11]. They represent an im-
Nevertheless, its combination with topiramate ER for
portant target for obesity treatment, given their effect
long-term therapy has been approved [14]. Notwith-
on energy expenditure and satiety or hunger (Fig. 1).
standing, phentermine available doses are 15.0, 30.0
Human eating behavior can be influenced by emotions
and 37.5 mg, many practitioners recommend using

Fig. (1). Appetite regulation. Monoaminergic systems involved in appetite center regulation. AgRP: Agouti-related protein;
ARC: hypothalamic arcuate nucleus; NOR: noradrenalin; NPY: neuropeptide Y; POMC: pro-opiomelanocortin; 5-HT: sero-
tonin.
Obesity Therapy: How and Why?
quarter or half tablets of these formulations in order to
individualize prescription to reach the lower effective
dose. In 2016, FDA approved the 8 mg formulation, the
usage of which runs up to 3 times daily, but to prevent
insomnia, it should be avoided to take the last dose in
the evening. It is noteworthy that in a short-range pe-
riod, continuous or intermittent treatment seems to
have the same effect [15]. Most common adverse ef-
fects include insomnia, irritability, headache, dry
mouth, dizziness, nausea/vomiting, and other gastro-
intestinal disturbances. The combination of phenter-
mine with other sympathomimetic amines or with
monoamine oxidase inhibitors should be avoided. Con-
traindications are pregnancy/nursing, history of CV
disease or drug abuse, hyperthyroidism, glaucoma, and
agitation.
4. PHENTERMINE/TOPIRAMATE
Phentermine/topiramate combination ER (USA
trade name is Qsymia) has been FDA approved in July
2012. Topiramate, approved in 1996 as an anticonvul-
sant, is also able to induce weight loss in most treated
patients the extent of which seems to correlate with
specific factors including treatment length or high
baseline BMI. The exact mechanism of action causing
weight loss is not completely clear, but it is thought to
be related to appetite suppression and increased sense
of satiety through a combination of increased γ-amino-
butyrate neurotransmitter activity, ion channel modula-
tion, inhibition of 2-amino-3-hydroxy-4-isozolepro-
pionic kainitic acid receptors and 5 carbonic anhydrase
inhibition [16]. In psychiatric patients, it is currently
used as a mood stabilizer, and this experience has re-
vealed the effect of topiramate in controlling Binge
Eating Disorder (BED). The FDA has approved the
association of drugs for use in obese adults with a BMI
≥ 30 or a BMI ≥ 27 with at least one related disease.
On the contrary, the EMA in 2012 again refused the
approval of the phentermine/topiramate ER association
in Europe, due to long-term effects exerted by phen-
termine on heart and blood vessels, and by topiramate
on psychiatric and cognitive functions. This formula-
tion differs from the mere association of the two active
components currently on the market, since it combines
phentermine HCl (readily absorbed in the gastrointesti-
nal tract, and acts early during the day), and a con-
trolled release of topiramate formulation (with persis-
tent effects on weight loss throughout the day). In this
way, a single daily administration is possible, thus re-
ducing the dose of individual active ingredients. Three
different formulations of phentermine/topiramate have
been studied: 3.75/23 mg, 7.5/46 mg, 15/92 mg, re-
Current Medicinal Chemistry, 2019, Vol. 26, No. 00 3
spectively [14]. The drug was evaluated during three
phase studies III (Equate, Equip, Conquer) who en-
rolled more than 4,500 patients. The average reduction
in body weight was 3% with the lower doses of the
drug and it raises to 11% with the highest dose. Studies
also have highlighted improvements in blood pressure
levels, lipid and glycemic profile. Its pharmacokinetic
profile is characterized by a good oral absorption, wide
distribution, a low bond with plasma proteins, poor me-
tabolism from part of monoamine oxidase and/or cyto-
chrome P450. The drug is mainly excreted through
urine, resulting in low variability between subjects. The
pharmacokinetics of phentermine/topiramate ER is not
affected by food intake, and the drug can therefore be
taken independently of the meal [17].
5. LORCASERIN
On June 27, 2012, the FDA approved the use of lor-
caserin, a new drug that acts on the serotonergic sys-
tem, registered in USA under the name of Belviq. The
EMA rejected lorcaserin marketing authorization, re-
ferring to an inadequate number of available clinical
trials that would confirm its efficacy and safety
in weight reduction. Lorcaserin is a selective and po-
tent agonist of serotonin receptor 5-HT2C. Its action is
carried out centrally and has not shown any affinity for
5-HT2B receptors, especially present at a peripheral
level. Very weak affinity has also been demonstrated
for 5-HT2A receptors, mainly present at a central level.
