Pharmacotherapy in Pediatric Obesity: Current Status and Future Prospects

As obesity is principally a biologically mediated disease, biologically based interventions are often needed to counter the compensatory biological adaptations designed to maintain body weight at high levels. Pharmacotherapy can serve as an adjunctive treatment to lifestyle modification in some children and adolescents with obesity, especially those with severe forms of the disease and/or comorbidities. Despite the increasing number of anti-obesity drugs recently approved for the treatment of obesity in adults, few medications have been evaluated in terms of safety and efficacy in pediatric obesity. This mini review aims to provide some principles for the use of pharmacotherapy in pediatric obesity, summarizes results of some of the most important clinical trials on approved and “off-label” obesity medications and discusses some new options for the future of research on this field.


IOD.000582. 4(2).2020
It is important to acknowledge that obesity is a complicated and multifactorial disease necessitating a multifaceted approach.
Energy balance is regulated from homeostatic and non-homeostatic mechanisms which can be dysregulated in the event of obesity [16]. Following weight loss (when energy stores are depleted) homeostatic mechanisms which are affected by neurotransmitters and gut hormones promote increased food consumption and decreased energy expenditure. Hence weight loss is followed by decrease in levels of leptin, insulin and triiothothyronin and increase in insulin sensitivity and plasma ghrelin levels [17]. These changes stimulate appetite, decrease sympathetic nervous system tone and energy consumption and enhance lipogenesis, thus facilitating weight regain. Non homeostatic mechanisms, the nature of which has not been entirely elucidated, including reward, cognition and emotional factors associated with food intake also participate in weight regain. It is believed that palatable food hyper-consumption has caused habituation to rewarding neural dopamine signaling.
The weight loss is perceived as reward deficiency and leads to compensatory increase of food consumption [16]. Obviously these counter regulatory adaptations are observed in long term cases of obesity and are expected to persist for at least 12 months following weight loss and may even be permanent [18]. Therefore, it is reasonable to expect that the therapeutic approach must often combine lifestyle modification (focusing in external environment changing) with pharmacotherapy/bariatric surgery (focusing in internal biological environment changing) in order to be efficient and durable. This mini review focuses on pharmacotherapy as an adjuvant treatment to lifestyle modification, targeting homeostatic and non-homeostatic mechanisms of obesity in children and adolescents.

Indications for Pharmacotherapy
Despite the significant role of pharmacotherapy in obesity management and the increasing number of anti-obesity drugs approved for adults, only a few drugs have been assessed and fewer approved in children and adolescents with obesity. There is no concensus on the use of anti-obesity drugs in pediatric obesity regarding the appropriate age of treatment initiation and the necessity of treatment in obesity not associated with comorbidities.
The criteria for adult obesity pharmacotherapy include: a) BMI>27kg/m 2 with at least one obesity-related co-morbidity such as diabetes, sleep apnea, hypertension or hyperlipidemia or b) BMI>30kg/m 2 with or without comorbidity. Based on these established criteria, modified indications have been proposed for children and adolescents : a) class 1 obesity (BMI≥95 th percentile for age and sex or BMI>30kg/m 2 whichever is lower;) in the presence of at least one obesity-related co-morbidity or b) Class II (BMI≥120% of 95 th percentile for age and sex or BMI>35kg/m 2 whichever is lower) and Class III obesity (BMI≥140% 95 th percentile for age and sex or BMI>40kg/m 2 whichever is lower) irrespective of the presence of co-morbidities [19]. Clinically meaningful weight loss has been defined as BMI z-score reduction between 0.20-0.25 s.d. over 6-12 months which is equivalent to a 5% change in BMI which has been associated with improvements in cardiovascular and metabolic risk factors in adults [20]. Regarding the duration of treatment, it is recommended that medication should be continued if a >5% BMI reduction from baseline is maintained at 12 weeks or if arrest or slowing of weight gain is considered to be a reasonable clinical outcome [19]. Results and implications of the relatively small number of pediatric clinical trials of approved and off-label obesity drugs are discussed below.

