Peptide class
Incretin-based peptides that activate one or more of the GLP-1, GIP, and glucagon receptors to regulate insulin secretion, appetite, and metabolic homeostasis.
| Compound | Mechanism | Primary reported use | Profile |
|---|---|---|---|
| Retatrutide | GLP-1 / GIP / glucagon triple agonist | Metabolic health, weight management (Phase 2) | View profile → |
| Tirzepatide | GLP-1 / GIP dual agonist | Type 2 diabetes (Mounjaro), obesity (Zepbound) | View profile → |
| Semaglutide | GLP-1 mono-agonist | Type 2 diabetes (Ozempic), obesity (Wegovy) | View profile → |
| Liraglutide | GLP-1 mono-agonist | Type 2 diabetes, obesity (older generation) | Profile coming soon |
GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are endogenous incretin hormones secreted by enteroendocrine cells of the small intestine in response to nutrient ingestion. Both hormones potentiate insulin release from pancreatic beta cells in a glucose-dependent manner, meaning their insulinotropic effect is strongest when blood glucose is elevated and diminishes at euglycaemia — a property that substantially limits hypoglycaemia risk relative to other secretagogues. Beyond the pancreas, GLP-1 suppresses glucagon secretion from alpha cells, slows gastric emptying to blunt postprandial glucose excursions, and acts on central GLP-1 receptor pathways in the hypothalamus and brainstem to promote satiety and reduce food intake. The original GLP-1 analogue class — exemplified by liraglutide and semaglutide — mimics the GLP-1 hormone by binding the GLP-1 receptor with high affinity and a pharmacokinetic profile far exceeding that of endogenous GLP-1, which is cleared by dipeptidyl peptidase-4 (DPP-4) with a half-life of approximately two minutes. These analogues achieve half-lives of 13 hours (liraglutide) to approximately one week (semaglutide) through fatty acid conjugation and albumin binding strategies that confer DPP-4 resistance.
Dual and triple agonism represent the next evolutionary step in this class. Tirzepatide added GIP receptor agonism alongside GLP-1 receptor activation, producing greater weight loss than pure GLP-1 agonists in head-to-head trials — most notably SURPASS-2, which compared tirzepatide directly against semaglutide. The mechanisms underlying GIP's additive contribution are still being characterised, but research has investigated GIP's role in adipocyte metabolism (promoting lipid storage at physiological concentrations but potentially enhancing lipolysis in the obese state), as well as its insulin-potentiating synergy with GLP-1 at the beta cell level. Retatrutide extends this framework to the glucagon receptor as a third target, incorporating a tri-agonist pharmacology. Glucagon's thermogenic and hepatic effects — including stimulation of hepatic glucose production, fatty acid oxidation, and energy expenditure — may contribute to even greater caloric deficit than dual agonism alone. The potential hyperglycaemic liability of glucagon receptor activation is substantially offset by the dominant insulinotropic action of the co-present GLP-1 and GIP receptor agonism, producing a net metabolic effect that research has investigated for its potential role in achieving greater energy expenditure without clinically significant fasting hyperglycaemia.
At the molecular level, GLP-1R, GIPR, and the glucagon receptor are all class B (secretin family) G protein-coupled receptors (GPCRs), sharing significant structural homology in their seven-transmembrane domains and extracellular ligand-binding regions. Activation of any of these receptors triggers coupling to the Gs alpha subunit, stimulating adenylyl cyclase to produce cyclic AMP (cAMP), which in turn activates protein kinase A (PKA) and exchange proteins activated by cAMP (EPACs). In pancreatic beta cells, this signalling cascade potentiates insulin vesicle exocytosis through phosphorylation of components of the secretory machinery and modulation of ATP-sensitive potassium channels. In the hypothalamus and nucleus tractus solitarius, GLP-1R activation modulates appetite-regulating neural circuits, reducing neuropeptide Y and agouti-related peptide signalling while increasing pro-opiomelanocortin activity. The multi-receptor approach of newer compounds attempts to leverage additive or synergistic effects across these related but pharmacologically distinct signalling pathways, with the architecture of each compound's receptor selectivity and relative agonist activity being a primary determinant of its observed clinical profile.
