Clinical Endocrinology - 2021 - Apperley - Childhood obesity A review of current and future management options

Received: 19 May 2021 | Revised: 12 October 2021 | Accepted: 13 October 2021
DOI: 10.1111/cen.14625
REVIEW
Childhood obesity: A review of current and future

management options
Louise J. Apperley1 | James Blackburn2 | Karen Erlandson‐Parry3 | Lucy Gait4 |

Peter Laing1 | Senthil Senniappan1
1
Department of Paediatric Endocrinology,
Alder Hey Children's Hospital, Liverpool, UK Abstract
2
Centre for Endocrinology, William Harvey Obesity is becoming increasingly prevalent in paediatric populations worldwide. In
Research Institute, Barts and the London
School of Medicine, Queen Mary University of
addition to increasing prevalence, the severity of obesity is also continuing to rise.
London, London, UK Taken together, these findings demonstrate a worrying trend and highlight one of
3
Department of Paediatric Dietetics, Alder the most significant challenges to public health. Childhood obesity affects multiple
Hey Children's Hospital, Liverpool, UK
4
organs in the body and is associated with both significant morbidity and ultimately
Department of Paediatric Clinical
Psychology, Alder Hey Children's Hospital, premature mortality. The prevalence of complications associated with obesity, in-
Liverpool, UK cluding dyslipidaemia, hypertension, fatty liver disease and psychosocial complica-
Correspondence
tions are becoming increasingly prevalent within the paediatric populations.
Senthil Senniappan, Associate Professor, Treatment guidelines currently focus on intervention with lifestyle and behavioural
University of Liverpool and Consultant
modifications, with pharmacotherapy and surgery reserved for patients who are
Paediatric Endocrinologist, Alder Hey
Children's Hospital NHS Foundation Trust, refractory to such treatment. Research into adult obesity has established pharma-
Liverpool L12 2AP, UK.
cological novel therapies, which have been approved and established in clinical
Email: senthilkss@yahoo.co.uk
practice; however, the research and implementation of such therapies in paediatric
populations have been lagging behind. Despite the relative lack of widespread re-
search in comparison to the adult population, newer therapies are being trial-
led, which should allow a greater availability of treatment options for childhood
obesity in the future. This review summarizes the current evidence for the man-
agement of obesity in terms of medical and surgical options. Both future therapeutic
agents and those which cause weight loss but have an alternative indication are also
included and discussed as part of the review. The review summarizes the most
recent research for each intervention and demonstrates the potential efficacy and
limitations of each treatment option.
KEYWORDS
BMI, childhood obesity, lifestyle interventions, paediatrics, pharmacotherapy
1 | INTRODUCTION Programme measures children in reception year (aged 4–5 years) and
Year 6 (aged 10–11 years). In 2019/20, the results showed that the
Childhood obesity has become a public health problem worldwide. prevalence of obesity in reception years is 9.9%, and continued to
The prevalence of children who are either overweight or obese is increase to 21.0% in Year 6.1 The programme found that males were
increasing each year. In England, the National Child Measurement more likely to be obese and showed that children living in more
Louise J. Apperley and James Blackburn contributed equally to this study.
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APPERLEY ET AL. | 289
deprived areas had more than a twofold increase in obesity compared weight compared to age, reflecting the changing composition of the
to those living in affluent areas.1 The feedback from parents re- body during physical development. Many countries utilize country‐
garding this programme has been positive in areas such as parental specific reference charts for weight and height. This leads to differing
knowledge, perceptions and intentions.2 In the adult population, the definitions of obesity. The World Health Organisation (WHO) defines
prevalence of obesity has increased from 14.9% to 28.7% from 1993 overweight as BMI‐for‐age greater than 1 standard deviation above
to 2017, respectively.3 There are a number of complications that are the WHO Growth Reference median, and obesity as greater than 2
associated with obesity, such as cardiovascular disease, joint pro- standard deviations above the WHO Growth Reference median.7 The
blems, type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver dis- International Obesity Task Force definition of obesity utilizes cut‐off
ease, sleep apnoea, pubertal issues and raised intracranial pressure.4 values of BMI of 25 (overweight), 30 (obesity) at age 18, with LMS
These conditions have a significant effect not only on physical health multiple‐country curves produced for age‐specific paediatric popu-
but also on mental health and quality of life. lations.8 In the US the Centers for Disease Control and Prevention
It is important that childhood obesity is tackled early so that it defines overweight as 85th to less than the 95th percentile and
can be managed before the onset of complications. It is also clear that obesity as 95th percentile or greater, based upon age and sex‐
if the number of children with obesity is reduced, this should posi- adjusted BMI centiles.9 In the United Kingdom the Royal College of
tively reduce the prevalence of adult obesity. Paediatrics and Child Health define childhood obesity as BMI at or
At present, the management of childhood obesity focuses on above the 98th percentile for children and adolescents of the same
lifestyle interventions and the importance of expelling more calories age and sex. Overweight is defined as BMI at or above 91st per-
5
than taking in. Lifestyle interventions have been shown to work in centile and below 98th percentile for children and adolescents of the
some patients, but the general increasing trend of this problem shows same age and sex.
that it is not sufficient.6 Pharmacotherapy is developing rapidly in the
adult population and, even though data is limited for these medica-
tions in children and young people, there is potential that they could 3.1 | Nonpharmacological interventions
be a valuable adjunct in the management of obesity in children and
young people. National Institute for Health and Care Excellence (NICE) guidance
