Amycretin

Research Use Only: This page is for research and educational purposes only. It does not provide medical advice, treatment instructions, or guaranteed outcome claims.

What Is Amycretin?

Amycretin is a first-in-class unimolecular peptide co-agonist developed by Novo Nordisk that simultaneously activates both the glucagon-like peptide-1 (GLP-1) receptor and amylin receptor from a single molecule. As an amycretin peptide, it represents a genuinely novel approach to appetite and weight management — combining two proven satiety-related signalling pathways into one compound.

What makes amycretin particularly noteworthy is its oral formulation. While most GLP-1-based therapies — including semaglutide (Wegovy/Ozempic) and tirzepatide (Mounjaro) — require subcutaneous injection, oral amycretin is delivered as a simple tablet. This positions it as a potential breakthrough for individuals who prefer non-injectable treatment options.

Unlike orforglipron, which is also orally available but classified as a small-molecule GLP-1 agonist, amycretin is a true peptide. Its peptide backbone allows it to engage amylin receptors with an affinity that small molecules have struggled to replicate — a structural distinction with meaningful pharmacological implications.

Compound Profile

Mechanism of Action

Amycretin’s dual mechanism centres on the simultaneous activation of two distinct receptor systems involved in appetite regulation, glucose homeostasis, and energy balance.

GLP-1 Receptor Activation

The GLP-1 receptor component functions similarly to established incretin therapies like semaglutide and liraglutide. By activating GLP-1 receptors in the pancreas, gut, and brain, amycretin promotes insulin secretion in a glucose-dependent manner, slows gastric emptying, and reduces appetite through central nervous system signalling.

Amylin Receptor Activation

The amylin receptor component adds a complementary appetite-suppressing pathway. Amylin — a hormone naturally co-secreted with insulin from pancreatic beta cells — acts on the area postrema and other brainstem regions to reduce food intake, slow gastric emptying, and suppress post-meal glucagon release. By incorporating amylin receptor agonism, amycretin accesses satiety circuits that GLP-1 alone does not fully engage.

Preclinical research in rodent models indicates that this unimolecular GLP-1/amylin co-agonist approach produces weight loss and glycaemic improvements that exceed those achieved by either GLP-1 or amylin agonism alone. Kuhre et al. (2025) demonstrated in mice and rats that amycretin produced superior body weight reduction and metabolic improvements compared with semaglutide monotherapy, suggesting a genuinely synergistic interaction between the two receptor pathways rather than merely additive effects.

Clinical Evidence

The clinical programme for amycretin centres on the REDEFINE trials conducted by Amycretin Novo Nordisk‘s development team. To date, Phase 1 and Phase 2 data have been published, with results that have generated considerable interest in the obesity pharmacotherapy field.

Phase 1 Trial

The first-in-human Phase 1 trial, published in The Lancet by Gasiorek et al. (2025), was a double-blind, randomised, placebo-controlled study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of amycretin in healthy adults. The trial established that amycretin was generally well tolerated, with a pharmacokinetic profile supporting once-weekly administration. The estimated half-life of approximately 46 hours supports less frequent dosing schedules.

Phase 1b/2a Subcutaneous Trial

A parallel Phase 1b/2a study (Dahl et al., 2025) investigated subcutaneous amycretin in adults with overweight or obesity. Participants receiving the highest subcutaneous doses achieved substantial body weight reductions, confirming that dual GLP-1/amylin receptor engagement translates into meaningful clinical weight loss.

REDEFINE 1 — Phase 2 Oral Trial

The amycretin phase 2 REDEFINE 1 trial represents the most clinically significant dataset to date. This randomised, placebo-controlled study evaluated oral amycretin in adults with obesity or overweight with at least one weight-related comorbidity. Over 36 weeks, participants receiving oral amycretin achieved up to 13.1% body weight loss — a remarkable figure for an oral formulation that requires no injection.

To put the amycretin results in context: oral semaglutide (Rybelsus) in the OASIS 1 trial delivered approximately 15.1% weight loss at 68 weeks at its highest dose, but that required nearly twice the treatment duration. The amycretin weight loss achieved at 36 weeks suggests that longer-term studies could yield even more substantial reductions as dose escalation continues.

