South African Family Practice 2016; 58(4):16-21

S Afr Fam Pract

Open Access article distributed under the terms of the ISSN 2078-6190 EISSN 2078-6204
Creative Commons License [CC BY-NC-ND 4.0] © 2016 The Author(s)
http://creativecommons.org/licenses/by-nc-nd/4.0
REVIEW

The pharmacological management of obesity

André Marais

Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South Africa
Corresponding author, email: dramarais@gmail.com / andre.marais@up.ac.za

Abstract
Obesity is a growing phenomenon and a global concern. It is well-known that it plays a significant role in the development of
several preventable diseases. The physiological mechanisms in regulating energy intake and expenditure are complex and remain
a target area for current and future research. The absence of a golden standard in determining the body’s composition provides for
various measurement techniques, each with its own advantages and disadvantages. Lifestyle changes and reduced caloric intake
form the backbone of any pharmacological intervention. A myriad of therapeutic agents are available which offer the provision for
individualised treatment.

Keywords: anti-obesity agents, appetite, body composition, obesity, weight loss

Introduction with a population overweight rate (BMI 25–30 kg/m2) of 38.3%

(Figure 1).10
The World Health Organization (WHO) defines obesity and
overweight as the accumulation of excessive and abnormal body Determining the body fat composition
fat in such a way that it has the potential to impair the health
There are several methods of determining the body’s
of an individual.1 The global prevalence of overweight and composition. The most accurate determination, and still the
obesity has dramatically increased since 1980, when the average “theoretical golden standard”, has its foundation on Archimedes’
proportion of adults with a BMI of 25 kg/m2 was estimated at principle dating back to 250BC: “The buoyant force which water
28%.2 The latest WHO statistics indicate that approximately 39% exerts on an immersed object is equal to the weight of water that
(1.9 billion) of adults above the age of 18 years are overweight the object displaces.”11 Body fat can therefore be calculated by
and 13% (600 million) are classified as obese.1 Supporting completely submerging a person in water and measuring the
the trend in increase, it has been estimated that by the year weight (volume) of displacement. Fat free mass has a density
2025, this figure will have risen to three billion people being of 1.1 kg per litre (consisting of 72% water, 21% protein and 7%
overweight, and nearly 700 million being obese. The incidence minerals), where fat has an average density of 0.9 kg per litre.
of obesity in children is also on the increase, with an estimated Ignoring the presence of air and contents in the gastrointestinal
42 million children worldwide being affected. Many studies have tract, it can then be calculated that if a person weighs 100 kg, he
shown the increase in risk for obese and overweight individuals will displace 95 litres of water if he has a fat percentage of 50%.
to develop diabetes mellitus3, cardiovascular disease4, cancer5, This is obviously impractical to perform in the clinical setup,
musculoskeletal disorders6, endocrine disorders7 and psychiatric thus a lack of an acceptable golden standard has led to various
disorders.8 Obesity is responsible for 3.4 million global deaths methods attempting to measure and calculate body fat. Each
annually and accounts for 4% of years of life lost. It can therefore method has limitations, and therefore practitioners need to have
be classified as a pandemic.2 adequate knowledge of these measuring techniques in order to
make an accurate assessment.
According to the most recent data on obesity published by the
Social Progress Imperative (SPI), South Africa is ranked as the Bioelectrical Impedance Analysis (BIA)
seventh “fattest” (% of population with a BMI ≥ 30 kg/m2) country
The use of electrical impedance entails the resistance to the
in the world, while Bangladesh has the lowest global incidence flow of an electric current through the different body tissues.
of obesity.9 The SPI is an international organisation consisting An algorithm is used to calculate total body water and fat free
of businesses, governments and civil society representing 133 body mass, which is subtracted from the total body mass to
countries reporting on global progress and success concerning give an estimation of body fat.12 BIA devices are commercially
various social and environmental challenges. Similar studies available and frequently used due to the low cost, portability and
have shown South Africa to be very close to the global average, noninvasiveness of this procedure. Several factors may affect

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The pharmacological management of obesity 17

