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Meta-Analysis
. 2016 Nov 29;11(11):CD012436.
doi: 10.1002/14651858.CD012436.

Drug interventions for the treatment of obesity in children and adolescents

Emma Mead  1 , Greg Atkinson, Bernd Richter, Maria-Inti Metzendorf, Louise Baur, Nicholas Finer, Eva Corpeleijn, Claire O'Malley, Louisa J Ells
Affiliations
Meta-Analysis

Drug interventions for the treatment of obesity in children and adolescents

Emma Mead et al. Cochrane Database Syst Rev. .

Abstract

Background: Child and adolescent obesity has increased globally, and can be associated with significant short- and long-term health consequences.

Objectives: To assess the efficacy of drug interventions for the treatment of obesity in children and adolescents.

Search methods: We searched CENTRAL, MEDLINE, Embase, PubMed (subsets not available on Ovid), LILACS as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to March 2016. We checked references and applied no language restrictions.

Selection criteria: We selected randomised controlled trials (RCTs) of pharmacological interventions for treating obesity (licensed and unlicensed for this indication) in children and adolescents (mean age under 18 years) with or without support of family members, with a minimum of three months' pharmacological intervention and six months' follow-up from baseline. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity. In addition, we excluded trials which included growth hormone therapies and pregnant participants.

Data collection and analysis: Two review authors independently assessed trial quality and extracted data following standard Cochrane methodology. Where necessary we contacted authors for additional information.

Main results: We included 21 trials and identified eight ongoing trials. The included trials evaluated metformin (11 trials), sibutramine (six trials), orlistat (four trials), and one trial arm investigated the combination of metformin and fluoxetine. The ongoing trials evaluated metformin (four trials), topiramate (two trials) and exenatide (two trials). A total of 2484 people participated in the included trials, 1478 participants were randomised to drug intervention and 904 to comparator groups (91 participants took part in two cross-over trials; 11 participants not specified). Eighteen trials used a placebo in the comparator group. Two trials had a cross-over design while the remaining 19 trials were parallel RCTs. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up from baseline ranged from six months to 100 weeks.Trials generally had a low risk of bias for random sequence generation, allocation concealment and blinding (participants, personnel and assessors) for subjective and objective outcomes. We judged approximately half of the trials as having a high risk of bias in one or more domain such as selective reporting.The primary outcomes of this review were change in body mass index (BMI), change in weight and adverse events. All 21 trials measured these outcomes. The secondary outcomes were health-related quality of life (only one trial reported results showing no marked differences; very low certainty evidence), body fat distribution (measured in 18 trials), behaviour change (measured in six trials), participants' views of the intervention (not reported), morbidity associated with the intervention (measured in one orlistat trial only reporting more new gallstones following the intervention; very low certainty evidence), all-cause mortality (one suicide in the orlistat intervention group; low certainty evidence) and socioeconomic effects (not reported).Intervention versus comparator for mean difference (MD) in BMI change was -1.3 kg/m2 (95% confidence interval (CI) -1.9 to -0.8; P < 0.00001; 16 trials; 1884 participants; low certainty evidence). When split by drug type, sibutramine, metformin and orlistat all showed reductions in BMI in favour of the intervention.Intervention versus comparator for change in weight showed a MD of -3.9 kg (95% CI -5.9 to -1.9; P < 0.00001; 11 trials; 1180 participants; low certainty evidence). As with BMI, when the trials were split by drug type, sibutramine, metformin and orlistat all showed reductions in weight in favour of the intervention.Five trials reported serious adverse events: 24/878 (2.7%) participants in the intervention groups versus 8/469 (1.7%) participants in the comparator groups (risk ratio (RR) 1.43, 95% CI 0.63 to 3.25; 1347 participants; low certainty evidence). A total 52/1043 (5.0%) participants in the intervention groups versus 17/621 (2.7%) in the comparator groups discontinued the trial because of adverse events (RR 1.45, 95% CI 0.83 to 2.52; 10 trials; 1664 participants; low certainty evidence). The most common adverse events in orlistat and metformin trials were gastrointestinal (such as diarrhoea, mild abdominal pain or discomfort, fatty stools). The most frequent adverse events in sibutramine trials included tachycardia, constipation and hypertension. The single fluoxetine trial reported dry mouth and loose stools. No trial investigated drug treatment for overweight children.

Authors' conclusions: This systematic review is part of a series of associated Cochrane reviews on interventions for obese children and adolescents and has shown that pharmacological interventions (metformin, sibutramine, orlistat and fluoxetine) may have small effects in reduction in BMI and bodyweight in obese children and adolescents. However, many of these drugs are not licensed for the treatment of obesity in children and adolescents, or have been withdrawn. Trials were generally of low quality with many having a short or no post-intervention follow-up period and high dropout rates (overall dropout of 25%). Future research should focus on conducting trials with sufficient power and long-term follow-up, to ensure the long-term effects of any pharmacological intervention are comprehensively assessed. Adverse events should be reported in a more standardised manner specifying amongst other things the number of participants experiencing at least one adverse event. The requirement of regulatory authorities (US Food and Drug Administration and European Medicines Agency) for trials of all new medications to be used in children and adolescents should drive an increase in the number of high quality trials.

