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What Is Cagrilintide? The Amylin Analog Behind CagriSema

Part of Weight Loss Drug Profiles: Every GLP-1 and GLP3 Agonist.

What Is Cagrilintide? The Amylin Analog Behind CagriSema

Cagrilintide is a long-acting amylin receptor agonist developed by Novo Nordisk. It is a once-weekly injectable peptide that mimics amylin, a hormone naturally co-secreted with insulin from the pancreas after meals. Amylin reduces appetite, slows gastric emptying, and suppresses glucagon — a fundamentally different mechanism from GLP-1 receptor agonists like semaglutide and tirzepatide.
Cagrilintide is best known as one half of CagriSema, Novo Nordisk's combination of cagrilintide + semaglutide. In the REDEFINE 1 Phase 3 trial, cagrilintide as monotherapy produced 11.5% weight loss at 68 weeks — meaningful on its own, and additive when combined with semaglutide (20.4% as CagriSema). An NDA for CagriSema was filed with the FDA in December 2025.
Cagrilintide is also being studied on its own in the RENEW Phase 3 program. It remains investigational, and combination-trial results do not validate adding unapproved cagrilintide to another medicine. This article covers cagrilintide itself — how it works, what the clinical data shows, and how it compares to the incretin-based drugs most people are already familiar with.

How Cagrilintide Works

Cagrilintide targets a completely different receptor system than GLP-1 drugs. While semaglutide, tirzepatide, and retatrutide all work through incretin receptors (GLP-1, GIP, glucagon), cagrilintide works through amylin receptors in the brain.

The Amylin Pathway

Amylin is a 37-amino-acid peptide hormone co-secreted with insulin by pancreatic beta cells after meals. It was discovered in 1987 and has three main effects:

  • Reduces appetite by acting on the area postrema and hypothalamus in the brain
  • Slows gastric emptying, prolonging the feeling of fullness after eating
  • Suppresses post-meal glucagon secretion, preventing the liver from releasing excess glucose after meals

In people with type 2 diabetes, amylin secretion is reduced — just like insulin. In obesity, the amylin signaling pathway may become less effective over time.

What Makes Cagrilintide Different From Native Amylin

Native human amylin has a half-life of roughly 13 minutes — far too short for practical use as a medication. Cagrilintide solves this with structural modifications that extend its half-life to approximately 7 days, enabling once-weekly dosing.

Specifically, cagrilintide is an acylated analog with a C18 fatty diacid side chain (similar to the pharmacological strategy used in semaglutide and tirzepatide). This modification allows it to bind albumin in the bloodstream, creating a slow-release depot effect.

Receptor Binding

A 2025 study in Nature Communications determined the cryo-EM structures of cagrilintide bound to its target receptors. Cagrilintide activates:
  • AMY1R (amylin receptor 1) — calcitonin receptor + RAMP1
  • AMY2R (amylin receptor 2) — calcitonin receptor + RAMP2
  • AMY3R (amylin receptor 3) — calcitonin receptor + RAMP3
  • CTR (calcitonin receptor) — the base receptor without RAMP proteins
A separate 2025 study in eBioMedicine investigated how brain AMY1R and AMY3R contribute to cagrilintide’s effects in preclinical models.

The key point: amylin receptors are entirely separate from GLP-1, GIP, and glucagon receptors. This is why cagrilintide can produce additional weight loss when combined with drugs that target those incretin pathways.

Clinical Trial Data

Phase 2 (Monotherapy)

The 26-week Phase 2 trial enrolled 706 adults without diabetes. Across weekly cagrilintide doses of 0.3–4.5 mg, mean weight loss ranged from 6.0% to 10.8%, compared with 3.0% on placebo, in the trial-product estimand. The 4.5 mg group lost 10.8%, compared with 9.0% on daily liraglutide 3.0 mg.

These are trial results, not an approved dosing recommendation.

