GLP-1 drugs trace back to a Gila monster: the origin of semaglutide and its class

Full analysis

In the late 1980s, clinical endocrinologist John Eng at the Bronx VA Medical Center was curious about why the bite of a Gila monster — a slow-moving desert lizard — caused dramatic pancreatic inflammation in bitten animals. Using sensitive peptide-detection tools developed in Nobel laureate Rosalyn Yalow's lab, Eng systematically separated the venom's components. He found a peptide he named exendin-4, published in 1993, that shared roughly 53% amino acid sequence similarity to GLP-1 (glucagon-like peptide-1), a human gut hormone that stimulates insulin release after meals. Crucially, while native human GLP-1 is destroyed by an enzyme in the body within about two minutes — too fast to be useful as a drug — exendin-4 was resistant to that enzyme and lasted hours. It was, in effect, a long-acting version of our own meal-triggered insulin signal, sitting in lizard saliva.

The VA declined to patent the discovery; Eng eventually did so himself, and the rights reached Eli Lilly and Amylin. Synthetic exendin-4 was approved by the FDA in 2005 as exenatide (brand name Byetta), the first GLP-1 receptor agonist on the market. Subsequent drugs — liraglutide, semaglutide, and tirzepatide, which adds a second hormonal target — were engineered modifications of the human GLP-1 sequence designed to last longer and reduce side effects. These drugs are now reshaping treatment of type 2 diabetes and obesity, with ongoing trials in heart failure, kidney disease, sleep apnea, and Alzheimer's disease. Peter Attia notes that the entire class originated from a VA clinician wondering what endocrinology lessons a desert lizard's unusual pancreatic biology might hold.