GLP-1 receptor agonists explained: how they work, the full list, and where research is heading

GLP-1 receptor agonists are one of the most studied classes of peptide medicines. They are built to imitate glucagon-like peptide-1 (GLP-1), a hormone released from the gut after a meal, but to last hours or days in the body instead of minutes. Newer molecules go further, combining GLP-1 activity with activity at the receptors for GIP, glucagon or amylin.

This guide explains the biology of GLP-1, how the receptor agonists work, lists every FDA-approved agent by international non-proprietary name (INN) with its approval year, compares single, dual and triple agonists, and explains the chemistry that extends their half-life. Trial findings are reported neutrally, as published, with their evidence level. For a three-way structural comparison of the best-known molecules, see semaglutide vs tirzepatide vs liraglutide.

What is GLP-1?

GLP-1 is a peptide hormone cut from the precursor proglucagon. Proglucagon is processed differently by tissue: pancreatic alpha cells make glucagon, while enteroendocrine L-cells in the gut, most dense in the ileum and colon, release GLP-1, GLP-2 and oxyntomodulin [1]. A small population of neurons in the brainstem nucleus tractus solitarii is the main source of GLP-1 in the brain [1].

The two active circulating forms, GLP-1(7-36)amide and GLP-1(7-37), are equally potent at stimulating insulin secretion [1]. Their effects include glucose-dependent stimulation of insulin secretion, slower gastric emptying, reduced food intake and increased natriuresis [1]. GLP-1 also lowers glucose by suppressing glucagon secretion; clamp studies in type 2 diabetes suggest this is as important for glucose lowering as its effect on insulin [1].

Why native GLP-1 cannot be used as a drug

Native GLP-1 has a half-life of about 1 to 2 minutes, depending on species, for two reasons: the enzyme dipeptidyl peptidase-4 (DPP-4) cleaves off its N-terminal dipeptide, producing low-affinity metabolites, and the kidneys eliminate it [1]. The liraglutide label gives the half-life of GLP-1(7-37) as 1.5 to 2 minutes, citing DPP-4 and neutral endopeptidases [2]. Every GLP-1 receptor agonist on this page is, at heart, an answer to that problem.

How GLP-1 receptor agonists work: mechanism of action

The GLP-1 receptor (GLP-1R) is a class B G protein-coupled receptor. In rats and humans it comprises 463 amino acids, with seven transmembrane helices and a large N-terminal extracellular domain of about 120 amino acids [1]. GLP-1, GLP-2, glucagon, GIP, secretin and GHRH all act through structurally similar class B receptors [1], which is why a single engineered peptide can be tuned to hit more than one of them.

In pancreatic beta cells, receptor activation raises cAMP, which activates protein kinase A (PKA) and the exchange protein Epac; up to 50% of GLP-1-induced insulin release can be mediated through Epac signalling [1]. Because the insulin-releasing effect depends on glucose, the stimulus fades as glucose falls [1].

Effect of GLP-1 receptor activation	Where	Evidence level
Glucose-dependent increase in insulin secretion	Pancreatic beta cells	Shown in rodents, other species and humans [1]
Suppression of glucagon secretion	Pancreatic alpha cells (mechanism complex)	Shown in mice, dogs and humans [1]
Slower gastric emptying	Stomach	Physiological action of GLP-1 [1]
Reduced food intake	Brain	Physiological and pharmacological action [1]
Natriuresis and diuresis	Kidney	Physiological action [1]

List of GLP-1 receptor agonists by INN, with FDA approval year

The table lists agents by INN only. Approval dates are the original approval of each application in Drugs@FDA [3]; structural notes come from each product’s prescribing information.