The aim of this review is to evaluate both current and future currently recommends lifestyle intervention as the primary treatment
potential management options for childhood obesity, with the main in childhood obesity.10 As part of this, dietary changes are required to
focus on pharmacological interventions. reduce calorie intake.5 NICE guidance states that restrictive and
nutritionally unbalanced diets should not be encouraged as they are
ineffective in the long term and may not be safe. All children with
2 | MATERIALS AND METHODS obesity should be encouraged to make changes to their diet, but this
should not be the only approach to lose weight.11 Ojeda‐Rodriguez
The search engine PubMed was used to identify literature for this et al.12 showed that intense lifestyle intervention (moderate hypo-
review. Keywords used included childhood obesity, adolescents, caloric diet, exercise and nutritional education) is successful at re-
pharmacotherapy, metformin, orlistat, glucagon‐like peptide 1, sibu- ducing BMI standard deviation score (SDS) in children and young
tramine, topiramate, phentermine, lorcaserin, setmelanotide, lisdex- people with abdominal obesity.12
amfetamine, naltrexone, bupropion, fluoxetine, zonisamide, metreleptin Environmental factors are likely to influence the treatment of
and bariatric surgery. The main focus was on paediatric studies with childhood obesity. Schools are important to consider, and it has been
patients less than eighteen years of age, but where data was limited, recommended that water fountains are freely available in schools and
adult studies have been discussed. The references of specific articles that the catering is focused on to ensure children have healthy op-
were also analysed to ensure additional information was obtained tions for lunch.13 It is of no surprise that factors, such as not eating
where appropriate. breakfast, increased fat and carbohydrate content in the diet and a
lower intake of healthier options (e.g., fruit, vegetable and dairy) were
found to be associated with childhood obesity.14–16
3 | DEFINITION It has been shown that sugar‐sweetened drinks increase the risk
of children being overweight or obese5,17,18 and that there is an as-
Obesity is characterized by excessive fat accumulation in the adipose sociation between less sugar content and a reduction in BMI.18–21 In
tissue. Obesity is diagnosed based upon body mass index (BMI), 2015, WHO provided guidelines that recommended reducing sugar
which is calculated by dividing an individual's weight by their height. content in the diet for both adults and children.16,22 In 2018, the
In people with excess musculature, the degree of adiposity does not United Kingdom introduced tax on sugary drinks, and even though
correlate with their BMI; however, for most individuals, BMI is felt to total sales of soft drinks is unchanged, data shows that people appear
be an accurate assessment of adiposity and therefore obesity. In to be buying less sugary drinks and thus consuming less sugar, over
adults, obesity is defined as BMI ≥ 30 kg/m2 and overweight as the last couple of years.23 The UK government is continuing to
BMI ≥ 25 kg/m . In paediatric populations, obesity is defined by
2
support healthier choices, by restricting the promotion of unhealthy
290 | APPERLEY ET AL.
foods from April 2022.24 Hamano et al.25 found that accessibility to attention. Research suggests that children and adolescents living with
fast food outlets was significantly associated with childhood obesity. obesity experience a greater prevalence of mental health problems
The guideline produced by the Endocrine Society recommends re- such as depression, anxiety, low self‐esteem, as well as psychosocial
ducing fat and sugar consumption, fast food meals and eat whole fruit challenges.41–44 Park et al.,45 showed that children living with obesity
4,26,27
over juices. They also recommend portion control and regular experience 4.5 times higher stress than their peers of a healthy
meals to avoid snacks during the day.4,6,28–31 Trier et al.32 showed weight. It is conceptualized that the psychosocial challenges and
that a multidisciplinary treatment programme significantly reduces stigma of living with obesity, alongside the physical constraints and
the BMI SDS, but the intake of sugary drinks and snacks before the reduced quality of life, feed into a vicious cycle. This further perpe-
programme did not affect the degree of obesity at baseline or weight tuates the mental health difficulties and lifestyle choices that con-
loss during the year of treatment. tribute to obesity. Therefore, obesity has a role as a precipitating and
33
In view of more restricted diets, Eneli et al. investigated the maintaining factor that influences the wider outcomes for a young
effect of the protein‐sparing modified fast (PSMF) in 21 adolescents person's health.
with severe obesity over a 12‐month period. The PSMF aims to re- Given that the family system is the primary context for a child's
duce the calorie and carbohydrate content and increase protein in the development, it is widely acknowledged that parents' lifestyle choices
diet. The results showed that weight and BMI decreased significantly will shape a child's behaviour through processes, such as role mod-
at 3 and 6 months, but adherence and compliance dropped over the elling, parenting style, reinforcement, restriction and monitoring.46,47
33 34
study period. Andela et al. published a literature review to eval- The NICE guidelines highlight the most successful interventions for
uate the effect and safety of a very‐low‐energy diet (VLED) in chil- weight loss to be achieved are family‐based interventions.47,48 Family
dren and young people. VLED consists of a daily intake of less than approaches,47–51 behavioural therapy47 and cognitive behavioural
800 calories or less than 50% of the person's total energy ex- therapy (CBT)48,52 have been shown to be effective treatments when
34
penditure. This review shows that children and adolescents reduce used in conjunction with supported lifestyle modifications. Pro-
their weight significantly if a VLED is followed for at least 6 months.34 grammes including behavioural change approaches have been shown
Due to limitations, it is difficult to directly compare VLED with con- to be effective in weight management, with a focus on stimulus
ventional diet, but this present review has shown greater weight control, self‐monitoring and goal setting.48 CBT explores the re-
34
reduction with VLED. The analysis also showed improvements in lationships between thoughts, feelings and behaviours. It is used as a
blood pressure, glucose, insulin and total cholesterol levels.34 VLED directive and structured approach to treat many conditions and aims
has also been shown to improve glycated haemoglobin (HbA1c) and to alleviate distress and improve quality of life by helping patients to
reduction in pharmacotherapy in adolescents with T2DM.34–36 learn the skills to challenge their assumptions and develop more
Similar findings have been documented in the adult population.37 adaptive cognitions and patterns of behaviour.53 There are limited
The authors found that adverse effects were not well described in high‐quality studies that investigate the effectiveness of CBT and
the studies reviewed. Common effects reported included tiredness other therapeutic models making it difficult to draw conclusions
and postural hypotension.34 Concerns with possible electrolyte de- around this.48 However, the importance of considering the psycho-
ficiencies remain and supplementation is recommended. Therefore, logical and systemic components that precipitate and maintain obe-
the review reports that VLED is safe short‐term, but further research sity alongside the medical and physiological complications is clear.
is required for longer‐term adverse effects.34 Obesity must be managed through a multi‐faceted approach to
National guidance currently recommends children undertake provide the best care.
moderate to vigorous exercise for 60 min each day.11,15,16 A combi-
nation of aerobic and resistance training has shown to be more
beneficial with weight loss and waist circumference.38 It has been 3.2 | Pharmacotherapy
shown that school is an important factor in encouraging children and
young people to take part in physical activity and significantly lowers If lifestyle changes are not successful, drug therapy could be con-
the risk of obesity.39,40 A review on obesity interventions found that sidered in addition to lifestyle modification for managing obesity in
physical activity only interventions based in schools were able to children54,55 (see Table 1).
improve BMI, waist circumference in females, skin‐fold thickness and
body fat.39 It also showed that making physical activity more ac-
cessible, both in school and at home, is more beneficial for children 3.2.1 | Medications approved for obesity
39
with obesity.
At present, lifestyle changes are the first choice in managing Orlistat
childhood obesity. Ideally, this should be done as a combination of Orlistat has been licensed by the US Food and Drug Administration
improving diet and physical activity for a higher chance of success. (FDA) for the treatment of obesity in adolescent patients over 12
The physiological consequences of childhood obesity are widely years of age.58 NICE guidelines currently recommend starting orlistat
recognized in literature and in more recent years the emotional and in this age group if they have significant physical or psychological
psychological consequences of living with obesity have gained wider comorbidities.10,59 Orlistat is an intestinal lipase inhibitor, which
TABLE 1 A table of medications used in the clinical practice for managing obesity in adult and paediatric populations
Medication Mechanism of action Licensed/approved Dose Freq Route Adverse effects Contraindications
APPERLEY
Orlistat Lipase inhibitor, blocks fat FDA approved for obesity 120 mg TDS PO Anxiety, gastrointestinal disorders Cholestasis; chronic
ET AL.
absorption >12 years (abdominal pain, diarrhoea) malabsorption syndrome
Liraglutide GLP‐1 agonist EMA approval for obesity 0.6–3 mg OD SC Gastrointestinal symptoms, Renal failure, Family history of
>12 years hypoglycaemia, pancreatitis thyroid carcinoma/multiple
(uncommon), renal failure endocrine neoplasia
FDA approved for T2DM 0.6–1.8 mg
(uncommon) syndrome type 2 (MEN2)
>10 years
Setmelanotide MC4R agonist FDA and EMA approved for N/A OD SC Injection site reactions, None
POMC, PCSK1, or LEPR hyperpigmentation, nausea,
deficiency in patients >6 vomiting.
years
Metreleptin Recombinant analogue of FDA and EMA approved for Up to 0.13 mg/kg OD SC Fatigue, hypoglycaemia, weight loss, General obesity not associated
leptin the treatment of or 10 mg T‐cell lymphoma (uncommon) with congenital leptin
congenital leptin deficiency
deficiency and
generalized
lipodystrophy
Semaglutide GLP‐1 agonist FDA approved for T2DM in 0.25 mg (max Weekly SC Pancreatitis, retinopathy, hypoglycaemia, Medullary thyroid
adults 1 mg) (adults) acute kidney injury, hypersensitivity carcinoma, MEN2
Reactions, gastrointestinal
disturbance.
Exenatide GLP‐1 agonist None 5–10 mcg (adults) BD SC Gastrointestinal symptoms, Renal failure, Family history of
hypoglycaemia, pancreatitis thyroid carcinoma/MEN2
(uncommon), renal failure
(uncommon)
Metformin Inhibition of gluconeogenesis, FDA approved for T2DM in 200–500 mg BD PO Gastrointestinal disorders (abdominal Metabolic acidosis
improves insulin sensitivity children >10 years initially pain, reduced appetite, diarrhoea,
(max 2 g/day) nausea, altered taste, vomiting)
Topiramate Carbonic anhydrase inhibitor, None N/A OD or BD PO parasthesia, difficulty concentrating, Porphyria, pregnancy
appetite suppression mood changes and memory issues
through potential GABA
augmentation
Lisdexamfetamine TAAR1 agonists and vesicular None N/A OD PO Gastrointestinal symptoms, dizziness, Cardiovascular disease
monoamine transporter 2 dry mouth, reports of sudden death
inhibitors
Naltrexone SR with Opioid antagonist and FDA and EMA approved for N/A OD PO Nausea, headache, dry mouth and Opiate dependency
Bupropion SR antidepressant56,57 obesity in adults dizziness
|
(Continues)
291
Abbreviations: BD, twice daily; CV, cardiovascular; EMA, European Medicines Agency; FDA, Food and Drug Administration; LEPR, leptin receptor; OD, once daily; PCSK1, proprotein convertase subtilisin/kexin
reduces the hydrolysis of triglycerides and decreases intestinal fat
hyperthyroidism, pregnancy
adsorption.60 A recent meta‐analysis of the efficacy of orlistat sug-
Sulfonamide hypersensitivity
Poorly controlled epilepsy,
gested that orlistat reduced BMI by 0.5–4.2 kg/m2 compared to
CV disease, glaucoma,
placebo.60 This was also supported by a number of randomized
trials.61 It has also been shown that individuals taking orlistat are 2.44
Contraindications
times more likely to lose over 5% body weight after 12 weeks of