Weight Loss Research Context

The amycretin weight loss data from REDEFINE 1 sits within a rapidly evolving landscape of incretin-based obesity therapies. Several key comparisons help contextualise the significance of these findings.

Injectable semaglutide 2.4 mg (Wegovy) produces approximately 15–17% weight loss at 68 weeks. Tirzepatide, a dual GIP/GLP-1 agonist, has demonstrated up to 22.5% weight loss at 72 weeks. CagriSema — Novo Nordisk’s injectable combination of cagrilintide (an amylin analogue) and semaglutide — has shown approximately 22.7% weight loss at 68 weeks in Phase 3 trials.

What distinguishes the amycretin data is the route of administration. Achieving 13.1% weight loss at just 36 weeks via an oral tablet — without any injection — represents a meaningful advance. As clinical development progresses into Phase 3 with longer treatment durations and optimised dose titration, the full weight loss potential of oral amycretin remains to be defined.

Research also suggests that the dual GLP-1/amylin mechanism may offer advantages beyond raw weight loss numbers. The amylin pathway appears to preferentially reduce visceral adipose tissue and may support greater preservation of lean mass during weight loss — findings that, while primarily from preclinical data, could have significant implications for body composition outcomes in the context of fat loss and recomposition.

Metabolic Effects

Beyond weight reduction, amycretin demonstrates promising effects on markers of metabolic health and insulin sensitivity. The dual receptor mechanism positions it to address multiple aspects of metabolic dysfunction simultaneously.

Glycaemic Control

Preclinical studies by Kuhre et al. (2025) demonstrated that amycretin produced superior glycaemic control compared with semaglutide monotherapy in rodent models of metabolic dysfunction. The GLP-1 component enhances glucose-dependent insulin secretion, while the amylin component suppresses inappropriate glucagon release — together providing more comprehensive blood glucose regulation than either mechanism alone.

Insulin Sensitivity

Weight loss itself improves insulin sensitivity, and the degree of weight reduction observed with amycretin in Phase 2 trials would be expected to meaningfully improve insulin resistance. Additionally, the amylin receptor pathway has been associated with direct improvements in hepatic insulin sensitivity in preclinical models, though this remains to be confirmed in dedicated human metabolic studies.

Lipid Metabolism

GLP-1 receptor agonists as a class have demonstrated improvements in lipid profiles, including reductions in triglycerides and increases in HDL cholesterol. Research suggests that dual GLP-1/amylin agonism may amplify these effects, though dedicated cardiovascular outcome and lipid studies for amycretin have not yet been completed.

Oral Bioavailability & Formulation

One of the most significant challenges in peptide therapeutics is achieving adequate oral bioavailability. Peptides are typically degraded by gastrointestinal enzymes and poorly absorbed across the intestinal epithelium — which is why most GLP-1-based therapies require injection.

Novo Nordisk’s existing oral semaglutide formulation (Rybelsus) uses SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) as an absorption enhancer, but this approach has limitations including relatively low bioavailability and strict fasting requirements. The specific oral delivery technology used for oral amycretin has not been fully disclosed, but the Phase 2 data suggest that Novo Nordisk has achieved clinically relevant systemic exposure through oral administration.

The ability to deliver a peptide co-agonist orally — rather than as a small molecule mimic — is pharmacologically significant. Peptide structures can engage receptor binding sites, particularly at the amylin receptor, with greater specificity and affinity than small molecules. This is a key distinction between amycretin and small-molecule oral GLP-1 agonists like orforglipron, which lack amylin receptor activity entirely.

From a practical standpoint, an oral tablet formulation could dramatically improve treatment accessibility and adherence. Research consistently demonstrates that many individuals with obesity prefer oral medications over injectable alternatives, and removing the injection barrier could expand the reach of effective pharmacological weight management considerably.

