It did not meet its primary endpoint of non-inferiority. It still produced 23.0% weight reduction on the efficacy estimand, which is a large effect.

Why are two sets of numbers reported?

Two estimands. The efficacy estimand assumes adherence; the treatment-policy estimand counts everyone regardless. Same participants, different handling of discontinuation.

Was the trial blinded?

No. The registry lists allocation as randomised and masking as none.

Research & Regulatory News

REDEFINE 4: The Head-to-Head Novo Nordisk Lost

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-233 cited sources

REDEFINE 4, registered as NCT06131437, randomised 809 adults to CagriSema or tirzepatide 15 mg over 84 weeks. Its primary objective was to confirm non-inferiority of CagriSema, and that objective was not met — 23.0% against 25.5% on the efficacy estimand.

Key facts

Registration: NCT06131437
Sponsor: Novo Nordisk A/S
Phase: 3
Enrolment: 809
Design: Randomised, masking none (open-label)
Arms: CagriSema 2.4/2.4 mg vs tirzepatide 15 mg
Started: 27 November 2023
Completed: 9 January 2026
Efficacy estimand: 23.0% vs 25.5%
Treatment-policy estimand: 20.2% vs 23.6%
Primary endpoint: Non-inferiority — not met

What the registry says

The ClinicalTrials.gov record states the official title as an efficacy and safety study of cagrilintide 2.4 mg with semaglutide 2.4 mg once weekly compared to tirzepatide 15 mg. Phase 3, 809 participants, randomised, masking none. Started 27 November 2023, primary completion 8 December 2025, completed 9 January 2026. The primary outcome is written as confirming non-inferiority of CagriSema versus tirzepatide on relative change in body weight.

What was reported

On the efficacy estimand — which asks what happens if everyone adheres — CagriSema reached 23.0% and tirzepatide 25.5%. On the treatment-policy estimand, which counts everyone regardless of adherence, the figures were 20.2% and 23.6%. The primary objective of demonstrating non-inferiority was not met.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

What that does and does not mean

It means non-inferiority was not demonstrated. It does not mean inferiority was demonstrated — those are different findings, and coverage describing CagriSema as bested by or falling to its comparator collapses the distinction. It also does not mean CagriSema failed to work: 23.0% is a large weight reduction by any standard the field had before 2022.

The estimand gap is worth reading

Within this one trial, from the same participants, the two estimands differ by 2.8 points for CagriSema and 1.9 for tirzepatide. Nothing about the drugs changes between those numbers — only how discontinuation is handled. A figure quoted without stating which estimand produced it cannot be compared with anything.

The design limitation

Masking none. Participants and investigators knew which drug was being given, and body weight is an outcome behaviour influences. Blinding two injectables with different devices and side-effect profiles is genuinely hard, so this is a practical constraint rather than an oversight — but it weakens the comparison and belongs beside the numbers.

Why running it at all was notable

Head-to-head trials against a strong comparator are risky, and this one produced a public result the sponsor did not want. Novo Nordisk ran it anyway, at a time when prescribers and payers increasingly expect direct evidence rather than cross-trial comparison.

What this has no bearing on

Research material. Tirzepatide is a licensed medicine; CagriSema is filed and unapproved. Both were administered in a registered trial under clinical supervision. Nothing supplied here is related to either, is an alternative to either, or is described by these results.

Extended research context

The Research & Regulatory News deep dive

Deep dive: why 2026 was the year the incretin field split in two

For a decade every meaningful GLP-1 medicine was a peptide, and every one of them was injected. 2026 broke that pattern in both directions at once. In August the MHRA authorised orforglipron, a small molecule with no peptide bonds that works as an ordinary daily tablet. Three months earlier, retatrutide's TRIUMPH-1 reported a 28.3% mean weight reduction — the largest figure yet from a single molecule, and achievable only with a peptide capable of engaging three receptors at once. The field is not converging on one answer; it is separating into a convenience track and a magnitude track, and those tracks have different chemistry.

Deep dive: what a marketing authorisation actually means

An authorisation is granted to a specific product, in a specific formulation, for a specific indication, by a specific regulator. It is not a statement about a compound class and it does not transfer. Orforglipron being licensed in the UK tells you nothing about the legal or regulatory status of any other incretin, and nothing at all about compounds that remain investigational. Authorisation is also separate from funding: a licensed medicine is not automatically available on the NHS, which requires a further NICE appraisal.

Deep dive: reading trial results without being misled

Headline percentages are the least transferable part of a trial. A figure is only meaningful alongside its population, its duration, its comparator and its dropout rate. TRIUMPH-1's 28.3% came from an 80-week study in a relatively uncomplicated obesity population; TRIUMPH-3's 22.6% came from adults with severe obesity and established cardiovascular disease, and the gap between those two numbers is mostly population, not potency. Discontinuation rates deserve the same attention as efficacy: 11.3% of the TRIUMPH-1 12 mg arm stopped due to adverse events against 4.9% on placebo, and that figure is routinely dropped from summaries.

Research applications

▸Tracking regulatory status of investigational incretin compounds
▸Understanding the difference between authorisation, NICE appraisal and NHS availability
▸Comparing peptide and non-peptide receptor agonist pharmacology
▸Interpreting Phase 3 topline releases before peer-reviewed publication
▸Verifying trial identity against ClinicalTrials.gov registrations

Handling checklist

✓Check the compound named in a trial registration matches the compound being discussed
✓Confirm the NCT identifier resolves to the acronym being cited
✓Read topline press releases as preliminary until peer-reviewed publication
✓Separate the trial population from the headline percentage before comparing studies
✓Treat authorisation in one jurisdiction as saying nothing about status in another

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Treating a positive Phase 3 as approval

Fix: Filing begins a review that commonly takes a year or more and can end in a request for more data.

✗ Comparing weight-reduction percentages across different trials

Fix: Population, duration and comparator differ; the numbers are not interchangeable.

✗ Assuming one incretin's approval legitimises another compound

Fix: Authorisations are product-specific and do not transfer between compounds.

✗ Citing a TRIUMPH number without checking the NCT identifier

Fix: Verify against ClinicalTrials.gov — the numbering has been widely misreported.

✗ Reading research material as an alternative to a licensed medicine

Fix: Research material is supplied for laboratory use only and is not a substitute for anything prescribed.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Did CagriSema fail?: It did not meet its primary endpoint of non-inferiority. It still produced 23.0% weight reduction on the efficacy estimand, which is a large effect.
Why are two sets of numbers reported?: Two estimands. The efficacy estimand assumes adherence; the treatment-policy estimand counts everyone regardless. Same participants, different handling of discontinuation.
Was the trial blinded?: No. The registry lists allocation as randomised and masking as none.

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.

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.

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