Glucagon-Like Peptide-1 (GLP-1)

Glucagon-like peptide-1 is an incretin cut from proglucagon in enteroendocrine L-cells and released within minutes of nutrient arrival in the gut. The active forms are the amidated seven to thirty-six and the seven to thirty-seven fragments, acting at a class B receptor on beta cells, the gastric wall, the vagus and hypothalamic and brainstem nuclei. Four actions follow: insulin secretion that scales with glucose, suppression of inappropriate glucagon, slowed gastric emptying and reduced food intake.

The native hormone is useless as a drug: a half-life of one to two minutes under DPP-4 attack and renal clearance. Everything in the class is an engineering answer to that. Exenatide, from the lizard peptide exendin-4, arrived in 2005; liraglutide, acylated with a C16 chain for albumin binding, in 2010 for diabetes and 2014 for obesity; semaglutide, adding a C18 diacid and a substitution blocking DPP-4 cleavage, reached weekly dosing and about fifteen percent mean weight loss over sixty-eight weeks in STEP 1. An oral formulation with the absorption enhancer SNAC followed in 2019.

What changed the class's standing was outcome data rather than glucose data. LEADER and SUSTAIN-6 showed cardiovascular benefit in type 2 diabetes, and SELECT in 2023 reported a twenty percent relative reduction in major adverse cardiovascular events in people with cardiovascular disease and obesity but not diabetes. That moves the evidence off surrogate endpoints, which separates this class from most metabolic compounds sold on mechanism.

The naming causes confusion. GLP-1 is a hormone, not a product, so a patient saying they take a GLP-1 has not specified molecule, dose or indication, and research-grade material sold under that label is not the approved drug. It is also conflated with GLP-2 and with glucagon despite sharing a precursor with both.