Figure 1. Top 15 “obese countries”

the accuracy of the reading, such as hydration status, exercise, 24.9 kg/m2. Values less than 18.5 are considered underweight,
ambient temperature, position of electrode placement and whereas a value above 30 is classified as obese. Overweight
equipment calibration. The over- and underestimation of body represents values between 25 and 29.9.1 Although the definition
fat by using BIA ranges between 7–14%.13 and classification of obesity by the WHO make use of the BMI
scale, it has serious limitations. Omitted variables such as age
Dual-energy X-ray Absorptiometry (DEXA) (body fat physiologically increases with age), sex (females
The use of DEXA has recently been advocated as a possible inevitably have a higher body fat composition), fat distribution,
golden standard in determining body composition. Here an muscle mass and bone structure (athletes or bodybuilders
energy source produces photons at different energy levels, which with high muscle mass and lower body fat), may result in an
are measured and used to differentiate between non-identical individual being misclassified due to either overestimation or
elemental profiles such as fat, bone and muscle. Body fat can underestimation of body fat.4, 17 Some studies suggest that if the
accurately be calculated but the high costs involved make it an calculated BMI has to be compared to BIA, the overestimation of
unlikely tool to be used in everyday practice. The instruments obesity could be as high as 30–60%.18
also have a maximum capacity of approximately 180 kg, thus
Waist circumference (WC)
morbidly obese patients would not enjoy any benefit.14
Determining the waist circumference is another tool for
Anthropometric measurements
classifying obesity with regards to the cardiovascular risk profile.
Measuring triceps skinfold thickness (TSF) and mid-arm Waist circumference measurement is useful in patients who are
circumference (MAC) are noninvasive, inexpensive and easy to categorised as normal or overweight on the BMI scale (≤ 30 kg/m2
perform. From these two measurements the mid-arm muscle ). Men are classified as “high risk” if the measured circumference
circumference (MAMC) can be calculated: [MAMC = MAC - at the midpoint between the lower margin of the last palpable
(3.1416 x TSF)]. The determined value is then compared to rib and the top of the iliac crest exceeds 102 cm. For women the
standardised age and gender reference ranges. A value below threshold should not exceed 88 cm. Measuring circumference
the fifth percentile demonstrates underweight, whereas values at the level of the umbilicus may underestimate the true waist
above the 90th percentile imply obesity.15 Anthropometric circumference.19 Measuring the WC only alludes to the location
measurement arithmetic is more useful in monitoring long-term of fat, but not the absolute percentage of body fat. Using this
nutritional therapy in malnourished children than assessing method has an error rate of approximately 3%, making it a more
obesity in adults. Using this method may under- or overestimate suitable evaluation tool compared to measuring the waist-to-hip
body composition by up to 10% in severely obese individuals.16 ratio, BMI or BIA.18, 20

Body Mass Index (BMI) Pharmacological therapy

BMI is calculated by dividing the weight by the height squared Pharmacological therapy is indicated for obese persons (BMI
(kg/m2). It is easy to perform and is the most widely used ≥ 30 kg/m2), or overweight individuals with a BMI ≥ 27 kg/m2 with
clinical tool in the indirect assessment of obesity. A typical BMI, associated complicating risk factors such as diabetes mellitus,
representing a normal weight range, is between 18.5 kg/m2 and hypertension, dyslipidaemia, sleep apnea and symptomatic
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18 S Afr Fam Pract 2016;58(4):16-21

