CagriSema: The Amylin Combination
Every other compound in the modern obesity class works by stacking incretin receptors — GLP-1, then GIP, then glucagon. CagriSema does something different: it keeps one incretin and adds amylin, a separate satiety hormone with its own pathway. That makes it the most mechanistically distinct entry in the field, and it is the reason its results deserve reading on their own terms rather than as another row in a ranking.
What is in it
| Component | What it is | Evidence alone |
|---|---|---|
| Cagrilintide | Long-acting amylin analogue, engineered for once-weekly dosing | Phase 2 monotherapy: up to −10.8% over 26 weeks, beating the liraglutide comparator at −9.0% |
| Semaglutide 2.4 mg | GLP-1 receptor agonist | Approved; STEP-1: −14.9% over 68 weeks |
Amylin is co-secreted with insulin and signals satiety through a route independent of the incretin system. That independence is the pharmacological argument for the combination: two different satiety mechanisms rather than a stronger push on one.
The Phase 3 results
REDEFINE 1 — obesity
3,417 participants randomized over 68 weeks, published in the New England Journal of Medicine. On the treatment-policy estimand — the analysis counting every randomized participant — CagriSema produced −20.4% against−3.0% for placebo, a difference of 17.3 percentage points.
The trial design deserves a note: alongside the combination and placebo arms, it included 302 participants on semaglutide alone and 302 on cagrilintide alone. That four-arm structure is unusually informative, because it tests the combination against its own components rather than only against placebo — a question most combination trials leave unanswered.
REDEFINE 2 — type 2 diabetes
1,206 patients with type 2 diabetes, BMI 27 or above, over 68 weeks:−13.7% versus −3.4% on placebo. Glycemic control moved substantially too, with 73.5% reaching an HbA1c of 6.5% or lower against 15.9% on placebo. The smaller weight figure compared with REDEFINE 1 follows the usual pattern — weight loss in type 2 diabetes populations is consistently more modest across this entire drug class.
Where it sits in the class
| Compound | Mechanism | Counting everyone randomized | Status |
|---|---|---|---|
| Retatrutide | GIP + GLP-1 + glucagon | −25.0% at 80 weeks | Phase 3 |
| Tirzepatide | GIP + GLP-1 | −20.9% at 72 weeks | Approved |
| CagriSema | Amylin + GLP-1 | −20.4% at 68 weeks | Phase 3 |
| Semaglutide | GLP-1 | −14.9% at 68 weeks | Approved |
| Survodutide | Glucagon + GLP-1 | −13.0% at 76 weeks | Phase 3 |
CagriSema and tirzepatide look almost identical in this table — 20.4% against 20.9%, over 68 and 72 weeks respectively. That apparent tie is exactly the kind of cross-trial comparison the REDEFINE 4 head-to-head result should override, and it is why a single direct trial outweighs any number of matched-estimand tables. Full class context in theGLP-1 comparison.
Tolerability
The profile is the class profile — gastrointestinal effects concentrated during dose escalation. Because semaglutide is one of the two components, the boxed warning that applies to semaglutide, for thyroid C-cell tumors observed in rodents, is directly relevant to how this combination would be labeled if approved. Amylin analogues bring their own nausea burden, which is part of why titration schedules in the REDEFINE program are gradual.
What is still unknown
- No approval, and no cardiovascular outcome data of its own — semaglutide's outcome evidence belongs to semaglutide as a single agent, not automatically to the combination.
- The full REDEFINE 4 detail, which remains a company announcement without peer review or a disclosed margin.
- Discontinuation data — no published evidence on what happens after stopping. The semaglutide precedent, where the STEP-1 extension documented substantial regain, is the reasonable expectation.
Research on CagriSema
5 records in our research database, classified by evidence type:
- HumanREDEFINE 4 head-to-head results versus tirzepatideNovo Nordisk · Company announcement, 2026
- HumanCoadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1)Garvey WT et al. · New England Journal of Medicine, 2025
- HumanCagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2)Davies MJ et al. · New England Journal of Medicine, 2025
- HumanOnce-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trialLau DCW et al. · The Lancet, 2021
Cagrilintide — research vial — American Peptides
Cagrilintide sold separately for research use. The fixed-dose CagriSema combination studied in the REDEFINE trials does not exist outside them — a research vial of one component is not the trial product. Research use only.
We may earn a commission if you buy through this link (at no extra cost to you). Sold for research purposes only.
Frequently asked questions
What is CagriSema?
CagriSema is a fixed combination of cagrilintide, a long-acting amylin analogue, and semaglutide, a GLP-1 agonist, developed by Novo Nordisk. It is the only compound in the current obesity class that adds a non-incretin mechanism rather than a second incretin receptor. It is in Phase 3 and not approved.
How much weight does CagriSema produce?
In REDEFINE 1, 68 weeks produced −20.4% versus −3.0% on placebo using the treatment-policy estimand — the analysis that counts every randomized participant. In REDEFINE 2, in people with type 2 diabetes, the figure was −13.7% versus −3.4%.
Did CagriSema beat tirzepatide?
No. REDEFINE 4 was a head-to-head trial against tirzepatide, and Novo Nordisk announced in February 2026 that CagriSema did not win it. The non-inferiority margin was not disclosed, and the result has not been peer-reviewed.
What does cagrilintide add to semaglutide?
Amylin signalling, which is a different satiety pathway from the incretin system. As monotherapy in Phase 2, cagrilintide alone produced up to 10.8% weight reduction over 26 weeks. The combination result is larger than either component reported alone.
Can you buy CagriSema?
It is not approved and has no prescription pathway. Research suppliers sell cagrilintide separately and in retatrutide blends; the branded fixed-dose combination as studied in the REDEFINE trials is not something that exists outside the trials.
Sources
- Garvey WT et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). New England Journal of Medicine, 2025;393(7):635–647. PubMed
- Davies MJ et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). New England Journal of Medicine, 2025. PubMed
- Lau DCW et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a dose-finding phase 2 trial. The Lancet, 2021;398(10317):2160–2172. PubMed
- Kruse T et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry, 2021. PubMed
- Novo Nordisk. REDEFINE 4 head-to-head results versus tirzepatide, February 2026. Company announcement · NCT06131437. Not peer-reviewed; non-inferiority margin not disclosed.
- Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1). New England Journal of Medicine, 2021;384(11):989–1002. PubMed
Related guides
- GLP-1 comparison chart: every agonist on one analysis
- Semaglutide: one half of this combination
- Tirzepatide: the drug CagriSema was tested against
- Survodutide: the glucagon dual agonist
- Peptide reconstitution calculator