Cagrilintide vs Semaglutide: Amylin and GLP-1 Receptor Pharmacology Compared

Q: What is the difference between cagrilintide and semaglutide?

They act at different receptors and derive from different hormones. Semaglutide is an analogue of glucagon-like peptide-1 and an agonist at the GLP-1 receptor . Cagrilintide is a long-acting analogue of amylin, a 37-residue hormone secreted by pancreatic beta cells alongside insulin, and acts at amylin receptors . Neither can occupy the other's receptor.

Q: Why is an amylin receptor different from a GLP-1 receptor?

Because it is not a single protein. The GLP-1 receptor is one gene product, cloned from pancreatic beta cells in 1992 . Amylin receptors are assembled: the calcitonin receptor associates with one of the receptor activity-modifying proteins, and the resulting complexes have pharmacology that neither component has alone . There are several such complexes, their relative abundance differs by tissue, and selectivity against the calcitonin receptor itself is a design problem rather than a formality .

Q: Have cagrilintide and semaglutide been compared directly in a trial?

Once. A phase 2 trial randomised 92 adults with type 2 diabetes 1:1:1 to the combination, semaglutide alone, or cagrilintide alone, all escalated to 2.4 mg once weekly over 32 weeks . It is the only published trial in which each compound has a monotherapy arm measured on the same endpoints in the same participants. With roughly thirty participants per arm it is informative about direction and much weaker about magnitude.

Q: What did that three-arm trial report?

Mean glycated haemoglobin change at 32 weeks was −2.2 percentage points for the combination, −1.8 for semaglutide alone and −0.9 for cagrilintide alone; the combination was superior to cagrilintide alone but not to semaglutide alone (p = 0.075). Mean change in body mass was −15.6%, −5.1% and −8.1% respectively . The two monotherapy arms separated in opposite directions on the two measures, which in a trial this size is a hypothesis about differing receptor pharmacology rather than a finding about magnitude.

Q: Why are the two usually studied together rather than against each other?

Because they engage separate receptors in separate systems, so there is a mechanistic rationale for combining them, and the published pharmacokinetic work found no interaction — co-administration did not affect semaglutide exposure or elimination . The phase 3 REDEFINE programme tests the fixed co-formulation against its components and placebo, which answers what the combination adds rather than which component does more .

Q: Is either compound approved by the FDA?

Semaglutide is an approved medicine in the United States in defined indications. Cagrilintide is investigational and is not approved for any indication. Approval in the United States attaches to a specific compound and a specific indication.

Q: Does cagrilintide have outcome-trial evidence?

No amylin analogue has reported a clinical-outcome trial. Cagrilintide's published single-agent record is phase 1b and phase 2 . Semaglutide, by contrast, has reported cardiovascular and kidney outcome trials in 17,604 and 3,533 participants . A surrogate endpoint and a counted clinical event are different categories of evidence.

Q: Is cagrilintide the only amylin analogue studied clinically?

No. Pramlintide, a short-acting amylin analogue, was studied as an adjunct to insulin in type 1 diabetes and reported in randomised trials two decades earlier , and eloralintide, a selective amylin receptor agonist, has reported phase 1 and phase 2 results . Amylin receptor agonism is a distinct pharmacological programme with its own history rather than a variant of incretin pharmacology.

Cagrilintide acts at amylin receptors, semaglutide at the GLP-1 receptor. One randomised trial compared them directly and in combination.

By Elegance Peptides Editorial TeamUpdated September 22, 2026

Most comparisons in this part of the library set one incretin analogue against another. This one does not. Cagrilintide and semaglutide act at entirely different receptors, descend from entirely different hormones, and are most often studied together rather than against each other — which is precisely why the pharmacological distinction is worth drawing carefully.

One randomised trial did put them against each other, with a monotherapy arm for each and a combination arm alongside. That trial is the backbone of this page, and its size — roughly thirty participants per arm — is the first thing to know about it.