The receptor selectivity of this molecule should protect
against the risk of cardiac valvulopathy and pulmonary
hypertension appearance. On the other hand, the sup-
pression of appetite is mediated especially from 5-
HT1B and 5-HT2C receptors [18]. Clinical trials have
shown that lorcaserin reduced weight loss of 4 kg more
than placebo in studies at one year, maintaining posi-
tive effects on weight after two years of treatment. Re-
garding comorbidities, lorcaserin improves glycemic
control in addition to facilitating weight loss
in individuals with T2DM, and has positive effects on
lipid profile and on blood pressure. Lorcaserin is nor-
mally well tolerated, and the most common adverse
effects are infections of the upper respiratory tract,
headache and nausea [19]. Lorcaserin is available in 10
mg capsules to be taken once or twice a day. The FDA
advises against continuing treatment with lorcaserin for
more than three months, if the weight loss after 12
weeks is less than 5%.
6. NALTREXONE/BUPROPION
Naltrexone/bupropion (NB, trade name for USA:
Contrave; for Italy/Europe Misymba) is a pharmacol-
ogical combination, approved by the FDA in Septem-
4 Current Medicinal Chemistry, 2019, Vol. 26, No. 00
ber 2014, after the required studies of safety. Mysimba
has been approved by the EMA in March 2015 (13th
November 2017 in Italy), for the management of
weight in patients ≥18 years with an initial BMI ≥ 30
kg/m2, or ≥ 27 kg/m2 to < 30 kg/m2 with at least one
weight-related co-morbidities. Bupropion is a tricyclic
antidepressant, while naltrexone is an antagonist of
opioid receptors, primarily used to manage alcohol or
opioid dependence. There are four double-blind RCT
for evaluating the effect of NB plus lifestyle modifica-
tion in 4536 patients with overweight or obesity (BMI
of 27 kg/m2 or greater COR-I, COR-II) and at least one
weight-related comorbidity (Contrave Obesity Re-
search Behavior Modification; COR-BMOD) or
T2DM with or without hypertension and/or dyslipide-
mia (COR-Diabetes) [20-23]. In the COR-I trial, there
was an increase of 4.8% in weight loss and an increase
of 32% of weight loss greater than 5% from baseline in
patients receiving NB 360/32 mg compared to placebo.
In COR-Diabetes, the latter increase was 25.6 % [23].
In most trials, this combination NB significantly
contributed to improve the values of waist circumfer-
ence, lipid panel, insulinemia, quality of life when
compared to placebo. More recently, combination of
naltrexone/bupropion sustained release has been evalu-
ated for weight loss in a phase 3b, randomized, open-
label, controlled study for 26 weeks [24]. Treatment
with NB significantly improved weight loss over usual
care alone at week 26 (8.52% difference; P< 0.0001).
Interestingly, it was sustained for 78 weeks, deemed
safe, and well tolerated [24]. NB is available in tablets
containing 8 mg naltrexone/ 90 mg bupropion. Dosing
of NB is rather cumbersome. The treatment that starts
with 1 tablet extending to 2 twice daily from week 4
onwards. Most frequent adverse effects are
gastrointestinal (nausea, vomiting, constipation, dry
mouth) and nervous system related (headache, dizzi-
ness, insomnia, anxiety). In some cases, such as
patients with uncontrolled hypertension, seizure
disorders, anorexia nervosa, or bulimia, NB is
contraindicated because of the potential adverse effects
of bupropion. NB use could be problematic also in
bipolar disorder or schizophrenia patients as well as in
patients receiving chronic treatment with opioids, and
in those abruptly stopping alcohol, benzodiazepines,
barbiturates, or AEDs. Patients using NB at the mainte-
nance dose should be evaluated after 12 weeks, to
determine if the treatment is efficacious.