Safety & Side Effects

Understanding the safety profile is essential context for any investigational compound. The available data on amycretin side effects comes primarily from Phase 1 and Phase 2 clinical trials, which provide useful but limited safety information compared with the larger datasets generated by Phase 3 studies and post-marketing surveillance.

Gastrointestinal Effects

Consistent with the broader GLP-1 receptor agonist class, the most commonly reported amycretin side effects are gastrointestinal in nature. Nausea, vomiting, and diarrhoea were the most frequent adverse events reported in clinical trials. These effects were generally mild to moderate in severity, typically occurred during dose escalation phases, and tended to diminish with continued treatment.

Tolerability Profile

The Phase 1 trial by Gasiorek et al. (2025) reported that amycretin was generally well tolerated across the dose ranges tested. Discontinuation rates due to adverse events appeared comparable to those observed with other incretin-based therapies, though direct head-to-head safety comparisons have not been conducted.

Class-Level Considerations

As a GLP-1 receptor agonist, amycretin carries theoretical risks common to the broader class, including potential effects on gallbladder function, pancreatic enzyme levels, and heart rate. The amylin receptor component introduces additional theoretical considerations, though pramlintide (the only approved amylin analogue) has an established safety profile that provides some reassurance. Long-term safety data from Phase 3 trials will be essential to fully characterise the risk profile of this dual-mechanism compound.

No signal of increased pancreatitis or thyroid C-cell tumours has emerged from clinical trials to date, though these studies were not powered to detect rare events.

Research Limitations

While the amycretin data to date are encouraging, several important limitations warrant consideration.

Limited clinical dataset: The evidence base rests primarily on Phase 1 and Phase 2 trials. These studies involve relatively small participant numbers and short durations compared with the Phase 3 programmes that typically support regulatory approval. The amycretin phase 2 REDEFINE 1 trial lasted 36 weeks — meaningful, but shorter than the 52–72 week durations common in pivotal obesity trials.

No Phase 3 data yet: Phase 3 trials are expected to begin in 2026, but until they report, the full efficacy and safety profile of amycretin remains uncertain. Phase 3 studies will involve larger, more diverse populations and longer treatment periods that may reveal efficacy ceiling effects or safety signals not apparent in earlier trials.

No cardiovascular outcomes data: GLP-1 receptor agonists have demonstrated cardiovascular benefits in dedicated outcomes trials (SUSTAIN-6, SELECT), but no such data exist for amycretin. Whether the added amylin component enhances, diminishes, or has no effect on cardiovascular outcomes remains unknown.

Weight regain after discontinuation: A well-established limitation of incretin-based therapies is weight regain upon treatment cessation. Whether amycretin’s dual mechanism offers any advantage in weight maintenance has not been studied.

Undisclosed molecular details: Novo Nordisk has not fully disclosed amycretin’s molecular structure, absorption enhancement technology, or detailed pharmacokinetic parameters. This limits independent scientific scrutiny of the compound’s properties.

Verdict

Amycretin represents one of the most interesting compounds in the current obesity pharmacotherapy pipeline. As the first oral unimolecular GLP-1/amylin co-agonist, it occupies a unique position — combining dual receptor engagement (previously only achievable through injection) with the convenience of a daily tablet.

The Phase 2 amycretin results — up to 13.1% weight loss at 36 weeks via oral administration — are clinically meaningful and suggest genuine synergy between the GLP-1 and amylin receptor pathways. The preclinical evidence of superiority over semaglutide monotherapy adds mechanistic credibility to the clinical findings.

However, the evidence confidence remains moderate. Until Phase 3 data from the REDEFINE programme confirm these results in larger populations over longer durations, and until safety is characterised more comprehensively, amycretin should be understood as a promising but unproven investigational compound. Amycretin Novo Nordisk‘s development programme is expected to advance into Phase 3 in 2026, which should provide the definitive data needed to assess its place alongside — or potentially ahead of — existing GLP-1-based therapies.

For the broader field, amycretin’s success would validate two important principles: that oral delivery of complex peptides is pharmacologically viable, and that dual GLP-1/amylin agonism from a single molecule can produce clinically superior outcomes to either mechanism alone.

