Cagrilintide and amylin: the fourth hormone in the incretin conversation

Most of the conversation about metabolic peptides is about three receptors: GLP-1, GIP and glucagon. Semaglutide acts at one, tirzepatide at two, retatrutide at three. Cagrilintide is interesting because it acts at none of them. It is an analogue of amylin, a different hormone with a different receptor family, and the reason it keeps appearing next to semaglutide is that the two were developed to be studied together.

This page sets out what amylin is, what was changed to make cagrilintide, and what its trial programme measured. NovaEvum does not carry cagrilintide; it is here because it is the compound most often confused with the incretin agonists we do carry.

Amylin is a pancreatic hormone, not an incretin

Amylin is a 37-amino-acid peptide secreted by the beta cells of the pancreas, released together with insulin when a meal arrives. Its physiology is reviewed at length by Hay and colleagues (PMID 26071095): it slows gastric emptying, suppresses glucagon after a meal, and acts in the brainstem on signals related to satiety.

An incretin is a gut hormone that amplifies insulin release — GLP-1 and GIP are the two. Amylin is not one. It comes from the same cell as insulin rather than from the gut, and it acts through its own receptors. That is the whole reason combining it with a GLP-1 agonist is a research question rather than a repetition: the two pathways overlap in what they influence, but not in how they are reached.

The receptor is a partnership

There is no single "amylin receptor" gene. Amylin receptors are formed when the calcitonin receptor pairs with one of three receptor activity-modifying proteins, RAMP1, RAMP2 or RAMP3. Muff and colleagues showed the principle by co-expressing the calcitonin receptor with RAMPs and finding that an amylin-preferring receptor appeared (PMID 10342886).

That makes three amylin receptor subtypes, AMY1 to AMY3, plus the calcitonin receptor on its own. Which of those a given analogue engages is a large part of what distinguishes one amylin compound from another, and cagrilintide was characterised as acting at both amylin and calcitonin receptors rather than selectively at one.

Why native amylin could not be used

Human amylin has a practical problem: in solution it aggregates into amyloid fibrils, the same material found deposited in the pancreas in type 2 diabetes. A peptide that clumps on standing is difficult to formulate and to study.

The first answer was pramlintide, an analogue with proline substitutions borrowed from rat amylin, which does not aggregate. Pramlintide was approved in the United States in 2005 as Symlin, as an adjunct to mealtime insulin in type 1 and type 2 diabetes. Its half-life is short, measured in minutes to hours.

What was changed to make cagrilintide

Cagrilintide is Novo Nordisk's long-acting answer. Kruse and colleagues describe its development (PMID 34288673): a sequence altered to resist fibrillation, and a fatty-acid side chain attached so that the peptide binds circulating albumin. Albumin binding slows clearance, and the result has a half-life measured in days rather than hours.

That lipidation strategy is the same one used for semaglutide. It is why the two can be developed in parallel: two molecules built to the same pharmacokinetic design, aimed at different receptor families.

What the trial programme measured

Cagrilintide has a human trial literature, which most compounds discussed on this site do not.

Two features of that table matter for reading it.

Most of the large trials are of the combination. The phase 3 programme studied cagrilintide co-administered with semaglutide, the pairing known as CagriSema. A result for CagriSema is not a result for cagrilintide, and the trials that included single-component arms are the only ones that say anything about what each part contributes.

The endpoints are weight and glycaemia in defined populations. The trials enrolled adults with obesity, or with obesity and type 2 diabetes, under clinical supervision, with pharmaceutical-grade material. Nothing in them describes research material from another source, and nothing in them extends to people outside those populations.

Regulatory position

Cagrilintide is not approved as a stand-alone medicine anywhere. The combination with semaglutide has completed phase 3 trials, and its regulatory position is moving; Health Canada's Drug Product Database is the authoritative place to check whether anything containing cagrilintide has been authorised in Canada. Until it is, cagrilintide is an investigational compound, and anything sold under that name outside a trial is research material and nothing more.

Where the evidence stops

The combination data does not transfer to the component. Most of what is published about cagrilintide is published about CagriSema. Material containing only cagrilintide is described by the phase 2 monotherapy trial and the single-component arms, and by nothing else.

Weight change is a measured endpoint, not a property of a vial. The trials report what happened to a population under controlled conditions over a fixed period. That is a fact about those trials.

Long-term data is still accumulating. The phase 3 trials ran for little more than a year. What follows over longer periods is a question they were not designed to answer.

Common questions

Is cagrilintide a GLP-1 agonist? No. It acts at amylin and calcitonin receptors, a different receptor family from GLP-1, GIP and glucagon. It is studied alongside GLP-1 agonists because the pathways are different, not because they are the same.

How is it different from retatrutide? Retatrutide is one molecule acting at three incretin-family receptors. Cagrilintide is one molecule acting at a different family entirely, and its main programme combines it with a second molecule. Tirzepatide and retatrutide covers the incretin side of that comparison.

What is the difference between cagrilintide and pramlintide? Both are amylin analogues built to avoid the aggregation of native amylin. Pramlintide is short-acting and approved in the United States; cagrilintide carries a fatty-acid chain that extends its half-life to days, and is not approved as a medicine on its own.

Does NovaEvum sell cagrilintide? No. For the incretin agonists we do carry, see the retatrutide guide and the GLP-1 and metabolic category. Nothing here is medical, dosing, or therapeutic guidance.

Selected Research References

1. Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacological Reviews. 2015;67(3):564-600. pubmed.ncbi.nlm.nih.gov/26071095
2. Muff R, Bühlmann N, Fischer JA, Born W. An Amylin Receptor Is Revealed Following Co-Transfection of a Calcitonin Receptor with Receptor Activity Modifying Proteins-1 or -3. Endocrinology. 1999;140(6):2924-2927. pubmed.ncbi.nlm.nih.gov/10342886
3. Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry. 2021;64(15):11183-11194. pubmed.ncbi.nlm.nih.gov/34288673
4. Enebo LB, Berthelsen KK, Kankam M, et al. 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;397(10286):1736-1748. pubmed.ncbi.nlm.nih.gov/33894838
5. Lau DCW, Erichsen L, Francisco AM, et al. 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;398(10317):2160-2172. pubmed.ncbi.nlm.nih.gov/34798060
6. Frias JP, Deenadayalan S, Erichsen L, et al. 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;402(10403):720-730. pubmed.ncbi.nlm.nih.gov/37364590
7. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2025;393(7):635-647. pubmed.ncbi.nlm.nih.gov/40544433
8. Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine. 2025;393(7):648-659. pubmed.ncbi.nlm.nih.gov/40544432

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