Medication Available for Pediatric Obesity-FDA Approved
Orlistat is the only FDA approved medication for obesity ≥12 years of age. It inhibits gastric and pancreatic lipase, thus reducing hydrolysis of food triglycerides to FFA. In the proposed dose of 120mg trice a day with meals, decreases fat absorption from food by 30%. In a recent meta-analysis [20] including 779 adolescents 12-18years old, with mean BMI 37.4kg/m 2 , there was a slightly higher improvement in BMI in the group with orlistat: -0.94 [95% CI, -1.58 to -0.30] vs placebo group : -0.50 (95% CI, -7.62 to 6.62),with absolute weight change varying between +0.5 to -5.5kg in the orlistat group. In a randomized-controlled study assessing the effect of orlistat combined with lifestyle modification for 1 year on 352 adolescents resulted in a significant -2.61kg placebosubtracted weight loss (p<0.001) [10]. In general, orlistat treatment had a modest effect on cardiometabolic risk factors in contrast to data from adults where orlistat resulted in significant improvement of serum lipid profile and decrease od diabetes type 2 incidence [21,22]. The most common side effects were abdominal pain, flatus with discharge fatty/oily stool, increased defecation, and fecal incontinence. In conclusion orlistat produces small weight loss with no significant cardiometabolic benefit. The limited efficacy and low tolerability of the drug limits its clinical usefulness.
Phentermine is FDA-approved for age >16 years for short-term treatment (12 weeks) It has also been used as off-label drug in obese children <16 years or as long-term monotherapy. Phentermine is an amphetamine analogue that has been used in USA from 1959 in combination with topiramate [phentermine/topiramate extendedrelease] for obesity in adults. It produces appetite reduction, acting directly in hypothalamic satiety centers through cathecholamine release [23]. In a small retrospective study, 25 adolescents [mean age 16.1±1.3 years] who were treated with phentermine plus lifestyle modification were compared to 274 adolescents with only lifestyle modification. At 6 months, a reduction of -4.1% BMI (95% CI: -7.1, -1.0%; p=0.009) with phentermine plus lifestyle modification therapy was reported compared to lifestyle therapy alone [24]. The most commonly reported side effects are increase in heart rate and blood pressure, nervousness/and or insomnia.
Less frequently, dizziness, dry mouth, difficulty sleeping, irritability, nausea/vomiting, diarrhea and constipation have been reported.

Non FDA-approved medication with evidence from offlabel use in pediatric obesity
Metformin is FDA-approved in USA and Europe for the treatment of type 2 diabetes in adults and children >10years old.
Metformin was well tolerable with minimal discontinuation rate (<5%). No cases of lactic acidosis, hypoglycemia, rhabdomyolysis or hypertransaminasemia have been reported in children. The most commonly observed adverse effects were gastrointestinal symptoms (nausea, vomiting, and loose stools/diarrhea, bloating, flatus). Regarding cardiometabolic risk factors the comparison between metformin and placebo showed a modest superiority of metformin in reducing glucose, insulin and HOMA-IR and no benefit in change lipid profile or blood pressure [28,30,32,33,35].
Moreover, although meta-analysis showed only a small weight improvement of obese children, metformin has been proved notably effective in loss of weight gain related to anti-psychotic drugs in non-diabetic children [weight loss: -4.1%, 95% CI 2.2-6.0] [36] and in adults with weight gain during mood/cognitive disorders leading to emotional eating, steroid use etc [37,38]. Metformin has also been extensively used in polycystic ovary syndrome in adolescents with or without obesity with good results in terms of weight loss and improvement of lipid profile and hirsuitism [39][40][41]. It is also noteworthy that metformin administration in adults with prediabetes was reported to lead to significant reduction in incidence of type 2 diabetes [42]. Similar studies have not been performed in children and adolescents to date, but it is very likely that metformin could have an important role in prevention of type 2 diabetes in high risk pediatric population. Until to date, the management of obese children with prediabetes is individualized.

The European Society of Endocrinology and the Pediatric
Endocrine Society guidelines propose to avoid metformin use only for weight loss in obese children [43]. But they also suggest that the negative health impact may justify medication. Hence, in each case different aspects such as the metabolic profile, the comorbidities, the capacity of lifestyle modification etc should be considered in treatment decision. In conclusion, metformin is a safe drug with proven benefits and can be the first choice in certain cases.
Further research is needed for the evaluation of its efficacy in the prevention of type 2 diabetes and long-term benefit in children and

