What Is Zenagamtide? The GLP-1 and Amylin Peptide Moving Into Phase 3

Zenagamtide is one of the more unusual next-generation obesity peptides now entering late-stage clinical development.

Previously known as amycretin, zenagamtide is a single peptide molecule designed to activate both GLP-1 and amylin-related receptors.

That gives it a different strategy from drugs such as semaglutide, which primarily target GLP-1, or tirzepatide, which targets GIP and GLP-1.

Rather than combining two separate medicines, zenagamtide attempts to bring GLP-1 and amylin biology together within one molecule.

As of October 2026, both injectable and oral versions are in the Phase 3 development pipeline. (Novo Nordisk⁠)

What Is Zenagamtide?

Zenagamtide is an investigational long-acting peptide developed by Novo Nordisk.

It was previously known as amycretin.

The molecule has been designed as a unimolecular GLP-1 and amylin receptor agonist.

“Unimolecular” simply means the different biological activities are incorporated into one molecule rather than administering two separate drugs.

Zenagamtide is being developed in:

• once-weekly subcutaneous form
• oral form

This gives the programme considerable flexibility compared with injectable-only treatments. (Novo Nordisk Annual Report⁠)

What Is GLP-1?

GLP-1 is a naturally occurring hormone released after food is consumed.

It contributes to:

• appetite regulation
• satiety
• insulin secretion
• glucose control
• gastric emptying

GLP-1 receptor agonism has already become one of the most successful approaches in modern obesity and diabetes treatment.

What Is Amylin?

Amylin is another naturally occurring hormone involved in meal-related signalling.

It is released alongside insulin from pancreatic beta cells.

Amylin can influence:

• fullness after eating
• food intake
• gastric emptying
• post-meal glucose regulation

This makes the amylin pathway an increasingly important target in obesity research.

Why Combine GLP-1 and Amylin?

GLP-1 and amylin both influence appetite and metabolic regulation, but they do so through different receptor systems.

Researchers therefore want to know whether activating both pathways simultaneously can produce stronger or more balanced effects than GLP-1 activation alone.

Zenagamtide is designed to test that idea within a single peptide.

The strategy is different from combining two separately manufactured drugs.

Does Zenagamtide Only Activate Two Receptors?

The biology is slightly more complicated.

Published research describes zenagamtide as a unimolecular agonist involving GLP-1, amylin and calcitonin receptor signalling. (ScienceDirect⁠)

This occurs because amylin receptors themselves are formed from receptor complexes involving the calcitonin receptor and receptor-activity-modifying proteins.

For a general audience, it is still reasonable to describe zenagamtide primarily as a GLP-1/amylin agonist, but its receptor pharmacology is more complex than simply targeting two isolated receptors.

What Did Early Injectable Research Show?

Novo Nordisk’s early Phase 1b/2a obesity programme produced substantial weight-loss signals.

In participants with overweight or obesity, estimated average body-weight reductions reported by Novo included approximately:

• 9.7% with 1.25 mg
• 16.2% with 5 mg
• 22.0% with 20 mg
• 24.3% in a 60 mg dose-escalation arm

over treatment periods extending to approximately 36 weeks, depending on the study arm. (Novo Nordisk⁠)

These were early-stage data from a relatively small study, so they should not be interpreted as definitive Phase 3 effectiveness estimates.

How Many Participants Were in the Early Study?

The early subcutaneous trial included 125 randomised participants, with 101 receiving zenagamtide and 24 receiving placebo. (Novo Nordisk⁠)

That is much smaller than the thousands of participants normally involved in late-stage obesity programmes.

The results were promising enough, however, for Novo Nordisk to advance zenagamtide into Phase 3 development.

Has Zenagamtide Been Studied in Type 2 Diabetes?

Yes.

In 2026, The Lancet published Phase 2 trials evaluating both oral and once-weekly injectable zenagamtide in adults with type 2 diabetes.

Both studies examined the dose-response relationship, safety, glucose control and changes in body weight over 36 weeks. (PubMed⁠)

This is important because it provides peer-reviewed human evidence for both delivery formats rather than relying only on company announcements.

Is There an Oral Version?

Yes.

This is one of zenagamtide’s most interesting features.

Novo Nordisk is developing an oral version of the same broader GLP-1/amylin concept.

Oral zenagamtide has already reached Phase 2 clinical testing in people with type 2 diabetes, and Novo Nordisk currently lists oral zenagamtide in its Phase 3 obesity pipeline. (ScienceDirect⁠)

That makes it one of a relatively small number of peptide-based metabolic programmes being advanced in both injectable and oral formats.

Why Is Oral Peptide Delivery Difficult?

Peptides are generally poor candidates for ordinary tablets.

The digestive system is designed to break peptide molecules apart.

They also do not cross the intestinal wall particularly easily.

For an oral peptide drug to work, pharmaceutical formulation must overcome both:

• degradation in the gastrointestinal tract
• poor absorption into the bloodstream

This is why successful oral peptide delivery remains a technically demanding area of drug development.

Has Zenagamtide Reached Phase 3?

Yes.

Novo Nordisk currently lists subcutaneous zenagamtide as an ongoing Phase 3 programme in both obesity and diabetes.

Oral zenagamtide is also listed within the company’s Phase 3 obesity pipeline. (Novo Nordisk⁠)

That places zenagamtide considerably further along than most experimental peptides discussed online.

What Is the AMBIENCE Trial?

One of the most important new zenagamtide studies is called AMBIENCE.

This is a large Phase 3 cardiovascular-outcomes trial sponsored by Novo Nordisk.

