Amycretin is an investigational weight-loss and diabetes drug from Novo Nordisk. It is a single peptide that activates two hormone systems at once: the GLP-1 receptor (the target of semaglutide) and the amylin receptors (the target of cagrilintide). Its research code is NNC0487-0111, and in 2026 publications it was renamed zenagamtide (Mora et al., Lancet 2026).
Amycretin follows the same idea as CagriSema, Novo Nordisk’s combination of cagrilintide and semaglutide, but puts both activities into one molecule. It is being tested as a once-weekly injection and as a once-daily tablet. The single most important fact: amycretin is not approved anywhere. Published human data come from phase 1 and phase 2 trials lasting up to 36 weeks, and phase 3 trials only began in 2026.
This page summarizes what the published trials and trial registries report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Unimolecular GLP-1 and amylin receptor agonist (also activates the calcitonin receptor) |
| Other names | Zenagamtide; NNC0487-0111 |
| Developer | Novo Nordisk |
| Routes studied | Subcutaneous injection once weekly; oral tablet once daily |
| Doses studied | Injection 0.2–60 mg/week; tablet 1–100 mg/day (phase 1 and 2 trials) |
| Half-life | ≈ 88 h (≈ 3.7 days) after a single 0.3 mg injection in people with normal kidney function |
| Molecule | 68-amino-acid peptide with a fatty-acid side chain; molecular weight ≈ 7,847 Da |
| US status | Investigational; not FDA-approved; phase 3 trials started in 2026 |
| WADA status | Not named on the 2026 List; as an unapproved drug it falls under S0 (non-approved substances), prohibited at all times |
What it is
Structure
Novo Nordisk’s preclinical paper describes amycretin as a 68-amino-acid peptide (formula C₃₄₃H₅₅₀N₉₄O₁₁₆, average molecular weight 7,847 Da) built from three parts (Kuhre et al., EBioMedicine 2025):
- A GLP-1 receptor agonist segment. It carries the unnatural amino acid 2-aminoisobutyric acid near its start, which protects it from DPP-4, the enzyme that normally breaks down GLP-1.
- A short linker of four glycine residues and one glutamic acid residue.
- An amylin receptor agonist segment. This is a 32-amino-acid, calcitonin-based amylin sequence without the disulfide bridge found in amylin itself and in cagrilintide.
A C18 fatty diacid side chain is attached to the GLP-1 segment. It binds reversibly to albumin, the main blood protein, which slows clearance and gives the drug a long half-life. The same albumin-binding approach is used in semaglutide and cagrilintide.
The authors report that simply attaching the cagrilintide or pramlintide sequence to the end of semaglutide did not work: amylin receptor potency fell 20- to 50-fold compared with cagrilintide. Potency was only regained with a disulfide-free, calcitonin-based amylin sequence. The design goal was a single molecule with in-vitro potency matching CagriSema at both receptor types (Kuhre et al., 2025).
Receptor activity
In cell-based assays, amycretin was about as potent as semaglutide at the human GLP-1 receptor. At the amylin and calcitonin receptors it was in the same low-picomolar range as cagrilintide, though significantly less potent than cagrilintide at the AMY2 and AMY3 receptors (Kuhre et al., 2025). EC50 is the concentration that gives half the maximal response; lower means more potent.