treatment compared to placebo.62 Maahs et al.63 investigated 40
mania
adolescents and found that the BMI reduction between the orlistat
and placebo groups was not significant. The BMI reduction within
each group was found to be significant.46 The longest running of
disturbances, dizziness, insomnia and

prolongation, tinnitus, tremor, urinary
headache, paraesthesia, QT interval
nystagmus, paraesthesia, peripheral

confusion, drowsiness, dry mouth,
these studies with a follow‐up of >12 months suggested a sustained

Alopecia, anxiety, confusion, fatigue,
reduction in BMI with the continuation of orlistat (BMI: −4.2 kg/m2 at

memory loss, mood changes,
urolithiases, vision disorders

Anxiety, arrhythmias; arthralgia,
15‐month follow‐up).64 The side effects of orlistat include diarrhoea,

oedema, speech disorder,
Tachycardia, gastrointestinal
faecal incontinence, flatulence and abdominal pain.61 Due to the

significant side effects associated with orlistat, a UK‐wide study
showed the discontinuation rate of the medication to be 45% by the
Route Adverse effects
dry mouth
end of the first month and 75% by the end of 3 months.65 In addition
disorders
to the gastrointestinal side‐effects, orlistat also reduced the adsorp-

tion of dietary fat‐soluble vitamins and therefore supplementation of
vitamins A, D, E and K is recommended.4
PO
PO
PO
type 1; PO, oral; POMC, proopiomelanocortin; SC, subcutaneous; T2DM, type 2 diabetes mellitus; TDS, three times a day.
Glucagon‐like peptide‐1 analogues

Glucagon‐like peptide‐1 (GLP‐1) is a peptide secreted by the L cells in
the intestine.66 There are reports that GLP‐1 is released by neurons
Freq
OD
OD
OD
in the central nervous system that regulates appetite.66,67 This pep-

tide is secreted throughout the day but increases during food in-
gestion.67 It triggers the release of insulin and inhibits glucagon.67
GLP‐1 also slows gastric motility and therefore suppresses appe-
tite.67–69 The half‐life is 2 minutes for GLP‐1 due to rapid breakdown
Dose
N/A
N/A
FDA approved in >16 years N/A
by an enzyme called dipeptidyl peptidase 4 (DPP‐4).68 Two me-

chanisms have been used to prevent rapid GLP‐1 degradation, which
for weight loss, but not
available in the United
are direct DPP‐4 inhibition and production of DPP‐4 degradation

resistant GLP‐1 analogues.68 DPP‐4 inhibitors are used for the
Licensed/approved
management of diabetes in adults and include sitagliptin and vilda-

gliptin.66,68 DPP‐4 resistant analogues, include liraglutide, semaglu-
Kingdom
tide and exenatide.66,68 In terms of childhood obesity there is

Note: N/A, dosage recommendations for clinical use not available.
None
None
growing evidence to show the DPP‐4 resistant GLP‐1 analogues

could potentially be effective in reducing obesity, each is discussed
below.
Sulphonamide antiepileptic,
facilitates dopaminergic
Selectively inhibition of
Liraglutide
serotonin reuptake
neurotransmission
Mechanism of action
and serotonergic
Subcutaneous liraglutide has been approved by FDA for paediatric

TAAR1 agonist
patients with T2DM (maximum dose 1.8 mg) aged 10 years and
over.70,71 Recently, the European Medicines Agency (EMA) has
licensed liraglutide (maximum dose 3 mg) as an adjunct to healthy
nutrition and increased physical activity for weight management in
(Continued)
adolescent patients from the age of >12 years with obesity and body
weight above 60 kg.71
In terms of treatment for T2DM, there is growing evidence to
suggest an important role for liraglutide. Klein et al.72 performed a
Phentermine
Medication
Zonisamide
Fluoxetine
TABLE 1
double‐blinded randomized controlled trial (RCT) in nineteen 10–17‐