Research into GLP-1's physiological role began in the 1980s following the cloning of the glucagon gene and the identification of GLP-1 as a potent insulinotropic peptide derived from its post-translational processing. Early work in the 1990s established the glucose-dependent nature of GLP-1-stimulated insulin secretion, positioning it as a conceptually attractive therapeutic target. Exendin-4, a naturally occurring GLP-1 receptor agonist isolated from Gila monster venom with DPP-4 resistance, provided the proof-of-concept for long-acting analogues and led to exenatide, the first approved GLP-1 receptor agonist. Liraglutide followed as the first human GLP-1 analogue with once-daily dosing, and the LEADER cardiovascular outcomes trial subsequently established a cardiovascular mortality benefit in patients with type 2 diabetes and high cardiovascular risk — a landmark finding for the class. Semaglutide represented a further generational advance, achieving once-weekly subcutaneous dosing and later an oral formulation (Rybelsus), with the STEP trial programme demonstrating unprecedented weight loss magnitudes in obesity for a pharmaceutical intervention. Tirzepatide, the first approved dual GLP-1/GIP agonist, completed this progression with SURMOUNT and SURPASS programmes showing consistent superiority over semaglutide in weight reduction. Retatrutide remains in Phase 2 clinical development as of the knowledge cutoff, with published data representing the most advanced investigational compound in the class.
The key trial landscape for this class is the most extensive of any peptide category represented on this site. The STEP programme (semaglutide 2.4 mg weekly) demonstrated mean weight loss of approximately 15% over 68 weeks in adults with obesity. The SURMOUNT-1 trial for tirzepatide at 15 mg reported mean weight reductions of approximately 22%, with a substantial proportion of participants achieving weight loss exceeding 20% — a threshold previously associated only with surgical interventions. The SURPASS-2 head-to-head trial demonstrated statistically significant superiority of tirzepatide over semaglutide 1 mg on both glycaemic and weight endpoints. The SELECT trial (2023) was particularly notable in establishing that semaglutide 2.4 mg reduced the risk of major adverse cardiovascular events by approximately 20% in non-diabetic individuals with obesity and established cardiovascular disease — demonstrating cardiovascular benefit independent of diabetes as a mechanism. Phase 2 data for retatrutide reported mean weight loss of approximately 24% at the highest doses evaluated, representing the greatest percentage weight loss reported for any single pharmacological compound in a randomised controlled trial at the time of publication. This class has by far the most robust human efficacy and safety evidence base of any peptide class covered on WikiPeptide, with outcomes data spanning glycaemic control, weight reduction, cardiovascular endpoints, and hepatic steatosis.
Still in Phase 2 trials as of the knowledge cutoff; represents the furthest extension of incretin agonism to date, incorporating simultaneous activity at GLP-1, GIP, and glucagon receptors in a single molecule. Phase 2 data reported the greatest percentage weight loss of any single compound in this class, approximately 24% at the highest doses evaluated, a figure that compares favourably even to surgical weight loss benchmarks in the published literature. No approved brand name exists yet; all use remains investigational, and Phase 3 programme design and timeline details were not fully available at the knowledge cutoff.
The first approved dual GLP-1/GIP agonist, representing a substantial advance over pure GLP-1 monotherapy in terms of weight reduction magnitude — SURMOUNT-1 reported approximately 22% mean weight loss at 15 mg over 72 weeks, with a considerable proportion of participants achieving 25% or greater. Head-to-head data from SURPASS-2 demonstrates statistically significant superiority over semaglutide 1 mg on both HbA1c reduction and body weight endpoints, making it the highest-efficacy approved agent in the class at comparable doses. The SURPASS-CVOT cardiovascular outcomes trial is ongoing, and data from this programme are anticipated to further define the cardiovascular risk-benefit profile of the dual agonist mechanism.
The reference GLP-1 mono-agonist and, by post-marketing volume and published evidence, the best-characterised compound in the incretin class; the STEP programme, SUSTAIN programme, and SELECT trial collectively represent one of the largest randomised controlled trial datasets for any pharmaceutical agent in metabolic medicine. The SELECT trial (2023) is particularly notable for demonstrating a 20% reduction in major adverse cardiovascular events as a primary endpoint in non-diabetic patients with obesity and established cardiovascular disease, establishing a cardiovascular benefit mechanism independent of glycaemic improvement. Available in both subcutaneous formulations (Ozempic for diabetes, Wegovy for obesity) and an oral formulation (Rybelsus), the latter making it the only approved oral GLP-1 receptor agonist and expanding the population for whom incretin-based approaches have been investigated.
An earlier generation GLP-1 mono-agonist requiring daily subcutaneous injection rather than once-weekly dosing; largely superseded in both clinical and research practice by semaglutide, which achieves greater weight loss and improved convenience at comparable or lower doses. Despite this, liraglutide retains an extensive published evidence base accumulated over more than a decade of use, anchored by the LEADER cardiovascular outcomes trial, which demonstrated a reduction in cardiovascular mortality in patients with type 2 diabetes and high cardiovascular risk — the first such demonstration for a GLP-1 receptor agonist. Research has investigated liraglutide for its potential role in non-alcoholic fatty liver disease, neurodegenerative conditions, and polycystic ovary syndrome, areas where subsequent compounds in the class are now building on liraglutide's mechanistic groundwork.