What they are

Property	Cagrilintide	Semaglutide
Development code	NNC0174-0833	NN9535
Compound type	Synthetic lipidated peptide analogue of human amylin	Synthetic acylated peptide analogue of human GLP-1
Peptide family	Calcitonin / amylin (CGRP) peptide superfamily	Glucagon / secretin peptide superfamily (GLP-1 receptor ligands)
Primary target	Amylin receptors (calcitonin receptor in complex with receptor activity-modifying proteins)	Glucagon-like peptide-1 receptor (GLP-1R)
Secondary targets	Calcitonin receptor	Not established
Receptor family	Class B1 (secretin-like) G protein-coupled receptors	Class B1 (secretin-like) G protein-coupled receptors
Agonist / antagonist	Agonist	Agonist at the GLP-1 receptor
Highest research phase	Phase 3 (completed and reported, as a co-administration with semaglutide); phase 2 as a single agent	Approved; phase 3 programmes and cardiovascular and kidney outcome trials completed and reported
Regulatory status (United States)	Not approved. Cagrilintide is an investigational compound and has not been approved by the U.S. Food and Drug Administration for any indication, alone or in the fixed combination in which it has been most extensively studied.	Approved as a finished pharmaceutical product. Semaglutide is the active ingredient of products approved by the U.S. Food and Drug Administration and marketed by Novo Nordisk. That approval attaches to those finished products as manufactured, formulated and labelled by their sponsor. It does not attach to semaglutide as a chemical, and it confers nothing on research-grade material supplied for laboratory use.
Human trials published	Yes	Yes

Every value in this table is read from the two compounds’ own library entries when the site is built, so it cannot disagree with them. Nothing here ranks one compound against the other.

Semaglutide is an acylated analogue of human glucagon-like peptide-1, developed by Novo Nordisk and first described in 2015. It is an agonist at the glucagon-like peptide-1 receptor ^[6]. It is an approved medicine in the United States in defined indications.

Cagrilintide is a long-acting, lipidated analogue of human amylin, also from Novo Nordisk, described in the medicinal-chemistry literature in 2021 ^[10]. Amylin is a 37-residue hormone secreted by pancreatic beta cells alongside insulin. Cagrilintide is investigational and has not been approved by the U.S. Food and Drug Administration for any indication.

The two hormones they derive from are secreted by different cells in response to different signals: GLP-1 from enteroendocrine L cells of the gut, amylin from pancreatic beta cells co-secreted with insulin ^{[8, 5]}. The only design idea the two analogues share is lipidation for duration. Cagrilintide's reported plasma half-life in early clinical study was 159 to 195 hours; semaglutide's, measured in the same participants, was 145 to 165 hours ^[9].

Receptor and mechanistic differences

The GLP-1 receptor is a conventional, dedicated class B1 G protein-coupled receptor: one gene, one protein, cloned from pancreatic beta cells in 1992, signalling through Gs to raise intracellular cyclic AMP ^{[1, 8]}. Semaglutide engages it and nothing else.

Amylin receptors are not built that way at all, and this is the substantive pharmacological difference between the two compounds. There is no dedicated amylin receptor gene. Amylin receptors are heterodimers formed when the calcitonin receptor — itself class B1 — associates with one of the receptor activity-modifying proteins, and the resulting complexes have pharmacology that neither component has on its own ^{[2, 3, 5]}. The combinations are conventionally designated AMY1, AMY2 and AMY3 after which receptor activity-modifying protein is involved.

Three consequences follow, and they matter more than any potency figure.

First, there is no single target to describe. There is a family of complexes whose relative abundance differs by tissue, so "amylin receptor agonism" names a distribution of activities rather than one activity ^[5].

Second, selectivity is a real design problem rather than a formality. Because the calcitonin receptor is the shared component, selectivity between the amylin receptor complexes and the calcitonin receptor itself is something a molecule has to be engineered for ^{[3, 5]}.

Third, the two compounds cannot compete or cross-react. They occupy separate receptors in separate systems, which is the mechanistic basis for studying them together — and the published pharmacokinetic work confirms the absence of interaction: co-administration did not affect semaglutide exposure or elimination ^[9].

Receptor target: Semaglutide — GLP-1R, a dedicated class B1 receptor ^{[1, 6]}. Cagrilintide — amylin receptor complexes formed by the calcitonin receptor with receptor activity-modifying proteins ^{[2, 3]}.
Parent hormone: GLP-1, from enteroendocrine L cells. Amylin, from pancreatic beta cells, co-secreted with insulin ^{[8, 5]}.
Receptor architecture: One gene and one protein for GLP-1R. A heterodimer family — AMY1, AMY2, AMY3 — for amylin ^[3].
Reported half-life: Semaglutide 145–165 hours and cagrilintide 159–195 hours, measured in the same phase 1b participants ^[9].
Regulatory position: Semaglutide is approved in the United States in defined indications. Cagrilintide is not approved for anything.

