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Centrally Acting Agents for Obesity: Past, Present, and Future

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Abstract

For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term. This review of central nervous system (CNS) acting anti-obesity drugs evaluates current therapies such as phentermine/topiramate, which act through multiple neurotransmitter pathways to reduce appetite. In the synergistic mechanism of bupropion/naltrexone, naltrexone blocks the feed-back inhibitory circuit of bupropion to give greater weight loss. Lorcaserin, a selective agonist of a serotonin receptor that regulates food intake, and the glucagon-like-peptide-1 (GLP-1) receptor agonist liraglutide are reviewed. Future drugs include tesofensine, a potent triple reuptake inhibitor in Phase III trials for obesity, and semaglutide, an oral GLP-1 analog approved for diabetes and currently in trials for obesity. Another potential new pharmacotherapy, setmelanotide, is a melanocortin-4 receptor agonist, which is still in an early stage of development. As our understanding of the communication between the CNS, gut, adipose tissue, and other organs evolves, it is anticipated that obesity drug development will move toward new centrally acting combinations and then to drugs acting on peripheral target tissues.

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Fig. 1

Reproduced with permission from Elsevier Ltd. The Lancet, 2008;372:1906–1913 [117]

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Acknowledgements

This work is supported in part by 1 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health which funds the Louisiana Clinical and Translational Science Center and in part on work that was supported by the National Institutes of Health under an award (T32 A T004094) from the National Center for Complementary and Integrative Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Ann A. Coulter, Candida J. Rebello & Frank L. Greenway

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  1. Ann A. Coulter
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Frank Greenway has served on the advisory boards for BAROnova, Eisai Inc., Curves, Novo Nordisk, Microbiome Therapeutics, Orexigen, Pamlab, PlenSat, Zaluvida and Zafgen. He has consulted for Basic Research, General Nutrition Corporation, Neothetics, Takeda, and Tech Enterprises.

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Coulter, A.A., Rebello, C.J. & Greenway, F.L. Centrally Acting Agents for Obesity: Past, Present, and Future. Drugs 78, 1113–1132 (2018). https://doi.org/10.1007/s40265-018-0946-y

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