7. GLP-1 ANALOGS AND OBESITY THERAPY
GLP-1 is a peptide hormone produced by L cells of
intestine. The active form of 30 aa derives from a pro-
Paccosi et al.
teolytic processing of proglucagon. Moreover, the bio-
logically active peptide GLP-1 resulted from an en-
dogenous cleavage of the first six residues amide. Nu-
trient ingestion, especially meals with high content of
fat or carbohydrates, induces GLP-1 secretion [25] that
delays gastric emptying, stimulates insulin secretion
and mediates satiety in CNS. All together, these actions
are beneficial to individuals both with obesity and
T2DM, given the reduction in plasma glucose and im-
proving in glucose tolerance when native GLP-1 is pre-
prandial administered in T2DM patients [26]. Dipepti-
dylpeptidase- 4 (DPP- 4) is responsible for the short
half-life of 1-2 minutes in humans. The proteolytic
cleavage of the N-terminal dipeptide inactivates GLP-1
[27] that is quickly cleared by renal filtration. The most
frequent adverse effect of GLP-1 or its analogues is
nausea, often mild, that is dose dependent and may
limit higher doses usage in order to increase weight
loss [28]. The rising risk of pancreatitis with GLP-1
therapies seems to be decreased in the last two years
[29]. Among GLP-1 analogs, liraglutide has received
EMA approval in 2009 and FDA in 2010 with glucose-
lowering therapy indication, and at the higher dose of 3
mg/ die for the treatment of obesity. Liraglutide has a
97% structural homology to human GLP-1 but, given
the huge increase in half-life (about 13 h), its indication
is once daily by subcutaneous injection. Main modifi-
cation of GLP-1 is a C16 palmitoyl moiety which is
covalently linked to the lysine (position 20) by means
of a γ-glutamic acid chemical spacer. There is an argin-
ine substitution at position 28. Liraglitide also pos-
sesses an alanine (position 2) which does not prevent
its enzymatic degradation, although palmitoylation for
its association with serum albumin, results in steric
protection [30]. In individuals with T2DM, liraglutide
induces weight loss of 1.3–8.6 kg [31]. Actually, lira-
glutide at the dose of 3 mg/ die is the unique GLP-1
analog used in the treatment of obesity. The rational of
this indication is based on the mechanism of action of
the molecule. In fact, as shown in (Fig. 2), it has differ-
ent points of action both at central and peripherical
side. Liraglutide acts by reducing appetite, increasing
metabolic rate and/or inhibiting gastrointestinal caloric
uptake probably combining its effect on gastrointestinal
tract and brain. Clinical studies compared liraglutide
effect with the approved orlistat also assessing its
safety and tolerability at higher doses. In a milestone
double-blind, placebo-controlled 20-week trial in com-
parison with orlistat. The highest liraglutide dose of 3
mg/die was demonstrated to induce a mean weight loss
of 7.2 kg compared with 4.1 kg of orlistat 120 mg and
2.8 Kg for placebo [32]. Additional liraglutide effects
Obesity Therapy: How and Why?
Fig. (2). Schematic representation of the effects of liraglutide. ↑ stimulation; ↓ reduction. GSIS: glucose-stimulated insulin
secretion.
were the reduction of blood pressure and the incidence
of prediabetes in response to 1.8 and 3mg/die.
8. ORLISTAT
Lipid turnover involves various targetable steps for
anti-obesity drug development. The digestion of lipids
begins in the oral cavity followed by stomach enzyme,
and then pancreatic lipase secreted into the intestinal
lumen, such as carboxyl ester lipase, group 1B Phos-
pholipase A2, pancreatic lipase-related protein-1 and
pancreatic lipase-related protein-2 [33, 34]. Triacyl-
glycerol molecules are metabolized by pancreatic li-
pase that releases fatty acids (FA) and monoacylglyc-
erols [35]. It is noteworthy that for pancreatic lipase
activity, the presence of a colipase is crucial [33, 36],
the active enzyme obtained after the N-terminus modi-
fication of the precursor procolipase. Three mecha-
nisms, depending on digested FA length, are needed for
their uptake across the apical surface of enterocytes:
passive diffusion for short-chain ones that are after-
wards absorbed into the mesenteric venous blood. Me-
dium- and long-chain FA enter cells via fatty acid
translocase, called CD36 or platelet glycoprotein 4,
with or without the plasma membrane-associated fatty
acid-binding protein (FABPpm) [37]. Following their
entrance into cells, they bind cytoplasmic FABP
(FABPc) [38] and then are activated by plasma mem-
brane acyl-CoA synthetase 1 to form acyl- CoA esters.