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Conflict of interest statement

EM: none known. GA: none known. BR: none known. MIM: none known. LB: none known. NF: has provided medical consultancy to several pharmaceutical companies developing and marketing (outside of the UK at present) treatments for obesity. Since March 2016 he is employed by Novo Nordisk, Denmark in Global Medical Affairs. The review was submitted for publication in November 2015, pre‐dating an offer of employment by Novo Nordisk A/S made in December 2015. NF made no further contributions to the review after this date. NF’s employment by NovoNordisk during review production violated Cochrane’s Commercial Sponsorship Policy, the review group assured NF did not contribute to the review after this employment started, and the Funding Arbiters reviewed and approved an exception for this case. EC: none known. CO: none known. LE: none known.

Figures

1
1
Trial flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
4
4
Funnel plot of comparison: 1 Body mass index (BMI): pharmacological interventions versus comparators, outcome: 1.1 Change in BMI (all trials) (kg/m2).
5
5
Funnel plot of comparison: 2 Weight: pharmacological interventions versus comparators, outcome: 2.1 Change in weight (all trials) (kg).
1.1
1.1. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 1 Change in BMI (all trials).
1.2
1.2. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 2 Change in BMI (drug type).
1.3
1.3. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 3 Change in BMI (dropout rate).
1.4
1.4. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 4 Change in BMI (intention‐to‐treat (ITT) analysis).
1.5
1.5. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 5 Change in BMI (funding).
1.6
1.6. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 6 Change in BMI (publication date).
1.7
1.7. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 7 Change in BMI (quality of trial).
1.8
1.8. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 8 Change in BMI (country).
1.9
1.9. Analysis
Comparison 1 Body mass index (BMI): pharmacological interventions versus comparators, Outcome 9 Change in BMI (mean age).
2.1
2.1. Analysis
Comparison 2 Weight: pharmacological interventions versus comparators, Outcome 1 Change in weight (all trials).
2.2
2.2. Analysis
Comparison 2 Weight: pharmacological interventions versus comparators, Outcome 2 Change in weight (drug type).
3.1
3.1. Analysis
Comparison 3 Adverse effects: pharmacological interventions versus comparator, Outcome 1 Serious adverse events.
3.2
3.2. Analysis
Comparison 3 Adverse effects: pharmacological interventions versus comparator, Outcome 2 Discontinued trial because of adverse events.
See this image and copyright information in PMC

References

References to studies included in this review

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References to studies excluded from this review