adolescents.
Topiramate although it is FDA approved for epilepsy ≥2 years of age and migraine prophylaxis in ≥12 years old, it has been shown to have beneficial effect on weight loss [44]. A possible mechanism of action is the inhibition of glutamate and carbonic anydrase receptors and the enhancement of γ-aminobutyrate (GABA) activity at calcium-sodium cell receptors [45]. Topiramate produces weight loss not only through reduction of food intake, but through increased energy consumption as well [44]. There are limited data from off-label topiramate use in children and adolescents. A small randomized controlled study evaluating topiramate (75mg daily) in 30 adolescents (12-17 years) with severe obesity, reported approximately a 2% BMI reduction at 6 months compared to placebo following short-term meal replacement intervention. The difference was not statistically significant (-1.9%; 95% CI: -5.2% to +1.5%; P = 0.291) [46]. In another study assessing topiramate (75mg daily) for at least 3 months plus lifestyle intervention on 28 adolescents with severe obesity, a clinically meaningful BMI reduction was reported (-4.9%, 95% CI:-7.1, -2.8; P< 0.001) [47]. There were not any serious adverse events in both studiew, except for paresthesia [46] in two patients. Paresthesia depression and anxiety have been also reported in studies on adults using phentermine/topiramat ER. There is strong recommendation for adolescents not using the medication during pregnancy, as the drug is a teratogen.

GLP-1 Receptor Agonists [exenatide, liraglutide]
Exenatide [GLP-1 receptor agonist] is FDA approved for diabetes type 2 in adults >18 years old. It is administered via subcutaneous injection. It stimulates GLP1 receptors in hypothalamus decreasing appetite and increasing satiety, with subsequent weight loss [48].
Liraglutide another GLP1 receptor agonist is approved for diabetes type 2 in adults (1.2-1.8mg), for obesity >18 years (3mg) and recently (2019) approved for diabetes type 2 in children >10 years.It was evaluated in a randomized, placebo-controlled, doubleblind study in 21 adolescents (12-17years), BMI ≥30 kg/m 2 to ≤45 kg/m 2 [51]. Adolescents were randomized to receive either liraglutide for 5 weeks (0.6mg/week with weekly dose increase to a maximum of 3.0mg) or placebo there was a greater decrease in both BMI and weight in those receiving liraglutide compared to controls, however the difference did not reach statistical significance. Similar randomized double blind study was performed in 24 children (7-11years), out of whom 14 received liraglutide (0.3mg daily with weekly increase to 3mg) and 6 received placebo for 7-13 weeks [52]. A significant reduction in BMI z-score was observed (-0.28; p=0.0062). The medication was safe and well-tolerated.

FDA-approved obesity medications with no evidence in pediatric obesity
Lorcaserin is approved for obesity in adults in USA. It reduces food intake through selective activation of serotonin 2c receptors (5HT2C) in anorexiogenic neurons of propiomelanocortin (POMC) of hypothalamus. Studies in adults with obesity demonstrate a 3% placebo subtracted weight loss [56]. The most commonly reported side effects are headache, dizziness, fatigue, nausea, dry mouth and constipation. Ti must mot be coadministers with serotonergic medications. Naltrexone SR/bupropion SR (NB). Recently approved for obesity in adults in USA and Europe. It acts on hypothalamus by competitive binding of opioid receptors (naltrexone opioid antagonist) and selective inhibition of dopamine and noradrenaline reuptake (bupropion-antidepressant). The dose is 2 tb 8/90mg twice a day and the most common side effects include nausea, constipation, and dizziness. In adults the produce weight loss 4.8% greater than placebo. There are limited data from isolated use of each of the two components in children for other than obesity indications. Monotherapy with bupropion was applied in adolescents (12-17 years) for depression-without official approval even for this indication-and weight loss was observed as side effect in the majority of patients [57]. There is however great concern as for other antidepressants-for increased risk of suicide in children and adolescents [58]. Monotherapy with naltrexone has been applied in adolescents [>13 years] opioid users [59] and in children with PWS for appetite control [60], but its long term safety in pediatric population has not yet been confirmed. There is one literature report of NB use from a girl with PWS who showed small BMI reduction and binge-eating improvement [61]. In an open-label study setmelanotide was administered in two patients with POMC deficiency and produced substantial weight loss [62]. Adverse effects such as dry mouth, darkening of nevi and injection sites' induration have been reported. There are great expectations for its use in rare genetic forms of obesity which should be considered for children with hyperphagia and severe gradually aggravating obesity at a young age [<5 years] [63].

Conclusion
Pharmacotherapy may often constitute a useful additional tool to intensive lifestyle modification for the treatment of pediatric obesity for some patients, especially those with severe forms. As energy balance is complicated with mechanisms directing against weight loss, pharmacotherapy often becomes a reasonable choice to target the underlying biology. The need for the development of well designed pediatric obesity trials is stressed to evaluate the long term safety and efficacy of obesity medication in pediatric populations. Furthermore the optimal time for starting, discontinuing, or intensifying treatment remains to be defined.