Alternatively, medium-chain and long chain FA may
be transported by fatty acid transport protein 4
Current Medicinal Chemistry, 2019, Vol. 26, No. 00 5
(FATP4). The apical membrane of enterocytes is
strictly involved in the transport of other important me-
tabolites, such as cholesterol via Niemann-Pick C1 like
1 protein and receptor class B type I for vitamin E up-
take. Orlistat, (S)-2 formylamino-4 methyl-pentanoic
acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]
methyl]- docdecyl ester) or tetrahydrolipstatin, is a
molecule partially hydrated derivative of endogenous
lipostatin, a potent natural inhibitor of pancreatic li-
pases isolated from the Streptomyces toxytricini [39,
40]. Orlistat is a specific long-acting inhibitor of li-
pases [39, 41, 42] in the gastrointestinal tract, and was
approved by EMA in 1998 and by FDA in 1999. It pre-
vents absorption of about 1/3 of the fats introduced
with the diet [43], leading to a fecal loss of 25-35% of
dietary fat, compared to 5% with placebo [44] (Fig. 3).
The latter effect described appears within 24-48 hours
following drug administration; after interruption of
treatment, the fat content in the feces generally returns
to the pre-treatment levels in 2-3 days. However,
orlistat also reduces the absorption of fat-soluble vita-
mins and beta-carotene; if the patient's diet is adequate
for the daily needs, specific vitamin supplements are
not necessary. When accompanied by a balanced diet,
orlistat is reported to cause a daily reduction of about
200 calories. The duration of treatment should never
exceed 2 years of therapy and should be followed by a
treatment program that includes a slightly hypocaloric
diet, dietary advice and a modification of eating behav-
ior. The hypolipidic diet aims at reducing not only the
6 Current Medicinal Chemistry, 2019, Vol. 26, No. 00
Fig. (3). mechanism of action of orlistat. Inhibition of lipase (left) and pleiotropic mechanisms (right). TG: triglycerides; MG:
monoglycerides; FA: fatty acids; IL-6: interleukine-6; CRP: c-reactive protein; GLP-1: glucagon-like peptide-1.
body weight, but also the gastrointestinal side effects of
the drug. Although orlistat is one of the few anti-
obesity drugs allowed, its activity is associated with a
modest degree of weight loss (5 – 10% of baseline
weight after 2 years) [45-47]. One of the first meta-
analyses published, that analyzed 14 randomized trials,
reported that orlistat induced a weight loss of 2.9% Kg
greater than placebo; the number of patients achieving
a reduction of at least 10% of their initial weight was
12% more in the orlistat arm compared to the placebo
arm [48]. These data have been confirmed in a succes-
sive meta-analysis which included thirty-three studies,
which show that orlistat significantly reduced body
weight by7 2.12% (p < 0.001). Authors also high-
lighted that orlistat treatment significantly reduced
plasma concentrations of total cholesterol, LDL,
triglycerides and HDL, while no significant effect on
lipoprotein-a was observed [49]. These data suggest
pleiotropic effects of orlistat that could be beneficial
for CV risk. Twenty-eight RCTs of FDA-approved
weight loss medications with 29018 patients show that
orlistat had only modest favorable effects on cardiome-
tabolic risk profile [50]. However, a clinically signifi-
cant reduction in LDL-cholesterol was observed, with a
modest reduction in HDL-cholesterol and blood pres-
sure, compared to placebo [51]. This effect on dyslipi-
daemia and blood pression has been observed also in
overweight and obese polycystic ovary syndrome sub-
jects with insulin resistance [52]. This study demon-
strated that orlistat was more efficacious in reducing
Paccosi et al.
weight, lipid profile, and was better tolerated than met-
formin.
Childhood obesity has seriously increased world-
wide. In adolescents aged 12 to 19 years, obesity
prevalence ranged from 5% in 1980 to nearly 21% in
2012 in the USA [53]. Southern countries of Europe
tend to have higher children overweight/obesity preva-
lence (20– 35%) than northern ones [54]. In Italy, the
Health Behavior in School-aged Children survey has
shown a high prevalence of overweight/obese children,
greater in males than in females, that decreases in both
genders with age, ranging from 28.1% in males and
18.8% in females of 11 years to 25.2% in males and
11.9% in females of 15 years [55]. Among anti-obesity
drugs approved by FDA, orlistat is currently the unique
weight loss medication for adolescents. A recent sys-
tematic review that analyzed 133 RCTs, supported
orlistat treatment of adolescents, since it reduced BMI
and waist circumference [56]. Although off-label
sibutramine and metformine showed same results in
reducing body weight, orlistat is the only FDA–
approved medication for the treatment of obese child-
hood aged>12 years, because of increased CV effects
with sibutramine. The effect on blood pressure is of
particular interest, for CV risk of obese patients and an
increased BMI is an important element of treatment–
resistant hypertension [57]. A meta-analysis of 27 ran-
domized controlled clinical trials with orlistat reported
a statistically significant decrease in both systolic (1.15
mmHg [2.11, 0.19]) and diastolic blood pressure (1.07
Obesity Therapy: How and Why?