year olds with T2DM for 5 weeks. Interestingly, when compared to
placebo, higher doses showed a significant improvement of the
HbA1c level but did not have an effect on the body weight.72 randomized trial is currently being undertaken to investigate the ef-
A recent study by Tamborlane et al.73 investigated the role of fect that liraglutide has on the BMI of paediatric patients with PWS.82
liraglutide in the management of adolescent patients with T2DM,
already treated with metformin. At 1‐year follow‐up, patients taking Setmelanotide
liraglutide had a significantly reduced HbA1c compared to placebo. A Setmelanotide, a melanocortin 4 receptor (MC4R) agonist, has shown
reduction in BMI was also reported; however, this did not achieve potential for patients with a proopiomelanocortin (POMC) muta-
73
statistical significance. The most commonly reported adverse tion83 and possibly other genetic conditions.56 It has been shown to
effects were gastrointestinal disturbances with nausea being promote weight loss in patients with MC4R deficiency. Previous
the most commonly reported symptom. Gastrointestinal symptoms MCR4 agonists have had concerns with tachycardia and/or hy-
were most frequently reported in the first 8 weeks of treatment.73 pertension, but Collet et al.84 did not report any of these effects over
Evidence from trials of T2DM suggests that weight loss is a 4‐week course. Clément et al.85 recently reported the results from a
74
achieved with higher doses of liraglutide, as shown by Kochar et al. single‐arm, open‐label, multicentre, phase 3 trial across seven coun-
The safety of such doses was established by Danne et al.75 in a tries in the patients with POMC or leptin receptor (LEPR) deficiency
double‐blind RCT which had a sample size of 21 adolescents. Lir- who received either setmelanotide or placebo for a year and it was
aglutide was given once daily for 5 weeks, with a maximal dose of noted that 80% participants in the POMC group and 45% participants
3 mg. Mild hypoglycaemic episodes also occurred in the liraglutide in the LEPR group achieved at least 10% weight loss.85 Hunger scores
75
group, but there were no reported severe episodes. were also significantly reduced for both POMC and LEPR deficiency
76
In 2020, Kelly et al. published data from an RCT, which in- groups.85
cluded adolescents with obesity who had not successfully lost weight In view of these findings, setmelanotide was approved by FDA in
with lifestyle measures alone. In total, 125 participants were given November 2020 and EMA in July 2021.86,87 Setmelanotide is in-
liraglutide (up to 3 mg), whereas 126 participants had placebo. The dicated for chronic weight management in patients aged 6 years or
results showed that body weight and BMI reduced significantly in the over with confirmed POMC, proprotein convertase subtilisin/kexin
76
liraglutide group, compared to the placebo group, after 56 weeks. A type 1 and LEPR deficiency.86
BMI reduction of over 5% was seen in 51/113 participants receiving
liraglutide, compared to 20/105 in the placebo group.76 Following Metreleptin
discontinuation, weight gain was observed in both groups. Gastro- Metreleptin is a synthetic, recombinant analogue of leptin, which has
intestinal adverse effects were noted in the liraglutide group and been used successfully for weight loss in patients with leptin defi-
highlighted that the medication may not suit all individuals.76 ciency.88 It is licensed both in the United Kingdom and the United
77
Mastrandrea et al. have recently investigated liraglutide as a weight States for the treatment of congenital leptin deficiency and gen-
77
loss therapy in individuals aged 7–11 years. A group of 24 children eralized lipodystrophy.89,90 The efficacy of using metreleptin in
was randomized into a liraglutide group and placebo group with 16 paediatric patients with leptin deficiency has been shown in multiple
and 8 children in each, respectively.77 The results of the study studies.91,92 Similarly in patients with lipodystrophy outcomes are
showed a BMI Z‐score reduction of −0.28 (p = .0062) in the liraglutide favourable when patients are treated with metreleptin.93 Metreleptin
group.77 A recent UK‐based study has shown that when combined is not currently recommended for the treatment of patients with
with an intense weight management programme, patients treated nonleptin deficiency‐associated obesity. Adult studies have shown
with liraglutide dropped BMI by 2.1 kg/m2 over a period of 3 months. that antimetreleptin antibodies develop in a majority of patients with
Liraglutide was shown to be well tolerated by all patients receiving obesity and is associated with a reduction of treatment efficacy.94
the treatment.78 Liraglutide has also shown promise as a potential The complications of metreleptin therapy include T‐cell lymphoma
74
therapeutic option in treatment‐resistant obesity by Kochar et al. (reported in patients with lipodystrophy)95 fatigue, hypoglycaemia
Adolescents with obesity which was initially managed by lifestyle and weight loss.96
changes and then oral medications but had failed to achieve weight
loss, were trialled on liraglutide for 12 weeks.74 The study showed
that 51% of patients lost 5%–10% of their body weight and 23% lost 3.2.2 | Under investigation, but not yet licensed for
over 10%.74 The results also demonstrated a significant improvement obesity
in systolic blood pressure, insulin, glucose, HbA1c and lipid profile
levels and liver function tests.74 Semaglutide (GLP‐1 analogue)
Prader–Willi syndrome (PWS) is a genetic disorder associated Evidence for semaglutide as a potential therapeutic option has largely
with progressive obesity, which may lead to early mortality and been established in adults. O'Neil et al.97 undertook a double‐blinded
morbidity. The use of liraglutide has been shown to improve BMI and RCT in the adult population comparing semaglutide with liraglutide
79,80
glycaemic control in small numbers. In contrast, liraglutide was and placebo at varying doses, via subcutaneous injection, over a
given at standard diabetes dosing to three females aged between 19 1‐year period. Patients treated with semaglutide had a significant
and 22 years old for 3 months. There was no reduction in BMI, improvement in weight compared to placebo.97 Doses of 0.2 mg and
81
glycaemic levels or appetite scores during this time. A blinded greater of semaglutide were also shown to have a significant
reduction in weight compared to liraglutide.97 The most common resistance have been widely accepted, the effect of metformin on
effects reported were gastrointestinal symptoms.97 Once‐weekly reducing weight in patients with obesity is limited. A recent meta‐
subcutaneous semaglutide has recently been approved by FDA for analysis suggested BMI improvement of −1.38 kg/m2 (95% CI: −1.93
T2DM in adults. 98
Recent published data has shown impressive to −0.82) from baseline compared with control at 6 months; however,
weight loss following the use of once‐weekly semaglutide in adults, this effect was not statistically significant at 12 months.109 Over
compared to placebo. In total, five‐phase 3 trials called semaglutide three randomized trials, metformin was shown to have a small, but
treatment effect in people with obesity (STEP) have been performed, nonsignificant, effect on weight loss in adolescents with hyper-
with the results published from four (STEP 1–4).99 STEP 1 was a insulinaemic, nondiabetic obesity at 6 months.61 The most common
double‐blind trial with a sample size of 1961 adults with a BMI side effects of metformin are gastrointestinal (nausea, bloating and
≥ 30 kg/m2 or ≥27 kg/m2 with ≥1 weight‐related comorbidity. The diarrhoea),110 however gradual dose increase and titration can help
100
participants were randomized in a 2:1 ratio (treatment:control). to ameliorate these effects.111 Importantly, the addition of metformin
The treatment group received 2.4 mg (titrated up over 16 weeks) of to weight loss regimes is not associated with the development of
semaglutide, compared to the control group who received placebo. lactic acidosis in paediatric populations.112
The results showed a mean body weight reduction of 14.9% in those
who had semaglutide, compared to 2.4% in the control group Topiramate
(p < .001), over 68 weeks.100 Approximately 86.4% of the semaglu- Topiramate is currently licensed for the treatment of seizures and
tide group lost over 5% of their weight (31.5% in placebo group; migraine prophylaxis.69 Topiramate was shown to significantly reduce
p < .001).100 Promisingly, these results have been replicated in STEP weight in the adult population initially.113,114 It is thought that its
2–4 trials (average weight loss over 68 weeks ranged from −9.6% to mechanism is through a number of neurotransmitters and works by
17.4%).99 suppressing appetite and reducing daily intake.56,67,115 It has since
Further research has shown that daily oral semaglutide has a been investigated in adolescents and has shown similar results with
significant effect on weight compared to subcutaneous liraglutide or weight reduction while on the medication.116,117 Interestingly, Fox
101
placebo in adults with T2DM. Both semaglutide and liraglutide had et al.118 did not find a significant difference in weight with topiramate
the same effect on HbA1c levels. Clinical trials to assess the effect of treatment compared to meal replacements. The authors did report