INN	Receptor target(s)	Molecule type	First FDA approval	Later FDA approvals and notes
Exenatide	GLP-1R	39-residue peptide amide [4] developed from Gila monster venom exendin-4 [5] [6]	28 April 2005, type 2 diabetes [3]	Extended-release microsphere formulation, 27 January 2012 [7] [3]; original application now listed as discontinued [3]
Liraglutide	GLP-1R	Acylated GLP-1 analogue, 97% homologous to human GLP-1 [2]	25 January 2010, type 2 diabetes [3]	Chronic weight management, 23 December 2014 [3]
Albiglutide	GLP-1R	Two GLP-1 copies fused to human albumin [8]	15 April 2014, type 2 diabetes [8] [3]	Listed as discontinued [3]
Dulaglutide	GLP-1R	GLP-1 analogue fused to a modified IgG4 Fc, about 63 kDa [9]	18 September 2014, type 2 diabetes [3]
Lixisenatide	GLP-1R	44-residue peptide, C-terminally amidated [10]	27 July 2016, type 2 diabetes [10] [3]
Semaglutide	GLP-1R	Acylated GLP-1 analogue, 94% homologous to human GLP-1 [11]	5 December 2017, type 2 diabetes (injection) [3]	Oral tablet, 20 September 2019 [6] [3]; chronic weight management, 4 June 2021 [3]
Tirzepatide	GIPR and GLP-1R	39-residue acylated peptide [12]	13 May 2022, type 2 diabetes [3]	Chronic weight management, 8 November 2023 [3]
Orforglipron	GLP-1R	Non-peptide small molecule, oral [13]	1 April 2026, chronic weight management [14]
Mazdutide	GLP-1R and glucagon receptor	Peptide dual agonist [15]	Not FDA-approved	Approved in China for chronic weight management, announced 27 June 2025 [16]
Survodutide	Glucagon receptor and GLP-1R	Peptide	Not approved	Investigational; phase 3 SYNCHRONIZE programme [17]
Retatrutide	GIPR, GLP-1R and glucagon receptor	Peptide	Not approved	Investigational; phase 3 TRIUMPH programme [18]

Cagrilintide is not on this list because it is an amylin analogue, not a GLP-1 receptor agonist [19]; it appears below as a combination partner.

Single vs dual vs triple agonists

The newest molecules are “unimolecular multi-agonists”: one peptide chain engineered to activate two or three related receptors. The rationale was set out in rodent work: a 2015 Nature Medicine study reported a monomeric peptide triagonist of the GLP-1, GIP and glucagon receptors that, in rodent models, reduced body weight and improved glycaemic control more than dual co-agonists or monoagonists [20]. The authors attributed the effect to glucagon action increasing energy expenditure, GLP-1 action reducing intake, and GIP action potentiating the incretin effect and buffering the glucose-raising effect of glucagon [20]. That is animal evidence; human results are summarised in the next section.

Class	Receptors	Examples	Status
Single (mono) agonist	GLP-1R	Exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, orforglipron	Approved [3] [14]
Dual agonist (GIP/GLP-1)	GIPR + GLP-1R	Tirzepatide	Approved [3]
Dual agonist (glucagon/GLP-1)	GCGR + GLP-1R	Survodutide, mazdutide	Investigational; mazdutide approved in China [17] [16]
Triple agonist	GIPR + GLP-1R + GCGR	Retatrutide	Investigational, phase 3 [18]
GLP-1 agonist plus amylin analogue (two molecules)	GLP-1R + amylin pathway [19]	Semaglutide with cagrilintide	Investigational, phase 3a [21]

Key studies and findings

The trials below are the pivotal or first published studies for each molecule. Results are percentage change in body weight versus placebo, as reported in each publication. Doses are not given here; where several dose arms were tested, the range across arms is shown.

Molecule	Study	Phase	Participants (n)	Duration	Main reported finding	Ref
Semaglutide	STEP 1	3	1,961 adults with overweight or obesity, without diabetes	68 weeks	Mean change −14.9% vs −2.4% with placebo	[22]
Tirzepatide	SURMOUNT-1	3	2,539 adults with obesity or overweight, without diabetes	72 weeks	−15.0% to −20.9% across three dose arms vs −3.1%	[23]
Retatrutide	Phase 2 obesity trial	2	338 adults	48 weeks	−8.7% to −24.2% across dose groups vs −2.1%	[24]
Survodutide	Phase 2 dose-finding	2	387 enrolled	46 weeks	−6.2% to −14.9% across dose arms vs −2.8% (planned treatment)	[25]
Mazdutide	GLORY-1	3	610 Chinese adults	48 weeks	Week 32: −10.09% and −12.55% vs +0.45%; week 48: −11.00% and −14.01% vs +0.30%	[15]
Cagrilintide with semaglutide	REDEFINE 1	3a	3,417 adults	68 weeks	−20.4% with the combination vs −3.0%	[21]
Orforglipron	Phase 2 obesity trial	2	272 adults	36 weeks	−9.4% to −14.7% across dose cohorts vs −2.3%	[13]
Tirzepatide (as LY3298176)	Phase 1 and 1b	1	142 received LY3298176, dulaglutide or placebo	4 weeks (multiple dose)	Dual GIP/GLP-1 activity confirmed; gastrointestinal effects most frequent	[26]

These were not head-to-head comparisons, and populations, durations and estimands differ, so the percentages should not be ranked against each other.