mmHg [1.69, 0.45]), regardless of its dosage [49]. Ad-
ditionally, orlistat positively modulates insulin sensitiv-
ity and glycemic control in T2DM patients. One of the
first randomized clinical trials studying the effect of
orlistat on insulin resistance and markers of inflamma-
tion, was from Derosa [58], who reported an improve-
ment in glycemic and lipid profile, and insulin resis-
tance parameters in orlistat-treated obese and T2DM
patients compared to control subjects. A systematic
review of RCTs on T2DM subjects reported that
orlistat treatment together with lifestyle intervention
significantly improved glycemic control and induced a
greater weight loss in overweight/ obese and T2DM
patients, compared to lifestyle intervention alone [59],
thus proving orlistat to be an effective additional treat-
ment to life style for T2DM patients. In particular, the
mean weight difference between orlistat and control
groups observed was −2.10 kg, the mean HbA1c dif-
ference was −6.12 mM and the mean fasting blood glu-
cose difference was −1.16 mM. These pleiotropic ef-
fects of orlistat are still under investigation. Some of
the suggested mechanisms are the reduction of circulat-
ing IL-6 and highly sensitive C-reactive protein
(HsCRP) as well as the reduction of postprandial
plasma non-esterified FA, increase of Glp-1 secretion
in the intestine and reduction of visceral adipose tissue.
Interestingly, these effects occur even in the absence of
weight loss [60]. Even if orlistat possesses a good
safety profile, its use is limited by its gastrointestinal
adverse effects (56%), such as oily stools/spotting, fla-
tus with discharge, faecal urgency, which are responsi-
ble for almost 10% of patients discontinuing therapy
[61]. Other adverse effects reported are upper respira-
tory tract infections, nervous system, bone, muscu-
loskeletal and connective tissue disorders. A case- re-
port has shown a kidney failure developed in two pa-
tients due to oxalate deposition in the kidney while tak-
ing orlistat, and this clinical condition was followed by
partial recovery after interruption of orlistat. The
mechanism by which orlistat causes hyperoxaluria, and
the management of orlistat-induced oxalate nephropa-
thy, is still under investigation [62].
9. SELF-MADE TREATMENT OF OBESITY
Serious side effects attributed to anorectic drugs,
and the withdrawal from trade of most medicinal prod-
ucts used in the past, have brought a widespread ten-
dency to search for possible alternatives in the world of
dietary supplements. Considering also the charming
properties of herbal anti- obesity products, many peo-
ple think to easily achieve their goals using the ones
found on websites. The most frequently purchased are
Current Medicinal Chemistry, 2019, Vol. 26, No. 00 7
garcinia cambogia, camellia sinensis, chromium picoli-
nate, hoodia gordonii and so on. Although these herbal
supplements are commonly marketed, few clinical data
on their safety for long-term obesity treatment are
available, and they are full of conflicting results [63].
