- Generic name: Cagrilintide · Developer code: AM833 (Novo Nordisk)
- CAS: 2382095-92-1
- Type: Long-acting acylated amylin analogue
- Receptor targets: CTR (calcitonin receptor), AMY1/2/3 receptor complexes
- Dosing: Once-weekly subcutaneous injection (2.4 mg in trials)
- CagriSema Ph2 weight loss: 22.7% at 32 weeks
- Status: Phase 3 (REDEFINE programme)
01 What Is Cagrilintide?
Cagrilintide (AM833) is a fatty acid-conjugated amylin analogue developed by Novo Nordisk. It mimics native amylin — a 37-amino acid peptide co-secreted with insulin from pancreatic beta cells — but with a dramatically extended half-life enabling once-weekly subcutaneous dosing.
Native amylin was recognised in the 1980s as a co-regulator of postprandial glucose metabolism. Pramlintide, the first approved amylin analogue, required three-times-daily injection and demonstrated modest weight loss (~1–2 kg). Cagrilintide's long-acting design enables combination with once-weekly GLP-1 agonists, creating a novel dual-mechanism metabolic regimen with substantially greater weight loss than either agent alone.
02 Amylin Biology and Metabolic Role
Amylin is a 37-amino acid peptide hormone forming amyloid fibrils in pancreatic beta cell secretory granules. In health, it is co-secreted with insulin in a ~1:100 molar ratio after meals. Its physiological roles include:
- Postprandial satiety: Acts on area postrema CTR to reduce meal size and terminate feeding
- Gastric emptying: Slows gastric emptying, reducing the rate of glucose appearance in circulation
- Glucagon suppression: Suppresses postprandial glucagon release from alpha cells
- Glycaemic control: Collectively reduces postprandial glucose excursion independent of insulin
In type 2 diabetes, amylin secretion is impaired alongside insulin secretion — contributing to postprandial hyperglycaemia and loss of satiety signalling. In obesity without diabetes, amylin resistance (analogous to insulin resistance) has been proposed as a contributing mechanism to impaired satiety.
03 Calcitonin Receptor Agonism Mechanism
Amylin and its analogues exert their CNS effects via calcitonin receptor (CTR) complexes in the area postrema (AP) — a circumventricular organ that lacks the blood-brain barrier, making it uniquely accessible to circulating peptide hormones. The amylin receptor complexes (AMY1, AMY2, AMY3) are heterodimers of CTR with receptor activity-modifying proteins (RAMP1, RAMP2, RAMP3).
Key downstream effects of CTR/AMY activation:
- Area postrema neurons: Activation reduces feeding drive via projections to NTS and hypothalamic nuclei
- Gastric vagal afferents: Slows gastric emptying via vagal CTR pathways
- Pancreatic alpha cells: Suppresses postprandial glucagon secretion
- Adipose tissue: CTR expression on adipocytes suggests direct peripheral metabolic roles
Importantly, the amylin/CTR pathway is anatomically and pharmacologically distinct from GLP-1/GLP-1R signalling — explaining why their combination produces synergistic rather than additive weight loss.
04 CagriSema Combination — Phase 2 Data
- CagriSema (2.4+2.4 mg): −22.7% mean body weight
- Semaglutide 2.4 mg alone: −15.6% mean body weight
- Cagrilintide 2.4 mg alone: −11.8% mean body weight
- Placebo: −1.8% mean body weight
- HbA1c (T2D subgroup): −2.2% for CagriSema vs −1.5% semaglutide alone
The 22.7% weight loss at 32 weeks for CagriSema exceeded the 20.9% seen with tirzepatide 15 mg at 72 weeks in SURMOUNT-1 — though direct comparison is confounded by different trial durations, populations, and designs. The data confirms that amylin + GLP-1 co-agonism operates through additive-to-synergistic mechanisms.
Phase 3 REDEFINE trials are ongoing with primary endpoints at 68 weeks. Novo Nordisk has reported positive topline Phase 3 results from REDEFINE 1 (obesity without T2D) showing ~22.7% weight reduction, broadly consistent with Phase 2.
05 Cagrilintide vs Pramlintide
| Property | Cagrilintide | Pramlintide (Symlin) |
|---|---|---|
| Half-life | ~7 days (once-weekly) | ~48 minutes (3×/day) |
| Dosing frequency | Once weekly | 3× daily (with meals) |
| Fatty acid conjugation | Yes (C18 diacid) | No |
| Approval status | Phase 3 (investigational) | Approved (T1D/T2D with insulin) |
| Phase 2 weight loss | −11.8% mono; −22.7% + sema | ~1–2 kg (add-on to insulin) |
| Combination therapy | Yes (CagriSema) | Insulin only |
06 Frequently Asked Questions
What is Cagrilintide?
Cagrilintide (AM833) is a long-acting acylated amylin analogue developed by Novo Nordisk. It agonises the calcitonin receptor (CTR) and amylin receptor complexes (AMY1, AMY2, AMY3), mimicking the actions of native amylin — a pancreatic hormone co-secreted with insulin that regulates satiety, gastric emptying, and postprandial glucose excursion. Its long half-life enables once-weekly subcutaneous dosing.
How does amylin differ from GLP-1 in satiety signalling?
GLP-1 and amylin both reduce appetite but via different neural circuits. GLP-1 acts primarily on vagal afferents and brainstem GLP-1R to slow gastric emptying and signal satiety. Amylin acts on area postrema (AP) calcitonin receptors — a circumventricular organ outside the blood-brain barrier — to directly suppress feeding. This distinct mechanism makes amylin + GLP-1 co-agonism potentially synergistic rather than redundant.
What is CagriSema and what does the research show?
CagriSema is the fixed-dose combination of cagrilintide (2.4 mg) and semaglutide (2.4 mg) studied by Novo Nordisk. Phase 2 COMBINING data (32 weeks) showed CagriSema produced 22.7% mean weight loss versus 15.6% for semaglutide alone and 11.8% for cagrilintide alone — suggesting synergistic benefit of dual amylin + GLP-1 agonism. Phase 3 REDEFINE programme is ongoing.
What does the calcitonin receptor do in appetite regulation?
The calcitonin receptor (CTR) is expressed in the area postrema and nucleus tractus solitarius — brainstem regions critical for appetite control and nausea. When amylin or amylin analogues (cagrilintide, pramlintide) activate CTR in the area postrema, they reduce meal size and slow gastric emptying. CTR is also expressed on adipocytes and bone cells, suggesting additional peripheral metabolic roles.
What is the difference between Cagrilintide and Pramlintide?
Pramlintide (Symlin) is an amylin analogue approved for use alongside insulin in T1D and T2D. It requires multiple daily injections due to its short half-life (~48 min). Cagrilintide is structurally optimised with a fatty acid conjugation enabling once-weekly dosing — comparable to semaglutide or tirzepatide's dosing schedule — making it practical for combination regimens.
Related research: