This article reviews the history of obesity drug therapy and discusses ongoing challenges and recent advances in the development of AOMs. Although mechanistic understanding of energy homeostasis has dramatically progressed since the discovery of leptin just over 25 years ago47, the translation to targeted therapies has largely been empirical, with rodent models remaining of seminal importance, but of variable value for drug candidate selection. This is prominently witnessed in the ongoing debate pertaining to the gut hormone glucose-dependent insulinotropic polypeptide (GIP), where, based on rodent pharmacology studies, both GIPR agonism or antagonism can provide supplemental pharmacology to GLP1 agonism48. Lifelong pharmacological management of chronic diseases such as hypertension might offer relevant benchmarks for obesity treatment strategies. In these diseases, it is common practice to target multiple mechanisms to achieve optimal disease management. It seems inevitable, and with good precedent, that such a conceptual approach to lowering body weight will eventually prevail40.
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Unquestionably, advances in understanding the molecular elements that control appetite and energy utilization have provided a road map for more informed AOM development (Box 1; Fig. 2). The sizeable and rapid lowering of body weight achieved by bariatric surgery that results in much improved long-term mortality29 has further provided a vision of what might be pharmacologically possible. Indeed, mimicking the effects of bariatric surgery has become one vision for discovery of future AOMs.
The pursuit of AOMs has been a long-standing endeavour propelled in recent years by several concurrent developments. These include the dramatic increase in the global prevalence of obesity, the significant advances in molecular understanding of appetite homeostasis along with the identification of several novel drug targets, as well as the success in developing incretins as drugs for T2D that has provided unprecedented efficacy in body weight management. It seems plausible that a 20% or greater reduction in body weight may yet be possible based on late-phase clinical reports. If so, it is interesting to ponder whether patients of far higher initial body weight might find the next 20% reduction to be easier or harder to achieve in a relative sense, as these are the individual subjects of greatest need.
The quality of evidence from these observational studies is very low, mainly because patient groups were not comparable at baseline with regard to important prognostic characteristics, such as tumor stage or size. Tumor stage was, on average, lower in patients with laparoscopic surgery as compared with open surgery. In few studies (151, 158), treatment effects were adjusted for differences in tumor stage. Mostly, however, only uncorrected estimates of recurrence-free and overall survival were reported. Moreover, most studies had imprecise effect estimates.
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