What the research compares

Unusually for this library, a direct comparison exists — and it exists because the combination was the thing being tested, so the trial needed monotherapy arms to interpret it.

The phase 2 trial in type 2 diabetes randomised 92 adults 1:1:1 to the combination, semaglutide alone, or cagrilintide alone, all escalated to 2.4 mg once weekly over 32 weeks ^{[13, 20]}. This is the only published trial in which each compound has a monotherapy arm and both are measured on the same endpoints in the same participants and the same period.

Its size is the limiting fact. Roughly thirty participants per arm, at sites in one country, over 32 weeks. A three-arm trial of that size is informative about direction and much weaker about magnitude, and its confidence intervals reflect that.

Everything else is not a comparison. The phase 1b study administered cagrilintide to every participant alongside semaglutide, so nothing in it separates the two ^[9]. The phase 2 monotherapy trial of cagrilintide used liraglutide 3.0 mg as its active comparator, not semaglutide ^[11]. The REDEFINE phase 3 programme tests the fixed combination against its components and against placebo, which addresses what the combination adds rather than which single agent does more ^{[16, 17]}. And semaglutide's own large trials — SELECT, FLOW, SUSTAIN-6, STEP 1 — contain no amylin analogue at all ^{[7, 12, 14, 15]}.

What the human research compares

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The three-arm trial — the only direct comparison

Population. 92 adults with type 2 diabetes and a body-mass index of 27 kg/m² or higher, on metformin with or without an SGLT2 inhibitor, at 17 sites in the United States. Mean age 58 years; 64% male ^{[13, 20]}.

Endpoint and design. Primary endpoint the change from baseline in glycated haemoglobin at 32 weeks. Randomised 1:1:1 to the combination, semaglutide alone, or cagrilintide alone, all escalated to 2.4 mg once weekly ^[13].

Result. Mean glycated haemoglobin change to week 32 was −2.2 percentage points for the combination, −1.8 for semaglutide alone and −0.9 for cagrilintide alone. The combination was superior to cagrilintide alone — estimated treatment difference −1.3 percentage points, 95% CI −1.7 to −0.8, p < 0.0001 — but not to semaglutide alone, −0.4 percentage points, 95% CI −0.8 to 0.0, p = 0.075. Mean change in body mass was −15.6%, −5.1% and −8.1% respectively, the combination exceeding either single agent, p < 0.0001 for both ^[13].

Adverse events. Reported by 68%, 71% and 80% of the three groups. Mild or moderate gastrointestinal events were most common. No level 2 or 3 hypoglycaemia and no fatal adverse events ^[13].

Limitations. Ninety-two participants across three arms — roughly thirty per group — over 32 weeks, at sites in one country, with a glycaemic surrogate as the primary endpoint.

One structural feature of that result is worth stating plainly and without extrapolation: the two monotherapy arms separated in opposite directions on the two measures. Glycated haemoglobin moved further under semaglutide alone; body mass moved further under cagrilintide alone ^[13]. In a trial of this size that pattern is a hypothesis about differing receptor pharmacology, not a finding about either compound's magnitude of effect, and it is reported here as such.

What each compound's own trials add

Cagrilintide as a single agent was examined in a phase 2 trial of 906 adults without diabetes, against placebo and against liraglutide 3.0 mg. Mean percentage reductions in body mass across the cagrilintide groups were 6.0% to 10.8% against 3.0% for placebo at week 26; cagrilintide 4.5 mg reached 10.8% against 9.0% for liraglutide, an estimated treatment difference of 1.8%, p = 0.03 ^[11]. That comparator is not semaglutide.

Semaglutide's own record is both larger and of a different kind. STEP 1 randomised 1,961 adults without diabetes and reported mean change in body weight at 68 weeks of −14.9% against −2.4% for placebo ^[12]. SELECT randomised 17,604 participants with cardiovascular disease and without diabetes and reported a primary cardiovascular composite in 6.5% against 8.0%, hazard ratio 0.80 ^[14]. FLOW reported a composite kidney outcome hazard ratio of 0.76 in 3,533 participants ^[15]. No amylin analogue has reported a clinical-outcome trial of any kind.

