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What Is Amycretin (Zenagamtide)? Oral and Injectable Trial Data

Part of Weight Loss Drug Profiles: Every GLP-1 and GLP3 Agonist.

What Is Amycretin? Novo Nordisk's Oral GLP-1/Amylin Weight Loss Drug

Amycretin is a first-in-class, unimolecular dual agonist that activates both the GLP-1 receptor and the amylin receptor in a single molecule. Developed by Novo Nordisk, it is being investigated as both a once-daily oral tablet and a once-weekly subcutaneous injection for obesity and type 2 diabetes.
In a Phase 1 trial published in The Lancet, the oral formulation produced 13.1% body weight loss in just 12 weeks — with no sign of plateauing. The subcutaneous formulation achieved 22.0% at 20 mg and 24.3% at 60 mg at 36 weeks in a Phase 1b/2a trial. These small early trials do not establish superiority to an approved medicine.
Amycretin is now called zenagamtide. Novo Nordisk’s August 2026 update confirms the AMAZE Phase 3 program, including AMAZE 8 in people with overweight or obesity and type 2 diabetes. The drug remains investigational.

How Amycretin Works

A Dual GLP-1 and Amylin Receptor Agonist

Amycretin is the first drug designed to combine GLP-1 receptor agonism and amylin receptor agonism into a single peptide molecule. Unlike CagriSema (which co-injects two separate drugs — semaglutide and cagrilintide), amycretin fuses both mechanisms into one molecular structure.

The molecule contains two functional parts connected by a short linker (four glycine residues and one glutamate residue):

  • A GLP-1 receptor agonist moiety — drives the same appetite suppression, insulin secretion, and gastric emptying effects as semaglutide and other GLP-1 drugs
  • An amylin receptor agonist moiety — activates amylin receptors, which consist of a calcitonin receptor paired with a receptor activity-modifying protein, which is involved in satiety signaling, gastric emptying, and glucagon suppression

The peptide is acylated with a C18 diacid-based sidechain that enables reversible albumin binding, giving it a long enough half-life for once-daily oral dosing or once-weekly injection.

Why Add Amylin?

Amylin is a hormone co-secreted with insulin by pancreatic beta cells after meals. It acts on the brain's area postrema and hypothalamus to:

  • Reduce appetite and food intake — through a distinct pathway from GLP-1
  • Slow gastric emptying — complementing GLP-1's similar effect
  • Suppress glucagon secretion — preventing excess liver glucose output after meals
By combining GLP-1 and amylin signaling, amycretin attacks appetite and metabolism through two independent hormonal pathways. In preclinical studies, amycretin reduced total energy intake by 47% and lowered body weight by 18% over 21 days in animal models — while maintaining energy expenditure.

What It Does in the Body

Amycretin simultaneously:

  • Suppresses appetite via both GLP-1 receptors in the hypothalamus and amylin receptors in the area postrema
  • Stimulates insulin secretion in a glucose-dependent manner
  • Slows gastric emptying through complementary GLP-1 and amylin pathways
  • Suppresses glucagon after meals
  • May preserve energy expenditure — preclinical data suggests amylin receptor activation helps maintain metabolic rate during weight loss

Clinical Trial Data

Phase 1 — Oral Amycretin in Obesity (The Lancet, June 2025)

The first-in-human Phase 1 trial tested once-daily oral amycretin in 144 participants with overweight or obesity (BMI 27.0-39.9), randomized to amycretin or placebo for up to 12 weeks.
DoseWeight LossDuration
Oral 50 mg-10.4%12 weeks
Oral 100 mg (2x50 mg)-13.1%12 weeks
Placebo-1.2%12 weeks

Weight continued to decline during the short trial. Longer studies are needed to establish the eventual weight loss and durability; the early trajectory does not guarantee a larger Phase 3 result.

Phase 1b/2a — Subcutaneous Amycretin in Obesity (The Lancet, July 2025)

A Phase 1b/2a trial enrolled 125 participants with overweight or obesity, testing once-weekly subcutaneous amycretin at multiple dose levels over up to 36 weeks.
Dose (SC)Weight LossDuration
1.25 mg weekly-9.7%20 weeks
5 mg weekly-16.2%28 weeks
20 mg weekly-22.0%36 weeks
60 mg weekly-24.3%36 weeks
Placebo-1.1% to +2.3%—

The dose cohorts differed in size and treatment duration. These early results cannot rank amycretin against tirzepatide or retatrutide tested in separate trials.

Phase 2 — Amycretin in Type 2 Diabetes (The Lancet, August 2026)

The peer-reviewed Phase 2 reports now describe the weekly injection and daily tablet separately. Participants had type 2 diabetes treated with metformin, with or without an SGLT2 inhibitor. The primary outcome was change in HbA1c at 36 weeks, rather than weight loss.
FormulationRandomized participantsHbA1c change at 36 weeks
Weekly injection262, including 37 on placebo−1.7 percentage points at 40 mg
Daily tablet186, including 30 on placebo−1.4 percentage points at 50 mg

These are changes from baseline at the highest studied doses, using the efficacy analysis based on treatment taken without rescue medication. The corresponding differences versus placebo were −1.56 percentage points for the injection and −1.09 for the tablet. They are blood-glucose results, not percentages of body weight lost, and do not establish a comparison between formulations.