osteoarthritis.21 Potentially serious side-effects limit its use to Pancreatic lipase inhibitors
the short-term, although chronic therapy is indicated in resistant
The enzyme, pancreatic lipase, is present in the lumen of the
cases and where the benefit outweighs the risk. To date, no
stomach and small intestine. It is responsible for breaking
clinical trials on any anti-obesity drugs have been conducted for
down triglycerides into monoglycerides and absorbable free
longer than four years. Patients should be extensively counselled
fatty acids.29 When lipase activity is blocked, triglycerides are
prior to initiating drug treatment and unrealistic expectations
excreted undigested, thereby reducing fat absorption from the
explained. During the first month weight loss should exceed 2 kg
diet and a reduction in caloric intake. Achieved weight loss with
and thereafter 5% within the next 3–6 months. Pharmacotherapy orlistat is dose dependent. A maximum dose of 120 mg three
is considered to be effective if a patient achieves a weight loss of times per day reduces intestinal fat absorption by almost 30%,
10–15% in combination with lifestyle modifications in a period after which a ceiling effect is reached.30 The ordinary expected
of 1–2 years.22 In order to maintain the achieved weight loss, weight loss in 12 weeks is 4% of the initial body weight, but could
patients should furthermore reduce their energy intake by at increase to > 10% if treatment is continued beyond six months.31
least 8 kcal/kg (34 kJ/kg).23 Orlistat is a preferred option for obese patients with diabetes,
dyslipidaemia and hypertension considering its efficacy and
For a substance to be regarded as an anti-obesity drug, it
favourable safety profile. Adverse gastrointestinal side-effects
has to demonstrate a reduction of at least 5% in the baseline
are frequent, whereby 15–30% of patients will experience
body weight. Agents used to treat obesity include appetite
gastro-oesophageal reflux disease, flatus, faecal incontinence,
suppressants (sympathomimetic drugs), pancreatic lipase
frequent bowel movements or steatorrhoea.32 Drug interactions
inhibitors, antidiabetic drugs, serotonin agonists, antiepileptic with orlistat are uncommon, except with cyclosporine, but it may
drugs, atypical antidepressants, hormones, combination prep- inhibit the absorption of fat soluble vitamins A, D, E and K.
arations and various herbal and complementary medicines. The
choice of agent should be individualised and governed by patient Antidiabetic drugs
comorbidities, relative contraindications, available clinical trial Antidiabetic drugs commonly used to achieve weight loss
evidence and clinical expertise. In addition to pharmacological include metformin (a biguanide) and liraglutide (a long-acting
therapy, all anti-obesity drugs should be prescribed with the GLP1 agonist). Although the precise mechanism of these agents
premise of dietary caloric restriction and exercise. Table I below in weight reduction is not fully understood, several hypotheses
indicates some of the available and pending preparations in have been proposed.
South Africa.
Metformin
Appetite suppressants
Neuropeptide Y (NPY) is a neurotransmitter present in the
All of the appetite suppressants are β-phenylamine derivatives sympatho-adrenomedullary nervous system. The NPY pathway is
which are structurally related to noradrenaline, dopamine stimulated by exercise, fasting, and energy loss which results in a
and amphetamine. They increase the synaptic concentrations suppression of sympathetic activity and an increased appetite.33
of noradrenaline and dopamine by 1) displacing these Recent studies suggest that unlike its antidiabetogenic effects,
transmitters from their storage vesicles (amphetamine), 2) metformin’s anorectic properties are unrelated to its peripheral
stimulating the release and inhibiting reuptake into presynaptic suppression of hepatic gluconeogenesis, increased insulin
vesicles (phentermine, diethylpropion, phendimetrazine, sensitivity or enhanced peripheral glucose uptake, but that
d-norpseudoephedrine and sibutramine) and 3) directly a central mechanism is responsible. Metformin, like leptin,
agonising adrenergic receptors (phenylpropanolamine). inhibits neuropeptide Y expression, thereby reducing food
intake and decreasing body weight.34 Metformin is not primarily
Appetite is resultantly suppressed by the stimulation of the
indicated as a weight loss drug, seeing that it does not achieve
hypothalamic satiety centre in the brain.24 Sympathomimetic
the required reduction of 5% or more loss in baseline weight.
drugs therefore reduce food intake by causing early satiety.
It is nonetheless useful in overweight individuals with elevated
All of these drugs have a rapid onset of action and relatively short
insulin levels at risk for type 2 diabetes. A customary weight loss
half-lives. They have been associated with numerous systemic
of approximately 3 kg in eight weeks can be expected on a dose
side-effects including hypertension, palpitations, insomnia,
of 1000 mg per day.35 If adherence to treatment is continued,
cardiovascular toxicity and valve disease, stroke, depression metformin can sustain weight loss for at least 10 years. Side-
and a high potential for abuse. This has led to them being effects are uncommon and mainly include gastrointestinal upset
highly scheduled substances, with some being discontinued (4%) which usually resolves spontaneously. Patients with renal or
worldwide (sibutramine and phenylpropanolamine).25 It is hepatic insufficiency are at risk for developing lactic acidosis and
generally accepted that these agents should not be used for a it is therefore contraindicated in these individuals.
period exceeding 12 weeks. Calculating or predicting a dose-
response relationship is difficult and the original degree of Liraglutide
obesity has a considerable effect on the rate of absolute weight Glucagon-like peptide 1 (GLP-1) is an incretin hormone which is
loss. Clinical data sheet reviews for the trial periods of 12 weeks secreted by the ileal L cells in the presence of nutrients in the
have shown the following average weight loss per substance: lumen of the small intestines. It stimulates the release of insulin
phendimetrazine 140 mg (3.6 kg)26, phentermine 30 mg from the pancreatic beta cells and inhibits glucagon release from
(8.1 kg)27, diethylpropion 75 mg (7.2 kg)28 the alpha cells, thereby causing a decrease in blood glucose
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The pharmacological management of obesity 19