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    1. Giovannini C, Ciucci E, Facchinetti F. Plasma levels of beta‐endorphin, ACTH and cortisol in obese patients subjected to several weight‐loss treatments [Livelli Plasmatici Di Beta‐Endorfinemia, Acth E Cortisolo In Pazienti Obesi Sottoposti A Differenti Trattamenti Dimagranti]. Recenti Progressi In Medicina 1990;81:301‐5. - PubMed
Godefroy 1968 {published data only}
    1. Godefroy G, Napolier A, Andriambao‐Damasy S. Study of the action of concentrated lucofen with prolonged effect [Etude de l'action du lucofène fort à effet prolongé]. Marseille Medical 1968;105:289‐93. - PubMed
Goldrick 1973 {published data only}
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Goldstein 1993 {published data only}
    1. Goldstein DJ, Rampey AH, Dornseif BE, Levine LR, Potvin JH, Fludzinski LA. Fluoxetine: a randomized clinical trial in the maintenance of weight loss. Obesity Research 1993;1:92‐8. - PubMed
González Barranco 1974 {published data only}
    1. González Barranco J, Rull JA, Lozano Castañeda O. L‐Thyroxine propylhexedrine in the treatment of obesity. Crossed double blind study [Propilhexedrina L‐tiroxina en el tratamiento de la obesidad. Estudio doble ciego gruzado]. La Prensa Médica Mexicana 1974;39:298‐9. - PubMed
Griboff 1975 {published data only}
    1. Griboff SI, Berman R. A double blind clinical evaluation of a phenylpropanolamine‐caffeine‐vitamine combination and a placebo in the treatment of exogenous obesity. Current Therapeutic Research, Clinical and Experimental 1975;17:535‐43. - PubMed
Grube 2014 {published data only}
    1. Grube B, Chong WF, Chong PW, Riede L. Weight reduction and maintenance with Iqp‐Pv‐101: a 12‐week randomized controlled study with a 24‐week open label period. Obesity 2014;22:645‐51. - PubMed
Guazzelli 1987 {published data only}
    1. Guazzelli R, Piazzini M, Conti C, Papi L, Strazzulla G, Matassi L. Clinical use of mazindol in the treatment of essential obesity [Impiego clinico del mazindolo nel trattamento dell'obesità essenziale]. Clinica Terapeutica 1987;120:385‐91. - PubMed
Gwinup 1967 {published data only}
    1. Gwinup G, Poucher R. A controlled study of thyroid analogs in the therapy of obesity. American Journal of the Medical Sciences 1967;254:416‐20. - PubMed
Halpern 2006 {published data only}
    1. Halpern A, Mancini MC, Cercato C, Villares SMF, Costa AP. Effects of growth hormone on anthropometric and metabolic parameters in android obesity [Efeito Do Hormônio De Crescimento Sobre Parâmetros Antropométricos E Metabólicos Na Obesidade Andróide]. Arquivos Brasileiros de Endocrinologia & Metabologia 2006;50:68‐73. - PubMed
Hamilton 2003 {published data only}
    1. Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D. Metformin as an adjunct therapy in adolescents with type 1 diabetes and insulin resistance: a randomized controlled trial. Diabetes Care 2003;26:138‐43. - PubMed
Hansen 2001 {published data only}
    1. Hansen D, Astrup A, Toubro S, Finer N, Kopelman P, Hilsted J, et al. Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi‐centre Storm trial (Sibutramine Trial of Obesity Reduction and Maintenance). International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity 2001;25:496‐501. - PubMed
Haug 1973 {published data only}
    1. Haug E, Myklebust R. The therapeutic effect of fenfluramine on body weight in overweight patients. A controlled clinical study [Den terapeutiske effekt av fenfluramin på kroppsvekten hos overvektige. En kontrollert klinisk undersøkelse]. Tidsskrift For Den Norske Lægeforening : Tidsskrift For Praktisk Medicin, Ny Række 1973;93(35):2545‐9. - PubMed
Hawkins 2012 {published data only}
    1. Hawkins FP. Metformin and placebo therapy in adjunct with lifestyle intervention both improve weight loss and insulin resistance in obese adolescents. Archives of Disease in Childhood ‐ Education and Practice 2012;97:79‐80. - PubMed
Honzak 1976 {published data only}
    1. Honzak R, Rath R, Vondra K. Effect of cafilon in the treatment of obesity (author's translation). Ceskoslovenska Gastroenterologie A Vyziva 1976;30:155‐61. - PubMed
Hooper 1972 {published data only}
    1. Hooper AC. Comparison of fenfluramine (with ad libitum food intake) with 1,000 calorie diet in obesity. Journal of the Irish Medical Association 1972;65:35‐7. - PubMed
Huston 1966 {published data only}
    1. Huston JR. Obesity: phenmetrazine effect without dietary restriction. Ohio State Medical Journal 1966;62:805‐7. - PubMed
IRCT2013021012421N1 {published data only}
    1. Shiasi Arani K, Taghavi Ardakani A, Moazami Goudarzi R, Talari HR, Hami K, Akbari H, et al. Effect of vitamin E and metformin on fatty liver disease in obese children ‐ randomized clinical trial. Iranian Journal of Public Health 2014;43(10):1417‐23. - PMC - PubMed
IRCT2014020116435N1 {unpublished data only}
    1. Shahrekord University of Medical Sciences. The effect of folic acid on homocysteine ​​and plasma insulin levels in weight gain and obesity in children and adolescents. en.search.irct.ir/view/16869 Date first received: 23 May 2014.
Israsena 1980 {published data only}
    1. Israsena T, Israngkura M, Srivuthana S. Treatment of childhood obesity. Journal of the Medical Association of Thailand 1980;63:433‐7. - PubMed
