Chronic diseases account for approximately three-quarters of the United States’ $2.7 trillion in annual healthcare spending and nutrition is a major contributor to the top five causes of chronic disease and top leading causes of death in the USA . The dramatic rise of paediatric obesity , a condition typically associated with increased insulinemia and type II diabetes, has reached 16.9% of paediatric individuals older than 2 years, affecting especially minorities and individuals from underserved areas. Lifestyle changes continue to be the cornerstone for paediatric weight management. Behaviour recommendations are based on the same principles in primary care and specialty clinics, regardless of the severity of obesity . Although weight measures may improve during primary care interventions, body weight reductions of more than 5% require specialized staff , numerous clinical visits, motivation, time , as well as access to health-promoting food and physical activity environments . Few obese children and adolescents have access to other treatment options such as weight loss medications or surgery . The purpose of this article is to evaluate antiobesity drugs currently available to treat paediatric obesity and to provide an update on emerging pharmacotherapies.
BARRIERS TO USING MEDICATIONS FOR OBESITY
Although our understanding of obesity pathophysiology has increased, access to paediatric antiobesity drugs is limited. The pharmacological treatment of paediatric obesity has not only been limited by the understanding of the pathophysiology of obesity but also by the lack of consensus on the appropriate weight measures for drug dosing and the lack of patient adherence to treatment , ethical considerations  and postmarket complications. Many antiobesity drugs have been discontinued or withdrawn from the US market due to their side-effects. Fenfluramine (Fen-Phen) was removed from the market in 1997 for valvulopathy, Rimonabant (Acomplia) in 2009 for suicidal ideation, sibutramine (Meridia, Reductil) in 2010 for increased risk of heart attack and stroke, leaving orlistat as the only US Food and Drug Administration (FDA) approved agent available for long-term weight management until 2012, when additional antiobesity drugs for adults were approved. Moreover, a meta-analysis of treatment of obesity in childhood [8▪] suggests that current data in paediatrics are of low to moderate quality and that the current effect of orlistat along with behaviour therapy may not be more effective than behavioural therapy alone. The rebound effect of most antiobesity drugs is not well established, which is of major concern. Finally, the cost of antiobesity drugs may be prohibitive, especially for individuals from underserved areas. The estimated monthly cost of antiobesity drugs vary between $6 and $240, and is higher than $200 for prescription orlistat at a dose of 120 mg three times a day [9▪▪]. The daily cost of new combination antiobesity drugs can be even higher.
A limited number of drugs are currently under investigation in the European and the US market. Both European Medicines Agency (EMA) and FDA agencies have recently issued guidelines for antiobesity drug safety and efficacy . In order to obtain approval for a new antiobesity drug, investigators have to demonstrate that more than 35% of individuals in the treatment group lose at least 5% of their baseline weight and that the mean weight loss between the treatment and the placebo group differs significantly by at least 5% (P < 0.05). In addition, they have to show that the rate at which individuals lose 5% of their baseline weight is at least twice as high in the treatment compared with the placebo group (P < 0.05). Although a 5% weight loss has been identified as a relevant target for antiobesity drug approval in adult studies by the FDA, another recommendation in paediatrics include 5% BMI loss. Recent paediatric studies provide both endpoints [11,12] (also see clinicaltrials.org for updates).
PHARMACOLOGICAL OPTIONS: PAST AND CURRENT
Various expert panels providing guidelines for the treatment of paediatric obesity recommend using a stepwise individualized approach for paediatric weight management and include antiobesity drugs when multidisciplinary lifestyle modification interventions have failed [13,14]. Once family function and parenting styles have been addressed, and underserved families have been connected to appropriate psychosocial and community resources, clinicians can shift their focus to food and physical activity behaviours . The specialty team initially targets lifestyle behaviours to reduce weight gain and BMI, and may also discuss weight loss medications and surgery where appropriate.
Current antiobesity drug effects can be classified into three categories: centrally acting agents that suppress appetite, peripherally acting agents that impair absorption and agents that affect energy expenditure. Most agents currently affect appetite with or without an effect on energy expenditure. Drugs approved by the FDA to treat obesity in adults include benzphetamine, diethylpropion, phendimetrazine and phentermine for short-term treatment of morbid obesity (Fig. 1) [9▪▪,15▪▪]. In addition to orlistat, lorcaserin, a combination of naltrexone/bupropion, and a combination of low-dose phentermine/topiramate are approved for long-term management of weight loss in adults (Table 1) [9▪▪,15▪▪]. Although adult studies are conducted among individuals aged 18 years and older, the FDA approves the medication for children aged 16 years and older. At the present time, only one agent (orlistat) holds FDA approval to treat obesity in adolescents aged 12–16 years. Antiobesity drugs approved for use in children younger than 12 years are currently inexistent. In this review, we are describing the mechanism of action and safety of two pharmacological agents commonly prescribed by paediatric clinicians (orlistat and metformin) and emerging drug therapies.