REDEFINE 1 (Phase 3a — Obesity Without Diabetes)

The landmark REDEFINE 1 trial was a 68-week, double-blind, placebo-controlled trial in 3,417 adults without diabetes. It included cagrilintide as monotherapy, semaglutide as monotherapy, and the CagriSema combination. The following results use the treatment-policy analysis, which includes outcomes regardless of treatment discontinuation:
Treatment ArmWeight Loss at 68 Weeks
CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg)-20.4%
Semaglutide 2.4 mg alone-14.9%
Cagrilintide 2.4 mg alone-11.5%
Placebo-3.0%

Cagrilintide monotherapy produced meaningful weight loss (11.5%), though less than semaglutide alone (14.9%). The combination was clearly additive — the extra amylin pathway provided roughly 5-6 additional percentage points of weight loss on top of semaglutide.

REDEFINE 2 (Phase 3a — Type 2 Diabetes)

In adults with type 2 diabetes and overweight/obesity, CagriSema produced -13.7% weight loss at 68 weeks (vs -3.4% for placebo). HbA1c reduction was also significant: 73.5% of CagriSema participants achieved HbA1c of 6.5% or below, compared to 15.9% on placebo.

REDEFINE 4 (Head-to-Head vs Tirzepatide)

The REDEFINE 4 trial compared CagriSema directly to tirzepatide 15 mg over 84 weeks. CagriSema achieved 23.0% weight loss vs 25.5% for tirzepatide (in the adherence analysis), failing to demonstrate non-inferiority. This result is for CagriSema as a combination — not cagrilintide alone.

Cagrilintide Dosage

There is no approved cagrilintide dosing schedule. REDEFINE 1 studied a target of 2.4 mg weekly, alone or with semaglutide, using protocol-controlled dose escalation. The trial publication describes the research regimen.

A trial target dose is not a recommendation for self-treatment or stacking. The Phase 2 monotherapy study also tested doses up to 4.5 mg; the doses and escalation rules belong to their individual protocols.

Cagrilintide Side Effects

The side effect profile of cagrilintide is broadly similar to GLP-1 drugs, with gastrointestinal symptoms being the most common.

From REDEFINE 1 (CagriSema vs Placebo)

Swipe sideways to see every column.

Side EffectCagriSemaSemaglutide AloneCagrilintide AlonePlacebo
Any GI event79.6%73.8%54.0%39.9%
NauseaMost commonMost commonMost common—
ConstipationCommonCommonCommon—
DiarrheaCommonCommonCommon—
VomitingCommonCommonLess common—

Most GI events were mild to moderate. Nausea, diarrhea and vomiting peaked during escalation, while constipation remained relatively constant afterward. Injection-site reactions occurred in 16.9% with cagrilintide alone versus 3.0% with placebo.

Serious adverse events were reported in 9.8% with CagriSema, 5.0% with semaglutide, 8.9% with cagrilintide and 6.1% with placebo. These reports do not establish that treatment caused each event.

How Cagrilintide Compares to Other Weight Loss Drugs

Cagrilintide targets amylin receptors. Semaglutide targets GLP-1, tirzepatide targets GLP-1 and GIP, and retatrutide targets GLP-1, GIP and glucagon.

REDEFINE 1 directly compared cagrilintide, semaglutide and their combination: the combination produced more weight loss than either component. It did not test cagrilintide against tirzepatide or retatrutide, or combined with them. Results from separate trials cannot establish those comparisons.

Why People Are Interested in Cagrilintide

Stacking With GLP-1 Drugs

REDEFINE 1 supports the specific studied combination of cagrilintide and semaglutide: 20.4% mean weight loss versus 14.9% with semaglutide alone at 68 weeks. It does not validate adding cagrilintide to tirzepatide or retatrutide.

For the evidence and uncertainties about that separate question, see cagrilintide and tirzepatide.

Plateau Breaker

Adding another appetite medicine is sometimes proposed for a plateau. REDEFINE 1 does not establish that adding cagrilintide after a plateau on tirzepatide or retatrutide is safe or effective. Its randomized treatment arms answer a different question.

Different Side Effect Profile

Cagrilintide can itself cause gastrointestinal symptoms and injection-site reactions. The Phase 2 study reported GI events in 41–63% across cagrilintide doses, versus 32% with placebo. These data do not establish that it is a safer substitute for someone who cannot tolerate a GLP-1 medicine.

Cagrilintide vs Retatrutide

The two drugs target different receptors, but that does not establish that combining them helps. REDEFINE 1 did not include retatrutide. Trial results for either drug alone do not validate the combination.