James 2000 {published data only}
    1. James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rössner S, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Storm study group. Sibutramine trial of obesity reduction and maintenance. Lancet 2000;356:2119‐25. - PubMed
Kasa‐Vubu 2008 {published data only}
    1. Kasa‐Vubu JZ. Metformin as a weight‐loss tool in "at‐risk" obese adolescents: a magic bullet?. Journal of Pediatrics 2008;152(6):750‐2. - PubMed
Kay 2001 {published data only}
    1. Kay JP, Alemzadeh R, Langley G, D'angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism: Clinical and Experimental 2001;50:1457‐61. - PubMed
Kelly 2012 {published data only}
    1. Kelly AS, Metzig AM, Rudser KD, Fitch AK, Fox CK, Nathan BM, et al. Exenatide as a weight‐loss therapy in extreme pediatric obesity: a randomized, controlled pilot study. Obesity 2012;20:364‐70. - PMC - PubMed
Kelly 2013a {published data only}
    1. Kelly AS. The role of glucagon‐like peptide‐1 receptor agonists for the treatment of adolescent obesity. Expert Review of Endocrinology and Metabolism 2013;8:315‐7. - PubMed
Kelly 2013b {published data only}
    1. Kelly AS, Rudser KD, Nathan BM, Fox CK, Metzig AM, Coombes BJ, et al. The effect of glucagon‐like peptide‐1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo‐controlled, clinical trial. JAMA Pediatrics 2013;167:355‐60. - PMC - PubMed
Kendall 2014 {published data only}
    1. Kendall DL, Amin R, Clayton PE. Metformin in the treatment of obese children and adolescents at risk of type 2 diabetes. Paediatric Drugs 2014;16:13‐20. - PubMed
Klein 2006 {published data only}
    1. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double‐blind, placebo‐controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. American Journal of Psychiatry 2006;163:2072‐9. - PubMed
Kneebone 1968 {published data only}
    1. Kneebone GM. Fenfluramine in the treatment of obesity. Medical Journal of Australia 1968;2:833‐5. - PubMed
Knoll 1975 {published data only}
    1. Knoll G, Spahn U, Plenert W. Therapy of obesity in childhood. Kinderarztliche Praxis 1975;43:412‐26. - PubMed
Komarnicka 1975 {published data only}
    1. Komarnicka R, Gorzko M. Results of treatment of obesity with low calorie diet and additional drugs (author's translation) [Wyniki leczenia otyłości dieta niskokaloryczna i lekami wspomagajacymi]. Przeglad Lekarski 1975;32:814‐7. - PubMed
Komorowski 1982 {published data only}
    1. Komorowski JM, Zwaigzne‐Raczynska J, Owczarczyk I, Golebiowska M, Zarzycki J. Effect of mazindol (Teronac) on various hormonal indicators in children with simple obesity. Pediatria Polska 1982;57:241‐6. - PubMed
Kreze 1967 {published data only}
    1. Kreze A, Kiselá J. Biguanides and the treatment of obesity [Biguanidy a terapia obezity]. Bratislavské Lekárske Listy 1967;48:184‐9. - PubMed
Lamberto 1993 {published data only}
    1. Lamberto M, Novi RF, Mantovan M. Fluoxetine and obesity [Fluoxetina ed obesità]. Minerva Endocrinologica 1993;18:41‐3.. - PubMed
Leite 1971 {published data only}
    1. Leite AC, Liepen LL, Costa VP. Clinical trial of stimsem thozalinone in the treatment of obese patients [Ensaio clĩnico com o stimsem thozalinone no tratamento de pacientes obesos]. Revista Brasileira De Medicina 1971;28:475‐8. - PubMed
Lewis 1978 {published data only}
    1. Lewis EA, Adeleye GI, Ukponmwan OO. Comparison of fenfluramine and placebo on obese Nigerians. Nigerian Medical Journal 1978;8:104‐7. - PubMed
Libman 2015 {published data only}
    1. Libman IM, Miller KM, Dimeglio LA, Bethin KE, Katz ML, Shah A, et al. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes a randomized clinical trial. JAMA 2015;314:2241‐50. - PubMed
Liebermeister 1969 {published data only}
    1. Liebermeister H, Probst G, Jahnke K. Experience with the appetite depressant, fenfluramine hydrochloride, in adiposity [Erfahrungen mit dem Appetithemmer Fenfluraminhydrochlorid bei der Adipositas]. Medizinische Klinik 1969;64:1201‐7. - PubMed
Liu 2013 {published data only}
    1. Liu AG, Smith SR, Fujioka K, Greenway FL. The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss. Obesity 2013;21:1991‐6. - PubMed
Lorber 1966 {published data only}
    1. Lorber J. Obesity in childhood. A controlled trial of anorectic drugs. Archives of Disease in Childhood 1966;41:309‐12. - PMC - PubMed
Love‐Osborne 2008 {published data only}
    1. Love‐Osborne K, Sheeder J, Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. Journal of Pediatrics 2008;152:817‐22. - PMC - PubMed
Maclay 1977 {published data only}
    1. Maclay WP, Wallace MG. A multi‐centre general practice trial of mazindol in the treatment of obesity. Practitioner 1977;218:431‐4. - PubMed
Malchow‐Møller 1980 {published data only}
    1. Malchow‐Møller A, Larsen S, Hey H, Stokholm KH, Juhl E, Quaade F. Effect of elsinore tablets in the treatment of obesity. A controlled clinical trial. Ugeskrift For Laeger 1980;142:1496‐9. - PubMed
Marques 2016 {published data only}
    1. Marques P, Limbert C, Oliveira L, Santos MI, Lopes L. Metformin effectiveness and safety in the management of overweight/obese nondiabetic children and adolescents: metabolic benefits of the continuous exposure to metformin at 12 and 24 months. International Journal of Adolescent Medicine and Health 2016 Feb 19;[Epub ahead of print]. - PubMed
