- GLP-1 peptides are synthetic versions of gut hormones (incretins) that signal fullness, slow stomach emptying and trigger glucose-dependent insulin release.
- Each generation has added potency or receptors: GLP-1 only (exenatide, liraglutide, semaglutide), GIP + GLP-1 (tirzepatide), then GIP + GLP-1 + glucagon (retatrutide).
- Mean weight loss in pivotal trials climbed from about 8 kg with liraglutide (2015) to 14.9 % with semaglutide (2021), 20.9 % with tirzepatide (2022) and 28.3 % with retatrutide (company-reported, 2026).
- Semaglutide cut major cardiovascular events by 20 % in the SELECT trial (NEJM, 2023), showing benefits beyond weight.
- Exenatide, liraglutide, semaglutide, tirzepatide and orforglipron are approved medicines; retatrutide remains investigational in 2026.
What GLP-1 peptides are
GLP-1 (glucagon-like peptide-1) is a 30-amino-acid hormone released by L-cells in the gut within minutes of eating. It tells the pancreas to release insulin when glucose is high, suppresses glucagon, slows gastric emptying and acts on appetite centres in the brain. Together with GIP (glucose-dependent insulinotropic polypeptide), it belongs to the incretins, the hormones responsible for the stronger insulin response to oral glucose than to intravenous glucose.
The problem with the natural hormone is lifespan: native GLP-1 is cleaved by the DPP-4 enzyme and lasts only about two minutes in circulation. A GLP-1 receptor agonist is a molecule engineered to activate the same receptor but survive far longer. Most are peptides with amino-acid substitutions that block DPP-4 and a fatty-acid chain that binds albumin, stretching activity from minutes to days. The newest members, such as orforglipron, are small non-peptide molecules that can be taken as a pill.
GLP-1, GIP and glucagon: three receptors, three roles
- GLP-1 receptor: fullness, slower gastric emptying, glucose-dependent insulin release, lower glucagon. The foundation of every drug in this class.
- GIP receptor: a second incretin signal for insulin and fat-tissue metabolism; paired with GLP-1 it produced larger weight loss and appears to improve tolerability.
- Glucagon receptor: raises hepatic fat oxidation and energy expenditure; added in triple agonists to push weight and liver-fat reduction further.
A short history: from lizard venom to triple agonists
GLP-1 was identified in the early 1980s from the proglucagon gene, work recognised by the 2024 Lasker Award for Joel Habener, Svetlana Mojsov and Lotte Bjerre Knudsen. The first usable drug came from an unexpected source: in 1992 John Eng isolated exendin-4 from the saliva of the Gila monster, a lizard peptide that activates the human GLP-1 receptor but resists DPP-4.
- 2005 - Exenatide (Byetta), synthetic exendin-4, becomes the first GLP-1 receptor agonist approved by the FDA, for type 2 diabetes, dosed twice daily.
- 2009-2010 - Liraglutide (Victoza), a human GLP-1 analogue with a fatty-acid chain, is approved in the EU and US for once-daily use. As Saxenda it became the first GLP-1 drug approved for weight management (US, 2014); the SCALE trial (NEJM, 2015) reported 8.4 kg vs 2.8 kg weight loss at 56 weeks.
- 2017-2021 - Semaglutide extends the albumin-binding idea to once-weekly action (Ozempic 2017), becomes the first oral GLP-1 peptide (Rybelsus 2019) and, as Wegovy (2021), reaches 14.9 % mean weight loss at 68 weeks in STEP 1.
- 2022-2023 - Tirzepatide (Mounjaro, Zepbound), the first dual GIP/GLP-1 agonist, reports up to 20.9 % weight loss in SURMOUNT-1.
- 2025 - Mazdutide, a GLP-1/glucagon dual agonist, is approved in China for weight management (June) and type 2 diabetes (September). Oral semaglutide for obesity (Wegovy pill) is approved by the FDA in December.
- 2026 - Orforglipron (Foundayo), an oral non-peptide GLP-1 agonist, is approved by the FDA on 1 April. Retatrutide, a triple GIP/GLP-1/glucagon agonist, reports phase 3 TRIUMPH results and heads for a planned US filing in Q1 2027.
