(A) Data revealing GLP-1–stimulated insulin secretion supported the approval of the first GLP-1RA for the treatment of T2D in 2005. Nine years later, the link between GLP-1 and reduced food intake resulted the development and approval of the first GLP-1RA for obesity. The cardiovascular safety of GLP-1–based medicines was first demonstrated in T2D in 2016, and in people with obesity in 2023. GLP-1RA are currently being studied in phase 3 trials for the treatment of HFpEF, peripheral artery disease (PAD), diabetic kidney disease (DKD), metabolic liver disorders such as nonalcoholic steatohepatitis (NASH), and neurodegenerative disorders. (B) GLP-1 and GLP-1RAs act through the GLP-1R, which is a G protein coupled receptor. GLP-1 potentiates glucose-dependent insulin secretion in β-cells. The GLP-1R is also widely expressed in multiple tissues including several regions of the brain. Notably, activation of GLP-1R⁺ neurons in the hypothalamus and brainstem reduces food intake and promotes weight loss. GLP-1R⁺ neurons in the hindbrain also suppress hepatic glucose production. Further, GLP-1R influences BP and HR via the autonomic nervous system.