McDuffie 2002 {published data only}
    1. McDuffie JR, Calis KA, Uwaifo GI, Sebring NG, Fallon EM, Hubbard VS, et al. Three‐month tolerability of orlistat in adolescents with obesity‐related comorbid conditions. Obesity Research 2002;10:642‐50. - PubMed
Molnár 2000 {published data only}
    1. Molnár D, Török K, Erhardt E, Jeges S. Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double‐blind placebo‐controlled pilot study in adolescents. International Journal of Obesity and Related Metabolic Disorders 2000;24:1573‐8. - PubMed
Muls 2001 {published data only}
    1. Muls E, Kolanowski J, Scheen A, Gaal L, Obelhyx Study Group. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double‐blind, placebo‐controlled, multicentre study. International Journal of Obesity and Related Metabolic Disorders 2001;25:1713‐21. - PubMed
Nadeau 2015 {published data only}
    1. Nadeau KJ, Chow K, Alam S, Lindquist K, Campbell S, Mcfann K, et al. Effects of low dose metformin in adolescents with type I diabetes mellitus: a randomized, double‐blinded placebo‐controlled study. Pediatric Diabetes 2015;16:196‐203. - PMC - PubMed
Nathan 2016 {published data only}
    1. Nathan BM, Rudser KD, Abuzzahab MJ, Fox CK, Coombes BJ, Bomberg EM, et al. Predictors of weight‐loss response with glucagon‐like peptide‐1 receptor agonist treatment among adolescents with severe obesity. Clinical Obesity 2016;6:73‐8. - PMC - PubMed
NCT00076362 {unpublished data only}
    1. Novartis Pharmaceuticals. Pediatric hypothalamic obesity. clinicaltrials.gov/ct2/show/NCT00076362 Date first received: 21 January 2004.
NCT00284557 {unpublished data only}
    1. Emory University. A primary care behavioral approach for addressing childhood overweight. clinicaltrials.gov/ct2/show/NCT00284557 Date first received: 30 January 2006.
NCT00775164 {unpublished data only}
    1. University of Minnesota ‐ Clinical and Translational Science Institute. Pioglitazone therapy in obese children with insulin resistance: a randomized, controlled pilot study. clinicaltrials.gov/ct2/show/NCT00775164 Date first received: 16 October 2008.
NCT00845559 {unpublished data only}
    1. Yale University. The effects of exenatide on post‐meal sugar peaks and vascular health in obese/pre‐diabetic young adults. clinicaltrials.gov/ct2/show/NCT00845559 Date first received: 16 February 2009.
NCT01023139 {unpublished data only}
    1. Brooke Army Medical Center. "Efficacy in adolescents of continued behavior modification following a six month sibutramine‐based weight management intervention" (AOS). clinicaltrials.gov/ct2/show/NCT01023139 Date first received: 1 December 2009.
NCT01061775 {unpublished data only}
    1. Children's Hospitals and Clinics of Minnesota. Effects of exenatide on hypothalamic obesity. clinicaltrials.gov/ct2/show/NCT01061775 Date first received: 2 February 2010.
NCT01107808 {published data only}
    1. University of Alabama at Birmingham. Calcium, vitamin D and metformin to treat insulin resistance in obese African American adolescent females. clinicaltrials.gov/ct2/show/NCT01107808 Date first received: 1 April 2010.
NCT01169103 {published data only}
    1. NCT01169103. Effect of recombinant human growth hormone (rhGH) on abdominal fat and cardiovascular risk in obese girls. clinicaltrials.gov/ct2/show/NCT01169103 Date first received: 22 July 2010.
NCT01242241 {unpublished data only}
    1. Baylor College of Medicine. Propofol in obese children. clinicaltrials.gov/ct2/show/NCT01242241 Date first received: 15 November 2010.
NCT01329367 {unpublished data only}
    1. Clinica Universidad de Navarra, Universidad de Navarra. Nutrigenomics and children obesity: a moderate weight loss intervention study (NUGENOI). clinicaltrials.gov/ct2/show/NCT01329367 Date first received: 20 January 2011.
NCT01332448 {unpublished data only}
    1. GlaxoSmithKline. Meta‐analysis of orlistat laboratory data from placebo‐controlled clinical trials. clinicaltrials.gov/ct2/show/NCT01332448 Date first received: 7 April 2011.
NCT01410604 {unpublished data only}
    1. Hospital Regional de Alta Especialidad del Bajio. Adipokines in obese adolescents with insulin resistance. clinicaltrials.gov/ct2/show/NCT01410604 Date first received: 4 August 2011.
NCT01456221 {unpublished data only}
    1. Coordinación de Investigación en Salud, Mexico. Intervention study with omega‐3 fatty acids for weight loss and insulin resistance in adolescents (O3WLIRADOL). clinicaltrials.gov/ct2/show/NCT01456221 Date first received: 12 October 2011.
NCT01910246 {unpublished data only}
    1. University of California, San Francisco. Cardiovascular effects of metformin on obesity. clinicaltrials.gov/ct2/show/NCT01910246 Date first received: 22 April 2013.
NCT02022956 {unpublished data only}
    1. Arena Pharmaceuticals. Single dose study to determine the safety, tolerability, and pharmacokinetic properties of lorcaserin hydrochloride (BELVIQ) in obese adolescents from 12 to 17 years of age. clinicaltrials.gov/ct2/show/NCT02022956 Date first received: 23 December 2013.
NCT02063802 {published data only}