| Receptor (human, in cell culture) | Amycretin EC50 | Comparator EC50 |
|---|---|---|
| GLP-1 receptor | 1.1 pM | Semaglutide 1.2 pM |
| Amylin receptor 1 (AMY1) | 1.3 pM | Cagrilintide 0.62 pM |
| Amylin receptor 2 (AMY2) | 13 pM | Cagrilintide 2.0 pM |
| Amylin receptor 3 (AMY3) | 17 pM | Cagrilintide 2.7 pM |
| Calcitonin receptor | 1.9 pM | Cagrilintide 1.1 pM |
| CGRP and adrenomedullin receptors | No meaningful activity (over 100 nM) | — |
How it compares with semaglutide and CagriSema
| Feature | Amycretin | CagriSema | Semaglutide |
|---|---|---|---|
| Molecules | One peptide | Two peptides (cagrilintide 2.4 mg + semaglutide 2.4 mg) | One peptide |
| Receptors targeted | GLP-1, amylin and calcitonin | GLP-1 (semaglutide) plus amylin and calcitonin (cagrilintide) | GLP-1 only |
| Routes in trials | Weekly injection; daily tablet | Weekly injection | Weekly injection; daily tablet |
| Largest weight-loss data | Phase 1b/2a, 125 people, 36 weeks | Phase 3 REDEFINE 1, 3,417 people, 68 weeks | Phase 3 STEP 1, 1,961 people, 68 weeks |
| Status | Investigational (phase 3) | See the cagrilintide page | Approved; see the semaglutide page |
Sources: Dahl et al., Lancet 2025; Garvey et al., NEJM 2025; Wilding et al., NEJM 2021. The cagrilintide and semaglutide pages cover those drugs in detail.
Pharmacokinetics
Human pharmacokinetic data are limited to early-phase studies.
| Study | Design | Key findings |
|---|---|---|
| Kidney impairment study (Oldenburg et al., Diabetes Obes Metab 2026) | Single 0.3 mg injection; 42 adults with normal kidney function or mild to end-stage kidney disease | Half-life 88.1 h with normal function and 94–113 h with impairment; median time to peak ≈ 48 h (36 h in end-stage disease); total exposure 543 h·nmol/L with normal function vs 520–715 h·nmol/L with impairment |
| Oral phase 1 (Gasiorek et al., Lancet 2025) | Single and multiple doses of tablets, 144 adults | Blood levels rose in proportion to dose across all groups |
Key points:
- Half-life of about 4 days. The kidney study authors considered this, and the slightly longer half-life with kidney impairment, appropriate for once-weekly dosing.
- No dose change for kidney disease. The authors concluded that kidney impairment did not have a clinically relevant effect on exposure or safety, so dose adjustment did not appear necessary. Each impairment group had only 7 people.
- Animal half-lives are much shorter. The half-life was 29 h in monkeys, and it was given twice daily in mouse studies because of its short half-life in mice (Kuhre et al., 2025).
How much of an oral dose is absorbed in humans has not been published in the sources reviewed here.
Regulatory status
Amycretin is an investigational drug. It is not approved by the FDA, the EMA or any other regulator, and the ClinicalTrials.gov record for its cardiovascular outcomes trial describes it as “not yet available for prescription by doctors” (NCT07861100).
Novo Nordisk registered a phase 3 program in 2026, called AMAZE for weight management and AMBITION for type 2 diabetes. Examples from ClinicalTrials.gov:
| Trial | Population | Design | Primary endpoint |
|---|---|---|---|
| AMAZE 1 (NCT07339423) | Adults with obesity; target 1,150 people | Four weekly injection doses vs placebo; started February 2026 | Body weight change at 84 weeks |
| AMAZE 8 (NCT07400107) | Overweight or obesity with type 2 diabetes; target 1,000 people | Weekly amycretin vs weekly semaglutide | Body weight change at 84 weeks |
| AMAZE 9 (NCT07720271) | Adults with obesity; target 950 people | Five daily tablet doses vs placebo | Body weight change at 76 weeks |
| AMBIENCE (NCT07861100) | Established atherosclerotic cardiovascular disease with overweight or obesity; target 8,500 people | Weekly injection vs placebo | Time to first major cardiovascular event or heart failure event |
None of these trials had reported results as of October 2026.
