Amycretin vs Cagrilintide (2026): One Molecule vs CagriSema's Two-Drug Approach
Amycretin vs cagrilintide: 24.3% at 36 weeks vs CagriSema's 20.4% at 68 weeks. See how one dual-agonist molecule compares with a two-drug amylin approach.
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Amycretin vs cagrilintide is now one of the main comparisons in amylin research. Both come from Novo Nordisk, and both are built to engage amylin receptors. Cagrilintide is a selective long-acting amylin analogue. Clinically it is studied mostly as one half of CagriSema, a co-administration with semaglutide. Amycretin (zenagamtide, NNC0385-0434) is a single molecule that activates both the GLP-1 receptor and amylin receptors. For researchers, the question is whether one dual-acting peptide can do what two separately dosed molecules do.
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Quick Answer: Cagrilintide is a selective amylin analogue. Phase 3 studies have tested it with semaglutide as CagriSema (20.4% mean weight reduction at 68 weeks in REDEFINE 1). Amycretin builds GLP-1 and amylin receptor agonism into one peptide and is in Phase 3. Its subcutaneous Phase 1b/2a study reported up to 24.3% reduction at 36 weeks.
TL;DR:
- Cagrilintide acts on amylin receptors only, and its main clinical role is as the amylin half of CagriSema.
- Amycretin is a unimolecular GLP-1 and amylin receptor agonist, studied as a weekly injection and a daily oral formulation.
- CagriSema has Phase 3 outcome data and an FDA filing (December 2025). Amycretin's obesity data are still Phase 1–2.
- In the head-to-head REDEFINE 4 trial, CagriSema (23.0%) did not show non-inferiority to tirzepatide (25.5%) at 84 weeks.
- Cross-trial figures differ in duration, population and design, so they cannot be ranked directly.
| Parameter | Amycretin (zenagamtide) | Cagrilintide (CagriSema) |
|---|---|---|
| Developer | Novo Nordisk | Novo Nordisk |
| Molecular design | One peptide, GLP-1R + amylin receptor agonist | Amylin analogue, co-administered with semaglutide |
| Trial phase (obesity) | Phase 3 (initiated 2026) | Phase 3 complete; NDA filed Dec 2025 |
| Key weight figure | Up to 24.3% at 36 weeks (SC, Phase 1b/2a) | 20.4% at 68 weeks (REDEFINE 1); 11.8% cagrilintide alone |
| Dosing interval in trials | Once weekly SC; once daily oral | Once weekly SC |
| Placebo comparator | 1.1% (36 weeks) | 3.0% (68 weeks) |
Amycretin: mechanism and evidence base
Amycretin is a 68-amino-acid peptide that activates the GLP-1 receptor and the amylin receptor complexes. These complexes are built from the calcitonin receptor paired with receptor activity-modifying proteins. GLP-1 receptor signalling is linked in the literature to hypothalamic and brainstem satiety pathways, slower gastric emptying and glucose-dependent insulin secretion. Amylin receptor signalling acts mainly in the area postrema and hindbrain, where it is associated with smaller meals and lower postprandial glucagon. Because both signals come from one molecule, the ratio of GLP-1 to amylin activity is set by the peptide's design rather than by separate doses.
The first-in-human Phase 1 study, published in The Lancet in 2025 (PMID 40550229), tested an oral formulation co-formulated with the absorption enhancer SNAC. Investigators reported a mean bodyweight reduction of about 13.1% at 12 weeks at the highest dose, compared with about 1.1% for placebo. A companion Phase 1b/2a study of the subcutaneous form, published in the same Lancet issue (DOI 10.1016/S0140-6736(25)01185-7), escalated weekly doses up to 60 mg. It reported bodyweight reductions of about 22.0% at 20 mg and 24.3% at 60 mg after 36 weeks, versus 1.1% with placebo. Gastrointestinal adverse events were the most common and matched what is reported for GLP-1 and amylin agonists.
In 2026 two Phase 2 trials in type 2 diabetes appeared in The Lancet under the name zenagamtide. The weekly subcutaneous trial (PMID 42532080; 262 participants) reported HbA1c reductions of 0.9 to 1.7 percentage points at 36 weeks. The daily oral trial (PMID 42532079; 186 participants) reported reductions of 0.9 to 1.4 percentage points, with up to 10.3% weight loss at the 25 mg dose.
Cagrilintide: mechanism and evidence base
Cagrilintide is a lipidated, long-acting amylin analogue that activates the AMY1, AMY2 and AMY3 receptor subtypes. Its structure includes proline substitutions taken from rat amylin, which resist fibril formation, and a C20 fatty-acid side chain that binds albumin. Together these extend its half-life to roughly a week. Unlike amycretin, cagrilintide has no meaningful GLP-1 receptor activity. Its GLP-1 partner is supplied separately as semaglutide.
As monotherapy, the 26-week dose-finding Phase 2 trial (PMID 34798060; Lancet, 2021) randomised 706 adults. The 4.5 mg dose produced a mean weight reduction of 10.8%, compared with 3.0% for placebo and 9.0% for daily liraglutide 3.0 mg. The main evidence base, though, is the combination. In REDEFINE 1 (PMID 40544433; NEJM, 2025), once-weekly cagrilintide 2.4 mg plus semaglutide 2.4 mg produced a mean reduction of 20.4% at 68 weeks, compared with 3.0% for placebo. The cagrilintide-only arm reached 11.8% and the semaglutide-only arm 16.1%. About 60% of CagriSema participants reached at least 20% weight reduction.
