From a Gila monster's saliva to triple agonists: how weight-loss peptides evolved
A gut hormone that lasts two minutes, a lizard peptide that lasts for hours, and three decades of chemistry. The story of GLP-1 drugs, and why "GLP-3" is a nickname rather than a hormone.
At a glance
- GLP-1 is a gut hormone that boosts insulin and curbs appetite after a meal, but the natural version survives only about 1–2 minutes in the blood [1].
- The first GLP-1 drug came from exendin-4, a peptide isolated from Gila monster venom in 1992; its synthetic version, exenatide, was approved by the FDA in 2005 [2,3].
- Each generation since has lasted longer or hit more receptors: liraglutide, semaglutide, tirzepatide, and now the triple agonist retatrutide.
- Average weight loss in the headline obesity trials rose from 8.0% with liraglutide to 25.0% with retatrutide, counting everyone randomised [4,8].
- "GLP-3" is not a hormone. The proglucagon gene makes GLP-1 and GLP-2, and nothing called GLP-3 [1].
- A parallel branch builds on a different hormone, amylin: cagrilintide and its combination with semaglutide, CagriSema [9,10].
A message written in disappearing ink
After a meal, cells in the gut release glucagon-like peptide-1 (GLP-1). It tells the pancreas to release more insulin when blood sugar is high, and it signals fullness. For a drug designer, that is an attractive profile. The catch is speed: an enzyme called DPP-4 and the kidneys clear natural GLP-1 with a half-life of about one to two minutes [1].
Injecting the natural hormone is like sending a letter in disappearing ink. The message is right, but it fades before it can be read. Every drug in this story is, at heart, a way of making the ink last.
The lizard that solved the half-life problem
The first answer came from the American Southwest. In 1992, John Eng and colleagues at the Bronx Veterans Affairs Medical Center isolated a 39-amino-acid peptide from the venom of the Gila monster (Heloderma suspectum) and called it exendin-4 [2]. Its first 30 amino acids are about 53% identical to human GLP-1, and a glycine at position 2 makes it resistant to DPP-4 [1].
The first drug of the GLP-1 era was not designed from scratch. It was found in the venom of a lizard.
A synthetic copy, exenatide, was approved by the FDA on 28 April 2005 for type 2 diabetes, under the brand name Byetta [3]. It was approved to control blood sugar, not weight.
Generation two: a fatty-acid tail
The next step stayed closer to the human hormone. Liraglutide is human GLP-1 with a fatty-acid chain attached, which lets it bind to albumin, the most common protein in blood, and slows its clearance [1]. It was approved for type 2 diabetes in January 2010 and, at a higher dose, for weight management in December 2014 [3].
In the SCALE trial, 3,731 adults without diabetes received liraglutide 3.0 mg or placebo once a day for 56 weeks. Average weight loss was 8.0%, against 2.6% on placebo [4].
Generation three: once a week
Semaglutide pushed the same idea further: a DPP-4-resistant amino acid (Aib) at position 2 and a longer fatty diacid chain, so that one injection lasts a week [1]. It was approved for type 2 diabetes in December 2017 and for weight management, as Wegovy, in June 2021 [3].
The trial that changed the conversation was STEP 1: 1,961 adults, 68 weeks, average weight change of −14.9% on semaglutide 2.4 mg versus −2.4% on placebo [5].
Generation four: two hormones in one molecule
Tirzepatide added a second gut hormone, GIP (glucose-dependent insulinotropic polypeptide), so one peptide activates both the GIP and GLP-1 receptors. In SURMOUNT-1, 2,539 adults without diabetes were treated for 72 weeks; the 15 mg arm lost an average of 20.9%, against 3.1% on placebo [6]. The FDA approved it for type 2 diabetes in May 2022 and for weight management in November 2023 [3].
Generation five: adding glucagon
Retatrutide adds a third receptor, for glucagon, a hormone that tells the liver to release fuel and is thought to raise energy expenditure. In a phase 2 trial of 338 adults, the 12 mg arm lost an average of 24.2% over 48 weeks [7]. In TRIUMPH-1, a phase 3 trial of 2,339 adults without diabetes, the 12 mg arm lost 25.0% over 80 weeks, against 3.9% on placebo, counting everyone randomised [8]. It is still investigational; our retatrutide article covers the full trial programme and its side effects.
Why "GLP-3" is a nickname
In the body, a single gene makes a precursor protein called proglucagon. Depending on the tissue, it is cut into glucagon, GLP-1, GLP-2, glicentin and oxyntomodulin [1]. That is the whole family. There is no GLP-3.
The label "GLP-3" is used online as shorthand for retatrutide, a drug that works on three receptors or represents a third generation after GLP-1 drugs and dual agonists. It is a handy nickname, but it can mislead: it suggests a newly discovered hormone, when the drug is an engineered peptide acting on three receptors that were already well known.
The amylin branch
Amylin is a fullness hormone made in the pancreas alongside insulin, and it acts through different receptors from GLP-1. Novo Nordisk's cagrilintide is a long-acting amylin analogue. In the REDEFINE 1 trial, 3,417 adults received the combination of cagrilintide and semaglutide (CagriSema), either drug alone, or placebo for 68 weeks [9]. Counting everyone randomised, the combination produced −20.4%, cagrilintide alone −11.5%, semaglutide alone −14.9% and placebo −3.0% [9,10]. Our cagrilintide article explains the amylin story.