Table I. Available agents in the management of obesity

Drug Active ingredient Dosage Maximum duration SEP*/quantity

Schedule of therapy
Appetite suppressants
Duromine® – iNova 5 Phentermine 15 mg Once daily 3 months R215.75 (30)
Phentermine 30 mg R278.41 (30)
Obesan X® – Technikon 6 Phendimetrazine 30 mg 1–2 twice daily 6 weeks R110.52 (30)
Obex LA® – Al Pharm 6 d-Phendimetrazine 105 mg Once daily 6 weeks R786.72 (30)
Relislim – Loock Pharm
®
6 d-norpseudoephedrine 20 mg Max 60 mg per day 4 weeks R49.13 (30)
Tenuate Dospan® – Al Pharm 6 Diethylpropion 75 mg Once daily 4 weeks R333.77 (30)
Pancreatic lipase inhibitors
Xenecal® – Roche 3 Orlistat 120 mg Three times daily 12 weeks R876.00 (84)
Serotonin agonists
Belviq** N/A Lorcaserin 10 mg Twice daily 12 weeks N/A
Antidiabetic drugs
Glucophage® – Merck+ 3 Metformin 500 mg Max dose per day = N/A R44.05 (90)
Metformin 850 mg 2550 mg R64.32 (60)
Metformin 1000 mg R69.85 (60)
Metformin XR 500 mg R68.86 (90)
Metformin XR 1000 mg R92.40 (40)
Victoza® – Novo Nordisk+ 4 Liraglutide 6 mg/ml Max 1.8 mg daily 12 months R617 (3 ml pen)
Antiepileptic drugs
Topamax® – Janssen Pharm+ 3 Topiramate 25 mg Max 400 mg daily N/A R380.25 (60)
Topiramate 50 mg R598.18 (60)
Topiramate 100 mg R1008.40 (60)
Topiramate 200 mg R1534.29 (60)
Atypical antidepressants
Wellbutrin® – GSK+ 5 Bupropion 150 mg Max 360 mg daily 12 months R378.32 (60)
Bupropion 150 mg XL R350.93 (30)
Bupropion 300 mg XL R350.93 (30)
Hormones
Eltroxin® – Aspen+ 3 Levothyroxin 0.05 mg N/A N/A R96.16 (100)
Levothyroxin 0.1 mg R121.72 (100)
Ovitrelle® – Merc+ 4 α-Choriogonadotropin 6500 iU 125 iU daily 6 weeks R371.91(0.5 ml
prefilled syringe)
Combination preparations
Qsymia** N/A Topiramate 46 mg or 92 mg Max 92 mg/15 mg 2 years N/A
Phentermine 7.5 mg or 15 mg once daily
Contrave** N/A Naltrexone 8 mg Max 32 mg/360 mg 24 weeks N/A
Bupropion 90 mg
SEP: single exit price, XR and XL: extended-release tablets
* Single exit price, as listed in the Monthly Index of Medical Specialities. 2016;56(1)

** Not available in South Africa

+ Not registered for weight loss

levels. In addition it reduces gastric emptying, thereby slowing Serotonin 2c agonists

the rate of nutrient absorption and reducing food intake.36
Pro-opiomelanocortin (POMC) is a protein present in the central
Liraglutide is an agonist on GLP-1 receptors used to diminish
nervous system. It is cleaved into several smaller peptides, each
weight in obese diabetic and non-diabetic patients. Mean weight
controlling important metabolic and physiological functions
loss on daily subcutaneous dosages between 1.2–3 mg during a
in the brain. One of these peptides, β-melanocyte stimulating
20 week period ranges from 4.8–7.2 kg.37 Nausea and vomiting
hormone (β-MSH) interacts with the melanocortin 4 receptor in
are the most common side-effects (45%) and are experienced by the hypothalamus which regulates the balance between energy
> 5% of patients. Other adverse effects include hypoglycaemia, from food taken into the body, and energy spent by the body.
diarrhoea, constipation, headache, fatigue, dizziness, abdominal Eating and weight is thus maintained through this mechanism.38
pain and increased lipase levels. Treatment should not exceed Stimulation of 5-HT2C receptors in the hypothalamus enhances
12 months as there is an increased risk for developing pancreatitis. pro-opiomelanocortin production, resulting in weight loss
Liraglutide is contraindicated during pregnancy, gall bladder through satiety.39 Lorcaserin, a selective serotonin 2c receptor
disease and thyroid abnormalities. agonist, has been available in the United States since 2012 for
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20 S Afr Fam Pract 2016;58(4):16-21

the treatment of obesity with comorbid conditions. Its efficacy homeostasis, it is suggested that combining two drugs with
is comparable to orlistat, with an average weight loss of 3.6 kg different mechanisms of action could improve efficacy,
in 12 weeks on a dose of 20 mg per day.40 Side-effects are dose- tolerability and the need for lower doses of individual drugs.
dependent, and include headache (18%), nausea, dizziness, Regulatory authorities seem to disagree on which combinations
fatigue, dry mouth and constipation.41 It should not be taken by are suitable for registration and which ones are not.25 Currently
patients with renal dysfunction or those on other serotonergic there are no approved combination anti-obesity drugs registered
agents due to the possibility of developing serotonin syndrome. by the South African Medicines Control Council, however the
Currently lorcaserin is not yet available in South Africa. individual substances are available independently.

