Why do people with diabetes lose less weight on these drugs?

It is a consistent and unexplained-in-detail observation across the whole class. Suggested contributors include improved glycaemia reducing urinary glucose loss, concomitant medications that promote weight gain, and longer metabolic disease duration. It is a real pattern rather than a property of any one drug.

Is a 5% weight reduction endpoint meaningful?

It is the conventional threshold at which metabolic benefits become measurable in trials, which is why it appears as a co-primary endpoint so often. It is a low bar for a modern incretin agent, which is why reductions of 10%, 15% and 20% are also reported.

Why does the registry say 1,200 and the paper 1,206?

The registry records enrolment and the publication records the number randomised. Small differences are routine; the published figure is the one to cite for the trial's results.

Does this trial support use in diabetes?

It supports an application. CagriSema is not licensed for anything in any jurisdiction, and no conclusion about clinical use follows from a trial result on this site.

Research & Regulatory News

Less Weight Loss, and That Is the Expected Result

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-243 cited sources

REDEFINE 2 (NCT05394519) randomised 1,206 adults with type 2 diabetes and a BMI of 27 or more, 3:1 to CagriSema or placebo for 68 weeks. Mean weight change was -13.7% against -3.4%, and 73.5% reached an HbA1c of 6.5% or less.

Key facts

Registration: NCT05394519
Registered acronym: REDEFINE 2
Design: Phase 3a, double-blind, placebo-controlled, 12 countries
Randomisation: 3:1, CagriSema or placebo
Randomised: 1,206 - 904 and 302
Entry criteria: BMI 27 or more, HbA1c 7 to 10%, type 2 diabetes
Weight change: -13.7% vs -3.4% (treatment-policy estimand)
HbA1c 6.5% or less: 73.5% vs 15.9%
Gastrointestinal adverse events: 72.5% vs 34.4%

The trial

A Phase 3a, double-blind, randomised, placebo-controlled trial in 12 countries. Adults with a body-mass index of 27 or more, a glycated haemoglobin of 7 to 10% and type 2 diabetes were assigned 3:1 to once-weekly cagrilintide-semaglutide at 2.4 mg of each, or placebo, with lifestyle intervention, for 68 weeks. 1,206 were randomised - 904 to the combination and 302 to placebo. The two primary endpoints were percent change in body weight and the proportion achieving a weight reduction of at least 5%, with effect estimates calculated using the treatment-policy estimand.

The results, both kinds

Estimated mean change in body weight from baseline to week 68 was -13.7% with the combination and -3.4% with placebo, an estimated difference of -10.4 percentage points with a 95% confidence interval of -11.2 to -9.5. On glycaemia, 73.5% of the combination group reached a glycated haemoglobin of 6.5% or less, against 15.9% on placebo. Gastrointestinal adverse events were reported by 72.5% of the combination group and 34.4% of placebo, most transient and mild or moderate.

Why the weight figure is lower than REDEFINE 1's, and why that is not a disappointment

REDEFINE 1, in adults without diabetes, reported -20.4%. REDEFINE 2, in adults with type 2 diabetes, reported -13.7%. A reader encountering both without context might conclude the drug performed worse in the second trial. It did not - this gap appears with every agent in this class, in every programme, and it is one of the most reproducible findings in the field. People with type 2 diabetes lose consistently less weight on incretin therapy than people without it. The candidate explanations include the effect of improving glycaemic control on urinary glucose loss, differences in background medication, longer duration of metabolic disease and differences in body composition. None is fully established, which is itself worth knowing.

The difference in design between the two trials

REDEFINE 1 has four arms including both monotherapies. REDEFINE 2 has two: combination and placebo. So this trial can establish that CagriSema outperforms placebo in this population, and it cannot say anything about whether the cagrilintide component contributed. That is a normal design for a population-extension trial - the component question is asked once, in the trial designed for it - but it means figures from REDEFINE 2 should never be used to argue about the combination's advantage over semaglutide alone.

The glycaemic figure deserves its own reading

73.5% reaching an HbA1c of 6.5% or less against 15.9% on placebo is a very large difference, and it is a responder proportion rather than a mean change. Responder proportions are easier to grasp and more sensitive to where the threshold sits: a population starting at 7 to 10% has a wide spread, and the same underlying effect would produce a different percentage at a threshold of 7.0% or 6.0%. The threshold used here is a recognised one, and the comparison against placebo within the same trial is what makes the figure meaningful.

Status

REDEFINE 2 is listed as completed with primary completion on 28 January 2025. It is one of the two pivotal trials supporting the CagriSema application to the FDA. CagriSema is not licensed anywhere. Semaglutide is a licensed prescription medicine and research material is not an alternative to it.

Quick reference

	REDEFINE 1	REDEFINE 2
Population	No diabetes	Type 2 diabetes
Randomised	3,417	1,206
Arms	4	2
Weight change	-20.4%	-13.7%
Placebo weight change	-3.0%	-3.4%
Difference	-17.3 points	-10.4 points
GI adverse events	79.6%	72.5%

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

Why do people with diabetes lose less weight on these drugs?: It is a consistent and unexplained-in-detail observation across the whole class. Suggested contributors include improved glycaemia reducing urinary glucose loss, concomitant medications that promote weight gain, and longer metabolic disease duration. It is a real pattern rather than a property of any one drug.
Is a 5% weight reduction endpoint meaningful?: It is the conventional threshold at which metabolic benefits become measurable in trials, which is why it appears as a co-primary endpoint so often. It is a low bar for a modern incretin agent, which is why reductions of 10%, 15% and 20% are also reported.
Why does the registry say 1,200 and the paper 1,206?: The registry records enrolment and the publication records the number randomised. Small differences are routine; the published figure is the one to cite for the trial's results.
Does this trial support use in diabetes?: It supports an application. CagriSema is not licensed for anything in any jurisdiction, and no conclusion about clinical use follows from a trial result on this site.

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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