Headline trials side by side
| Drug (receptors) | Trial | Participants | Duration | Arm | Mean weight change | Placebo |
|---|---|---|---|---|---|---|
| Liraglutide (GLP-1) | SCALE [4] | 3,731 | 56 weeks | 3.0 mg daily | −8.0% | −2.6% |
| Semaglutide (GLP-1) | STEP 1 [5] | 1,961 | 68 weeks | 2.4 mg weekly | −14.9% | −2.4% |
| Tirzepatide (GIP + GLP-1) | SURMOUNT-1 [6] | 2,539 | 72 weeks | 15 mg weekly | −20.9% | −3.1% |
| Cagrilintide (amylin) | REDEFINE 1 [10] | 302 in arm | 68 weeks | 2.4 mg weekly | −11.5% | −3.0% |
| CagriSema (amylin + GLP-1) | REDEFINE 1 [9] | 2,108 in arm | 68 weeks | 2.4 mg + 2.4 mg | −20.4% | −3.0% |
| Retatrutide (GIP + GLP-1 + glucagon) | Phase 2 [7] | 338 | 48 weeks | 12 mg weekly | −24.2% | −2.1% |
| Retatrutide (GIP + GLP-1 + glucagon) | TRIUMPH-1 [8] | 2,339 | 80 weeks | 12 mg weekly | −25.0% | −3.9% |
All figures are for adults without diabetes and use each trial's main analysis, which counts participants regardless of whether they stayed on treatment (SCALE used an older imputation method). The trials differ in length, population and design, so the table shows a trend, not a ranking. Analyses that assume everyone stayed on the drug give larger numbers: for example, 11.8% for cagrilintide alone and 22.7% for CagriSema in REDEFINE 1 [10].
What the timeline leaves out
Bigger numbers came with familiar trade-offs. Nausea, diarrhoea, vomiting and constipation are the most common side effects across the class, and they generally rise with dose [1,5,6,7]. The trials above lasted one to two years, while obesity is a lifelong condition. And the headline trials compared each drug with placebo rather than with its predecessor; head-to-head trials are still relatively few. For how to weigh evidence like this, see our guide to levels of evidence.
FAQ
What is the difference between GLP-1 and GLP-3?
GLP-1 is a real gut hormone, and GLP-1 drugs mimic it [1]. "GLP-3" is not a hormone; it is an informal nickname for retatrutide, a triple agonist of the GLP-1, GIP and glucagon receptors.
Was Ozempic made from Gila monster venom?
Which weight-loss peptide produced the most weight loss in trials?
Among the trials in the table, retatrutide's TRIUMPH-1 reported the largest average loss, 25.0% at 80 weeks [8]. Because the trials differ in length and design, that is not a direct comparison.
Are triple agonists approved?
No. As of October 2026, retatrutide is still investigational; see our retatrutide article for its regulatory timeline.
Research Library
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Further reading elsewhere
Coverage and explainers from other publications, picked and checked by our team.
- The Pharmaceutical Journal · May 2026Phase III retatrutide study demonstrates 30% weight loss ↗News coverage of the first main phase 3 obesity results for the triple agonist retatrutide.
- BioSpace · Dec 2024Amylin Commands Weight Loss Attention as Industry Anticipates Novo's Phase III CagriSema Readout ↗An overview of the amylin branch of obesity drug development and the programmes competing in it.
- AAAS · Dec 2023Science's 2023 Breakthrough: GLP-1 Agonists Show Promise Against Obesity-Associated Disease ↗Why the journal Science named GLP-1 drugs its Breakthrough of the Year, and the open questions it flagged.
- The Golden Goose Award · Sep 20142013: Diabetes Medication ↗The story of how VA endocrinologist John Eng found exendin-4 in Gila monster venom and how it became the diabetes drug exenatide.
References
- Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. GLP-1 half-life, proglucagon products, exendin-4 homology, and the chemistry of liraglutide and semaglutide. PubMed
- Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J Biol Chem. 1992;267(11):7402-7405. Discovery of exendin-4. PubMed
- U.S. Food and Drug Administration. Drugs@FDA: original approval dates for Byetta (NDA 021773, 28 April 2005), Victoza (NDA 022341, 25 January 2010), Saxenda (NDA 206321, 23 December 2014), Ozempic (NDA 209637, 5 December 2017), Wegovy (NDA 215256, 4 June 2021), Mounjaro (NDA 215866, 13 May 2022) and Zepbound (NDA 217806, 8 November 2023). FDA
- Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. SCALE results. PubMed
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. STEP 1 results and side effects. PubMed
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. SURMOUNT-1 results and side effects. PubMed
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. Retatrutide phase 2 results and side effects. PubMed
- Jastreboff AM, Kaplan LM, Davies MJ, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. N Engl J Med. Published online 29 September 2026. doi:10.1056/NEJMoa2604169. TRIUMPH-1 phase 3 results. PubMed
- Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):635-647. REDEFINE 1 design and CagriSema results. PubMed
- Novo Nordisk. CagriSema demonstrates superior weight loss in adults with obesity or overweight in the REDEFINE 1 trial. Company announcement, 20 December 2024. Results for each REDEFINE 1 arm under both analyses. Novo Nordisk
This article summarises published research for education and laboratory context. It is not medical advice. Synthos products are sold for laboratory research only and are not approved for human use.