The most common supplements used exert anorectic
properties tracing the action of synthetic amphetamine
(caffeine, sinephrine, yohimbe), or are supplements
based on dietary fibers (for example bran, guar, xan-
than gum, karaya gum, psyllium, agar agar, glucoman-
nan, pectin, konjac flour, carrageenan) that taken to-
gether, give generous amounts of water, swell inside
the stomach, favouring a sense of satiety. Approxi-
mately, 15% of American adults have used a weight-
loss dietary supplement during their lives [64]. The
Italian Medicines Agency (AIFA) has recently
launched an alarm on the unscrupulous and self-made
use of drugs; one out of four people buy drugs online:
27.57% of them is indicated for weight loss, and only
0.6% of drugs available online is legal; the rest is a col-
lection of fake, counterfeit, unapproved and without
any control products [65]. Galenical preparations based
on drugs illegally sold in pharmacies (such as phendi-
metrazine, chlorazepate and benfluorex that cause men-
tal problems, humoral instability, severe headaches,
hallucinations, and severe sexual dysfunction, even
permanent) represent a serious health concern regard-
ing self-made treatment of obesity. The perception of
risks linked to self-made treatment is still largely insuf-
ficient, and it is common that patients hide the use of
weight loss supplements from their physicians [64],
thus exposing themselves to potential risks of drug-
supplement interactions [66, 67]. An important aspect
regarding their dangerousness is their heterogeneous
nature: they often have ambiguous levels of active in-
gredients (some contain more than 90) [68], resulting
in unpredictable and potentially harmful effects. An
audit conducted in metropolitan area of Columbia
(USA) identified 402 available products containing
4,053 separate ingredients, among them are botanicals
(herbs and other plant components) that could be
highly toxic (e.g. aristolochia species), or not recom-
mended for use in weight control (e.g. ephedra sinica).
Other compounds could be laxatives with potential
toxic 15 effects for liver and kidney (e.g. anthraqui-
nones), and their presence may not be shown on the
product label [69]. Moreover, most of the supplements
contain stimulants [64, 70] such as amphetamine and
derivatives [71], sibutramine [72], adulterants (drug
analogues and thyroid extracts) or medications that
have been withdrawn from the market (e.g. fenflu-
ramine) [69]. Notwithstanding their broad utilization,
8 Current Medicinal Chemistry, 2019, Vol. 26, No. 00
Table 1. Characteristics of anti-obesity drugs FDA and/or EMA approved for medical use.
Drug Regulatory Control Approvation
Phentermine FDA, 1959
Orlistat EMA, 1998;
FDA, 1999
Liraglutide EMA,2009;
FDA, 2010
Phentermine/topiramate FDA, 2012
Lorcaserin FDA, 2012
Naltrexone/bupropion FDA, 2014
EMA, 2015
evidences of health benefits related to their use in well-
nourished adults are limited. In contrast, a modest
number of these products present the risk of produc-
ing significant toxicity, and in some cases death as re-
ported for ephedra, caffeine and Bofutsushosan, as re-
ported in a systematic review on safety and efficacy of
herbal medicines used for obesity treatment [73].
Synephrine- and caffeine- containing dietary supple-
ments are object of many case reports regarding ad-
verse cardiovascular effects (hypertension, cardiac ar-
rhythmia, myocardial infarction) [74]. Another CNS
stimulant, yohimbine, given its property to produce
serious adverse effects increasing pressure and heart
rate, should be carefully used only under medical su-
pervision [75]. It is well known that thyroid hormones
(THs), boost metabolism burning calories and the ex-
ceeding adipose tissue, thus they represent a very use-
ful mean to lose weight. Their synthesis depends on the
availability of adequate amounts of iodine. Most of the
"thyroid supplements" contain iodine or sources that
are particularly rich in it, such as extracts of marine
algae fucus vesiculosus or laminaria. Selenium is also
often present in iodine supplements, and being an es-
sential component of the enzymatic system that trans-
forms thyroxine (T4) into triiodothyronine (T3), it
plays a major role in supporting thyroid function. An-
other TH metabolite, 3,5- diiodo-L-thyronine (T2) is
used as dietary supplement often accompanied with
shortage of adequate information about its safety, and a
different content per pill that ranges from being not
stated to 50 – 300 µg [76]. Among risks linked to
Paccosi et al.
Mechanism of Action Recommended Use
CENTRAL: anorectic sympath- short-term use (3 months)
omimetic amine
PERIPHERAL: inhibits gastric and long-term
pancreatic lipases
CENTRAL: mediates satiety in the long-term
central nervous system (CNS)
PERIPHERAL: delay gastric emp-
tying, stimulates insulin secretion.
