Mihir Rao

Ozempic, Wegovy, and Mounjaro seemed to arrive all at once, somewhere around 2021, and appeared to change what medicine considered possible for obesity, but the hormone behind them was discovered in the early 1980s. The gap between the lab and the pharmacy counter was roughly forty years, and that gap is the actual story: scientists understood the potential almost immediately, and the problem was that the hormone, in its natural form, fell apart in the body in about a minute.

A peptide hidden inside another hormone

The discovery began with a gene, not a drug. In the early 1980s, Joel Habener's lab at Massachusetts General Hospital was studying glucagon, the hormone that raises blood sugar, by cloning the gene that encodes it from anglerfish pulled out of Boston Harbor. Around the same time, Graeme Bell's group at the University of Chicago cloned the human version and found something unexpected: the proglucagon gene didn't code for one hormone. It coded for several, including two previously unknown peptides that were named GLP-1 and GLP-2.

GLP-1 was the interesting one, but it took a chemist, Svetlana Mojsov, a peptide chemist at MGH, to figure out why: she suspected that the full predicted sequence wasn't the active form, worked out that a shorter, truncated version, GLP-1(7-37), was the biologically potent one, synthesized it, made antibodies to find it in the gut, and helped prove it triggered insulin release in pancreatic tissue. That truncated fragment is the molecule every modern GLP-1 drug imitates.

Mojsov's role is worth pausing on because for a long time it was nearly erased: when MGH filed patents on the early GLP-1 work in the late 1980s, they listed Habener as sole inventor, and Mojsov hired lawyers and spent roughly a decade getting the patent office to correct four of them to name her as co-inventor. Only in 2024, when the Lasker Award went to her, Habener, and Novo Nordisk's Lotte Bjerre Knudsen, did the recognition catch up to the work.

The one-minute problem

Native human GLP-1 is chewed up almost instantly by an enzyme called DPP-4, giving it an active life of only one to two minutes in the bloodstream, and a hormone that vanishes that fast is useless as a medicine because you would need a continuous IV drip to keep any of it around. Knowing GLP-1 lowered blood sugar and curbed appetite was not enough; someone had to build a version that survived.

The breakthrough came from an unlikely animal: in the early 1990s, John Eng, an endocrinologist at the Bronx VA Medical Center, was investigating the venom of the Gila monster, a desert lizard that can go months without eating while keeping its blood sugar steady.

Eng isolated a peptide he called exendin-4 and found it was about 53% structurally identical to human GLP-1, but crucially it resisted the enzyme that destroyed the human version. The VA declined to patent it, so Eng patented it himself and licensed it to Amylin Pharmaceuticals. A synthetic copy, exenatide, became Byetta, the first GLP-1 drug approved by the FDA, in 2005, more than a decade after the discovery. It required two injections a day and was a modest commercial success, but it proved the concept worked in people.

From blood sugar to body weight

After Byetta proved the concept in people, drugmakers learned to attach fatty-acid chains and make other modifications that let a GLP-1 molecule linger for days instead of minutes, and Novo Nordisk released the once-daily Victoza in 2010 and the once-weekly Ozempic in 2017, both approved for type 2 diabetes.

The pivot to obesity came from watching patients lose significant amounts of weight on these drugs, when the appetite-suppressing effect Mojsov's generation had noted decades earlier turned out to be powerful, which led to Wegovy, a higher-dose semaglutide aimed at obesity, and then Eli Lilly's tirzepatide (Mounjaro and Zepbound), which raised the ceiling by hitting two gut-hormone receptors at once. In a head-to-head trial, tirzepatide produced about 20% average weight loss versus roughly 14% for semaglutide, numbers that used to require bariatric surgery.

Everything else the hormone touches

The most consequential discovery may be that these drugs do more than shrink waistlines: the SELECT trial, which followed more than 17,000 people with cardiovascular disease and obesity but not diabetes, found semaglutide cut major adverse cardiovascular events (heart attacks, strokes, cardiovascular death) by 20%, and a related analysis showed a benefit for kidney outcomes as well. There is also growing, if still preliminary, evidence that GLP-1 drugs blunt craving across substances (alcohol, nicotine, opioids), apparently by acting on the reward circuitry itself rather than any one drug.

Not every hope has panned out: the neurodegeneration angle, often discussed as a possible next frontier, hit a wall in November 2025 when Novo Nordisk's large EVOKE and EVOKE+ trials found that oral semaglutide did not slow Alzheimer's progression, despite some movement in biomarkers, and Daniel Drucker, one of the field's founders, called it a setback even as the drugs may still prove transformative in other indications.

That's the shape of the whole forty-year arc: a hormone found by accident inside another hormone, made usable by a lizard, redirected toward obesity by a side effect, and now being tested against half the chronic diseases of modern life, some of which it may help and some of which it may not, because the overnight success took four decades and the hard part was never the idea but making the idea last longer than a minute.