Cagrilintide

AM833 / NNC0174-0833 · Novo Nordisk · Amylin Receptor Agonist

"Novo Nordisk's amylin analogue — it works the satiety pathway GLP-1 drugs leave untouched. Around 11% weight loss as a once-weekly monotherapy in Phase 3, and the backbone of CagriSema. Already circulating grey-market in blends with semaglutide, tirzepatide and retatrutide — which is exactly why it is worth understanding honestly. Investigational, not approved anywhere."

Type

Amylin receptor agonist (analogue)

Origin

Novo Nordisk · AM833

Status

UK: legal to buy or possess (investigational compound) · WADA: not specifically listed · Not approved anywhere — Phase 3 monotherapy + CagriSema combo under FDA review

Phase 3 weight loss

~11.8% monotherapy at 68 wks (REDEFINE 1)

Protocol summary

Trial dose

2.4 mg weekly SubQ

Mechanism

Amylin receptor agonist

Status

Phase 3 ongoing · pre-approval

Clinical-trial

Escalation 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg weekly SubQ (4 wks/step)

Not approved anywhere; investigational. Grey-market blends are unverified for dose/purity

How we read the evidence

Long-acting amylin analogue · ~10.8% Phase 2 / ~11.8% Phase 3 as monotherapy · backbone of CagriSema · investigational, not approved anywhere

Preclinical & pharmacology

Cagrilintide (AM833 / NNC0174-0833) is a long-acting analogue of amylin — the pancreatic hormone co-secreted with insulin that signals fullness via the hindbrain (area postrema). It is an agonist at amylin and calcitonin receptors. The molecule is engineered with a fatty-acid side chain for albumin binding, giving a half-life of roughly 180 hours (~7 days) — long enough for once-weekly subcutaneous dosing, in contrast to the original short-acting mealtime amylin analogue pramlintide. The pharmacological rationale is that amylin acts on a satiety pathway largely separate from GLP-1, so it can add to GLP-1 effects rather than overlap them — the basis for the CagriSema combination.

Community & clinical practice

Cagrilintide is investigational — not approved or commercially available anywhere. In practice it circulates grey-market through research-peptide vendors, very often sold in fixed blends with semaglutide, tirzepatide or retatrutide ("cagri blends"). These blends are the main real-world exposure — and the riskiest: dose accuracy, purity and sterility are unverified, the ratios are arbitrary, and stacking an amylin agonist on top of a potent GLP-1 compounds gastrointestinal and lean-mass risk while making it impossible to attribute effects or side effects. Pep IQ does not endorse pre-approval or blended use; the monotherapy safety profile is only now being characterised in Phase 3.

Human trial data

Solid monotherapy data, plus a powerful combination. Phase 2 dose-finding (Lancet 2021, 706 adults, 26 weeks): once-weekly cagrilintide produced ~9.7% weight loss at 2.4 mg and ~10.8% at 4.5 mg versus ~3.0% on placebo. Phase 3 REDEFINE 1 included a cagrilintide 2.4 mg monotherapy arm — the first and only Phase 3 of a long-acting amylin used alone — reporting roughly 11.8% mean weight loss versus 2.3% placebo at 68 weeks, with ~31.6% of participants achieving over 15% loss. As the combination CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg), REDEFINE 1 showed about −20.4% at 68 weeks with ~60% achieving ≥20%, and REDEFINE 2 (NEJM, June 2025) confirmed significant weight loss in type 2 diabetes. Gastrointestinal events (nausea, constipation, diarrhoea) and injection-site reactions are the common adverse effects, generally mild to moderate.

Regulatory status

Not approved by any regulatory agency. Novo Nordisk submitted the CagriSema combination to the US FDA in December 2025, with a decision anticipated around late 2026; cagrilintide as a standalone monotherapy has not yet been filed. An important honest caveat: in REDEFINE 4 (reported February 2026) CagriSema 2.4/2.4 did not meet non-inferiority versus tirzepatide 15 mg at 84 weeks, and higher-dose CagriSema trials are planned to explore the full effect. WADA does not list cagrilintide specifically. Pre-approval grey-market supply is unauthorised and quality-uncertain.

Convergence

Cagrilintide is genuinely important: a novel mechanism (amylin) hitting a satiety pathway the GLP-1 drugs miss, with credible Phase 2 and Phase 3 monotherapy data and a powerful role inside CagriSema. But it is not approved anywhere, the headline combination missed non-inferiority against tirzepatide in one Phase 3 trial, and — crucially — almost all real-world exposure is happening through unverified grey-market blends with semaglutide, tirzepatide or retatrutide. That blended route compounds GI and lean-mass risk, can't be quality-assured, and makes any effect impossible to attribute. Pep IQ's read: scientifically one to track closely; pre-approval blended self-use is the riskiest possible way to encounter it. Follow the regulatory timeline rather than the grey market.

Origin & Background

The satiety hormone the GLP-1 race skipped

Amylin is a hormone co-secreted with insulin from pancreatic beta cells. It acts mainly on the hindbrain (the area postrema) to promote fullness, slow gastric emptying and reduce food intake — a satiety signal that runs largely parallel to GLP-1 rather than overlapping it. The GLP-1 boom (semaglutide, tirzepatide) was built on the incretin axis; amylin is a different lever on appetite, and one the headline GLP-1 drugs do not pull.

The first amylin analogue, pramlintide, has been approved for years but is short-acting and must be injected at mealtimes, which limited its use. Cagrilintide (AM833) is Novo Nordisk's long-acting successor — re-engineered with an albumin-binding side chain to give a roughly 7-day half-life, so it can be dosed once weekly like the modern GLP-1s.