What the research shows
Weekly injection in overweight and obesity (phase 1b/2a)
The first injection trial randomized 125 adults aged 18–55 with a BMI of 27.0–39.9 to amycretin (n=101) or placebo (n=24) at a single US research center (Dahl et al., Lancet 2025). Doses were raised step by step from 0.3 mg to a maintenance dose, which was held for the last 12 weeks. Group sizes come from a 2026 network meta-analysis that extracted the trial data (Kamrul-Hasan et al., Endocrinol Diabetes Metab 2026).
| Part | Maintenance dose | Duration | n (amycretin / placebo) | Weight change: amycretin | Weight change: placebo |
|---|---|---|---|---|---|
| B | 60 mg/week | 36 weeks | 17 / 5 | −24.3% | −1.1% |
| C | 20 mg/week | 36 weeks | 34 / 5 | −22.0% | +1.9% |
| D | 5 mg/week | 28 weeks | 16 / 4 | −16.2% | +2.3% |
| E | 1.25 mg/week | 20 weeks | 16 / 4 | −9.7% | +2.0% |
Every dose beat placebo (p under 0.0001 for parts B–D; p = 0.0003 for part E). Reviewers noted that weight had not yet reached a plateau at 36 weeks (Alhazmi and le Roux, Diabetes Obes Metab 2026).
Important limits of this trial:
- Very small groups. Each placebo group had 4–5 people.
- Many dropouts. The authors reported that “a large number of participants withdrew,” often for reasons not related to side effects.
- Short and single-site. It was an early safety study, not a trial designed to prove efficacy.
Daily tablet in overweight and obesity (phase 1)
The first-in-human trial tested oral amycretin in 144 adults at one US site (Gasiorek et al., Lancet 2025). Its longest part gave escalating daily tablets for 12 weeks to three groups of 16 people, with 12 on placebo (Kamrul-Hasan et al., 2026). Mean weight change at 12 weeks was up to −13.1% with the highest dose (two 50 mg tablets daily) vs −1.2% with placebo (Oldenburg et al., 2026; Panou et al., Diabetes Ther 2026). Weight change was an exploratory endpoint in this trial.
Type 2 diabetes (phase 2)
Two parallel 36-week phase 2 trials enrolled adults with type 2 diabetes on metformin, with or without an SGLT2 inhibitor, at 83 sites in 11 countries. The primary outcome was HbA1c, a measure of average blood sugar over about three months.
| Trial | Arms | Baseline HbA1c | HbA1c change on amycretin | Difference vs placebo (95% CI) |
|---|---|---|---|---|
| Weekly injection (Mora et al., Lancet 2026) | 262 people; 0.4, 1.5, 5, 10, 20 or 40 mg/week (about 37 per dose) vs placebo (37) | 7.8% (mean) | −0.9% (0.4 mg) to −1.7% (40 mg) | −0.77 (−1.26 to −0.28) at 0.4 mg; −1.56 (−2.05 to −1.07) at 40 mg |
| Daily tablet (Mora et al., Lancet 2026) | 186 people; 6 mg (54), 25 mg (51) or 50 mg (51) per day vs placebo (30) | 7.9–8.1% | −0.9% (6 mg), −1.3% (25 mg), −1.4% (50 mg) | −0.5 (−1.04 to −0.04) at 6 mg; −1.09 (−1.59 to −0.59) at 50 mg |
All doses of both forms lowered HbA1c more than placebo. These results used the efficacy estimand, which counts data only while people stayed on treatment without rescue medication.
Indirect comparisons
A 2026 network meta-analysis pooled six trials of amylin-based drugs in people without diabetes. High-dose injected amycretin ranked first for weight loss vs placebo (mean difference −23.95%), ahead of high-dose CagriSema (−17.18%) and semaglutide 2.4 mg (−11.45%) (Kamrul-Hasan et al., 2026). The authors rated most of the evidence as low or very low certainty and called the findings preliminary. The comparison set a 36-week, 125-person early-phase trial against 68-week phase 3 trials of thousands of people.
For context, in their own placebo-controlled phase 3 trials over 68 weeks:
- Semaglutide 2.4 mg produced −14.9% vs −2.4% with placebo in STEP 1 (Wilding et al., NEJM 2021).
- CagriSema produced −20.4% vs −3.0% with placebo in REDEFINE 1 (Garvey et al., NEJM 2025).