Amycretin Side Effects

The side effect profile is consistent with both GLP-1 and amylin-based therapies. Gastrointestinal events are the most common adverse effects and tend to peak during dose titration.

From the Phase 1b/2a Subcutaneous Trial

The injectable Phase 1b/2a publication reports gastrointestinal events as a key tolerability issue, including nausea, vomiting and diarrhea. Most were mild to moderate. Small dose-escalation cohorts do not establish long-term safety or equivalence to approved GLP-1 medicines.

The oral and injectable formulations have separate trial populations and dosing regimens. Their adverse-event rates should not be treated as interchangeable.

How Amycretin Compares to Other Weight Loss Drugs

Amycretin combines GLP-1 and amylin activity in one peptide and is being developed in oral and injectable forms. Orforglipron is a non-peptide GLP-1 agonist already approved in the US as Foundayo; semaglutide is also available in approved oral and injectable products.

The 12-week oral amycretin trial and small injectable dose cohorts cannot establish better efficacy or tolerability than those approved medicines. Phase 3 studies must answer the longer-term questions.

Amycretin vs Retatrutide

Amycretin targets GLP-1 and amylin; retatrutide targets GLP-1, GIP and glucagon. Both remain investigational.

Amycretin’s oral development may matter to people who prefer tablets, but neither a receptor count nor separate headline weight-loss results identifies the better treatment. Direct evidence and eventual approved labels would be needed for that decision.

Amycretin vs CagriSema

Both amycretin and CagriSema are Novo Nordisk drugs that combine GLP-1 and amylin mechanisms. The difference is architectural:
  • CagriSema is a fixed-dose combination of two separate drugs (semaglutide + cagrilintide) co-injected once weekly. It produced 20.4% weight loss in the REDEFINE 1 trial.
  • Amycretin fuses both mechanisms into a single molecule, enabling oral delivery and potentially better pharmacokinetic properties.

Whether the single-molecule approach offers a clinical advantage over CagriSema remains to be established.

Phase 3 Development and FDA Timeline

Novo Nordisk’s August 2026 update confirms the AMAZE Phase 3 program. It also reports initiation of AMAZE 8, comparing zenagamtide with semaglutide in people with overweight or obesity and type 2 diabetes, and the HF-POLARIS heart-failure outcomes trial.
There is no confirmed FDA approval date or launch price. Trial readout forecasts are sponsor plans, not regulatory decisions.

Frequently Asked Questions

What is amycretin?

Amycretin (also known as zenagamtide) is a first-in-class dual GLP-1 and amylin receptor agonist developed by Novo Nordisk. It is a single molecule that activates both appetite-regulating pathways simultaneously. It is being developed as both a once-daily oral pill and a once-weekly injection for obesity and type 2 diabetes.

How much weight can you lose on amycretin?

Early trials reported 13.1% average loss with the oral formulation at 12 weeks, and 22.0% with 20 mg or 24.3% with 60 mg injected weekly at 36 weeks. These small early cohorts do not predict an individual outcome or guarantee a larger Phase 3 result.

Is amycretin a pill or injection?

Both formulations are in development: a daily oral tablet and a weekly injection. Neither is an approved amycretin product.

How is amycretin different from Ozempic or Wegovy?

Amycretin targets GLP-1 and amylin in one molecule; Ozempic and Wegovy contain semaglutide, which targets GLP-1. Amycretin remains investigational. Wegovy already has approved oral and injectable formulations.

When will amycretin be FDA approved?

There is no confirmed approval date. Novo Nordisk’s AMAZE Phase 3 program is underway; trial completion, filing and FDA review are separate steps.

What are amycretin's side effects?

The most common side effects are gastrointestinal: nausea, vomiting, diarrhea, and decreased appetite. In early trials, these were mostly mild to moderate and peaked during dose titration. The side effect profile is consistent with other GLP-1 and amylin-based therapies.

How does amycretin compare to retatrutide?

Amycretin targets GLP-1 and amylin, while retatrutide targets GLP-1, GIP and glucagon. Amycretin has oral and injectable development programs. Separate trials do not establish which drug is better.

What is the difference between amycretin and CagriSema?

Both are Novo Nordisk drugs combining GLP-1 and amylin mechanisms. CagriSema co-injects two separate drugs (semaglutide + cagrilintide). Amycretin fuses both mechanisms into one molecule, enabling oral delivery. Amycretin is the next-generation approach.

Is amycretin better than orforglipron?

That has not been established. Amycretin remains investigational, while orforglipron is FDA approved as Foundayo. Their different mechanisms and results from separate trials do not establish comparative benefit.

Sources

  1. Dahl K, et al. "Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin." The Lancet. 2025. PubMed
  2. Dahl K, et al. "Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study." The Lancet. 2025;406(10499):149-162. The Lancet
  3. Mora P, et al. Phase 2 zenagamtide trials in type 2 diabetes. The Lancet. August 2026. Weekly injection; daily tablet.
  4. Novo Nordisk. "Novo Nordisk advances early-stage obesity medication, amycretin, to phase 3 clinical development." Press Release
  5. Andreasen CR, 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. PMC
This article is for informational purposes only and does not constitute medical advice. Amycretin is an investigational compound that has not been approved by the FDA or any regulatory agency. Always consult a healthcare provider before starting any medication.
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Retatrutide and similar peptides are investigational — not approved by the FDA or any regulator. Semaglutide and tirzepatide are prescription-only medicines, available only through a licensed prescriber.
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