Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid hormone released from intestinal L-cells after a meal. It is one of the two incretins, gut hormones that increase insulin release in response to nutrients, the other being glucose-dependent insulinotropic polypeptide (GIP). Native GLP-1 survives only a couple of minutes in circulation before the enzyme DPP-4 cleaves it, which is why the research and therapeutic interest has centred on engineered analogues that last for hours or days.
What the GLP-1 receptor does
The GLP-1 receptor is a class B G-protein-coupled receptor expressed on pancreatic beta cells, in the gut, in the brainstem and hypothalamus, and in the heart and kidney. Activation on beta cells raises cyclic AMP and increases insulin secretion, but only when glucose is elevated, a glucose-dependence that distinguishes the incretin pathway from older secretagogues. Receptors in the brain and gut are linked in the literature to reduced appetite and slower gastric emptying, which is where most of the metabolic research of the last decade has focused.
Semaglutide: a single-receptor agonist
Semaglutide is a GLP-1 analogue with three changes to the native sequence: two substitutions that protect it from DPP-4, and a C18 fatty-diacid side chain that binds albumin and extends its half-life to about a week. The STEP 1 trial (Wilding et al., 2021) randomised 1,961 adults with overweight or obesity to weekly semaglutide 2.4 mg or placebo alongside lifestyle intervention and reported a mean body-weight change of −14.9% versus −2.4% at 68 weeks. Earlier SUSTAIN trials established its glycaemic effects in type 2 diabetes. Gastrointestinal adverse events, mainly nausea and diarrhoea, were the most common findings in both programmes.
Tirzepatide: GIP and GLP-1 together
Tirzepatide is a 39-amino-acid peptide engineered to activate both the GIP and GLP-1 receptors, with a similar albumin-binding side chain. The rationale is that GIP receptor signalling appears to add to GLP-1's effects on appetite and glucose handling rather than duplicate them. In SURMOUNT-1 (Jastreboff et al., 2022), 2,539 adults received weekly tirzepatide at 5, 10 or 15 mg or placebo; mean weight change at 72 weeks was −15.0%, −19.5% and −20.9% respectively against −3.1% for placebo. The SURPASS programme reported its effects on glycated haemoglobin in type 2 diabetes.
Retatrutide: adding the glucagon receptor
Retatrutide extends the idea to three receptors: GIP, GLP-1 and glucagon. Glucagon receptor activation raises energy expenditure and hepatic fat oxidation in animal models, which on its own would raise blood glucose; pairing it with the two incretin receptors is intended to offset that. A phase 2 trial (Jastreboff et al., 2023) in 338 adults reported mean weight change of up to −24.2% at 48 weeks at the highest dose studied, with gastrointestinal events again the most frequent. Phase 3 trials are ongoing at the time of writing, so the phase 2 results should be read as preliminary.
Comparing the three in the laboratory
- Receptor profile: semaglutide is GLP-1 only; tirzepatide is GIP/GLP-1 with an imbalance favouring GIP; retatrutide adds glucagon. In vitro potency at each receptor is reported in the respective primary papers.
- Half-life: all three use fatty-acid acylation for albumin binding and are studied on weekly schedules.
- Readouts: cyclic AMP accumulation in receptor-expressing cell lines is the standard functional assay; body weight, HbA1c and gastric emptying dominate the clinical literature.
- Evidence maturity: semaglutide and tirzepatide have approved indications and large phase 3 datasets; retatrutide does not yet.
For laboratory work, the practical differences are stability and handling rather than pharmacology: all three are supplied lyophilised, reconstituted with bacteriostatic water and kept refrigerated. PepChat supplies them for research use only; none of the above describes a use in people.
Key takeaways
- GLP-1 is an incretin hormone; engineered analogues extend its two-minute half-life to days.
- Semaglutide targets GLP-1 alone, tirzepatide adds GIP, and retatrutide adds glucagon; each step has been studied for additional metabolic effect.
- STEP 1, SURMOUNT-1 and the retatrutide phase 2 trial are the landmark weight-change studies; gastrointestinal events were the common finding in all three.
- Retatrutide's evidence is phase 2 only at the time of writing.