No trial has yet compared amycretin directly with semaglutide or CagriSema. AMAZE 8, against semaglutide, is registered but has not reported.
Animal studies
In rats with diet-induced obesity, 21 days of amycretin cut energy intake by 47% and lowered body weight by about 18% compared with untreated rats. It also improved insulin sensitivity and reduced fat in the liver (Kuhre et al., 2025). These are animal results and do not show what happens in people.
What is still unknown
- Long-term efficacy and safety. No trial longer than 36 weeks has reported.
- Cardiovascular and other outcomes. The AMBIENCE outcomes trial has an estimated primary completion date in 2030 (NCT07861100).
- Lean mass. Body composition data in humans have not been published in the sources reviewed here.
- What happens after stopping. No published data.
Side effects and risks
Gastrointestinal effects
As with GLP-1 and amylin drugs, nausea, vomiting, diarrhea and constipation are the main side effects:
- Oral phase 1. Across all parts, 89 of 144 participants (62%) had 364 adverse events, all mild or moderate and more frequent at higher doses. Gastrointestinal events made up 49% of events and affected 81% of those who had any event (Gasiorek et al., 2025).
- Injection phase 1b/2a. Gastrointestinal events were the most common and were mostly mild to moderate and resolved by the end of the study (Dahl et al., 2025). A 2026 review listed nausea in 50–82% and vomiting in 25–53% across amycretin groups in the early trials, with events concentrated during dose escalation (Alhazmi and le Roux, 2026).
- Oral phase 2 in type 2 diabetes. Gastrointestinal events occurred in 26% (6 mg), 41% (25 mg) and 47% (50 mg) vs 23% on placebo (Mora et al., 2026).
In the network meta-analysis, the oral form had the highest risk of gastrointestinal events among the drugs compared (relative risk 5.25 vs placebo for the high dose, and 9.00 for nausea). The low-dose injection did not significantly increase gastrointestinal events (Kamrul-Hasan et al., 2026).
Serious adverse events
| Trial | People with serious adverse events: amycretin | Placebo |
|---|---|---|
| Weekly injection, type 2 diabetes (36 weeks) | 18 across six dose groups of about 37 each (1–5 per group, no clear dose pattern); 21 of 261 (8%) overall including placebo | 3 of 37 |
| Daily tablet, type 2 diabetes (36 weeks) | 7 across three dose groups of 51–54 (2, 2 and 3) | 0 of 30 |
No deaths occurred in either phase 2 trial or in the oral phase 1 trial (Mora et al., 2026, injection; Mora et al., 2026, tablet; Gasiorek et al., 2025). These trials were too small and short to detect uncommon harms.
Class risks
Amycretin has no label, so it has no boxed warning or official list of contraindications. The trial authors describe its safety profile as consistent with GLP-1 and amylin drugs. The labeled risks of approved GLP-1 drugs, including the boxed warning on thyroid C-cell tumors seen in rodents, pancreatitis and gallbladder disease, are described on the semaglutide page. Whether each applies to amycretin will only be known from larger, longer trials.
Unregulated products
In October 2026 JAMA reported on a growing black market for two unapproved GLP-1 drugs, retatrutide and zenagamtide (amycretin), sold online (Rubin, JAMA 2026). Because no approved product exists, anything sold outside a clinical trial comes from outside the regulated drug supply. Its identity, purity, dose and sterility have not been checked by any regulator, and it is not the material tested in Novo Nordisk’s trials.
Legal status and use in sport
Amycretin is not named on the WADA Prohibited List. However, the S0 class bans any pharmacological substance not covered elsewhere on the List that has no current approval by any government health authority, explicitly including “drugs under pre-clinical or clinical development” (WADA 2026 Prohibited List). As an unapproved investigational drug, amycretin falls into that class and is prohibited at all times. Its status could change if a regulator approves it.
