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

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.

Bardet‐Biedlsyndrome: Weight patterns and genetics in a rare obesity syndrome

“…Current clinical trials with a melanocortin-4 receptor agonist may provide targeted therapy in children with BBS. [45][46][47] Strengths of this study include the largest sample to date of children with a rare obesity syndrome and the inclusion of different countries representing a range of socioeconomic environments. We have examined a large variety of BBS genotypes generating important questions about molecular mechanisms mediating syndromic obesity.…”

Anti-Obesity Drugs: Long-Term Efficacy and Safety: An Updated Review

“…To date, however, there has been no approved combination agent for obesity management, besides phentermine/ topiramate and naltrexone/bupropion. Other co-administered medications have been investigated to elucidate their long-term efficacy and adverse events [15,16]. Most combinations primarily focus on both controlling hunger/appetite/satiety and inhibiting peripheral calorie absorption (i.e., phentermine/sodium glucose co-transporter 2 [SGLT-2] inhibitor, a GLP-1 agonist/other gut hormones, or an SGLT-2 inhibitor).…”

Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5

“…The hypothalamus, mesolimbic system, and executive functioning are all implicated in the physiology of obesity (9). Thus, there is a necessity for developing more effective novel treatment approaches that address these central nervous system processes (2,9,10).…”