GLP-1 & Incretin Science
Two Answers to the Same Question
GLP-1 alone was not enough, and two answers emerged for what to add. Tirzepatide adds GIP receptor agonism within one molecule; CagriSema adds an amylin analogue as a second molecule. REDEFINE 4 tested those strategies against each other for the first time.
Key facts
- Tirzepatide's second target
- GIP receptor
- CagriSema's second target
- Amylin receptor
- Tirzepatide format
- One molecule
- CagriSema format
- Two molecules combined
- First direct test
- REDEFINE 4 (NCT06131437)
- Retatrutide's answer
- Glucagon, as a third receptor
Why a second target was needed
GLP-1 receptor agonism alone reached a ceiling. Semaglutide's 13.7% in SURMOUNT-5 was a genuine achievement and clearly not the end of what was possible. Every subsequent programme is an answer to the same question — what to add — and the answers diverged sharply.
The GIP answer
Add the other incretin. GIP and GLP-1 are the two hormones behind the incretin effect, and their receptors are structurally related enough that one engineered peptide can engage both. Tirzepatide does this within a single molecule, which is why it has one pharmacokinetic profile rather than two. The mechanism by which GIP contributes remains genuinely disputed.
Research material referenced
Retatrutide 10mg — third-party HPLC tested
The amylin answer
Add a different satiety pathway entirely. Amylin is co-secreted with insulin and signals satiety through routes distinct from the incretins, including hindbrain structures. Cagrilintide is a long-acting amylin analogue, and CagriSema pairs it with semaglutide as two molecules in one injection — a different pharmacology and a different format at once.
Why REDEFINE 4 could not cleanly separate them
Because the two things vary together. CagriSema differs from tirzepatide in both its second target and its format — amylin versus GIP, and two molecules versus one. A single trial comparing them cannot attribute the difference to either, which is a real limitation of what that comparison could ever establish.
What it did establish
That on this comparison, at these doses, over 84 weeks, CagriSema did not demonstrate non-inferiority to tirzepatide 15 mg — 23.0% against 25.5% on the efficacy estimand. That is one comparison at one dose pair, not a verdict on amylin as a target, and amylin agonists continue in development including within single molecules such as amycretin.
And the third answer
Retatrutide adds glucagon receptor agonism as a third target rather than a second, staying within one molecule. Its direct comparison with tirzepatide, TRIUMPH-5, completes in November 2026. All three of these are licensed medicines or investigational compounds in registered trials, and none is related to research material.
Quick reference
| Targets | Molecules | Status | |
|---|---|---|---|
| Semaglutide | GLP-1 | One | Approved |
| Tirzepatide | GLP-1 + GIP | One | Approved |
| CagriSema | GLP-1 + amylin | Two | Filed |
| Retatrutide | GLP-1 + GIP + glucagon | One | Investigational |
Extended research context
The GLP-1 & Incretin Science deep dive
Deep dive: the two routes to a bigger effect
Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.
Deep dive: why a percentage is not a result
The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.
Deep dive: what happens after the trial stops
Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.
Research applications
- ▸Comparing incretin and amylin compounds on a like-for-like basis
- ▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
- ▸Tracking the obesity pipeline across sponsors and jurisdictions
- ▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
- ▸Distinguishing licensed medicines from investigational compounds
Handling checklist
- ✓Identify which estimand a quoted percentage comes from before citing it
- ✓Check the trial population and baseline BMI against the comparison you are making
- ✓Confirm the duration and whether the reduction curve had plateaued
- ✓Read discontinuation rates alongside efficacy figures
- ✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting
Common research-handling mistakes
Learnt from thousands of researcher orders across our UK labs.
✗ Comparing headline percentages across different trials
Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.
✗ Quoting the larger of two figures from the same trial
Fix: Name the estimand. Efficacy and treatment-policy answer different questions.
✗ Treating peak reduction as a durable outcome
Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.
✗ Assuming an oral route means a weaker mechanism
Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.
✗ Reading investigational compounds as available treatments
Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.
Continue researching
Peer-reviewed guides, comparators and matched reference materials.
Related questions researchers ask
- Which weight-loss compound produces the largest reduction?
- What is the difference between CagriSema and amycretin?
- What is an amylin receptor agonist?
- How much weight is regained after stopping a GLP-1?
- Why does CagriSema report two different percentages?
- Why is orforglipron less effective than retatrutide?
Frequently asked questions
- What is amylin?
- A hormone co-secreted with insulin that signals satiety through pathways distinct from the incretins, including hindbrain structures.
- Did REDEFINE 4 show GIP beats amylin?
- No. CagriSema differs from tirzepatide in both target and format, so one trial cannot attribute the difference to either.
- Is amylin finished as a target?
- No. Development continues, including single-molecule GLP-1/amylin agonists such as amycretin.
Primary sources & clinical trials
Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.
- TrialClinicalTrials.gov · CagriSema compared to tirzepatide (NCT06131437)clinicaltrials.gov
- PubMedDahl K et al., Amycretin, unimolecular GLP-1 and amylin receptor agonist — Lancet 2025 (PMID 40550231)pubmed.ncbi.nlm.nih.gov
- PubMedThe Paradox and Future of GLP-1/GIP Combination Therapies — Annu Rev Nutr 2026 (PMID 42166683)pubmed.ncbi.nlm.nih.gov
- RefSURMOUNT-5: Tirzepatide as compared with semaglutide — NEJMnejm.org
- TrialClinicalTrials.gov · TRIUMPH-1 (NCT05929066) — Retatrutide pivotal obesity trialclinicaltrials.gov
- TrialClinicalTrials.gov · TRIUMPH-6 (NCT06859268) — Maintenance of weight reductionclinicaltrials.gov
- RefNovo Nordisk · CagriSema REDEFINE 1, published in NEJMprnewswire.com
- RefTrajectory of weight regain after GLP-1 cessation — eClinicalMedicinethelancet.com
- PubMedOrforglipron: A Comprehensive Review — Int J Mol Sci 2026 (PMID 41683830)pubmed.ncbi.nlm.nih.gov
- EMAICH E9(R1) — estimands in clinical trials (EMA)ema.europa.eu
- GuidelineGoogle — Creating helpful, reliable, people-first contentdevelopers.google.com
Written and reviewed by
Jack Muncaster · Founder, UK Peptides
Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.
More GLP-1 & Incretin Science articles
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- The Attribution Problem Running Through Every IndicationHeart, kidney and liver benefits all appear alongside substantial weight reduction. Separating the two is harder than it looks, and mostly has not been done.
- Why Biopsy Endpoints Make Liver Trials HardMASH trials score liver biopsies for inflammation and fibrosis. A pathologist's judgement is a noisier endpoint than a number from a machine.
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