Orlistat (Xenical), a gastrointestinal lipase inhibitor, is an adjunct therapy to behaviour modification. It may be particularly beneficial for individuals who have difficulty avoiding the consumption of dietary fat and have underlying conditions requiring low fat and cholesterol diets (e.g. individuals who do not eat at home, have hypertension, diabetes or hypercholesterolemia). Orlistat is prescribed at a dose of 60 to 120 mg three times a day and its mechanism of action is based on fat malabsorption (Table 2) . As a result, it may have a beneficial effect on weight (about 2–3 kg/m2 loss in BMI) and metabolic markers. Fat-soluble vitamin supplements are recommended 2–3 h before or after the medication. Alli (orlistat 60 mg) is available over the counter. The most common side-effects of orlistat are nausea, bloating, oily spotting, liquid stools, faecal urgency and abdominal cramping. Study completion rates have ranged from 65 to 100% and adherence rates between 73 and 98%. Unfortunately, orlistat is not very popular in adolescent weight management programmes due to its gastrointestinal effects. In addition, it is contraindicated among individuals with malabsorption syndrome, cholestasis or advanced liver disease.
Metformin (Glucophage) is a biguanide derivative that has been recommended for use in individuals aged 10 years and older who have T2DM (Table 2) . Current guidelines for adults strongly recommend that physicians use medications for a condition (e.g. T2DM) that also shows weight loss but advise against using that medication for weight management outside of that condition (e.g. T2DM) until additional studies are available. Metformin is frequently prescribed by primary care and specialty physicians to treat paediatric obesity even though long-term effects are disappointing [9▪▪], weight gain may be exacerbated at discontinuation  and metformin is not approved by the FDA for paediatric obesity without T2DM. As observed in adults, metformin may be useful in adolescents with polycystic ovary syndrome and prediabetes, but more studies are needed. Metformin doses typically range from 500 mg (850 mg HR) to 2500 mg/day. Metformin's effect on weight loss has been linked to the activation of AMP-activated protein kinase (AMPK), which results in the inhibition of liver gluconeogenesis and lipid biosynthesis, and the stimulation of glucose uptake by the muscle.
Metformin is an antihyperglycemic agent that improves insulin sensitivity without affecting insulin secretion, has a modest effect on weight measures (about 1 kg/m2 BMI loss) and has inconsistent effects on serum metabolic markers in adolescents. However, metformin may be more effective in children aged 6–12 years with insulin resistance [9▪▪]. A supplement of vitamin and calcium is recommended to improve B12 absorption during metformin treatment . Metformin is available as Glucophage, Glucophage XR (extended release) or a generic preparation.
FUTURE ANTIOBESITY DRUGS OPTIONS
Exenatide is a glucagon-like (GLP-1) receptor agonist that has been recommended for use in adults with T2DM. GLP-1 agonist increases insulin secretion while decreasing glucagon secretion. There is evidence that exenatide improves weight measures by increasing satiety and decreasing appetite. A 3-month, open-labelled study was conducted in 11 obese children (BMI ≥120% of the 95th percentile or ≥35 kg/m2) aged 8–19 years. Analysis included those with a threshold compliance of 80% for their doses . The dose used in this study was 5 μg twice a day given subcutaneously. Compared with the controls, children on exenatide had a BMI reduction of 1.7 kg/m2 (5% BMI) and improvements in insulin and glucose markers. In 2013, the same authors published a randomized, double-blind, case–control study of exenatide with lifestyle changes in children aged 12–19 years with subcutaneous escalation of the drug at 1 month to 10 μg twice a day . The most common adverse events included gastroenterological symptoms (nausea, vomiting, diarrhoea) and headaches. No episodes of hypoglycemia were observed. The administration of exenatide subcutaneously may be a limitation of this antiobesity drug in children and adolescents.
Liraglutide, another GLP-1 agonist, is being investigated for use in obesity. As performed in adult studies, paediatric investigators are first studying the effect of liraglutide in paediatric individuals with T2DM. In adults, a review of randomized clinical trials of GLP-1 agonists vs. placebo showed that overall, this class of agent reduced HgbA1c by an average of 1% . The pharmacokinetics in children aged 10–17 years were similar as those on adults . Klein et al. randomized 14 children and adolescents aged 10–17 years with T2DM (A1C 6.5–11%) receiving lifestyle and metformin treatment to either liraglutide or placebo. They showed that liraglutide was well tolerated with only mild gastrointestinal symptoms and no hypoglycemic events, and had similar pharmacokinetic profiles as in adults. Study participants had stable mean body weight.
Lorcaserin is a serotonin agent with a selective action on type 2 receptor (5HT 2). It is believed to affect weight via appetite suppression. An open-label pharmacokinetic study of obese adolescents aged 12–17 years has been completed (see clinicaltrials.org for updates) and new trials are expected in paediatric obesity.
