The article by Daniel J. Drucker from the Department of Medicine at the Lunenfeld-Tanenbaum Research Institute, University of Toronto, reviews the journey of glucagon-like peptide 1 (GLP-1) from its discovery in the 1970s to its therapeutic impact. Initially characterized as a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 was later identified and found to potentiate glucose-dependent insulin secretion. The preservation of GLP-1's insulinotropic actions in type 2 diabetes (T2D) patients highlighted its therapeutic potential, leading to the development of GLP-1 receptor (GLP-1R) agonists (GLP-1RAs). GLP-1R signaling is crucial for glucose homeostasis, as demonstrated in knockout mice and humans. GLP-1R agonists like exendin(9-39) have been shown to increase insulin secretion and reduce glucagon levels, while having no effect on GIP's insulinotropic actions. The anorexigenic effects of GLP-1R agonists, which reduce food intake and promote weight loss, are also well-established. These effects are mediated through the activation of GLP-1R+ neurons in the hypothalamus and brainstem. Beyond its role in insulin secretion and body weight management, GLP-1R agonists have shown cardioprotective effects, reducing the risk of myocardial infarction, stroke, and cardiovascular death in T2D patients. Recent studies have extended these benefits to obesity and heart failure with preserved ejection fraction (HFpEF). The future of GLP-1-based medicines is promising, with new once-weekly GLP-1RAs and coagonists being developed for treating T2D, obesity, and other chronic cardiometabolic disorders. These advancements hold significant promise for improving the health of individuals living with these conditions.The article by Daniel J. Drucker from the Department of Medicine at the Lunenfeld-Tanenbaum Research Institute, University of Toronto, reviews the journey of glucagon-like peptide 1 (GLP-1) from its discovery in the 1970s to its therapeutic impact. Initially characterized as a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 was later identified and found to potentiate glucose-dependent insulin secretion. The preservation of GLP-1's insulinotropic actions in type 2 diabetes (T2D) patients highlighted its therapeutic potential, leading to the development of GLP-1 receptor (GLP-1R) agonists (GLP-1RAs). GLP-1R signaling is crucial for glucose homeostasis, as demonstrated in knockout mice and humans. GLP-1R agonists like exendin(9-39) have been shown to increase insulin secretion and reduce glucagon levels, while having no effect on GIP's insulinotropic actions. The anorexigenic effects of GLP-1R agonists, which reduce food intake and promote weight loss, are also well-established. These effects are mediated through the activation of GLP-1R+ neurons in the hypothalamus and brainstem. Beyond its role in insulin secretion and body weight management, GLP-1R agonists have shown cardioprotective effects, reducing the risk of myocardial infarction, stroke, and cardiovascular death in T2D patients. Recent studies have extended these benefits to obesity and heart failure with preserved ejection fraction (HFpEF). The future of GLP-1-based medicines is promising, with new once-weekly GLP-1RAs and coagonists being developed for treating T2D, obesity, and other chronic cardiometabolic disorders. These advancements hold significant promise for improving the health of individuals living with these conditions.