CENTRAL: (phentermine see short-term use
above)/antiepilectic drug with un-
clear anorectic mechanism
CENTRAL: selective serotoniner- short-term use (3 months)
gic receptor 5HT2c agonist
CENTRAL: bupropion is a tricyclic long-term
antidepressant, while naltrexone is
an opioid receptor antagonist
above mentioned supplements, a study on the content
of thyroid hormones in commercially available thyroid
supplements has evidenced that nine out of ten exposed
consumers to the risk of developing iatrogenic thyro-
toxicosis. That is attributable to the clinically relevant
content of T4 and T3 that sometimes exceeded the rec-
ommended doses used to treat hypothyroidism [77]. A
dysregulation of THs, and also fasting or starving con-
ditions, can lead to problems related to T4 conversion
in reverse-T3, the inactive form of the basal metabo-
lism activator T3, resulting in rt3/T3 ratio increase with
hypothyroidism symptoms. Supplements with extracts
of marine algae can cause auto-immune thrombocy-
topenic purpurea and disordered erythropoiesis, be-
cause algae can concentrate various heavy metals [78].
Clinical hyperthyroidism has also been reported in pa-
tients taking fucus-containing preparations as part of a
slimming regimen or dietary supplement [79]. In the
literature, it is reported that goiter and thyroid gland
inflammation can be caused not only by iodine defi-
ciency, but also by its high levels [80, 81]. Undoubt-
edly, it should be recognized that lifestyle changes are
the first-line treatment to lose burden, and the use
of complementary and alternative medicine should be
considered only as co-adjuvant after a careful evalua-
tion of composition, dosage and warnings that accom-
pany weight-loss supplements.
CONCLUSION
Whenever life style modifications fail to treat obe-
sity, long term use of pharmacotherapy could help lose
Obesity Therapy: How and Why? Current Medicinal Chemistry, 2019, Vol. 26, No. 00 9

weight, and later to sustain its mainte- EMA = European Medicines Agency
nance reducing appetite and/ or enhancing satiety. FA = Fatty acids
Once a desired weight has been achieved, reducing the
FABP = Fatty acid-binding protein
dose of medication or trying intermittent treatments,
could be possible strategies that in some cases have FDA = Food and Drug Administration
been demonstrated to work. Moreover, as clearly dem- GI = Gastrointestinal
onstrated for many other pathologies, a combination
GLP-1 = Glucagon-like peptide-1
therapy that targets multiple pathways can have addi-
tive or synergistic effects to achieve clinically signifi- GSIS = Glucose-stimulated insulin secretion
cant weight loss and using lower doses of single com- HbA1c = Glycated haemoglobin
ponents, consequently adverse effects should be low- 5-HT2 = 5-Hydroxytryptamine receptor 2
ered. In addition to phentermine/topiramate ER and
naltrexone SR/bupropion SR, other combinations are IL-6 = Interleukine-6
under investigation, including phentermine/lorcaserin LHA = Lateral hypothalamic area
and phentermine/canagliflozin [82]. Drugs such as lira- MG = Monoglycerides
glutide can act targeting both CNS and peripheral path-
ways with anorectic effects, clearly demonstrated also NB = Naltrexone/bupropion
in T2DM patients. NOR = Noradrenalin
Orlistat is a pancreatic lipase inhibitor, with a NPY = Neuropeptide Y
unique mechanism of action that involves local activity POMC = Pro-opiomelanocortin
in the small intestines, and with little systemic absorp-
PVN = Hypothalamic paraventricular nucleus
tion. Orlistat has been demonstrated to be associated
with salutary effects on many of the other fea- RCT = Randomized Controlled Trial
tures associated with metabolic syndrome and CV T2DM = Type 2 diabetes mellitus
risk. The lack of any major systemic side effects or ma- TG = Triglycerides
jor drug–drug interactions offers its utility in primary
care based settings, as an adjunct in the multi-faceted THs = Thyroid hormones
management of obesity. Table 1 summarizes anti- T3 = Triiodothyronine
obesity drugs FDA and/or EMA approved for medical T4 = Thyroxine
use. Self-made medication is widely used for obese
patients, and everyone can obtain them through the In- CONSENT FOR PUBLICATION
ternet, even though the dangers of purchasing medi-
cines online have been documented. Herbal products, Not applicable.
that contain damaging substances, are distributed FUNDING
worldwide, and health problems have been reported.
Among them, clinical hyperthyroidism has been de- None.
scribed in patients taking fucus- containing prepara-
tions as part of a slimming regimen. To avoid potential CONFLICT OF INTEREST
adverse events, there should be more vigilance regard- The authors declare no conflict of interest, financial
ing the possible health risks of taking products without or otherwise.
appropriate indications.
ACKNOWLEDGEMENTS
LIST OF ABBREVIATIONS
Declared none.
AgRP = Agouti-related protein
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