The open-label REDEFINE 4 trial (NCT06131437), reported in February 2026, compared CagriSema directly with tirzepatide 15 mg over 84 weeks. CagriSema produced 23.0% versus 25.5% and missed its non-inferiority endpoint.
Side-by-side comparison
| Feature | Amycretin | Cagrilintide |
|---|---|---|
| Receptor targets | GLP-1R + AMY1/2/3 (CTR-based) | AMY1/2/3 (CTR-based) only |
| Number of molecules for dual signalling | One | Two (cagrilintide + semaglutide) |
| Half-life basis | Lipidation, supports weekly SC dosing | C20 fatty-acid albumin binding, about 7 days |
| Routes studied | Subcutaneous and oral (SNAC) | Subcutaneous |
| Largest obesity dataset | Phase 1b/2a, 36 weeks | Phase 3, 68 and 84 weeks |
| Regulatory status | Investigational | Investigational; FDA decision expected Q4 2026 |
| Primary research applications | Unimolecular co-agonism, oral peptide delivery | Amylin pharmacology, combination dose ratios |
Differential research applications
The two compounds answer different research questions. Cagrilintide on its own isolates amylin receptor biology. Investigators who want to separate amylin effects from GLP-1 effects, or to test different ratios of the two signals, can do that with separately dosed molecules. REDEFINE 1's factorial design, with cagrilintide alone, semaglutide alone and the combination, is a clear example. It showed that adding the amylin component raised the reduction from 16.1% to 20.4%.
Amycretin is used to test whether a fixed ratio of both activities in one molecule can match or beat co-administration. It also brings an oral question that cagrilintide does not: whether a larger dual-agonist peptide can be absorbed well enough with SNAC to produce a meaningful effect. The 13.1% figure at 12 weeks for the oral form is the main early data point here.
Direct cross-trial comparison is limited. Amycretin's 24.3% comes from a single-centre study with small dose cohorts over 36 weeks. CagriSema's 20.4% comes from a multinational Phase 3 trial over 68 weeks. Researchers who want to line up the timing and status of these programmes can use the clinical trial tracker. Half-life differences can be explored in the half-life chart. Selective amylin analogues from other developers, such as eloralintide and petrelintide, are a further reference point for receptor-selectivity work.
Regulatory and compounding status
Neither compound is approved by the FDA or EMA as of October 2026. Novo Nordisk submitted a New Drug Application for CagriSema in December 2025, based on REDEFINE 1 and REDEFINE 2, and a decision is expected in the fourth quarter of 2026. The REDEFINE 11 trial, which tests a higher CagriSema dose, is expected to report in the first half of 2027. Amycretin entered Phase 3 obesity development in 2026, and a type 2 diabetes Phase 3 programme is planned.
Neither peptide is on the FDA 503A bulks list. Amycretin is not 503A eligible, and the library lists cagrilintide's 503A status as under review. Both fall under WADA's general prohibition of non-approved substances (S0) for in-competition and out-of-competition testing.
Cited studies
- PMID 40550229: "Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial" (The Lancet, 2025).
- "Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study" (The Lancet, 2025). https://doi.org/10.1016/S0140-6736(25)01185-7
- PMID 42532080: "Efficacy and safety of once-weekly subcutaneous zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in type 2 diabetes: a phase 2 trial" (The Lancet, 2026).
- PMID 42532079: "Efficacy and safety of once-daily oral zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in adults with type 2 diabetes: a phase 2 trial" (The Lancet, 2026).
- PMID 40544433, "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1)" (New England Journal of Medicine, 2025). https://doi.org/10.1056/NEJMoa2502081
- PMID 34798060: "Once-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 trial" (The Lancet, 2021).
Frequently asked questions
Q: Is amycretin the same as CagriSema?
A: No. CagriSema is two separate molecules, cagrilintide and semaglutide, given together. Amycretin is one peptide built to activate both the GLP-1 and amylin receptors. Both are Novo Nordisk programmes but differ in molecular design.
Q: Will amycretin replace CagriSema?
A: No replacement has been announced. CagriSema is under FDA review with a decision expected in late 2026, while amycretin only entered Phase 3 in 2026. The two programmes are continuing in parallel.
Q: Which produced more weight loss in trials, amycretin or cagrilintide?
A: Amycretin's subcutaneous Phase 1b/2a study reported up to 24.3% at 36 weeks. CagriSema reported 20.4% at 68 weeks in Phase 3. The trials differ in size, length and design, so the figures cannot be ranked directly.
Q: Does cagrilintide work without semaglutide?
A: As monotherapy, cagrilintide 4.5 mg produced 10.8% mean weight reduction at 26 weeks in Phase 2 (PMID 34798060), and the cagrilintide-only arm of REDEFINE 1 reached 11.8% at 68 weeks. Larger effects have been reported only with semaglutide added.
Q: Is there an oral version of amycretin or cagrilintide?
A: Amycretin has been studied as a daily oral tablet with the absorption enhancer SNAC, with about 13.1% weight reduction at 12 weeks in Phase 1. No oral cagrilintide formulation has published clinical data.
See also:
- Amycretin vs Semaglutide: how the unimolecular co-agonist compares with GLP-1 monotherapy
- Cagrilintide vs Semaglutide: the two components of CagriSema compared individually
- Eloralintide vs Amycretin: a selective amylin agonist set against the same dual-acting molecule
For laboratory research purposes only. Not for human or animal consumption. Compounds described are not approved by the FDA for human or veterinary use unless explicitly stated.