1. Introduction
The incretin field has expanded rapidly from single-receptor agonists to engineered multi-receptor peptides that engage two or three metabolic hormone receptors within one molecule. This review summarises the published, peer-reviewed literature describing how single (GLP-1), dual (GLP-1/GIP) and triple (GLP-1/GIP/glucagon) receptor agonists differ in receptor pharmacology, and what comparative trial literature has reported for each class. Amylin and dual-amylin co-agonism, an adjacent but mechanistically distinct strategy, is also discussed for context. The aim is comparative and thematic: rather than re-describing any single compound in isolation, the literature is read across compounds to clarify how receptor coverage maps to the metabolic signals reported in trial datasets. All statements here are summaries of findings reported by the cited investigators in academic journals.
2. The Incretin System: GLP-1, GIP and Glucagon Receptors
The incretin effect describes the observation, long established in the physiology literature, that orally delivered glucose elicits a greater insulin response than an equivalent intravenous load, an effect attributed largely to the gut-derived hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The comprehensive review by (Müller et al., 2019) catalogues GLP-1 biology in detail, describing its secretion from intestinal L-cells, its glucose-dependent insulinotropic action, and its reported central effects on satiety signalling. GIP, secreted from intestinal K-cells, is described in the same literature as the dominant incretin in healthy physiology, acting at its own receptor on islet and adipose tissue. The glucagon receptor (GCGR), by contrast, mediates hepatic glucose output and has been reported in the literature to influence energy expenditure and lipid handling. These three receptors form the pharmacological palette from which single, dual and triple agonists are constructed, and the comparative literature treats each added receptor as a distinct lever on the metabolic phenotype observed in trials.
3. Single Agonists: The GLP-1 Receptor Foundation
Single GLP-1 receptor agonists established the foundation on which later multi-agonists were built. The most extensively studied long-acting example in the comparative literature is semaglutide. The STEP 1 trial reported by (Wilding et al., 2021) remains a frequently cited reference point: in that 68-week study of adults with overweight or obesity, once-weekly semaglutide was associated with a mean reduction in body weight of approximately 14.9% versus 2.4% with placebo, with the investigators reporting that the majority of participants achieved a reduction of at least 5%. The literature frames these outcomes as the consequence of selective GLP-1 receptor agonism alone, and the magnitude reported set a benchmark against which dual and triple agonists were subsequently compared. The mechanistic review of (Müller et al., 2019) attributes the appetite-related findings of single GLP-1 agonists to a combination of central and peripheral signalling, providing the pharmacological rationale that later guided efforts to recruit additional receptors.
4. Dual Agonists: Adding GIP to GLP-1
The dual GLP-1/GIP receptor agonist tirzepatide represents the first widely studied step beyond single-receptor agonism. In the SURPASS-2 trial, (Frías et al., 2021) compared tirzepatide head-to-head with the single agonist semaglutide in adults with type 2 diabetes, reporting greater reductions in glycated haemoglobin and body weight across the tirzepatide dose groups in that 40-week dataset. The SURMOUNT-1 study reported by (Jastreboff et al., 2022) extended the dual-agonist literature to participants with obesity, describing mean body-weight reductions of up to approximately 20.9% over 72 weeks at the highest dose studied. Comparative reading of these two datasets is central to the field: the head-to-head SURPASS-2 design provides one of the clearest published contrasts between a single and a dual agonist, and the literature has interpreted the incremental effect of adding GIP receptor agonism in light of that comparison. The precise contribution of the GIP component remains an area of active discussion in the published mechanistic literature.
5. Triple Agonists: Recruiting the Glucagon Receptor
Triple GLP-1/GIP/glucagon receptor agonism is exemplified by retatrutide (LY3437943). The discovery-to-proof-of-concept account by (Coskun et al., 2022) describes the molecular engineering of a single peptide intended to add glucagon receptor agonism, hypothesised in that work to recruit increased energy expenditure on top of the appetite and insulinotropic signals of the GLP-1/GIP backbone; the authors report balanced GCGR and GLP-1R activity with relatively greater GIPR activity in vitro. The phase 2 trial reported by (Jastreboff et al., 2023) described mean body-weight reductions of approximately 24% at 48 weeks at the highest dose studied in participants with obesity. The comparative literature is careful to note that cross-trial comparison of percentage figures between the triple agonist, the dual agonist of (Jastreboff et al., 2022) and the single agonist of (Wilding et al., 2021) is confounded by differing trial durations, populations and designs, and that only head-to-head studies of the type reported by (Frías et al., 2021) permit direct between-class inference.