semaglutide on adolescent obesity are currently ongoing.102 significant associations between topiramate and reduced visceral fat
and very‐low‐density lipoprotein cholesterol compared to the pla-
Exenatide (GLP‐1 analogue) cebo group. Topiramate does have adverse effects that include
Exenatide is used for the treatment of T2DM in adults.56 Kelly paraesthesia, poor concentration, mood changes and memory is-
et al.103 recently reported data from 22 adolescent patients during a sues.57,113,118 A recent study of obese adolescent patients com-
3‐month course of exenatide.69 The exenatide group had a significant menced on topiramate for issues other than obesity (including
reduction in BMI (−1.13 kg/m2, 95% confidence interval [CI]: −2.03, migraine prophylaxis and seizure prevention) showed a statistically
−0.24; p = .015) and weight (−3.26 kg, 95% CI: −5.87, −0.66, p = .017) significant reduction of BMI SDS at 6 months (−0.26 SDS; p = .04),
compared to placebo.103 An improvement in the systolic blood although intolerable side‐effects caused the medication to be dis-
pressure was also noted but was not significant.103 All side effects continued in 16% of the cohort.119 Topiramate is a teratogenic drug,
103 104
reported were mild. In 2017, Salehi et al. completed a 6‐month hence this should be considered carefully when prescribing to
study that looked at the effect of exenatide in patients with PWS. females of child‐bearing age.120
104
The patients were aged between 13 and 25 years old. The data
showed that exenatide significantly reduced the individual's appetite Lisdexamfetamine
104
and HbA1c, but did not reduce their weight. Exenatide has been Lisdexamfetamine is currently FDA approved for attention‐deficit
piloted in eight adult patients with obesity secondary to hypotha- hyperactivity disorder (ADHD) in children over the age of 6 years and
lamic causes such as tumours.105 The medication was given twice for binge‐eating disorder in the adult population. It has been shown
daily for 1 year. The weight change was not significant, but the study to be successful in decreasing the number of binge‐eating episodes in
did demonstrate that the weight remained stable or dropped, rather adults.121 Srivastava et al.122 recently published a case of a 16‐year‐
105
than the typical increasing trend seen in such patients. old female who had a long history of gaining weight with multiple
unsuccessful lifestyle interventions. The patient was also diagnosed
with ADHD and binge‐eating disorder. With this history, the decision
3.2.3 | Off‐label medications was made to trial lisdexamfetamine and the patient dropped from a
BMI of 49–41 kg/m2 over an 18‐month period.122 The patient did
Metformin not report any side effects during this time. The patient also showed
Currently, metformin is licensed by the FDA for children with a di- improvements in mental health and binge‐eating episodes.122
106,107
agnosis of T2DM from 10 years of age. In paediatric patients Hansen and Darling123 investigated the adverse effects of lisdex-
with obesity, metformin has been shown to reduce insulin resistance amfetamine in paediatric patients with ADHD. The authors studied a
and the cardiovascular risk profile.108 While the effects on insulin sample size of 43 individuals and noted that 23.3% discontinued the
medication due to side effects. The most common problems were period.131 Fluoxetine was also compared to placebo over a 52‐week
decreased appetite, insomnia, abdominal pain and weight loss.123 period by Darga et al.132 Up to Week 45, fluoxetine induced sig-
There have been reports of sudden death in both the adult and nificant weight loss compared to placebo, but over time the fluox-
paediatric population following the use of lisdexamfetamine. There- etine group had a larger regain of weight and by the end of the study,
fore, it is contraindicated in patients with cardiovascular disease and the two groups were no longer significant.132 Both placebo and
patients must be monitored regularly.122 fluoxetine groups had significant weight loss at 1‐year follow‐up
(−4.5 vs. −8.2 kg).132 Goldstein et al.133 found higher doses of
Naltrexone SR with bupropion SR fluoxetine to be more effective in weight loss in the adult population,
Naltrexone SR and Bupropion SR combined (Contrave) are approved compared to placebo or lower doses. They also reported lack of
by FDA for weight loss in adults,124 whereas another brand Mysimba energy as a side effect but otherwise felt the medication was well
125
has EMA approval. NICE do not currently recommend this treat- tolerated.133 The effect of fluoxetine on binge‐eating in the adult
ment due to the lack of long‐term evidence and potential for overall population was inferior to cognitive behaviour therapy and placebo
high costs.126 The Contrave Obesity Research I (COR‐I) study in- over a 12‐month course.134
cluded participants aged between 18 and 65 years. Individuals were
randomly allocated to either the intervention group (naltrexone Zonisamide
32 mg SR and bupropion 360 mg SR or naltrexone 16 mg SR and Zonisamide is indicated for focal seizures in children. Adult patients
bupropion 360 mg SR) or the placebo group. Significant reductions in have experienced weight loss with the use of zonisamide.57 A small
body weight were found in both intervention groups compared to number of pilot data have shown that zonisamide may potentially be
control after 56 weeks.127 Results from COR‐II were published in effective for weight loss in the paediatric population.116,135 Further
2013. For this trial, the dose of naltrexone was 32 mg SR and com- research is required to investigate the efficacy and safety of this
pared to placebo. Significant weight loss was seen in the group taking medication for weight loss in children and young people.
naltrexone and bupropion compared to control at both Weeks 28
(−6.5% vs. −1.9%) and 56 (−6.4% vs. −1.2%).128 A total of 55.6% of
participants receiving naltrexone and buproprion lost over 5% of their 3.2.4 | Withdrawn medications or those not
body weight at Week 28 and 50.5% at Week 56. This compared to available in the United Kingdom
17.5% and 17.1% of the placebo group, retrospectively.128
These results were also supported by Halseth et al.,129 who Sibutramine
showed sustained weight loss for 78 weeks. Their primary endpoint Sibutramine is a selective noradrenaline reuptake inhibitor, a type of
was from baseline to Week 26, with 60 out of the 71 participants antidepressant, which was previously used as a treatment for obe-
receiving naltrexone and bupropion and lifestyle intervention losing sity.55,136 It works by suppressing appetite.136 It had been shown to
over 5% of their body weight, compared to 10 out of 82 in the group reduce weight significantly in adolescents with obesity, either alone
who received standard care.129 All studies reported nausea as the or in combination with orlistat or lifestyle interventions.61,137–139 It
127–129
main adverse effect. The medication is generally well toler- was also shown to reduce BMI by reducing fat mass in adoles-
ated, but further evidence is required to investigate the long‐term cents.140 In 2010, sibutramine was removed by FDA due to concerns
56
efficacy and safety. Bupropion SR has also been shown to improve about adverse effects.55,141–143 It was shown to increase the risk of
130
low mood in adolescents. Therefore, it is thought that bupropion cardiovascular diseases, such as hypertension.61 Initially this was
SR may have the potential to improve the mood and weight of monitored,136,143 but it was finally decided that the risks outweighed
adolescents with depression and obesity.130 As with other anti- the benefits. Sibutramine was noted to trigger reactive oxygen pro-
depressants, there are concerns that this medication may increase duction and reduce nitric oxide supply, which resulted in apoptosis
the risk of suicidal ideation, and thus has not been approved in the and contraction of aortic smooth muscle cells resulting in increased
paediatric population.124 There does not appear to be any current blood pressure.144
trials investigating the use of this medication in the paediatric
population. Lorcaserin
Lorcaserin, a selective 5‐hydroxytryptamine 2C receptor agonist that
Fluoxetine acts on the hypothalamus, is able to aid weight loss by reducing
Fluoxetine is a selective serotonin reuptake inhibitor and is approved appetite and therefore overall daily intake.56,57,67 It has been shown
131
for the treatment of depression in children aged over 8 years old. to successfully reduce weight in the adult population and improve
In 1987, Levine et al.131 compared treatment with fluoxetine versus biochemistry markers.57,67 It has been shown to be relatively safe and
placebo for weight loss in nondepressed adults with obesity. The to not increase cardiovascular disease in the population; however,
fluoxetine group significantly lost more weight (−4.5 ± 4.0 kg) over an the FDA identified increased malignancies in the treatment group
8‐week period, compared to the placebo group (−1.4 ± 0.1 kg).131 (including pancreatic, colorectal and lung) and therefore FDA ap-
This group did suffer from an increased lack of energy, but otherwise, proval was removed in 2020.145,146 At present, there is no published
the authors felt it was a safe and effective medication for this time data on the effect of lorcaserin in the paediatric population.
Phentermine increasing numbers of patients undergoing such procedures, the evidence