FAQ

What is amycretin?

Amycretin is a first-in-class unimolecular peptide co-agonist developed by Novo Nordisk that simultaneously activates both GLP-1 and amylin receptors. It is being developed as an oral tablet for the treatment of obesity, representing the first oral GLP-1/amylin co-agonist in clinical development.

How does amycretin differ from semaglutide?

While semaglutide acts solely on GLP-1 receptors, amycretin engages both GLP-1 and amylin receptors from a single molecule. Preclinical evidence suggests this dual mechanism produces superior weight loss and glycaemic control compared with GLP-1 agonism alone. Additionally, amycretin is being developed primarily as an oral formulation, whereas semaglutide’s most effective weight-loss formulation (Wegovy) requires injection.

What weight loss has amycretin shown in clinical trials?

In the Phase 2 REDEFINE 1 trial, oral amycretin produced up to 13.1% body weight loss at 36 weeks compared with placebo. This is notable because it was achieved with an oral tablet rather than an injection, and at a relatively early stage of dose optimisation.

Is amycretin a peptide or a small molecule?

Amycretin is a genuine peptide — a modified peptide sequence engineered for oral bioavailability and dual receptor activity. This distinguishes it from small-molecule oral GLP-1 agonists like orforglipron, which cannot engage amylin receptors due to their non-peptide structure.

What are the main amycretin side effects?

The most commonly reported amycretin side effects in clinical trials were gastrointestinal — primarily nausea, vomiting, and diarrhoea. These are consistent with the broader GLP-1 agonist class and were generally mild to moderate, often resolving during continued treatment. Long-term safety data from Phase 3 trials are still awaited.

When will amycretin be available?

Amycretin is currently an investigational compound. Phase 3 clinical trials are expected to commence in 2026. If successful, regulatory submissions and potential approval would follow — likely placing any market availability several years away. It is not currently approved for any indication.

How does amycretin compare with CagriSema?

CagriSema combines two separate injectable peptides — cagrilintide (amylin analogue) and semaglutide (GLP-1 agonist) — in a single injection. Amycretin achieves dual GLP-1/amylin activity from a single molecule delivered orally. While CagriSema has shown greater absolute weight loss in Phase 3 (approximately 22.7%), amycretin’s oral convenience and single-molecule design represent a different value proposition.

What is the REDEFINE clinical programme?

REDEFINE is Novo Nordisk’s clinical trial programme for amycretin. REDEFINE 1 was the Phase 2 study evaluating oral amycretin for weight loss in adults with obesity or overweight. The programme is expected to expand into Phase 3 trials to further evaluate efficacy, safety, and long-term outcomes.

Can amycretin be taken orally?

Yes — oral delivery is one of amycretin’s key differentiators. The Phase 2 REDEFINE 1 trial specifically evaluated oral amycretin as a daily tablet. Novo Nordisk has also studied a subcutaneous injectable formulation, but the oral route is considered the primary development pathway for weight management.

What is the evidence confidence for amycretin?

Evidence confidence is currently rated as moderate. The Phase 2 data are strong and published in high-impact peer-reviewed journals, but no Phase 3 results are available yet. As larger and longer studies report, the evidence base will strengthen considerably. Researchers should interpret the current data as promising but preliminary.

References

1. Gasiorek A 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
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.” Lancet, 2025; 406(10499):149-162. PubMed
3. Khoo B, Tan TM. “GLP-1 and amylin receptor multiagonism with amycretin for obesity management.” Lancet, 2025; 406(10499):104-106. PubMed
4. Kuhre RE 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
5. Fu L et al. “Amycretin in obesity: Mechanisms, clinical efficacy, and future perspectives.” Metabolism, 2026; 179:156594. PubMed
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9. Rejili M et al. “Amylin receptors as therapeutic targets in obesity: Emerging peptide-based strategies.” Vascular Pharmacology, 2026; 162:107563. PubMed
10. Nauck MA et al. “Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits.” Lancet, 2026; 407(10531):892-908. PubMed