What the research shows
Weight loss
The clearest trend in incretin research is the step change in weight reduction with each generation. In pivotal randomised trials of adults with obesity, mean weight loss rose from single digits with liraglutide to 14.9 % with semaglutide (STEP 1, NEJM 2021), 20.9 % with tirzepatide (SURMOUNT-1, NEJM 2022) and 28.3 % with retatrutide at 80 weeks (TRIUMPH-1, Lilly press release, May 2026). The oral small molecule orforglipron reported 11.2 % at 72 weeks in ATTAIN-1 (NEJM, 2025), trading some efficacy for pill convenience.
Blood sugar and type 2 diabetes
The class began as diabetes therapy and remains among the most effective glucose-lowering options. Because insulin release is glucose-dependent, the risk of hypoglycaemia on GLP-1 agonists alone is low. In the SURPASS-2 trial (NEJM, 2021) tirzepatide lowered HbA1c by up to 2.30 percentage points, more than semaglutide, and retatrutide lowered HbA1c by up to 1.94 points as monotherapy in the phase 3 TRANSCEND-T2D-1 trial (Lancet, 2026).
Heart, liver, kidneys and sleep
- Cardiovascular: in SELECT (NEJM, 2023; 17,604 adults with cardiovascular disease and overweight, no diabetes), semaglutide lowered major adverse cardiovascular events by 20 % (6.5 % vs 8.0 %).
- Liver: tirzepatide resolved MASH in up to 62 % of participants vs 10 % on placebo (SYNERGY-NASH, NEJM 2024); retatrutide reduced liver fat by up to 82.4 % in 24 weeks (Nature Medicine, 2024).
- Sleep apnea: tirzepatide reduced breathing events by about 25 per hour in SURMOUNT-OSA (NEJM, 2024), leading to a 2024 FDA approval for that use.
Side effects reported in trials
Across the class the most common adverse events are gastrointestinal: nausea, diarrhoea, vomiting and constipation, usually mild to moderate and most frequent while the dose is being raised. In STEP 1, 4.5 % of semaglutide participants stopped because of gastrointestinal events. Trials also track gallbladder events, pancreatitis and heart rate; retatrutide studies additionally reported a transient heart-rate rise and dysesthesia, an altered skin sensation. Muscle as well as fat is lost with any large weight reduction, which is an active research topic.
Approved vs investigational: the molecules at a glance
| Molecule | Receptors | Type | Status (Sept 2026) | Headline trial result |
|---|---|---|---|---|
| Exenatide | GLP-1 | Peptide (exendin-4) | Approved, US 2005 | First GLP-1 drug (type 2 diabetes) |
| Liraglutide | GLP-1 | Lipidated peptide | Approved, US/EU | 8.4 kg vs 2.8 kg at 56 wk (SCALE) |
| Semaglutide | GLP-1 | Lipidated peptide, injectable or oral | Approved, US/EU | 14.9 % at 68 wk (STEP 1) |
| Tirzepatide | GIP + GLP-1 | Lipidated peptide | Approved, US/EU | 20.9 % at 72 wk (SURMOUNT-1) |
| Mazdutide | GLP-1 + glucagon | Lipidated peptide | Approved, China 2025 | First GLP-1/glucagon dual approved |
| Orforglipron | GLP-1 | Oral small molecule, non-peptide | Approved, US 2026 | 11.2 % at 72 wk (ATTAIN-1) |
| Retatrutide | GIP + GLP-1 + glucagon | Lipidated peptide | Investigational, phase 3 | 28.3 % at 80 wk (TRIUMPH-1)* |
An approval always applies to a specific finished medicine - defined formulation, strength and manufacturer - prescribed under medical supervision. The same molecule supplied as a research-grade peptide is a laboratory reagent characterised by its identity and purity data, not a medicine with an indication.
Where the field is heading
Three directions dominate 2026 research. First, more receptors: triple agonists such as retatrutide, and GLP-1/glucagon duals such as mazdutide and survodutide, target liver fat and energy expenditure. Second, pills: oral semaglutide and orforglipron show that non-injectable options can reach double-digit weight loss. Third, outcomes beyond weight: heart, kidney, liver, joint and sleep endpoints increasingly define how these molecules are judged. The next big readout is TRIUMPH-5, the first head-to-head trial of retatrutide against tirzepatide.
Research information only, not medical advice. Cryopept products are for laboratory research use only, not for human or veterinary use.