For a comparison of retatrutide with the studied cagrilintide–semaglutide combination, see retatrutide vs CagriSema.

Current Status and Availability

Cagrilintide remains investigational. Novo Nordisk’s RENEW 1 and RENEW 2 trials are studying it as a standalone treatment in people with obesity, with and without type 2 diabetes.

CagriSema is a separate combination product. Its US application was filed in December 2025; a filing is not approval. Neither program provides an approved cagrilintide product for self-treatment.

Frequently Asked Questions

What is cagrilintide?

Cagrilintide is a long-acting amylin receptor agonist developed by Novo Nordisk. It mimics the hormone amylin, which is naturally released with insulin after meals to reduce appetite and slow gastric emptying. It is given as a once-weekly injection.

What is the difference between cagrilintide and semaglutide?

Cagrilintide targets amylin receptors in the brain, while semaglutide targets GLP-1 receptors. They work through completely different biological pathways. This is why they are combined in CagriSema — the two mechanisms are additive.

There is no approved recommended dose. REDEFINE 1 tested a target of 2.4 mg weekly with protocol-controlled escalation. That research regimen does not provide a prescribing schedule for self-treatment or combinations with other drugs.

What are the side effects of cagrilintide?

The most common side effects are gastrointestinal: nausea, constipation, diarrhea, and vomiting. Injection site reactions are also reported. Most GI side effects are mild to moderate and improve after the titration period.

Is cagrilintide the same as CagriSema?

No. Cagrilintide is a single drug (amylin analog). CagriSema is a combination product containing both cagrilintide and semaglutide in one injection. CagriSema is the product Novo Nordisk is seeking FDA approval for.

Can you take cagrilintide with tirzepatide?

The REDEFINE evidence summarized here does not establish this combination’s safety or effectiveness. Cagrilintide remains investigational; using an unapproved substance is not ordinary off-label prescribing. See our article on cagrilintide and tirzepatide.

Can you take cagrilintide with retatrutide?

REDEFINE 1 did not include retatrutide, and the evidence summarized here does not establish a safe or effective regimen combining them. Different receptor targets do not make an untested combination predictable.

How much weight can you lose on cagrilintide alone?

In the REDEFINE 1 Phase 3 trial, cagrilintide monotherapy (2.4 mg) produced 11.5% body weight loss at 68 weeks. When combined with semaglutide (as CagriSema), weight loss increased to 20.4%.

Is cagrilintide FDA approved?

No. Cagrilintide is not approved as a standalone drug. An NDA for CagriSema (cagrilintide + semaglutide) was filed with the FDA in December 2025, with a decision expected in 2026.

Where can I buy cagrilintide?

There is no approved cagrilintide product for routine prescribing. It is being studied alone in RENEW and with semaglutide as CagriSema. A research-peptide listing is not an approved treatment.

Sources

  1. Garvey WT, et al. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine. 2025;393:635-647. NEJM
  2. Carvas AO, et al. "Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3." eBioMedicine. 2025;118:105836. PMC
  3. Cao J, et al. "Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors." Nature Communications. 2025;16:3456. Nature
  4. Dutta D, et al. "Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide as Anti-Obesity Medications: A Systematic Review." Indian J Endocrinol Metab. 2024;28(5):436-444. PMC
  5. Novo Nordisk. "CagriSema demonstrated 23% weight loss in REDEFINE 4 trial." February 2026. Press Release
  6. ClinicalTrials.gov. TRIUMPH-4 record (NCT05931367) — retatrutide once-weekly in obesity and knee osteoarthritis. ClinicalTrials.gov
  7. ClinicalTrials.gov search: "retatrutide cagrilintide" returned 0 registered studies (verified May 2026). Search
This article is for informational purposes only and does not constitute medical advice. Cagrilintide is an investigational compound. Always consult a healthcare provider before starting any medication.
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Retatrutide and similar peptides are investigational — not approved by the FDA or any regulator. Semaglutide and tirzepatide are prescription-only medicines, available only through a licensed prescriber.
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Sources

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NEJMThe LancetJAMAFDAClinicalTrials.gov

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