    1. Laboratorios Silanes S.A. de C.V. Metformin vs conjugated linoleic acid and an intervention program with healthy habits in obese children. clinicaltrials.gov/ct2/show/NCT02063802 Date first received: 12 February 2014.
NCT02186652 {unpublished data only}
    1. Duke University. PK study with pantoprazole in obese children and adolescents (PAN01). clinicaltrials.gov/ct2/show/NCT02186652 Date first received: 3 July 2014.
NCT02378259 {published data only}
    1. NCT02378259. Randomized clinical trial; medical vs bariatric surgery for adolescents (13‐16 y) with severe obesity. clinicaltrials.gov/ct2/show/NCT02378259 Date first received: 26 August 2014.
NCT02398669 {published data only}
    1. Eisai Inc. A single dose pharmacokinetic study of lorcaserin hydrochloride in obese pediatric subjects 6 to 11 years of age. clinicaltrials.gov/ct2/show/NCT02398669 Date first received: 20 March 2015.
NCT02438020 {unpublished data only}
    1. Juan Pablo, C.‐C, Hospital Central "Dr. Ignacio Morones, P, Universidad Autonoma De San Luis. P. Study of efficacy of metformin in the treatment of acanthosis nigricans in children with obesity. clinicaltrials.gov/ct2/show/NCT02438020 Date first received: 3 May 2015.
NCT02515773 {unpublished data only}
    1. NCT02515773. Metformin for overweight & obese children and adolescents with BDS treated with SGAs. clinicaltrials.gov/ct2/show/NCT02515773 Date first received: 31 July 2015.
Nwosu 2015 {published data only}
    1. Nwosu BU, Maranda L, Cullen K, Greenman L, Fleshman J, Mcshea N, et al. A randomized, double‐blind, placebo‐controlled trial of adjunctive metformin therapy in overweight/obese youth with type 1 diabetes. PLoS One 2015;10:e0137525. - PMC - PubMed
O'connor 1995 {published data only}
    1. O'connor HT, Richman RM, Steinbeck KS, Caterson ID. Dexfenfluramine treatment of obesity: a double blind trial with post trial follow up. International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity 1995;19:181‐9. - PubMed
Park 2010 {published data only}
    1. Park MH, Kinra S. Metformin treatment for adolescent obesity has limited long‐term benefits. Journal of Pediatrics 2010;157:172. - PubMed
Pedrinola 1994 {published data only}
    1. Pedrinola F, Cavaliere H, Lima N, Medeiros‐Neto G. Is Dl‐Fenfluramine a potentially helpful drug therapy in overweight adolescent subjects?. Obesity Research 1994;2:1‐4. - PubMed
Persson 1973 {published data only}
    1. Persson I, Andersen U, Deckert T. Treatment of obesity with fenfluramine. European Journal of Clinical Pharmacology 1973;6:93‐7. - PubMed
Plauchu 1967a {published data only}
    1. Plauchu M, Montgolfier R, Noel P. Clinical study on a new appetite depressant Mg 559 [Etude clinique d'un anorexigène récent: le MG 559]. Lyon Medical 1967;217(15):1105‐16. - PubMed
Plauchu 1967b {published data only}
    1. Plauchu M, Kofman J, Chapuy H. Clinical study of a new anorexigen: RD 354 (Hepatrol) [Etude clinique d'un nouvel anorexigène: le RD 354]. Lyon Medical 1967;217(17):1247‐61. - PubMed
Plauchu 1972 {published data only}
    1. Plauchu M, Paffoy JC, Philippe LP, Nove‐Josserand G, Chollet A, Valancogne C. Clinical study of a current anorexigenic agent: T.D [Etude clinique d'un anorexigène récent: le T.D]. Lyon Medical 1972;228(15):291‐4. - PubMed
Pugnoli 1978 {published data only}
    1. Pugnoli C, Bandini L, Caronna S, Ciarlini E, Magnati G, Strata A, et al. Clinical trial of a new long‐acting fenfluramine in the treatment of obesity [Ricerca Clinica Controllata Su Un Nuovo Preparato Di Fenfluramina 'A Lenta Cessione' Nel Trattamento Dell'obesita]. Giornale Di Clinica Medica 1978;59:486‐510. - PubMed
Rauh 1968 {published data only}
    1. Rauh JL, Lipp R. Chlorphentermine as an anorexigenic agent in adolescent obesity. Report of its efficacy in a double‐blind study of 30 teen‐agers. Clinical Pediatrics 1968;7:138‐40. - PubMed
Resnick 1967 {published data only}
    1. Resnick M, Joubert L. A double‐blind evaluation of an anorexiant, a placebo and diet alone in obese subjects. Canadian Medical Association Journal 1967;97:1011‐5. - PMC - PubMed
Rodos 1969 {published data only}
    1. Rodos JJ. The treatment of obesity with voranil (Su‐10568), a new non‐amphetamine anorexigenic agent. Journal of the American Osteopathic Association 1969;69:161‐4. - PubMed
Rodriguez 2007 {published data only}
    1. Rodriguez JE, Shearer B, Slawson DC. Metformin therapy and diabetes prevention in adolescents who are obese. American Family Physician 2007;76:1357‐9. - PubMed
Roed 1980 {published data only}
    1. Roed P, Hansen PW, Bidstrup B, Kaern M, Helles A, Petersen KP. Elsinore banting tablets. A controlled clinical trial in general practice [Helsingor‐slankepiller: En kontrolleret klinisk undersogelse i almen praksis]. Ugeskrift For Laeger 1980;142:1491‐5. - PubMed
Roginsky 1966 {published data only}
    1. Roginsky MS, Barnett J. Double‐blind study of phenethyldiguanide in weight control of obese nondiabetic subjects. American Journal of Clinical Nutrition 1966;19:223‐6. - PubMed
Sabuncu 2004 {published data only}
    1. Sabuncu T, Ucar E, Birden F, Yasar O. The effect of 1‐yr sibutramine treatment on glucose tolerance, insulin sensitivity and serum lipid profiles in obese subjects. Diabetes, Nutrition & Metabolism ‐ Clinical & Experimental 2004;17:103‐7. - PubMed