Novo's strategic bet is twofold: cagrilintide as a once-weekly amylin monotherapy, and — more prominently — cagrilintide paired with semaglutide as the fixed-dose combination CagriSema, on the logic that hitting two separate satiety pathways at once should beat either alone. That combination, and the standalone, are what the Phase 3 REDEFINE programme has been testing.

Why amylin is complementary, not redundant: Because amylin and GLP-1 act on overlapping-but-distinct satiety circuitry, an amylin agonist can add to a GLP-1 drug rather than just duplicate it — which is the entire rationale for CagriSema. The honest counter-point, delivered by REDEFINE 4 in early 2026, is that "two mechanisms" did not automatically beat the best single triple-target rival (tirzepatide) on weight at 84 weeks. Complementary mechanisms are promising, not guaranteed to win.

Science & Mechanism

One hormone, a separate satiety lever

Mechanism of Action

Amylin receptor agonism: Activates amylin receptors (calcitonin receptor paired with RAMP subunits) concentrated in the hindbrain area postrema — the brain's satiety and nausea hub.

Promotes satiety: Enhances feelings of fullness and reduces food intake, signalling "enough" through a route distinct from GLP-1's central appetite suppression.

Slows gastric emptying: Food leaves the stomach more slowly, prolonging fullness after meals — a contributor to both the appetite effect and the gastrointestinal side effects.

Complementary to GLP-1: Because the pathway is largely separate, cagrilintide can stack additively with semaglutide — the mechanistic basis for CagriSema, rather than simply doubling a GLP-1 dose.

Long half-life by design: An albumin-binding fatty-acid side chain extends the half-life to ~180 hours (~7 days), enabling once-weekly subcutaneous dosing versus the mealtime dosing of older amylin analogues.

As a monotherapy the effect is meaningful but moderate by current standards: ~9.7–10.8% weight loss at 26 weeks in Phase 2, and ~11.8% at 68 weeks in the REDEFINE 1 monotherapy arm — broadly in the range of older single-agent GLP-1 therapy, and below the 20%+ seen with the strongest combinations and triple agonists.

The combination is where the numbers get large: CagriSema (cagrilintide + semaglutide) reached about −20.4% at 68 weeks in REDEFINE 1. But REDEFINE 4 (February 2026) found CagriSema 2.4/2.4 did not establish non-inferiority to tirzepatide 15 mg at 84 weeks, so its place against the best incretin therapy is still being worked out, with higher-dose trials planned.

Benefits & Evidence

What the data shows

⚖️

Weight loss — as monotherapy

Phase 2 (Lancet 2021): ~9.7% at 2.4 mg and ~10.8% at 4.5 mg over 26 weeks vs ~3.0% placebo. Phase 3 REDEFINE 1 monotherapy arm: ~11.8% at 68 weeks vs 2.3% placebo, with ~31.6% achieving over 15% loss — the first Phase 3 of a long-acting amylin used alone.

● Strong — Phase 2 + Phase 3 monotherapy data

🔗

CagriSema combination

With semaglutide 2.4 mg, REDEFINE 1 reached ~−20.4% at 68 weeks (~60% achieving ≥20%). The honest caveat: REDEFINE 4 (Feb 2026) did not show non-inferiority to tirzepatide 15 mg at 84 weeks, so its standing against the strongest incretin therapy is unresolved.

● Mixed — strong loss, missed a key head-to-head

🧠

Novel satiety mechanism

Amylin agonism works a fullness pathway largely separate from GLP-1 — meaningful because it offers a genuinely different lever on appetite and a rational partner for GLP-1 drugs, rather than another molecule doing the same thing.

● Strong — well-characterised pharmacology

🩸

Type 2 diabetes (combination)

REDEFINE 2 (NEJM, June 2025) showed CagriSema produced significantly greater weight loss and glycaemic improvement than placebo in adults with type 2 diabetes. Standalone glycaemic data for cagrilintide alone is more limited.

● Moderate — combination Phase 3 in T2D

Things to know

Risks & considerations

Moderate

GI side effects — nausea, constipation, diarrhoea and vomiting, predominantly during dose escalation. Slowed gastric emptying is part of the mechanism, so some GI effect is expected.

Moderate

Lean-mass loss — as with any potent appetite-reducing agent, weight lost without resistance training and adequate protein includes muscle. Risk rises when cagrilintide is stacked onto a GLP-1 for larger, faster loss.

Serious

Grey-market blends — cagrilintide is mostly encountered combined with semaglutide, tirzepatide or retatrutide. These products have unverified content, ratios and sterility; compounded GI/lean-mass risk; and make any adverse effect impossible to attribute to a single agent.

Unknown

Long-term & monotherapy safety — the standalone long-acting amylin safety profile is only now being characterised in Phase 3; long-term outcome and cardiovascular data are not yet available.

⚠ Key Warnings

Cagrilintide is NOT approved anywhere — it is investigational. CagriSema (the combination) is under FDA review with a decision anticipated around late 2026; cagrilintide monotherapy has not been filed.

Grey-market cagrilintide — especially in blends with semaglutide, tirzepatide or retatrutide — cannot be verified for dose, purity or sterility. Pep IQ does not endorse pre-approval or blended self-use.

Stacking an amylin agonist on top of a potent GLP-1 compounds gastrointestinal and lean-mass risk and obscures cause and effect; it is the riskiest way this compound is currently being used.

In REDEFINE 4 the CagriSema combination did not beat tirzepatide on the key endpoint — efficacy versus the best approved therapy is unsettled. This entry is educational and not medical advice.