Phentermine is a sympathomimetic amine, which inhibits the uptake to fully support this approach remains limited. Indeed, a review of the
of norepinephrine in the hypothalamus and results in a reduced ap- Cochrane database highlights the limited number of randomized control
petite.57,67 It is currently FDA approved as an antiobesity medication trials available with a single study included in the review, with limited
for patients over 16 years old.56,57 There is limited data for use in long‐term follow‐up.154 Studies which support the role of bariatric sur-
children and younger adolescents. In 2017, Ryder et al.147 published gery are ongoing, one of the most significant of these is the teen‐LABS
data on 25 adolescents receiving phentermine and lifestyle advice, study which showed that at 3‐year follow‐up, mean weight decreased by
compared to 274 adolescents who only received lifestyle advice. The 27% (95% Cl: 25–29) in the intervention group. The results for the type
results showed a significant reduction in BMI percentage in the of procedure showed a reduction of 28% (95% CI: 25–30) among par-
phentermine group compared to the control group over 6 months ticipants who underwent gastric bypass, and by 26% (95% CI: 22–30)
(−4.1%; 95% CI: −7.1, −1.0%; p = .009). 147
The heart rate of the who underwent sleeve gastrectomy.155 Weight loss was maintained at a
participants taking phentermine was noted to be higher than the 5‐year follow‐up.156 In terms of choice of intervention, the use of sleeve
147
control group. There was no difference in blood pressure. Other vertical sleeve gastrectomy is now much more frequent in adolescents,
side effects include gastrointestinal disturbances, dizziness, insomnia compared to Roux‐en‐Y gastric bypass, which had previously been the
and dry mouth.56 Further studies are required to fully appreciate the most common procedure.157 Recommendation of either gastric restrictive
147
effect and efficacy of this drug in the paediatric population. procedures (gastric sleeve, banding) or neurocognitive procedures (gastric
Phentermine is used worldwide, but at present, due to cardiovascular bypass) should be made on an individual basis with patient factors as a
concerns associated with phentermine use, it is not currently avail- key part of this decision.153
able in the United Kingdom. In addition to the effect on weight, the reduction in comorbidities
following surgery is also significant. A recent review comparing the
Phentermine/topiramate outcome of patients in the Teen‐LABS programme to those in the
This combination of therapy is FDA approved for use in adults with Treatment Options of Type 2 Diabetes in Adolescents and Youth
67
obesity. Similarly to phentermine alone, it is used worldwide, but (TODAY) programme (who received medication and lifestyle mod-
not available in the United Kingdom. It has been trialled by Hsia ifications) suggested HbA1c fell from 6.8% to 5.5% in Teen‐LABS, but
et al.148 in adolescents with obesity. One group was given a dose of increased from 6.2% to 7.8% in the TODAY group.158 Other co‐
7.5 mg phentermine and 46 mg topiramate (mid‐dose) and were obesity‐related comorbidities such as hypertension, dyslipidaemia
compared to a group with a dose of 15 mg phentermine and 92 mg and proteinuria were significantly reduced in the Teen‐LABS
topiramate (top‐dose). Both groups tolerated the medication well and group.158 Multiple other studies have supported the role of surgery
showed a significant reduction in their weight over an 8‐week peri- in reducing obesity‐related comorbidities.159–162
od.148 50% of those receiving top‐dose lost 5% or more of their body One of the largest concerns with regard to bariatric surgery is
weight along with 13.3% on mid‐dose and 0% on placebo.148 This the known immediate side‐effects and the longer‐term unknown
trial has shown that there is potential that this combination therapy effects. To date, there is a single case report detailing mortality
may be successful in treating childhood obesity, but further trials are post gastric bypass in a paediatric patient.163 Significant
required to investigate the efficacy and safety longer term. side‐effects following surgery include dumping syndrome,164 se-
vere gastro‐oesophageal reflux,165 cholelithiasis166 and surgery‐
related complications (hernias, wound infections, small bowel
3.3 | Surgical intervention obstructions).153 Other concerns with regard to long‐term out-
comes are driven by the relative lack of co‐ordinated national
3.3.1 | Bariatric surgery follow‐up data. One exception is the Swedish adolescent morbid
obesity surgery (AMOS) trial which is ongoing and has reported 2‐
Bariatric surgery is generally reserved for patients with severe obesity year follow‐up data on a large cohort of patients and aims to
with multiple comorbidities who are refractive to the measures described provide detailed follow‐up data.167 Given the paucity of long‐term
above. There is an increasing international trend for patients to undergo follow‐up data, it is likely that data for the efficacy and safety of
bariatric surgery to treat obesity.149 Current international guidelines bariatric surgery long‐term is limited.
suggest that bariatric surgery should be considered in individuals who
have undergone puberty and have a BMI of >40 kg/m2 or a BMI of
>35 kg/m2 with significant, extreme comorbidities and have failed a for- 4 | CONCLUSION
mal lifestyle modification programme.4,150–152 The drive towards the in-
creased surgical intervention appears to be driven by the clear efficacy To manage the growing public health crisis caused by increasing rates of
reported in multiple systematic reviews; BMI reduction at 1‐year follow‐ childhood obesity across the globe, effective and well‐researched treat-
up from bariatric surgery (multiple modalities) was −13.5 kg/m2 (95% CI: ment options are essential. In terms of paediatric populations, the number
−14.1 to −11.9)153 and from gastric banding alone was −12.7 kg/m2 (95% of potential therapies and the research to support their use is lacking
CI: 11.3–14.2).154 Despite the apparent efficacy of bariatric surgery and when compared to treatment available for adults with obesity, although
increasing research is being devoted towards childhood obesity. Cur- 3A/pathways/obesity/obesity-management-in-children-and-

