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 up to 22.0% weight loss at 36 weeks in a Phase 1b/2a trial, rivaling the best injectable GLP-1 drugs on the market.

Novo Nordisk initiated Phase 3 trials for obesity in Q1 2026, with Phase 3 diabetes trials also planned for 2026. Amycretin is also known by its development name zenagamtide.

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 the amylin receptor (also known as the calcitonin receptor), 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.

Weight loss had not plateaued at the end of the 12-week treatment period, suggesting further weight loss would occur with continued treatment. This is a striking result — most GLP-1 drugs take 36-72 weeks to reach their peak effect.

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.

The 22.0% weight loss at the 20 mg dose in 36 weeks puts subcutaneous amycretin in the same territory as tirzepatide (Zepbound) and approaches retatrutide territory — from a fundamentally different mechanism.

Phase 2 — Amycretin in Type 2 Diabetes (November 2025)

A Phase 2 trial enrolled 448 participants with type 2 diabetes inadequately controlled on metformin (with or without an SGLT2 inhibitor). Results at 36 weeks:

These results in people with type 2 diabetes — who typically lose less weight on GLP-1 drugs than people without diabetes — were strong enough for Novo Nordisk to advance both formulations to Phase 3 development.

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

These rates are higher than what is typically reported in late-phase GLP-1 trials, but early-phase studies generally report higher rates due to aggressive dose titration. As the American College of Cardiology noted, these rates were "similarly safe and tolerated as GLP-1 monoagonists" when accounting for trial design differences. Nearly all events were mild to moderate, and no unexpected safety signals were identified.

In the Phase 2 diabetes trial, the safety profile was described as "consistent with other incretin and amylin-based therapies," with a mix of mostly mild to moderate gastrointestinal adverse events.

How Amycretin Compares to Other Weight Loss Drugs

Key context on the weight loss numbers: amycretin's oral data comes from a 12-week Phase 1 study where weight loss was still accelerating. The subcutaneous data comes from a Phase 1b/2a study of up to 36 weeks. Most comparator drugs report results at 68-72 weeks. Amycretin's numbers are likely to increase significantly in longer Phase 3 trials.

Amycretin vs Retatrutide

Amycretin and retatrutide represent two fundamentally different strategies for next-generation weight loss drugs:

• Amycretin combines GLP-1 with amylin — two appetite-suppressing pathways. It is available in both oral and injectable formulations. Its strength is the oral option (a pill that produces GLP-1-level weight loss without injections) and the dual satiety mechanism.
• Retatrutide combines GLP-1 with GIP and glucagon — adding metabolic pathways that increase energy expenditure and clear liver fat. It is injectable only. Its strength is maximum weight loss (28.7% in Phase 3) and metabolic benefits from the glucagon component.

The drugs are not direct competitors — they come from different companies (Novo Nordisk vs Eli Lilly) and may serve different patient populations. Amycretin's oral formulation could become a first-line therapy for people who are needle-averse, while retatrutide's triple agonist approach targets people who need the most aggressive weight loss.

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.

Amycretin is Novo Nordisk's next-generation approach — if Phase 3 results hold up, it could eventually supersede CagriSema by offering similar dual-pathway efficacy in a once-daily pill.

Phase 3 Development and FDA Timeline

• Phase 3 obesity trials: Initiated Q1 2026
• Phase 3 diabetes trials: Planned for 2026
• Phase 3 program name: Not yet publicly confirmed
• Earliest possible FDA approval: 2028-2029 (estimated, based on typical Phase 3 timelines)
• Pricing: Not announced. As an oral formulation, manufacturing costs may be lower than injectable peptides, but pricing strategy will depend on competitive dynamics with orforglipron and existing injectable GLP-1 drugs.

Novo Nordisk's pipeline strategy positions amycretin as its next-generation obesity drug behind CagriSema — offering the potential for oral delivery and single-molecule simplicity.

Frequently Asked Questions

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. Novo Nordisk. "Phase 2 trial with amycretin reports significant weight loss and HbA1c reduction in type 2 diabetes." November 2025. Press Release
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.