It plans to enrol approximately 8,500 participants with:

• established atherosclerotic cardiovascular disease
• overweight or obesity

Participants will receive either weekly zenagamtide or placebo. (ClinicalTrials⁠)

Why Is the Cardiovascular Trial Important?

Weight loss alone is no longer enough to define the success of a major obesity medicine.

Researchers increasingly want to know whether treatment also reduces serious health outcomes.

The primary endpoint in AMBIENCE includes major cardiovascular events such as:

• cardiovascular death
• non-fatal heart attack
• non-fatal stroke
• hospitalisation or urgent treatment for heart failure

The trial is expected to follow participants for several years. (ClinicalTrials⁠)

This represents a major step in the development of zenagamtide.

How Large Is AMBIENCE?

Approximately 8,500 participants are expected to enrol.

The study’s estimated primary completion date is September 2030. (ClinicalTrials⁠)

That is vastly larger than the early studies that first generated interest in amycretin.

Large cardiovascular-outcomes trials are expensive and demanding, so beginning one usually indicates substantial confidence in a drug development programme.

Can People Switch From Semaglutide to Zenagamtide?

Researchers are actively investigating this.

A separate study registered in 2026 is examining adults with overweight or obesity who are already receiving semaglutide.

The trial is investigating which zenagamtide dose can be tolerated when participants switch directly from a maintenance dose of semaglutide. (ClinicalTrials⁠)

This is significant because future obesity treatment may increasingly involve switching between different hormone pathways rather than simply starting every patient from the beginning.

Why Study Switching?

As more obesity medicines become available, patients may change treatment because of:

• inadequate response
• weight-loss plateaus
• side effects
• treatment availability
• preference
• development of newer therapies

Researchers therefore need to understand how transitions can be performed safely.

The fact that Novo Nordisk is already studying switching from semaglutide suggests zenagamtide is being developed with real-world treatment pathways in mind.

How Is Zenagamtide Different From Semaglutide?

Semaglutide primarily activates:

GLP-1

Zenagamtide combines:

GLP-1 + amylin-related signalling

The addition of amylin biology could potentially produce different effects on appetite, food intake and weight regulation.

Whether this ultimately produces superior effectiveness or tolerability needs to be determined through larger trials.

How Is Zenagamtide Different From Tirzepatide?

Tirzepatide targets:

GIP + GLP-1

Zenagamtide targets:

amylin-related pathways + GLP-1

So both extend beyond GLP-1, but they use different second hormonal systems.

This makes them biologically distinct strategies.

How Is Zenagamtide Different From CagriSema?

CagriSema combines two separate molecules:

• semaglutide
• cagrilintide

Semaglutide activates GLP-1.

Cagrilintide is a long-acting amylin analogue.

Zenagamtide instead attempts to provide GLP-1 and amylin activity from one molecule.

That distinction could potentially affect:

• manufacturing
• pharmacokinetics
• dose balancing
• formulation
• oral delivery

Whether the single-molecule approach offers meaningful clinical advantages remains to be seen.

How Is Zenagamtide Different From Petrelintide?

Petrelintide is primarily an amylin analogue.

Zenagamtide combines amylin-related signalling with GLP-1 activity.

Petrelintide therefore represents a more focused amylin approach, while zenagamtide is a multi-pathway peptide.

Is Zenagamtide a Peptide?

Yes.

Zenagamtide is a peptide therapeutic candidate.

It has been engineered to provide prolonged activity while simultaneously engaging complementary metabolic hormone receptors.

The development of an oral version is particularly noteworthy because oral delivery of peptide therapeutics remains technically challenging.

Is Zenagamtide Approved?

No.

Zenagamtide remains an investigational medicine.

It is currently being evaluated in Phase 3 research and is not an approved routine treatment.

Early weight-loss figures should therefore not be treated as established clinical outcomes.

What Are the Main Unanswered Questions?

Phase 3 studies will need to establish:

• long-term weight reduction
• optimal dosing
• long-term tolerability
• cardiovascular outcomes
• effects on type 2 diabetes
• body-composition changes
• whether oral and injectable versions perform similarly
• comparative effectiveness against existing drugs
• whether switching from established GLP-1 therapies is practical

The cardiovascular programme will be especially important.

Why Is Zenagamtide Worth Watching?

Zenagamtide sits at the centre of several major trends in metabolic peptide research.

It combines:

• GLP-1 biology
• amylin biology
• single-molecule engineering
• once-weekly injections
• oral peptide development
• cardiovascular-outcomes research

Few emerging metabolic peptides currently combine all of those features.

The Bottom Line

Zenagamtide, formerly known as amycretin, is an investigational peptide designed to combine GLP-1 and amylin-related receptor activity within a single molecule.

Early injectable research produced substantial weight-loss signals, including estimated reductions exceeding 20% in some higher-dose study groups, although these findings came from relatively small early-stage trials. (Novo Nordisk⁠)

Peer-reviewed Phase 2 research has since investigated both oral and injectable zenagamtide in people with type 2 diabetes. (PubMed⁠)

The programme has now progressed into Phase 3, including the AMBIENCE cardiovascular-outcomes trial involving approximately 8,500 participants with established cardiovascular disease and overweight or obesity. (ClinicalTrials⁠)

This makes zenagamtide one of the most advanced and scientifically interesting emerging metabolic peptides currently in development.

Its biggest question is no longer simply whether it can reduce body weight.

Researchers are now asking whether a single GLP-1/amylin molecule can deliver durable metabolic and cardiovascular benefits at scale.

This article is for research and educational purposes only. Zenagamtide remains investigational and is not presented as an approved or established treatment.