6. Amylin and Dual-Amylin Context
Amylin co-agonism is a mechanistically distinct strategy frequently discussed alongside the incretin classes. The long-acting amylin analogue cagrilintide acts at amylin and calcitonin receptors rather than at the incretin receptors, and its dose-finding phase 2 literature reported by (Lau et al., 2021) described dose-dependent reductions in body weight in adults with overweight or obesity. The phase 1b study of (Enebo et al., 2021) examined concomitant administration of cagrilintide with semaglutide and reported acceptable tolerability and pharmacokinetics for the combination, establishing the research basis for the amylin-plus-incretin co-agonism that subsequent literature has explored. This positions amylin agonism as an orthogonal axis to the GLP-1/GIP/glucagon palette: where the incretin multi-agonists recruit additional receptors within one peptide, the amylin literature describes pairing a separate satiety pathway with an incretin backbone.
7. Comparative Receptor Pharmacology
Reading the cited works together, a comparative picture emerges in the published literature. Single GLP-1 agonism, as characterised by (Müller et al., 2019) and exemplified in (Wilding et al., 2021), engages glucose-dependent insulin secretion and appetite-related signalling. Dual GLP-1/GIP agonism adds a second incretin receptor, and the head-to-head dataset of (Frías et al., 2021) is the principal published evidence used to contrast it with the single-agonist class. Triple agonism, as engineered and characterised by (Coskun et al., 2022), layers glucagon receptor activity intended to recruit an energy-expenditure component. A recurring theme in the comparative literature is that receptor selectivity ratios differ markedly between molecules, that these ratios are reported to shape the metabolic phenotype observed in each trial, and that the relative contribution of GIP and glucagon agonism remains the subject of ongoing published debate. Amylin co-agonism, per (Lau et al., 2021) and (Enebo et al., 2021), sits outside this incretin axis entirely.
8. Research Applications
For in-vitro laboratory research, this comparative literature defines a structured set of investigational questions. Receptor-binding and functional assays referenced across these works support characterisation of relative GLP-1, GIP and glucagon receptor potency for a given peptide, allowing laboratory comparison of selectivity profiles of the type reported by (Coskun et al., 2022). Cell-based signalling studies enable investigation of downstream cyclic-AMP and β-arrestin responses across single, dual and triple agonist reference compounds. Analytical and stability work supports verification of peptide identity, purity and structural integrity prior to any in-vitro use. The amylin-context literature of (Enebo et al., 2021) additionally frames co-administration pharmacokinetics as a distinct laboratory question. In every case the research applications described here are confined to controlled in-vitro and analytical settings, consistent with how the cited investigators characterise their reference compounds.
9. Limitations and Research-Use-Only Note
Several limitations constrain the comparative interpretation summarised above. Most of the cited efficacy literature derives from phase 1b and phase 2 datasets of limited duration, with the notable exception of the larger phase 3 programmes; cross-trial comparison of effect sizes between classes is confounded by differences in design, population and endpoint definition, and direct between-class inference is reliable only where head-to-head designs such as (Frías et al., 2021) exist. The relative contributions of individual receptors within multi-agonist molecules remain incompletely resolved in the published mechanistic literature. The findings reported by the cited investigators describe observations made under specific study conditions and should not be generalised beyond them.
This review is a summary of published, peer-reviewed research provided for educational and scientific-reference purposes only. The peptides and compounds discussed are supplied strictly for in-vitro laboratory research use only. Nothing in this document constitutes medical, veterinary or therapeutic guidance, makes any health claim, or describes administration, dosing or treatment of humans or animals. These materials are not medicines, are not for human or animal consumption, and are not for any diagnostic or therapeutic application.