The combination programme sits on top of both. The phase 3 REDEFINE trials tested the fixed co-formulation of cagrilintide and semaglutide in adults with overweight or obesity and, separately, in adults who also had type 2 diabetes ^{[16, 17, 21, 22]}. Those trials answer what the combination adds; they are not a contest between its components.

Amylin pharmacology beyond cagrilintide

The amylin class is older than cagrilintide. Pramlintide, a short-acting amylin analogue, was studied as an adjunct to insulin in type 1 diabetes and reported in randomised trials two decades earlier ^[4]. More recently, eloralintide, a selective amylin receptor agonist, has reported phase 1 and phase 2 results ^{[18, 19]}. The relevance here is narrow: it establishes that amylin receptor agonism is a distinct pharmacological programme with its own history, not a variant of incretin pharmacology.

What the preclinical and in vitro research shows

In vitro research

The cell-based literature is where the receptor difference was actually established, and it predates both compounds by two decades.

Receptor activity-modifying proteins were shown in 1998 to determine the transport and ligand specificity of the calcitonin-receptor-like receptor ^[2]. The following year, multiple amylin receptor phenotypes were shown to arise from the interaction of those same proteins with the calcitonin receptor gene product — the experiment that defined what an amylin receptor is ^[3]. The reference pharmacology of the class was later consolidated in a review that sets out the receptor complexes, their tissue distribution and the selectivity problem they create ^[5].

Cagrilintide's own in vitro description is a medicinal-chemistry account of a stable lipidated long-acting analogue and the structure-activity work that selected it, rather than a receptor-profiling paper; quantitative potency figures at each amylin receptor subtype are not stated there and are not reproduced here ^[10]. Semaglutide's in vitro characterisation reports a GLP-1 receptor affinity of 0.38 ± 0.06 nM, approximately three-fold weaker than liraglutide, traded for substantially higher albumin affinity ^[6].

There is no assay in which the two compounds have been characterised against each other, and there could not straightforwardly be one: their receptors are different proteins, so there is no shared axis of potency on which to place them.

Research status of each

Semaglutide is an approved medicine in the United States in defined indications, with published cardiovascular, kidney and hepatic trials in addition to its obesity and diabetes programmes ^{[7, 14, 15]}.

Cagrilintide is investigational. It has not been approved for any indication. Its most advanced clinical work is the phase 3 REDEFINE programme, in which it is studied as a fixed co-formulation with semaglutide rather than as a single agent ^{[16, 17]}. Published single-agent evidence is limited to phase 1b and phase 2 ^{[9, 11, 13]}.

Every trial named here studied pharmaceutical material, manufactured to a regulatory standard, administered under a registered protocol in a defined population under clinical supervision. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

What is the difference between cagrilintide and semaglutide?

They act at different receptors and derive from different hormones. Semaglutide is an analogue of glucagon-like peptide-1 and an agonist at the GLP-1 receptor ^[6]. Cagrilintide is a long-acting analogue of amylin, a 37-residue hormone secreted by pancreatic beta cells alongside insulin, and acts at amylin receptors ^{[10, 5]}. Neither can occupy the other's receptor.

Why is an amylin receptor different from a GLP-1 receptor?

Because it is not a single protein. The GLP-1 receptor is one gene product, cloned from pancreatic beta cells in 1992 ^[1]. Amylin receptors are assembled: the calcitonin receptor associates with one of the receptor activity-modifying proteins, and the resulting complexes have pharmacology that neither component has alone ^{[2, 3]}. There are several such complexes, their relative abundance differs by tissue, and selectivity against the calcitonin receptor itself is a design problem rather than a formality ^[5].

Have cagrilintide and semaglutide been compared directly in a trial?

Once. A phase 2 trial randomised 92 adults with type 2 diabetes 1:1:1 to the combination, semaglutide alone, or cagrilintide alone, all escalated to 2.4 mg once weekly over 32 weeks ^[13]. It is the only published trial in which each compound has a monotherapy arm measured on the same endpoints in the same participants. With roughly thirty participants per arm it is informative about direction and much weaker about magnitude.

What did that three-arm trial report?

Mean glycated haemoglobin change at 32 weeks was −2.2 percentage points for the combination, −1.8 for semaglutide alone and −0.9 for cagrilintide alone; the combination was superior to cagrilintide alone but not to semaglutide alone (p = 0.075). Mean change in body mass was −15.6%, −5.1% and −8.1% respectively ^[13]. The two monotherapy arms separated in opposite directions on the two measures, which in a trial this size is a hypothesis about differing receptor pharmacology rather than a finding about magnitude.

