B tier · viable
CagriSema has a large positive placebo-controlled phase 3 trial and an NDA under FDA review, but it failed its primary non-inferiority endpoint against tirzepatide in the head-to-head REDEFINE 4 trial, which caps its evidentiary standing below the approved dual agonists.
cagrisema
CagriSema is an investigational once-weekly fixed-dose combination of the long-acting amylin analogue cagrilintide and semaglutide, which produced 22.7% mean weight reduction over 68 weeks in the placebo-controlled REDEFINE 1 trial. In the open-label head-to-head REDEFINE 4 trial it did not meet its primary endpoint of non-inferiority to tirzepatide, and it remains under FDA review following a December 2025 filing.
the explanation
CagriSema combines semaglutide with a second drug that mimics amylin, another hormone that signals fullness, and together they produced about 23 percent weight loss. However, when tested directly against tirzepatide, it lost, and it has not yet been approved.
regulatory status
Under FDA review — not approved (as of July 2026)
Novo Nordisk submitted an NDA for weight management on 18 December 2025; the FDA review was expected to conclude during 2026 and no approval had been granted as of July 2026.
how it works · proposed mechanism
CagriSema combines two hormone-mimicking agents that suppress appetite through separate receptor systems.
Amylin signals satiation
Cagrilintide activates amylin and calcitonin receptor complexes in the area postrema, a brainstem region that mediates meal termination. This pathway is distinct from GLP-1 signalling, providing the rationale for combination.
GLP-1 reduces hunger
The semaglutide component supplies the established GLP-1 receptor agonist effects on appetite, gastric emptying and glucose-dependent insulin secretion. Both components are lipidated for once-weekly dosing.
Additive, not synergistic
REDEFINE 1 showed CagriSema outperformed both semaglutide alone and cagrilintide alone. However, the combined effect did not exceed dual incretin agonism when tested head-to-head.
Favourable discontinuation profile
REDEFINE 1 reported adverse-event discontinuation of 6.0% for CagriSema versus 3.7% for placebo, lower than several comparable agents. Nausea affected 55% of recipients but was mostly mild to moderate and transient.
what’s reported
evidence shape
5 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
REDEFINE 4 was the decisive test and CagriSema failed it: it did not meet non-inferiority to tirzepatide 15 mg after 84 weeks, trailing by 2.5 percentage points on the efficacy estimand and 3.4 points on the treatment-regimen estimand. That leaves a two-component, higher-complexity product with no demonstrated efficacy advantage over an already-approved single molecule.
key published findings
- REDEFINE 1 (n=3,417, 68 weeks) reported 22.7% mean weight reduction with CagriSema 2.4/2.4 mg versus 2.3% with placebo on the efficacy estimand (20.4% versus 3.0% treatment-policy), published in NEJM in June 2025.
- REDEFINE 1 reported 60.2% of adherent CagriSema participants achieving ≥20% weight loss, 40.4% achieving ≥25%, and 23.1% achieving ≥30%.
- REDEFINE 4 (n=809, 84 weeks, open-label) reported 23.0% weight loss with CagriSema versus 25.5% with tirzepatide 15 mg on the efficacy estimand; the primary non-inferiority endpoint was not met.
- REDEFINE 1 reported adverse-event discontinuation of 6.0% for CagriSema versus 3.7% for placebo, with nausea in 55% versus 12.6%.
- REDEFINE 1 reported that 50.7% of CagriSema participants with baseline obesity reached a BMI below 30.
limitations of the evidence
- REDEFINE 4 was open-label, which introduces bias risk in a subjective-adherence weight endpoint, though it favoured neither arm by design.
- Whether higher cagrilintide doses or alternative ratios would close the gap to tirzepatide has not been tested in a registrational trial.
- No cardiovascular outcomes data exist for the combination, and the cardiovascular evidence for semaglutide cannot be assumed to transfer to a fixed-dose combination.
identity
| full name | CagriSema (cagrilintide 2.4 mg / semaglutide 2.4 mg fixed-dose combination) |
| category | Metabolic |
| modality | peptide |
| half-life | ~7 days for both components (once-weekly dosing) |
laboratory handling
| storage | Component peptides supplied as lyophilised reference material are typically stored at −20 °C in desiccated, light-protected vials; reconstituted solutions are generally held at 2–8 °C for short-term laboratory use or aliquoted at −80 °C. |
| solubility | Laboratory stocks of both cagrilintide and semaglutide are commonly reconstituted in bacteriostatic or sterile water; DMSO is used for in vitro assay preparations. |
| co-studied with | CagriSema is itself the archetypal incretin-plus-amylin combination and is the reference case for whether non-incretin satiety pathways add to GLP-1 agonism. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
5 citedNovo Nordisk company announcement · 2026 · official
Lancet · 2021 · peer-reviewed
Journal of Medicinal Chemistry · 2021 · peer-reviewed
NEJM / Novo Nordisk · 2025 · press release
Novo Nordisk · 2025 · press release
Sources marked tertiary or press release are the weakest citations on this page.
others in Metabolic