Amycretin

What is Amycretin?

Amycretin (proposed INN zenagamtide; development codes NN1213 and NN0487 for the SC and oral formulations respectively) is Novo Nordisk's investigational unimolecular dual agonist at the GLP-1 receptor and the amylin receptor — a single peptide engineered to engage both targets in one molecule rather than co-administering two separate drugs. The mechanism stacks two of the most-validated weight-loss biologies in modern obesity pharmacology: the GLP-1 anorectic and insulinotropic axis (semaglutide, tirzepatide) and the amylin receptor / calcitonin receptor axis that drives gastric emptying, postprandial glucagon suppression, and central satiety (cagrilintide, petrelintide). Both formulations are advancing in parallel: an oral once-daily version and a subcutaneous once-weekly version, the only major next-generation Novo program developing both routes simultaneously. Three Lancet papers published together on July 12, 2025 — a first-in-human Phase 1 trial of the oral formulation (Gasiorek et al.), a Phase 1b/2a randomised controlled trial of the subcutaneous formulation (Dahl et al.), and an accompanying commentary (Khoo and Tan) — established amycretin's clinical profile and triggered substantial industry attention. The SC Phase 1b/2a reported mean weight reductions of 9.7% to 24.3% across dose levels at 20 to 36 weeks, with the 60 mg dose at week 36 producing the headline 24.3% versus 1.1% on placebo (p<0.0001). A Phase 2 obesity program is underway. Amycretin is not approved by any regulator and is the next-generation companion to Novo's existing GLP-1 (semaglutide) and amylin (cagrilintide) franchises.

What Amycretin Is Investigated For

Amycretin is the most-watched investigational obesity peptide in the Novo Nordisk pipeline as of April 2026, and the reason is a remarkable Phase 1b/2a subcutaneous result published in Lancet on July 12, 2025 (Dahl et al.). In 125 participants randomized to amycretin (n=101) or placebo (n=24) across four dose-level cohorts at up to 36 weeks of treatment, the 60 mg arm achieved a 24.3% mean weight reduction versus 1.1% on placebo (p<0.0001) — among the largest weight-loss signals ever reported for any single peptide in obesity, on par with or exceeding the topline numbers from triple-agonist retatrutide and the cagrilintide-plus-semaglutide CagriSema combination. The 20 mg arm achieved 22.0% at week 36; the 5 mg arm 16.2% at week 28; the 1.25 mg arm 9.7% at week 20. The oral Phase 1 trial (Gasiorek et al., Lancet 2025) characterized first-in-human pharmacokinetics and tolerability of the once-daily oral formulation in 144 participants but did not report a primary weight-loss endpoint at the Phase 1 stage. The honest caveats are substantial. These are Phase 1 / 1b/2a results, not Phase 3 — full safety, tolerability, and durability profiles will not be known until the Phase 2 obesity program reports. The published SC trial flagged a high discontinuation rate (some attributed to reasons unrelated to treatment), and gastrointestinal adverse events were the dominant tolerability finding, consistent with the GLP-1 and amylin classes individually. No head-to-head data exist against tirzepatide, retatrutide, or CagriSema. The question for the next 18–24 months is whether the Phase 1/2 weight-loss signal — which is exceptional on paper — survives the larger, longer, more diverse Phase 2 and Phase 3 populations that the obesity drug class typically reveals tolerability ceilings in.