Why are the two usually studied together rather than against each other?

Because they engage separate receptors in separate systems, so there is a mechanistic rationale for combining them, and the published pharmacokinetic work found no interaction — co-administration did not affect semaglutide exposure or elimination ^[9]. The phase 3 REDEFINE programme tests the fixed co-formulation against its components and placebo, which answers what the combination adds rather than which component does more ^{[16, 17]}.

Is either compound approved by the FDA?

Semaglutide is an approved medicine in the United States in defined indications. Cagrilintide is investigational and is not approved for any indication. Approval in the United States attaches to a specific compound and a specific indication.

Does cagrilintide have outcome-trial evidence?

No amylin analogue has reported a clinical-outcome trial. Cagrilintide's published single-agent record is phase 1b and phase 2 ^{[9, 11, 13]}. Semaglutide, by contrast, has reported cardiovascular and kidney outcome trials in 17,604 and 3,533 participants ^{[14, 15]}. A surrogate endpoint and a counted clinical event are different categories of evidence.

Is cagrilintide the only amylin analogue studied clinically?

No. Pramlintide, a short-acting amylin analogue, was studied as an adjunct to insulin in type 1 diabetes and reported in randomised trials two decades earlier ^[4], and eloralintide, a selective amylin receptor agonist, has reported phase 1 and phase 2 results ^{[18, 19]}. Amylin receptor agonism is a distinct pharmacological programme with its own history rather than a variant of incretin pharmacology.

References

Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1 Proceedings of the National Academy of Sciences of the United States of America; 1992. PMID 1326760 doi:10.1073/pnas.89.18.8641
RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor Nature; 1998. PMID 9620797 doi:10.1038/30666
Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product Molecular Pharmacology; 1999. PMID 10385705 doi:10.1124/mol.56.1.235
Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial Diabetic Medicine; 2004. PMID 15498087 doi:10.1111/j.1464-5491.2004.01319.x
Amylin: Pharmacology, Physiology, and Clinical Potential Pharmacological Reviews; 2015. PMID 26071095 doi:10.1124/pr.115.010629
Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide Journal of Medicinal Chemistry; 2015. PMID 26308095 doi:10.1021/acs.jmedchem.5b00726
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes The New England Journal of Medicine; 2016. PMID 27633186 doi:10.1056/NEJMoa1607141
The physiology of glucagon-like peptide 1 Physiological Reviews; 2007. PMID 17928588 doi:10.1152/physrev.00034.2006
Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial The Lancet; 2021. PMID 33894838 doi:10.1016/S0140-6736(21)00845-X
Development of Cagrilintide, a Long-Acting Amylin Analogue Journal of Medicinal Chemistry; 2021. PMID 34288673 doi:10.1021/acs.jmedchem.1c00565
Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial The Lancet; 2021. PMID 34798060 doi:10.1016/S0140-6736(21)01751-7
Once-Weekly Semaglutide in Adults with Overweight or Obesity The New England Journal of Medicine; 2021. PMID 33567185 doi:10.1056/NEJMoa2032183
Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial The Lancet; 2023. PMID 37364590 doi:10.1016/S0140-6736(23)01163-7
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes The New England Journal of Medicine; 2023. PMID 37952131 doi:10.1056/NEJMoa2307563
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes The New England Journal of Medicine; 2024. PMID 38785209 doi:10.1056/NEJMoa2403347
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity The New England Journal of Medicine; 2025. PMID 40544433 doi:10.1056/NEJMoa2502081
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes The New England Journal of Medicine; 2025. PMID 40544432 doi:10.1056/NEJMoa2502082
Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept Molecular Metabolism; 2025. PMID 41109426 doi:10.1016/j.molmet.2025.102271
Eloralintide, a selective amylin receptor agonist for the treatment of obesity: a 48-week phase 2, multicentre, double-blind, randomised, placebo-controlled trial The Lancet; 2025. PMID 41207310 doi:10.1016/S0140-6736(25)02155-5
Research Study to Look at How Well Cagrilintide Together With Semaglutide Works in People With Type 2 Diabetes. NCT04982575
A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight. NCT05567796
A Research Study to See How Well CagriSema Helps People With Type 2 Diabetes and Excess Body Weight Lose Weight. NCT05394519

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.