Adverse events reported in trials

Across these studies, gastrointestinal events were the most commonly reported adverse events. In STEP 1, nausea and diarrhoea were most common, and 4.5% of semaglutide recipients versus 0.8% on placebo stopped treatment because of gastrointestinal events [22]. In SURMOUNT-1, adverse events led to discontinuation in 4.3% to 7.1% of tirzepatide arms versus 2.6% on placebo [23]. The retatrutide phase 2 trial reported dose-related gastrointestinal events and dose-dependent increases in heart rate that peaked at 24 weeks [24]. In the survodutide phase 2 trial, gastrointestinal adverse events occurred in 75% of survodutide recipients versus 42% on placebo [25]. In REDEFINE 1, gastrointestinal adverse events affected 79.6% of the combination group versus 39.9% on placebo [21].

US prescribing information for semaglutide, liraglutide and tirzepatide carries a boxed warning that these agents cause thyroid C-cell tumours in rodents, with unknown relevance to humans, and a contraindication in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [2] [11] [12].

Development history

Year	Milestone	Ref
1992	Exendin-4, a 39-residue peptide, isolated from Heloderma suspectum (Gila monster) venom	[5]
2005	Exenatide, developed from exendin-4, becomes the first FDA-approved GLP-1 receptor agonist (AstraZeneca is the current application holder)	[6] [3]
2010	Liraglutide (Novo Nordisk), a fatty acid-acylated GLP-1 analogue	[2] [3]
2014	Albiglutide (GlaxoSmithKline, albumin fusion) and dulaglutide (Eli Lilly, Fc fusion)	[8] [9] [3]
2015	Rodent proof of concept for a GLP-1/GIP/glucagon triagonist	[20]
2016	Lixisenatide (Sanofi)	[10] [3]
2017	Semaglutide (Novo Nordisk) injection; oral tablet in 2019	[11] [6] [3]
2018	LY3298176 (tirzepatide, Eli Lilly) dual GIP/GLP-1 agonist reported from discovery to clinical proof of concept	[26]
2022	Tirzepatide approved as a dual GIP and GLP-1 receptor agonist	[12] [3]
2025	Mazdutide (Innovent Biologics) approved in China	[16]
2026	Orforglipron (Eli Lilly), a non-peptide oral agonist, approved by FDA	[14]

Structural strategies for half-life extension

Each approved peptide uses one or more of a small set of chemical tricks to escape DPP-4 and renal clearance. These are the strategies a peptide chemist would recognise in the sequences.

Strategy	How it works	Examples (from labels)	Labelled elimination half-life
Native hormone (reference)	None	GLP-1(7-37)	1.5 to 2 minutes [2]
Venom-derived sequence	Exendin-4-based sequence that only partially overlaps human GLP-1 [4]	Exenatide	2.4 hours [4]
Longer non-native peptide	44-residue peptide with an amidated C-terminus [10]	Lixisenatide	About 3 hours [10]
Fatty acid acylation	Fatty acid conjugation increases plasma circulation time [6]; liraglutide is stable against DPP-4 and NEP [2]	Liraglutide	About 13 hours [2]
Aib substitution plus fatty diacid	Position 8 modified against DPP-4; Lys26 carries a hydrophilic spacer and C18 fatty diacid; >99% albumin bound	Semaglutide	About 1 week [11]
Two Aib residues plus C20 fatty diacid	Aib at positions 2 and 13; Lys20 linked to a C20 diacid (1,20-eicosanedioic acid); 99% albumin bound	Tirzepatide	About 5 days [12]
Albumin fusion	Two tandem GLP-1 copies genetically fused to human albumin, with DPP-4 resistance	Albiglutide	5 days [8]
Fc fusion	GLP-1 analogue linked to a modified human IgG4 Fc by a peptide linker; made in CHO cells	Dulaglutide	About 5 days [9]
Extended-release depot	Exenatide in poly(D,L-lactide-co-glycolide) microspheres	Exenatide extended-release	Formulation-driven [7]
Oral absorption enhancer	Co-formulation with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC)	Oral semaglutide	Same molecule [6]
Non-peptide small molecule	Small molecule agonist, oral	Orforglipron	n/a [13]

Semaglutide and tirzepatide structure

Semaglutide has the molecular formula C187H291N45O59 and a molecular weight of 4113.58 g/mol; its peptide backbone is produced by yeast fermentation, and its main protraction mechanism is albumin binding through the Lys26 spacer and C18 fatty diacid [11]. Tirzepatide is a 39-amino-acid modified peptide, formula C225H348N48O68 and molecular weight 4813.53 Da, with two non-coded aminoisobutyric acid (Aib) residues, a C-terminal amide and a C20 fatty diacid on Lys20 [12]. Both are covered in more depth in the molecule overviews for semaglutide and tirzepatide.