History & Discovery

Amycretin emerged from Novo Nordisk's strategic doubling-down on the amylin axis as the next pillar of obesity pharmacology beyond GLP-1. After cagrilintide established a long-acting amylin analog as a viable injectable obesity drug (Enebo et al. 2021 Lancet first-in-human; the CagriSema combination program with semaglutide following) and Zealand Pharma's petrelintide validated the amylin-monotherapy thesis with strong Phase 2b ZUPREME-1 data (2026), Novo internally pursued a unimolecular dual-receptor approach: a single peptide engineered to engage both the GLP-1 receptor and the amylin receptor in one molecule, eliminating the need for two parallel drugs in a CagriSema-style co-administration regimen. The molecule received the development codes NN1213 (subcutaneous) and NN0487 (oral), and the proposed International Nonproprietary Name (INN) is zenagamtide. The public clinical inflection point came on July 12, 2025, when The Lancet published a remarkable trio of papers on the same day. Gasiorek and colleagues reported the first-in-human Phase 1 trial of the oral formulation in 144 participants, characterising pharmacokinetics, pharmacodynamics, and safety across single, multiple, and titrated doses up to 100 mg daily over 12 weeks. Dahl and colleagues reported a Phase 1b/2a randomised controlled trial of the subcutaneous formulation in 125 participants over up to 36 weeks, with the 60 mg arm producing a striking 24.3% mean weight loss versus 1.1% on placebo (p<0.0001) — among the largest weight-loss signals ever reported for any single peptide in obesity, comparable to or exceeding triple-agonist retatrutide's Phase 2 number and the CagriSema REDEFINE-1 Phase 3 result. Khoo and Tan provided an accompanying Lancet commentary positioning amycretin within the broader GLP-1 and amylin landscape. The simultaneous publication of three papers in a single Lancet issue signaled both the magnitude of the Phase 1b/2a result and Novo's intent to position amycretin as a flagship next-generation asset. As of April 2026, a Phase 2 obesity program is underway in parallel for both the SC and oral formulations, with results expected to refine dose, durability, and tolerability and to set up Phase 3 design. Real-world questions remain. The Phase 1b/2a high discontinuation rate is unusual and the published abstract attributed some of it to reasons unrelated to treatment, but the full safety picture will not be clear until larger and longer trials. The mechanistic case for stacking GLP-1 and amylin in a single molecule is strong on paper, but whether amycretin's headline efficacy survives Phase 3 conditions and head-to-head comparisons against tirzepatide, retatrutide, and CagriSema is the central commercial question for the program. Anyone offering 'amycretin' or 'zenagamtide' through research-chemical channels is not selling an FDA-regulated product; the only legitimate access is enrollment in Novo Nordisk's registered clinical trials.

How It Works

Amycretin is a single peptide that hits two appetite-controlling receptors at once. It activates the GLP-1 receptor — the same target as Ozempic / Wegovy — which suppresses appetite and slows gastric emptying. And it activates the amylin receptor — the same target as cagrilintide and petrelintide — which adds another layer of fullness signaling, slows the stomach further, and dampens postprandial glucagon. Stacking these two well-validated weight-loss biologies in a single molecule is the entire premise: one drug, two mechanisms, with both an injectable weekly version and an oral daily pill in development.

Amycretin is a synthetic unimolecular peptide engineered to engage two distinct G-protein-coupled receptors with a single ligand: the GLP-1 receptor (GLP-1R, encoded by GLP1R) and the amylin receptor — which itself is a heterodimer of the calcitonin receptor (CTR) with one of the receptor activity-modifying proteins (RAMPs), specifically AMY1 (CTR + RAMP1), AMY2 (CTR + RAMP2), and AMY3 (CTR + RAMP3). The amycretin peptide is built on a backbone designed to retain both GLP-1R and amylin-receptor agonism while sharing a single set of pharmacokinetic-extending modifications (lipid side-chain or comparable strategies) that enable once-weekly subcutaneous dosing for the parenteral formulation and oral delivery via a permeation enhancer for the daily pill formulation. Novo Nordisk has not publicly disclosed the full sequence and modification details as of April 2026. Mechanistically, GLP-1R activation suppresses appetite through hypothalamic and brainstem circuits (arcuate POMC neurons, area postrema), enhances glucose-dependent insulin secretion from pancreatic beta cells, suppresses glucagon, and slows gastric emptying. Amylin-receptor activation (predominantly via the area postrema and adjacent hindbrain structures) reinforces satiety through a parallel central pathway, slows gastric emptying further, and suppresses postprandial glucagon. The two pathways converge on overlapping but mechanistically distinct satiety circuits, which is the rationale for combining them: amylin agonism may contribute satiety signal through a non-GLP-1-redundant mechanism, potentially achieving greater efficacy than dose-escalating either receptor alone and potentially smoothing the GI tolerability profile by recruiting different anorectic circuits at submaximal individual-receptor activation. Kuhre and colleagues (EBioMedicine 2025, PMID 40706446) demonstrated in mouse models that amycretin produces dose-dependent body-weight reduction and improvements in glucose homeostasis, confirming the dual-receptor pharmacology in vivo. The first-in-human oral Phase 1 trial (Gasiorek et al., Lancet 2025, PMID 40550229) characterized pharmacokinetics, pharmacodynamics, and safety in 144 participants over single-dose, multiple-dose, and titrated-dose regimens up to 100 mg daily over 12 weeks. The SC Phase 1b/2a trial (Dahl et al., Lancet 2025, PMID 40550231) randomised 125 participants to amycretin or placebo across four dose levels (1.25 mg, 5 mg, 20 mg, 60 mg weekly) over up to 36 weeks, with the 60 mg arm producing the headline 24.3% mean weight loss versus 1.1% on placebo. The accompanying Lancet commentary by Khoo and Tan (PMID 40550232) framed the results in the context of the broader incretin / amylin landscape.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Amycretin:

