The New Era of Drug Therapy for Obesity: The Evidence and the Expectations

Abstract

There is an urgent need for effective pharmacological therapies to help tackle the growing obesity epidemic and the healthcare crisis it poses. The past 3 years have seen approval of a number of novel anti-obesity drugs. The majority of these influence hypothalamic appetite pathways via dopaminergic or serotoninergic signalling. Some are combination therapies, allowing lower doses to minimize the potential for off-target effects. An alternative approach is to mimic endogenous satiety signals using long-lasting forms of peripheral appetite-suppressing hormones. There is also considerable interest in targeting thermogenesis by brown adipose tissue to increase resting energy expenditure. Obesity pharmacotherapy has seen several false dawns, but improved understanding of the pathways regulating energy balance, and better-designed trials, give many greater confidence that recently approved agents will be both efficacious and safe. Nevertheless, a number of issues from preclinical and clinical development continue to attract debate, and additional large-scale trials are still required to address areas of uncertainty.

Fig. 1

Simplified schematic of hypothalamic energy regulatory pathways. Other pathways, including the reward circuitry, are involved in appetite and energy expenditure, but an understanding of the central role of the hypothalamus is useful in order to appreciate the mechanisms of action of several weight loss agents. AgRP agouti-related peptide, BAT brown adipose tissue, CART cocaine- and amphetamine-regulated transcript, GLP-1 glucagon-like peptide-1, NPY neuropeptide Y, POMC pro-opiomelanocortin, PYY peptide YY