Sainani 1973 {published data only}
    1. Sainani GS, Fulambarkar AM, Khurana BK. A double‐blind clinical trial of fenfluramine in the treatment of obesity. British Journal of Clinical Practice 1973;27:136‐8. - PubMed
Scavo 1976 {published data only}
    1. Scavo D, Giovannini C, Sellini M, Fierro A. Therapy of obesity in childhood and adolescence. Comparison of results obtained with dietary and drug treatment [La terapia dell'obesita nell'infanzia e nell'adolescenza]. Clinica Terapeutica 1976;79:205‐18. - PubMed
Shutter 1966 {published data only}
    1. Shutter L, Garell DC. Obesity in children and adolescents: a double‐blind study with cross‐over. Journal of School Health 1966;36:273‐5. - PubMed
Spence 1966 {published data only}
    1. Spence AW, Medvei VC. Fenfluramine in the treatment of obesity. British Journal of Clinical Practice 1966;20:643‐4. - PubMed
Spranger 1963 {published data only}
    1. Spranger J. Anorexigenic drugs in the treatment of obesity in children. An enlarged double‐blind study with chlorphentermin. Munchener Medizinische Wochenschrift (1950) 1963;105:1338‐41. - PubMed
Spranger 1965 {published data only}
    1. Spranger J. Phentermine resinate in obesity. Clinical trial of Mirapront in adipose children [Phentermin‐Resinat bei Fettsucht. Klinische Prüfung von Mirapront bei adipösen Kindern]. Münchener medizinische Wochenschrift (1950) 1965;107:1833‐4. - PubMed
Sproule 1969 {published data only}
    1. Sproule BC. Double‐blind trial of anorectic agents. Medical Journal of Australia 1969;1:394‐5. - PubMed
Stewart 1970 {published data only}
    1. Stewart DA, Bailey JD, Patell H. Tenuate dospan as an appetite suppressant in the treatment of obese children. Applied Therapeutics 1970;12:34‐6. - PubMed
Sukkari 2010 {published data only}
    1. Sukkari SR, Sasich LD, Humaidan AS, Burikan O. Analysis of metformin treatment for adolescent obesity at 48 rather than 24 weeks after treatment cessation. Archives of Pediatrics & Adolescent Medicine 2010;164:678‐9 (author reply). - PubMed
TODAY study group 2013 {published data only}
    1. Arslanian SA, Pyle L, White NH, Bacha F, Caprio S, Haymond MW, et al. Racial disparity in maintenance of glycemic control in the TODAY trial: does insulin sensitivity, beta‐cell function, or both play a role?. Diabetes 2013;62:A338.
    1. Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, et al. Characteristics of adolescents and youth with recent‐onset type 2 diabetes: the TODAY cohort at baseline. Journal of Clinical Endocrinology and Metabolism 2011;96:159‐67. - PMC - PubMed
    1. Laffel L, Chang N, Grey M, Hale D, Higgins L, Hirst K, et al. Metformin monotherapy in youth with recent onset type 2 diabetes: experience from the prerandomization run‐in phase of the TODAY study. Pediatric Diabetes 2012;13:369‐75. - PMC - PubMed
    1. TODAY Study Group. Treatment effects on measures of body composition in the TODAY clinical trial. Diabetes Care 2013;36(6):1742‐8. - PMC - PubMed
    1. TODAY study group. Design of a family‐based lifestyle intervention for youth with type 2 diabetes: the TODAY study. International Journal of Obesity 2010;34:217‐26. - PMC - PubMed
Tong 2005 {published data only}
    1. Tong NW, Ran XW, Li QF, Tang BD, Li R, Yang FY, et al. Effects of sibutramine on blood glucose and lipids, body fat mass and insulin resistance in obese patients: a multi‐center clinical trial. Zhonghua Nei Ke Za Zhi 2005;44:659‐63. - PubMed
Toubro 2001 {published data only}
    1. Toubro S, Hansen DL, Hilsted JC, Porsborg PA, Astrup AV, James WPT, et al. The effect of sibutramine for the maintenance of weight loss: a randomised, clinical, controlled study [Effekt af sibutramin til vægttabsvedligeholdelse: en randomiseret klinisk kontrolleret undersøgelse]. Ugeskrift for Laeger 2001;163(21):2935‐40. - PubMed
Tsai 2006 {published data only}
    1. Tsai AG, Wadden TA, Berkowitz RI. Pharmacotherapy for overweight adolescents. Obesity Management 2006;2:98‐102.
Van Seters 1982 {published data only}
    1. Seters AP, Bouwhuis‐Hoogerwerf ML, Goslings BM, Nieuwkoop L, Slooten H, Struijk‐Wielinga T. Long‐term treatment of patients with obesity using mazindol and a reducing diet. Nederlands Tijdschrift Voor Geneeskunde 1982;126:990‐4. - PubMed
Warren‐Ulanch 2008 {published data only}
    1. Warren‐Ulanch J. Metformin may aid weight loss in overweight teenage girls. Journal of Pediatrics 2008;153:725‐6. - PubMed
Weintraub 1984 {published data only}
    1. Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. Double‐blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Archives of Internal Medicine 1984;144:1143‐8. - PubMed
Yanovski 2003 {published data only}
    1. Adeyemo MA, McDuffie JR, Kozlosky M, Krakoff J, Calis KA, Brady SM, et al. Effects of metformin on energy intake and satiety in obese children. Diabetes, Obesity & Metabolism 2015;17(4):363‐70. - PMC - PubMed
    1. Yanovski JA, Yanovski SZ. Treatment of pediatric and adolescent obesity. JAMA 2003;289:1851‐3. - PubMed
Yu 2013 {published data only}
    1. Yu CC, Li AM, Chan KO, Chook P, Kam JT, Au CT, et al. Orlistat improves endothelial function in obese adolescents: a randomised trial. Journal of Paediatrics and Child Health 2013;49:969‐72. - PubMed