• 01Phase 2 dose, durability, and tolerability data for both SC and oral formulations — the next 12–18 months of readouts will largely define amycretin's clinical profile.
• 02Head-to-head comparisons against tirzepatide, retatrutide, CagriSema, and petrelintide — none have been run; cross-trial comparison is methodologically weak and should not be over-interpreted.
• 03Long-term durability beyond 36 weeks — Phase 1b/2a data extend to 36 weeks; longer follow-up will determine whether the weight-loss curve plateaus or continues.
• 04Discontinuation-rate explanation — the SC Phase 1b/2a paper flagged a high discontinuation rate, partially attributed to non-treatment reasons. Phase 2 will need to clarify what fraction is genuinely tolerability-driven.
• 05Cardiovascular outcomes — no MACE data exist; a dedicated cardiovascular outcomes trial would normally be required for regulatory approval.
• 06MASH and hepatic outcomes — no dedicated liver-fat or histologic trials yet; the dual GLP-1 / amylin mechanism does not have the glucagon-receptor activation that has driven the strongest MASH signals (survodutide, retatrutide).
• 07Type 2 diabetes — theoretical mechanism applies, but no dedicated T2D Phase 2 published as of April 2026.
• 08Comparative efficacy of oral vs subcutaneous formulations — both are being developed in parallel; whether the oral version achieves comparable weight loss to the SC version at clinically usable doses is open.
• 09Pediatric efficacy and safety — not studied.
• 10Post-discontinuation weight regain — not yet characterised.

Forms & Administration

Two parallel formulations are in development: a once-weekly subcutaneous injection (NN1213) and a once-daily oral tablet (NN0487). The Phase 1b/2a SC trial used 1.25 mg, 5 mg, 20 mg, and 60 mg weekly doses over 20 to 36 weeks of treatment. The Phase 1 oral trial tested 1–25 mg single doses and up to 100 mg daily in titrated regimens over 12 weeks. Both formulations are administered by trained study personnel or, for the oral formulation, by participants under study supervision; neither is available outside Novo Nordisk's clinical trial program. There is no FDA-approved or commercially available form of amycretin. All injectable and oral peptides should only be administered under qualified clinical supervision; do not self-administer research-chemical material.

Common Questions

Who Amycretin Is NOT For

Drug & Supplement Interactions

No FDA-labeled drug interaction profile exists because amycretin is not approved. The interaction framework is extrapolated from the GLP-1 and amylin classes. The most clinically relevant domains are hypoglycemia risk when combined with insulin or sulfonylureas (downward titration of the concomitant agent will likely be required if amycretin reaches market), altered oral drug absorption secondary to delayed gastric emptying — particularly relevant for narrow-therapeutic-index agents including warfarin, levothyroxine, oral contraceptives, and oral antiepileptics — and the combined effect of dual GLP-1 and amylin agonism on postprandial glucagon, which may behave differently from either single-receptor class. The oral amycretin formulation may also have its own absorption-related interactions depending on the permeation-enhancer technology used (analogous to oral semaglutide's interaction with concomitant oral medications). Specific guidance will follow Novo Nordisk's Phase 3 program and prescribing information when and if regulatory approval is obtained.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions