Amycretin

Amycretin is an investigational peptide developed by Novo Nordisk under the codes NNC0487-0111 and NN9487. It has since been assigned the international nonproprietary name zenagamtide, which is why recent journal articles use that name while trial registries, conference abstracts and most press coverage still say amycretin. Both names refer to the same molecule.

What makes it scientifically notable is its design. Amycretin is described as the first unimolecular GLP-1 and amylin receptor agonist: a single chemical entity that activates two distinct appetite-regulating receptor systems. Every other combination approach in this space to date has required either two separate drugs given together or a fixed-dose combination of two molecules in one pen. Amycretin puts both pharmacologies into one peptide chain, with one pharmacokinetic profile and one fixed activity ratio.

It is also being developed in two routes of administration at the same time: a once-weekly subcutaneous injection and a once-daily oral tablet. That dual-track approach is unusual at such an early stage and is one reason the program attracted attention well before it reached late-phase testing.

As of October 2026, the published human evidence consists of two early-phase trials reported in The Lancet in June 2025 (a first-in-human trial of the oral formulation and a phase 1b/2a trial of the subcutaneous formulation), plus two phase 2 dose-finding trials in type 2 diabetes published in The Lancet in 2026. Novo Nordisk has announced phase 3 development in obesity and in type 2 diabetes. There are no phase 3 results, no cardiovascular outcome data and no regulatory approval anywhere.

This guide summarizes what those publications report and, just as importantly, what they do not yet establish. It is written for educational purposes and does not contain or imply any dosing guidance. If you are considering any weight management medication, speak with a qualified healthcare professional. For wider context on this drug class, see our overview of next-generation incretin molecules.

The GLP-1 arm of the molecule reproduces the familiar incretin pharmacology: glucose-dependent stimulation of insulin secretion, suppression of glucagon when glucose is elevated, slowed gastric emptying, and central signaling that reduces appetite and food intake. This is the mechanism shared by semaglutide and the rest of the GLP-1 receptor agonist class.

The amylin arm works through a different route. Amylin is a hormone co-secreted with insulin by pancreatic beta cells, and it signals through receptor complexes built from the calcitonin receptor paired with receptor activity-modifying proteins. Its main site of action for appetite is the area postrema in the hindbrain, where it contributes to meal-ending satiation. Because amylin and GLP-1 act on partly separate circuits, combining them has a plausible additive rationale rather than a merely duplicative one. That rationale is what the two-molecule combination of cagrilintide with semaglutide was built to test.

Structurally, amycretin is reported as a 68-amino-acid peptide of roughly 7,847 Da, in which a GLP-1 agonist moiety and an amylin agonist moiety are joined by a short linker of four glycine residues and one glutamic acid residue. A C18 diacid sidechain attached at position K37 of the GLP-1 portion allows reversible binding to albumin, which extends systemic half-life enough to support once-weekly subcutaneous dosing. An unnatural 2-aminoisobutyric acid residue near the N-terminus protects against degradation by dipeptidyl peptidase-4, and the C-terminus is amidated.

This single-molecule architecture carries a real trade-off that is easy to overlook in headline coverage. One molecule means one shared pharmacokinetic profile and a fixed ratio of GLP-1 to amylin activity. Clinicians cannot titrate the two components independently, so if the two pharmacologies turn out to have different optimal exposures for efficacy versus tolerability, a unimolecular agent cannot be adjusted to separate them. A two-drug combination can.

Delivering a peptide of this size orally is also non-trivial. Peptides are poorly absorbed from the gut, which is why the oral trial used daily milligram doses far higher than the weekly injected doses, and why absorption conditions matter considerably for an oral peptide formulation.

The preclinical characterization of amycretin was published in eBioMedicine in 2025 under the title "The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats." That paper is also the public source for the molecule's structural description, including its size, linker and albumin-binding sidechain.

The animal work reported reductions in body weight and improvements in markers of metabolic dysfunction in mouse and rat models, consistent with activation of both receptor systems. Preclinical studies of this kind are designed to demonstrate target engagement, establish a dose range and support the move into human testing. They are not evidence of clinical benefit in people.

This distinction deserves emphasis because it is routinely blurred in online summaries of early-stage molecules. Rodent models of diet-induced obesity respond more uniformly and more dramatically to appetite-suppressing agents than humans do, and the translation rate from impressive animal weight loss to durable human weight loss is imperfect. Several appetite-targeting mechanisms that performed well in rodents have failed or stalled in human trials.

What the preclinical package does provide is a mechanistic foundation: evidence that a single peptide can engage both receptor families meaningfully, rather than acting as a GLP-1 agonist with a vestigial amylin component. Whether the amylin contribution adds clinically meaningful benefit beyond GLP-1 agonism alone in humans is a question that only a head-to-head trial against a GLP-1 monoagonist can answer, and no such trial of amycretin has been published.

The subcutaneous trial, published in The Lancet in 2025 by Dahl and colleagues, was a randomized, placebo-controlled phase 1b/2a study conducted at a single clinical research centre in San Antonio, Texas, between September 15, 2023 and April 24, 2024. It enrolled 125 participants aged 18 to 55 years with overweight or obesity (BMI 27.0 to 39.9 kg/m²), of whom 101 received amycretin and 24 received placebo.

The design combined several parts: single ascending doses, multiple ascending doses, and a dose-response portion examining different maintenance levels. Single doses up to 1.0 mg and weekly doses escalated up to 60 mg were investigated, with a total treatment duration of up to 36 weeks in the longest parts. The investigators reported that single doses up to 1.0 mg and weekly doses up to 60 mg with dose escalation appeared safe and tolerable.

On body weight, the trial reported a dose-dependent effect, with reductions of up to 23.2% (95% CI 15.6 to 30.8) relative to placebo at the 60 mg weekly dose by week 36. At the ADA 2025 congress and in company communications, the same dataset was described as a 24.3% mean reduction in the 60 mg group versus 1.1% with placebo. Those two numbers are compatible: one is placebo-subtracted, the other reports the observed group means.

Three caveats matter for interpreting these figures. First, the primary endpoint was the number of treatment-emergent adverse events, not weight: this was fundamentally a safety and tolerability study, and the weight findings are supportive rather than confirmatory. Second, the sample is small, the confidence interval around the top-dose effect is wide (roughly 16% to 31%), the study ran at a single site and there was no active comparator. Third, participants were aged 18 to 55 with no diabetes, which excludes the older and more comorbid population that carries most of the clinical burden of obesity.

The doses described here are the doses studied under trial supervision. They are not recommendations, and no safe or appropriate dose of amycretin exists outside a clinical trial.

The companion publication, also in The Lancet in 2025, reported the first-in-human, double-blind, randomized, placebo-controlled phase 1 trial of oral amycretin in adults with overweight or obesity and no history of diabetes. It enrolled 144 participants at a single US centre and used a multi-part design of single ascending doses followed by multiple ascending doses, ranging from 1 mg per day up to two 50 mg tablets per day, for up to 12 weeks.

After 12 weeks, mean body weight change was reported as -10.4% with 50 mg once daily and -13.1% with two 50 mg tablets daily, versus -1.2% with placebo. Expressed as a placebo-subtracted effect, the highest dose produced a reduction of up to 11.8% (95% CI 9.0 to 14.6). Oral amycretin was described as safe and tolerable across the doses tested, with most treatment-emergent adverse events mild to moderate in severity and dose-dependent in frequency.

A 12-week result cannot be compared directly with a 36-week result, because weight loss on incretin-based agents continues to accumulate for many months before plateauing. The oral and subcutaneous figures in these two papers reflect different exposure durations, different dose ranges and different trial parts, so reading them as a like-for-like comparison of the two routes would be a mistake.

The oral route is nonetheless strategically important. An effective once-daily tablet would avoid injections, cold chain requirements and injection-related barriers to adherence, and could expand access substantially. The counterweight is manufacturing: oral peptide formulations deliver only a small fraction of the administered dose into circulation, so each tablet requires far more active substance than an injection, which has real consequences for supply at population scale. Small-molecule oral agents such as orforglipron avoid that constraint entirely, which is one of the central strategic contrasts in this field.

In November 2025, Novo Nordisk announced headline results from a phase 2 trial of amycretin in people with type 2 diabetes inadequately controlled on metformin with or without an SGLT2 inhibitor. According to the company, the trial involved 448 participants and tested both once-weekly subcutaneous and once-daily oral amycretin against placebo, reporting weight reductions of up to 14.5% with the subcutaneous formulation and up to 10.1% with the oral formulation at 36 weeks, alongside statistically significant reductions in HbA1c.

Peer-reviewed phase 2 data appeared in The Lancet in 2026 as two companion dose-finding trials published under the molecule's new name, zenagamtide. The subcutaneous trial was a 36-week, multicentre, randomized, double-blind, placebo-controlled study run across 83 hospital and clinic sites in 11 countries, enrolling adults aged 18 to 75 with type 2 diabetes and HbA1c between 7.0% and 10.0% on stable metformin with or without an SGLT2 inhibitor.

Dosing in that trial started at 0.2 mg weekly and escalated every four weeks to maintenance doses spanning 0.4 mg to 40 mg. The primary outcome was change in HbA1c from baseline to week 36, and estimated HbA1c change ranged from -0.9% at the lowest maintenance dose (0.4 mg) to -1.7% at 40 mg, with a treatment difference versus placebo of -0.77% at the 0.4 mg dose. A once-daily oral companion trial was published simultaneously.

Two details are worth noting. The maintenance doses studied in type 2 diabetes are considerably lower than the 60 mg weekly dose explored in the obesity study, which reflects both a different therapeutic target and the usual practice of dose-finding against a glycemic endpoint. And these were dose-finding phase 2 trials: they were sized to identify doses for phase 3, not to establish long-term efficacy, cardiovascular safety or comparative benefit against existing options.

People with type 2 diabetes who take insulin or sulfonylureas face a hypoglycemia risk when glucose-lowering agents are added or changed. Any decision in that setting belongs to a treating clinician, not to a guide such as this one.

Across both published early-phase amycretin trials, the most common adverse events were gastrointestinal: nausea, vomiting, diarrhea and decreased appetite. The investigators reported that the majority were mild to moderate in severity, that frequency increased with dose, and that most resolved by the end of the studies. This profile was characterized as consistent with what is seen with GLP-1 receptor agonists and amylin receptor agonists given separately.

Gastrointestinal tolerability in this class depends heavily on titration speed, and early-phase trials use slow, supervised escalation schedules. Tolerability observed under those conditions does not necessarily carry over to faster escalation, to real-world adherence patterns, or to broader populations with more comorbidities and more concomitant medications.

What the published trials cannot yet tell us is substantial. With roughly 270 participants across the two obesity trials and 36 weeks of maximum exposure, these studies are far too small and too short to characterize uncommon events. Risks that have required large datasets to quantify in the incretin class include acute pancreatitis, gallbladder disease, aspiration risk around anesthesia, and severe gastrointestinal events. Rodent thyroid C-cell findings have historically driven labeling for GLP-1 receptor agonists and would need addressing for any new agent in this class. Effects on lean mass, on bone, and on weight regain after discontinuation remain unquantified for amycretin specifically.

Nothing is known about amycretin in pregnancy or breastfeeding, in adolescents, in older adults, in people with significant renal or hepatic impairment, or over multi-year use. Nor are there cardiovascular outcome data, which have become an expected part of the evidence base for chronic obesity therapies.