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Clinical Endocrinology - 2021 - Apperley - Childhood obesity A review of current and future management options

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Clinical Endocrinology - 2021 - Apperley - Childhood obesity A review of current and future management options

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Received: 19 May 2021 | Revised: 12 October 2021 | Accepted: 13 October 2021

Childhood obesity: A review of current and future

Louise J. Apperley1 | James Blackburn2 | Karen Erlandson‐Parry3 | Lucy Gait4 |

Louise J. Apperley and James Blackburn contributed equally to this study.

absorption >12 years (abdominal pain, diarrhoea) malabsorption syndrome

times more likely to lose over 5% body weight after 12 weeks of

disturbances, dizziness, insomnia and

nystagmus, paraesthesia, peripheral

these studies with a follow‐up of >12 months suggested a sustained

reduction in BMI with the continuation of orlistat (BMI: −4.2 kg/m2 at

urolithiases, vision disorders

15‐month follow‐up).64 The side effects of orlistat include diarrhoea,

faecal incontinence, flatulence and abdominal pain.61 Due to the

to the gastrointestinal side‐effects, orlistat also reduced the adsorp-

Glucagon‐like peptide‐1 analogues

in the central nervous system that regulates appetite.66,67 This pep-

FDA approved in >16 years N/A

by an enzyme called dipeptidyl peptidase 4 (DPP‐4).68 Two me-

are direct DPP‐4 inhibition and production of DPP‐4 degradation

management of diabetes in adults and include sitagliptin and vilda-

tide and exenatide.66,68 In terms of childhood obesity there is

growing evidence to show the DPP‐4 resistant GLP‐1 analogues

Subcutaneous liraglutide has been approved by FDA for paediatric

double‐blinded randomized controlled trial (RCT) in nineteen 10–17‐

Phentermine increasing numbers of patients undergoing such procedures, the evidence

increasing research is being devoted towards childhood obesity. Cur- 3A/pathways/obesity/obesity-management-in-children-and-

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