GLP-1 Receptor Agonists and Weight Loss: A Critical Review of Mechanisms

GLP-1 receptor agonist medications have the potential to promote marked weight loss, but maximal and sustained benefit may be compromised by poor compliance and cessation of use. Development of next-generation medications that address current obstacles to effective use and development of effective adjunct treatments will benefit from better characterization of their mechanisms of action. This narrative review critically assesses eight purported mechanisms including modulation of appetite, chemosensory function, cravings/aversions, food noise, gastric emptying, the microbiome, incretin activity, and energy expenditure. Current evidence does not support a single dominant mechanism; a combination of subtle effects may underlie the efficacy of these medications. However, as experience with these medications and methods to assess their effects grows, it should be possible to better determine the relative importance of these and possibly other mechanisms.