Medical disclaimer: amycretin is an investigational molecule that has not been approved by the FDA, the EMA or any other regulatory authority for any indication. This section summarizes published adverse event reporting for educational purposes. It is not a safety assessment for any individual and not a substitute for professional medical advice. Consult a qualified healthcare professional about any medical decision.

The honest answer is that no direct comparison is possible, because amycretin has never been tested head-to-head against any of these agents. The table below places the published results side by side purely as a reference, and the differences in trial phase, duration, population and endpoint make any ranking drawn from it unreliable.

The clearest conceptual contrast is with CagriSema, which pursues the same GLP-1 plus amylin hypothesis using two separate molecules co-formulated in a fixed-dose combination. That approach has completed phase 3: in REDEFINE 1, estimated mean body weight change at week 68 was -20.4% with cagrilintide-semaglutide versus -3.0% with placebo, and in REDEFINE 2, in adults with type 2 diabetes, -13.7% versus -3.4%. Amycretin aims at the same biology with a simpler single-entity product, but it is several years behind in evidence. Our cagrilintide guide covers the amylin side of that combination in detail.

The contrast with orforglipron is about chemistry and scale rather than mechanism. Orforglipron is a non-peptide small molecule that activates the GLP-1 receptor only, which makes it straightforward to formulate as a tablet and to manufacture at volume. In its phase 3 obesity trial, mean weight change at week 72 was -11.2% at the 36 mg dose, with adverse events leading to discontinuation in 5.3% to 10.3% of orforglipron groups versus 2.7% on placebo. Oral amycretin targets the same convenience advantage but through a dual-mechanism peptide, with the manufacturing constraints that implies.

Against semaglutide, the single-mechanism benchmark, early amycretin numbers look numerically larger, but comparing a 36-week early-phase result in 125 highly selected participants with a 68-week phase 3 result in thousands is not a valid comparison. Early-phase effect sizes in small, closely supervised cohorts frequently shrink in larger and longer trials.

Novo Nordisk announced that it would advance both the subcutaneous and the oral formulations of amycretin into phase 3 development for adults with overweight or obesity, with the program planned to begin in the first quarter of 2026, and that a phase 3 program in type 2 diabetes would follow in 2026 on the basis of the phase 2 results. Those are company statements about intent and timing, and such timelines routinely shift.

Phase 3 is where the questions that matter clinically get answered. A late-phase program will need to show whether the weight loss seen over 36 weeks holds up over 68 weeks or longer, how many participants tolerate the regimen well enough to stay on it, how the molecule performs against an active comparator rather than placebo, what happens to body composition, what happens after discontinuation, and whether the safety profile remains clean in thousands of participants rather than hundreds. Until that evidence exists, amycretin is a promising candidate rather than an established option.

On availability, the position is unambiguous. Amycretin is not approved by any regulator, is not available by prescription, and exists legitimately only within sponsored clinical trials. The only lawful way to receive it is to enrol in a registered trial, which is a conversation to have with a physician.

Material advertised online as amycretin or zenagamtide by research chemical vendors is not the clinical product. Compounds sold in this channel carry no verified identity, purity, potency, endotoxin or sterility assurance, and independent testing across the research peptide market has repeatedly found mislabeled and underdosed or overdosed vials. These products are labeled for laboratory research use only, they are not manufactured to pharmaceutical standards, and their legal status varies by jurisdiction. Klow Peptide does not provide sourcing information, dosing protocols or administration guidance for unapproved molecules, and self-administration of an unapproved peptide carries risks that no published data can quantify.

This article is for educational purposes only. It describes published research and is not medical advice, a recommendation, or an endorsement of any use of amycretin. Research peptides are not approved for human use. If you are considering treatment for overweight, obesity or type 2 diabetes, discuss the approved options available to you with a qualified healthcare professional. For broader background on where this molecule sits among emerging metabolic agents, see our guide to next-generation incretin therapies.