Antiepileptic drugs Phentermine (immediate release) and topiramate (extended

release) capsules are only available in the USA. This combination
Topiramate’s mechanism of action as an antiepileptic involves
should not be used in patients with cardiovascular disease such
the enhancement of GABA, and modifying the excitatory
as hypertension, diabetes or dyslipidaemia, rendering it an
voltage-activated sodium and calcium channels in the brain.
inappropriate choice for the majority of obese patients. It carries
Its mechanism as an anti-obesity drug is not fully known, but
a risk of increased congenital malformations, especially orofacial
studies indicate that it may increase the brain noradrenaline
clefts when taken during the first trimester of pregnancy. It is
expression. Enhanced noradrenaline in the central nervous
considered as second-line therapy for obese postmenopausal
system resultantly suppresses appetite.42 Average weight loss on
women, or men without complicating risk factors not responding
a dose between 96–200 mg per day for 28 weeks is approximately
or unable to tolerate orlistat or lorcaserin. This formulation
6.5 kg.43 The most common side-effects include paresthesia,
however appears to produce the largest mean weight loss
psychomotor disturbances, memory impairment, diarrhoea and
(> 10%) after two years treatment.47
changes in vision. Topiramate is not recommended as a single-
use agent in the management of obesity. Naltrexone and bupropion sustained release formulations have
been available in Europe since 2012 and the USA from 2014. Both
Atypical antidepressants
these drugs have anorectic properties and their combination
Bupropion is a dopamine and noradrenaline reuptake inhibitor. proves favourable in the reduction of visceral fat. The proposed
Its mechanism is similar to other sympathomimetic agents, and mechanism involves the increased firing rate of POMC neurons,
is structurally related to diethylpropion. The additional effect of leading to appetite suppression.48 The combination shows an
raising the dopamine concentration in the brain’s reward centre increased risk of suicidal thoughts and behaviour and may
(ventral tegmental area), makes it useful in treating depression, precipitate seizures and adverse cardiovascular events in
smoking cessation and suppression of appetite. Published patients with epilepsy and uncontrolled hypertension. Expected
literature reports an average weight loss of 4.4 kg in six months weight loss is roughly 9 kg in a 24 week period.
on a daily dose of 300 mg.44 Bupropion is ordinarily well-tolerated
Conclusion
with few side-effects, but may cause agitation, headache, nausea,
sweating and abdominal discomfort in rare instances. Obesity rates are on the increase worldwide, and the cost to
the healthcare system can be significant. Modest weight loss
Hormones improves the risk of cardiovascular disease and morbidity.
Various hormones acting on the hypothalamus play a role Although a multitude of measurements to classify obesity and its
in appetite and energy homeostasis, some of which have associated risks are well known, a precise clinical relevant golden
been previously mentioned. One such hormone is leptin. It is standard is still lacking. All measurement tools should be seen
secreted by the adipose tissue, gastric epithelium and placenta. as imperfect and patients must be assessed on individual merit.
Hypothalamic stimulation by leptin suppresses appetite and It remains the healthcare practitioner’s imperative to adhere to
increases thermogenesis and metabolic rate in the long term.45 acceptable management protocols. Various pharmacological
Obese individuals typically have high plasma leptin levels, but substances are available and should be used in conjunction
display insensitivity and resistance towards its hypothalamic with advice on lifestyle modifications. Specific pharmacotherapy
stimulation. Early research done by Simeons recommended the should be discontinued or re-evaluated if a weight loss of at
injection of 125 iU human chorionic gonadotropin (HCG) daily to least 5% is not achieved after six months. Bariatric surgery could
restore hypothalamic-leptin sensitivity. The weight loss achieved be considered in individuals with a BMI of ≥ 35 kg/m2. Patients
by this method in combination with a calorie restricted diet was should be made aware that drug therapy is not a cure for obesity
between 9–14 kg in six weeks.46 This observation has been refuted and that further weight loss will cease when the maximal
by many researchers, yet the act of injecting HCG is still widely therapeutic effect of a drug is reached. Practitioners should be
practiced. Similarly the administration of thyroid hormones in vigilant in identifying drugs with no scientific merit and council
euthyriotic obese patients is considered inappropriate, since the patients against their use.
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