Setmelanotide
Setmelanotide, a melanocortin receptor 4 agonist administered by subcutaneous injection, is approved in the US and Europe for chronic weight management (weight loss and weight maintenance for at least 1 year) in children aged 6 years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency; proprotein subtilisin/kexin type 1 (PCSK1) deficiency; and leptin receptor (LEPR) deficiency, confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic, probably pathogenic, or of uncertain significance. Phase 3 trials indicate that setmelanotide is safe and effective in people with severe obesity due to genetic mutations causing POMC deficiency or LEPR deficiency.[125]Clément K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-70.
http://www.ncbi.nlm.nih.gov/pubmed/33137293?tool=bestpractice.com
In the UK, setmelanotide is recommended as an option for treating obesity and controlling hunger caused by pro-opiomelanocortin (POMC) deficiency, including proprotein convertase subtilisin/kexin type 1 or leptin receptor (LEPR) deficiency in people aged 6 years and over.[126]National Institute for Health and Care Excellence. Setmelanotide for treating obesity caused by LEPR or POMC deficiency. Highly specialised technologies guidance. HST21. Jul 2022 [internet publication].
https://www.nice.org.uk/guidance/hst21
Setmelanotide is also approved in the US and Europe for the treatment of obesity and hunger control in patients with confirmed Bardet-Biedl syndrome.
Amylin analogues
Amylin is a peptide that is co-secreted with insulin from the pancreatic beta cells and is thought to be important in the regulation of glucose and energy homeostasis. An analogue of amylin is available for the treatment of diabetes in adults and is undergoing clinical trials for the treatment of adult obesity.[127]Smith SR, Aronne LJ, Burns CM, et al. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care. 2008 Sep;31(9):1816-23.
https://care.diabetesjournals.org/content/31/9/1816.long
http://www.ncbi.nlm.nih.gov/pubmed/18753666?tool=bestpractice.com
[128]Boyle CN, Lutz TA, Le Foll C. Amylin - its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol Metab. 2018 Feb;8:203-10.
https://www.sciencedirect.com/science/article/pii/S2212877817308700
http://www.ncbi.nlm.nih.gov/pubmed/29203236?tool=bestpractice.com
Bupropion
Bupropion is a noradrenaline (norepinephrine) and dopamine reuptake inhibitor used in adults for depression and smoking cessation. It has been studied for treatment of obesity in adults. The combination of extended-release bupropion and the opioid antagonist naltrexone has been investigated.[129]Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2010 Aug 21;376(9741):595-605.
http://www.ncbi.nlm.nih.gov/pubmed/20673995?tool=bestpractice.com
[130]Kolotkin RL, Chen S, Klassen P, et al. Patient-reported quality of life in a randomized placebo-controlled trial of naltrexone/bupropion for obesity. Clin Obes. 2015 Oct;5(5):237-44.
http://www.ncbi.nlm.nih.gov/pubmed/26222044?tool=bestpractice.com
This combination has been approved in the US by the Food and Drug Administration (FDA) for the treatment of obesity in adults.
Zonisamide
Zonisamide is an anticonvulsant that induces weight loss. It has serotonergic and dopaminergic activity, and also inhibits sodium and calcium channels.[131]Nguyen ML, Pirzada MH, Shapiro MA. Zonisamide for weight loss in adolescents. J Pediatr Pharmacol Ther. 2013 Oct;18(4):311-4.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979054
http://www.ncbi.nlm.nih.gov/pubmed/24719592?tool=bestpractice.com
Exendin 4
Exendin is an incretin mimetic undergoing clinical trials in adults with obesity. Exenatide, a synthetic version, is used for the treatment of type 2 diabetes in adults. It has been shown to decrease gastric emptying time and decrease food intake in clinical studies.[132]Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008 Jan;24(1):275-86.
http://www.ncbi.nlm.nih.gov/pubmed/18053320?tool=bestpractice.com
Initial trials in children have shown a reduction in body mass index (BMI) in severely children with obesity.[133]Kelly AS, Rudser KD, Nathan BM, 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 Pediatr. 2013 Apr;167(4):355-60.
https://jamanetwork.com/journals/jamapediatrics/fullarticle/1567204
http://www.ncbi.nlm.nih.gov/pubmed/23380890?tool=bestpractice.com
[134]Kelly AS, Metzig AM, Rudser KD, et al. Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study. Obesity (Silver Spring). 2012 Feb;20(2):364-70.
https://onlinelibrary.wiley.com/doi/full/10.1038/oby.2011.337
http://www.ncbi.nlm.nih.gov/pubmed/22076596?tool=bestpractice.com
Peptide YY(3-36)
Peptide YY is released by the gastrointestinal tract following a meal and acts by suppressing appetite. Clinical trials with a nasal formulation in adults did not meet the primary endpoints, and thus were stopped. Peptide YY is being studied as a potential therapy in patients who did not lose sufficient weight following bariatric surgery.[135]Fenske WK, Bueter M, Miras AD, et al. Exogenous peptide YY3-36 and Exendin-4 further decrease food intake, whereas octreotide increases food intake in rats after Roux-en-Y gastric bypass. Int J Obes (Lond). 2012 Mar;36(3):379-84.
http://www.ncbi.nlm.nih.gov/pubmed/21694700?tool=bestpractice.com
Ghrelin antagonists
Ghrelin is a small peptide secreted from the stomach that is thought to be a signal for meal initiation. Thus, antagonism of ghrelin may be useful to suppress food intake.