The introduction of the highly potent incretin receptor agonists semaglutide and tirzepatide has marked a new era in the treatment of type 2 diabetes and obesity. With normalisation of glycated haemoglobin levels and weight losses around 15–25%, therapeutic goals that were previously unrealistic are now within reach, and clinical trials have documented that these effects are associated with reduced risk of cardiovascular events and premature mortality. Here, I review this remarkable development from the earliest observations of glucose lowering and modest weight losses with native glucagon-like peptide (GLP)-1 and short acting compounds, to the recent development of highly active formulations and new molecules. I will classify these agents as GLP-1-based therapies in the understanding that these compounds or combinations may have actions on other receptors as well. The physiology of GLP-1 is discussed as well as its mechanisms of actions in obesity, in particular, the role of sensory afferents and GLP-1 receptors in the brain. I provide details regarding the development of GLP-1 receptor agonists for anti-obesity therapy and discuss the possible mechanism behind their beneficial effects on adverse cardiovascular events. Finally, I highlight new pharmacological developments, including oral agents, and discuss important questions regarding maintenance therapy.

高效肠促胰岛素受体激动剂 semaglutide 和 tirzepatide 的推出标志着 2 型糖尿病和肥胖症治疗的新纪元。随着糖化血红蛋白水平正常化和体重减轻约 15-25%，以前不切实际的治疗目标现在触手可及，临床试验证明这些影响与降低心血管事件和过早死亡的风险有关。在这里，我回顾了这一显着的发展，从最早观察到天然胰高血糖素样肽 （GLP）-1 和短效化合物降低葡萄糖和适度减轻体重，到最近开发的高活性制剂和新分子。我将这些药物归类为基于 GLP-1 的疗法，因为这些化合物或组合也可能对其他受体起作用。讨论了 GLP-1 的生理学及其在肥胖中的作用机制，特别是感觉传入神经和 GLP-1 受体在大脑中的作用。我提供了有关用于抗肥胖治疗的 GLP-1 受体激动剂开发的详细信息，并讨论了它们对不良心血管事件有益影响背后的可能机制。最后，我强调了新的药理学发展，包括口服药物，并讨论了有关维持治疗的重要问题。