Exendin-4: a lizard peptide as a template

Exenatide owes its structure to venom. Exendin-4 was isolated from Heloderma suspectum venom in 1992 using an assay for peptides with an N-terminal histidine, and in guinea pig pancreatic acini it raised cAMP from 100 pM, an effect blocked by exendin-(9-39) amide [5]. The exenatide label describes the drug as a 39-amino acid peptide amide whose sequence partially overlaps that of human GLP-1, with a molecular weight of 4186.6 Da [4].

Molecule notes: the incretin multi-agonists

Tirzepatide was developed as LY3298176, a fatty acid-modified peptide with dual GIP and GLP-1 receptor activity. In mice it lowered body weight and food intake more than a selective GLP-1 receptor agonist; in phase 1 and 1b studies (142 participants received LY3298176, dulaglutide or placebo) the most frequent side effects were gastrointestinal and dose-dependent [26].

Retatrutide (LY3437943) is an agonist of the GIP, GLP-1 and glucagon receptors [24]. Its 48-week phase 2 trial in 338 adults with obesity reported a mean weight change of −24.2% in the highest dose group versus −2.1% with placebo [24]. The phase 3 TRIUMPH-1 study (NCT05929066) enrolled 2,335 participants and is listed as completed [18]. Evidence level: phase 2 (peer-reviewed); phase 3 completed (registry record).

Survodutide (BI 456906) is a glucagon receptor and GLP-1 receptor dual agonist [25]. Its phase 2 trial in 43 centres across 12 countries reported dose-dependent weight reduction over 46 weeks [25]. The phase 3 SYNCHRONIZE-1 study (NCT06066515) enrolled 726 participants and is listed as completed [17].

Mazdutide is a GLP-1 and glucagon receptor dual agonist [15]. GLORY-1, a phase 3 trial in 610 Chinese adults, met its week-32 primary end points [15]. China’s regulator approved it for chronic weight management in adults with overweight or obesity, as announced on 27 June 2025 [16]. It is not approved by the FDA or EMA.

Cagrilintide is a stable, lipidated, long-acting analogue of the pancreatic hormone amylin, a hormone whose high propensity to form amyloid fibrils makes drug design challenging [19]. It is not a GLP-1 receptor agonist; it is studied with semaglutide, and in the phase 3a REDEFINE 1 trial the combination produced a mean weight change of −20.4% at 68 weeks versus −3.0% with placebo [21].

Research directions

The literature points to several active directions, each at a different evidence level:

• Oral non-peptide agonists. Orforglipron, described as a nonpeptide GLP-1 receptor agonist, showed weight reduction in a 36-week phase 2 trial [13] and was approved by the FDA as a once-daily tablet in April 2026 [14].
• Unimolecular multi-agonists. Dual and triple agonists build on rodent evidence that balanced activity at several receptors adds to the effect of GLP-1 alone [20]; human evidence ranges from approval (tirzepatide, mazdutide in China) to phase 3 (retatrutide, survodutide) [3] [18] [17] [16].
• Amylin combinations. Cagrilintide was developed as a long-acting amylin analogue for combination with semaglutide [19] [21].
• Biased signalling. Exendin-4 and oxyntomodulin show a bias towards β-arrestin signalling relative to GLP-1, while the engineered peptide exendin P5 favours G protein signalling; in lean mice, exendin P5 improved glucose handling with greater potency than exendin-4, although efficacy was comparable in chronic studies in obese mice (animal and in vitro evidence) [1].
• Effects beyond glucose and weight. A 2019 review describes cardio- and neuroprotective effects of GLP-1, decreased inflammation and apoptosis, and roles in learning, memory and reward behaviour [1]. These remain areas of research rather than established findings for every agent.

GLP-1 peptides in the laboratory

In research settings, GLP-1 receptor agonists are typically characterised by cAMP accumulation assays in cells expressing the receptor (the method used to establish exendin-4 activity [5] and LY3298176 activity [26]), receptor binding, and in vivo glucose tolerance and food intake studies in rodents [26]. Identity and purity are typically confirmed by HPLC and mass spectrometry, and research material is commonly supplied as a lyophilized powder; see lyophilised peptide stability and storage and, for manufacturing routes, SPPS vs LPPS.

How Winhycare Pharma supplies GLP-1 and incretin peptides

Winhycare Pharma supplies semaglutide, tirzepatide, retatrutide, survodutide, mazdutide and cagrilintide as research-use-only material, with purity of ≥99% as stated in our product brochure, and offers custom peptide synthesis. Semaglutide, tirzepatide, retatrutide and cagrilintide are also supplied as API to licensed manufacturers; US-DMF and CTD Module 3 support is available for semaglutide only. See the peptide API hub and the GLP-1 research peptides page. For enquiries, use the peptide API form or the research peptide form.

For laboratory research use only. Not for human or veterinary use.