References to studies awaiting assessment

Golebiowska 1981 {published data only}
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NCT00934570 {unpublished data only}
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NCT01487993 {unpublished data only}
    1. Aa MP, Elst MA, Mil EG, Knibbe CA, Vorst MM. Metformin: an efficacy, safety and pharmacokinetic study on the short‐term and long‐term use in obese children and adolescents ‐ study protocol of a randomized controlled study. Trials 2014;15:207. - PMC - PubMed
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Smetanina 2015 {published data only}
    1. Smetanina N, Seibokaite A, Valickas R, Kuprionis G, Grigoniene JJ, Rokaite R, et. al. Metformin in combination with lifestyle changes effectively reduces BMI and waist circumference in overweight/obese children and adolescents. Hormone Research in Paediatrics 2015;84:229.

References to ongoing studies

EUCTR2010‐023061‐21 {unpublished data only}
    1. Pastor MB, Canete MD, Hoyos R, Latorre M, Vazquez‐Cobela R, Rangel‐Huerta OD, et al. Metformin in the treatment of obese children shows differential response according to pubertal stage. Acta Physiologica. 2014; Vol. 212:36‐7.
EUCTR2015‐001628‐45‐SE {unpublished data only}
    1. A study with lifestyle intervention and study medication once weekly or lifestyle intervention and placebo in adolescents with obesity to explore differences between groups with regard to change in BMI. Ongoing study Trial start date: not givenTrial completion date: not given.
NCT00889876 {unpublished data only}
    1. Effect of exercise or metformin on nocturnal blood pressure and other risk factors for CVD among obese adolescents. Ongoing study Trial start date: February 2009Trial completion date: December 2012 (estimated).
NCT01677923 {unpublished data only}
    1. Obesity in children and adolescents: associated risks and early intervention (OCA). Ongoing study Trial start date: May 2013Trial completion date: December 2015.
NCT01859013 {unpublished data only}
    1. Topiramate in Adolescents with Severe Obesity. Ongoing study Trial start date: June 2013Trial completion date: December 2015.
NCT02273804 {unpublished data only}
    1. Topiramate and Severe Obesity (TOBI). Ongoing study Trial start date: June 2015Trial completion date: December 2020.
NCT02274948 {unpublished data only}
    1. Use of Metformin in Treatment of Childhood Obesity. Ongoing study Trial start date: July 2014Trial completion date: February 2016.
NCT02496611 {unpublished data only}
    1. Enhancing Weight Loss Maintenance With GLP‐1RA (BYDUREON™) in Adolescents with Severe Obesity. Ongoing study Trial start date: December 2015Trial completion date: July 2020.

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