New approaches to the pharmacological treatment of obesity: Can they break through the efficacy barrier?

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2010-11, Vol.97 (1), p.63-83
• Main Authors: Kennett, G.A., Clifton, P.G.
• Format: Article
• Language: English
• Subjects: Animals; Anorectic; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Anti-obesity drug; Anticonvulsants; Clinical Trials as Topic - methods; Clinical Trials as Topic - trends; Humans; Neuropeptides - pharmacology; Neuropeptides - therapeutic use; Obesity; Obesity - drug therapy; Obesity - metabolism; Obesity - psychology; Treatment Outcome; Weight Loss - drug effects; Weight Loss - physiology
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2010.07.020

In this review we assess the range of centrally active anorectics that are either in human clinical trials, or are likely to be so in the near future. We describe their weight loss efficacy, mode of action at both pharmacological and behavioural levels, where understood, together with the range of side effects that might be expected in clinical use. We have however evaluated these compounds against the considerably more rigorous criteria that are now being used by the Federal Drugs Agency and European Medicines Agency to decide approvals and market withdrawals. Several trends are evident. Recent advances in the understanding of energy balance control have resulted in the exploitation of a number of new targets, some of which have yielded promising data in clinical trials for weight loss. A second major trend is derived from the hypothesis that improved weight loss efficacy over current therapy is most likely to emerge from treatments targeting multiple mechanisms of energy balance control. This reasoning has led to the development of a number of new treatments for obesity where multiple mechanisms are targeted, either by a single molecule, such as tesofensine, or through drug combinations such as qnexa, contrave, empatic, and pramlintide + metreleptin. Many of these approaches also utilise advances in formulation technology to widen safety margins. Finally, the practicality of peptide therapies for obesity has become better validated in recent studies and this may allow more rapid exploitation of novel targets, rather than awaiting the development of orally available small molecules. We conclude that novel, more efficacious and better tolerated treatments for obesity may become available in the near future. ►Review of novel approaches and drugs for the treatment of obesity ►Approaches e.g. gut and non-gut peptides monoamines cannabinoids and anticonvulsants ►Corresponding treatments including lorcaserin, combination therapies e.g. qnexa and CB1 ►Efficacy and tolerability are compared to those of current therapies ►Treatment efficacy and tolerability also reviewed vs current regulatory requirements