Key takeaways
- One molecule, two hormone systems. Amycretin (zenagamtide) is a single 68-amino-acid peptide that activates GLP-1 and amylin receptors, the targets that CagriSema reaches with two separate drugs.
- Not an approved drug. It is in phase 3 trials that started in 2026; no regulator has approved it.
- Large early weight losses, small trials. Weekly injections produced 22–24% weight loss at 36 weeks in a 125-person early-phase trial, but groups were tiny and dropout was high.
- Also tested as a tablet. Daily tablets lowered weight by up to 13.1% in 12 weeks and lowered HbA1c by up to 1.4 points in type 2 diabetes.
- Gastrointestinal side effects are common. Nausea and vomiting were frequent, especially during dose escalation and with the oral form.
- Prohibited in sport. As an unapproved drug it falls under WADA’s S0 class.
Sources
- Kuhre RE, Ballarín-González B, Brand CL, et al. The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats. EBioMedicine. 2025;118:105862. PubMed; PMC.
- Gasiorek A, Heydorn A, Gabery S, et al. 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. Lancet. 2025;406(10499):135–148. PubMed.
- Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet. 2025;406(10499):149–162. PubMed.
- Mora P, Aroda VR, Asong M, et al. Efficacy and safety of once-weekly subcutaneous zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial. Lancet. 2026;408(10555):621–635. PubMed.
- Mora P, Aroda VR, Asong M, et al. Efficacy and safety of once-daily oral zenagamtide, a novel unimolecular GLP-1 and amylin receptor agonist, in adults with type 2 diabetes: a multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial. Lancet. 2026;408(10555):607–620. PubMed.
- Oldenburg LIK, Haugaard SP, Karlsson T, et al. Renal Impairment Does Not Affect Pharmacokinetics, Safety or Tolerability of Zenagamtide. Diabetes Obes Metab. 2026;28(10):8946–8954. PubMed; PMC.
- Kamrul-Hasan ABM, Khalil I, Mahajan K, et al. Novel Amylin-Based Therapies for Weight Management in Adults With Overweight or Obesity Without Diabetes: A Network Meta-Analysis. Endocrinol Diabetes Metab. 2026;9(3):e70247. PubMed; PMC.
- Alhazmi A, le Roux CW. Amylin Analogs: The Next Major Class of Weight Loss Therapy: A Review of Experimental Data and Early-Phase Clinical Trials. Diabetes Obes Metab. 2026;28(Suppl 5):42–50. PubMed; PMC.
- Panou T, Gouveri E, Popovic DS, et al. New Amylin-Based Agonists for the Treatment of Obesity and Type 2 Diabetes Mellitus. Diabetes Ther. Published online September 28, 2026. PubMed.
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002. PubMed.
- Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2025;393(7):635–647. PubMed.
- Novo Nordisk. Efficacy and Safety of NNC0487-0111 s.c. Once-weekly in Participants With Obesity (AMAZE 1). ClinicalTrials.gov NCT07339423. ClinicalTrials.gov.
- Novo Nordisk. Efficacy and Safety of NNC0487-0111 s.c. Once-weekly Compared to Semaglutide s.c. Once-weekly in Participants With Overweight or Obesity, and Type 2 Diabetes (AMAZE 8). ClinicalTrials.gov NCT07400107. ClinicalTrials.gov.
- Novo Nordisk. Efficacy and Safety of Once-daily Oral Zenagamtide in Participants With Obesity (AMAZE 9). ClinicalTrials.gov NCT07720271. ClinicalTrials.gov.
- Novo Nordisk. Zenagamtide Use for the Reduction of Risk of Major Adverse Cardiovascular Events in People With Established Atherosclerotic Cardiovascular Disease and Either Overweight or Obesity (AMBIENCE). ClinicalTrials.gov NCT07861100. ClinicalTrials.gov.
- Rubin R. Unapproved GLP-1 Drugs Retatrutide and Zenagamtide Sold Online Are No Bargain. JAMA. Published online October 9, 2026. PubMed.
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA 2026 Prohibited List.