Topiramate is a GABA receptor modulator and an antiseizure medication. Fox et al. used a retrospective study of 28 patients who received behaviour therapy in a weight management programme and were offered topiramate for at least 3 months. The authors showed that the patients lost about 5% weight at 6 months. There is currently a phase 2, double-blind, randomized clinical trial of meal replacement therapy for 4 weeks followed by topiramate vs. placebo in obese adolescents aged 12–17 years. The primary outcome being considered in that study is percentage BMI change at 28 weeks. The study is expected to be completed by the end of 2015. A 4.5-year randomized, double-blind, placebo-controlled clinical trial of topiramate vs. placebo with a treatment period of 9 months will be conducted in France among 9–17 years old obese adolescents (expected completion 2020) with a percentage change in BMI z-score as a primary endpoint (see clinicaltrials.org for updates).
The identification of the mechanisms contributing to food intake in children and adults is resulting in the development of new treatment targets. Future pharmacological agents may also include agouti-related protein, leptin, neuropeptide Y5, dopamine 3 and pancreatic polypeptide analogue. The use of pharmacological doses of select nutrients to improve weight measures and metabolic markers is currently under study and is beyond the scope of this review (see the NIH office of dietary supplements website for excellent updates).
UNREGULATED WEIGHT LOSS SUBSTANCES
Unfortunately, many weight loss substances are or have been available on the market and are unregulated despite their significant adverse effects (see ProCon.org for reviews). The clinicians need to be aware of their existence to optimize their assessment and guide their recommendations. Uncontrolled substances on the market may be part of food and dietary supplements. They include, among other thyroid extracts from animals’ products, thyroxin and triidothyrronine, dinitrophenol, beta-methylphenethylamine (amphetamine), and may even contain illegal substances such as sibutramine and ephedra. Some substances have been removed from the market such as Rainbow pills (a combination of amphetamines, digitalis, diuretics, laxatives and thyroid hormones) and Hydroxicut dietary supplement (combination of caffeine and herbal extracts) due to severe associated health conditions and even death. The FDA maintains a list of undesirable weigh loss substances that is available on its website. The FDA has also a warning you-tube video available on-line. Between 21 January 2014 and 30 April 2015, more than 56 weight loss products containing hidden drug ingredients were listed by the FDA.
ANTIOBESITY DRUGS GUIDELINES
New guidelines on antiobesity drugs for adult patients are now available [15▪▪]. Some of those recommendations (Table 3) deserve further evaluation in paediatrics, given that current antiobesity recommendations in paediatrics are limited  and some of these medications may affect growth and development. Current paediatric guideline recommendations are to use pharmacological agents as an adjunct to lifestyles programme in individuals with severe obesity and in the stage four treatment tier for the management of paediatric obesity. However, there is no consensus on the classification of severe obesity. The proposed BMI cut-off points for severe obesity include thus far the 99th percentile for outpatient weight loss programmes , 35 kg/m2 with comorbidities or 40 kg/m2 without comorbidities for weight loss surgery  and 1.2 X 95th percentile or 35 kg/m2 for weight loss medications .
In general, weight loss medications demonstrate only modest efficacy (3–9%) [9▪▪] and have a range of side-effects in both children  and adults [15▪▪]. Major adverse side-effects identified thus far have included psychiatric and cardiac conditions. In addition, there are concerns of weight rebound with the discontinuation of some agents. There is not enough evidence at this time for long-term safety and efficacy of pharmacological agents to treat paediatric obesity.
Despite the current limited availability of antiobesity drugs in paediatrics and given that obesity contributes to chronic diseases, medications that favour weight loss and maintenance as an adjunct treatment to lifestyle changes may play an important role before examining possible weight loss surgery options. This is especially true given that antiobesity drugs further improve weight loss associated with lifestyle changes, that morbidity increases with duration of obesity and that the costs of obesity-related conditions are increasing dramatically. However, the effect of pharmacological agents on lifestyle changes should also be evaluated in a real-world setting, as product marketing may affect the patients’ willingness to continue to improve their lifestyles . Therefore, medications for obesity treatment must not only be evaluated for long-term safety and efficacy [9▪▪] but also in population studies .
Yanovski and Yanovski [9▪▪] noted that patients on an antiobesity drug who do not lose at least 5% of their baseline weight within 12 weeks (3 months) are unlikely to benefit from that treatment. In that case, the risk and cost of treatment may actually outweigh the potential benefits. Unfortunately, product inserts for antiobesity drugs do not always provide recommendation on length of therapy on the basis of amount of weight loss attained during a specific period of time. The prescription of an antiobesity drug may vary as physicians consider many factors prior to prescribing the antiobesity drug such as sex, age, cost, contraindications, obesity-related conditions, underlying disease or condition, family and school support, antiobesity drug safety and efficacy, short-term or long-term use. New guidelines have been developed for the use of antiobesity drugs in adults but not in paediatrics even though pharmacological treatment options offered to adult medications can technically be used in adolescents aged 16 years and older. Therefore, there is a need for paediatric and nutrition societies to work together to initiate such guidelines.
I would like to thank the Boston Nutrition Obesity Research Center (P30 DK46200) and the Department of Pediatrics at Boston Medical Center for their support.
Financial support and sponsorship
We would like to thank the New Balance Foundation for their support.
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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