Quick Answer
Cagrilintide is a synthetic analogue of amylin, a hormone released with insulin that slows stomach emptying and signals fullness to the brain. Novo Nordisk built it on the pramlintide sequence, with substitutions that counter amylin's tendency to form fibrils and a fatty acid side chain that extends its half-life to about a week. It activates all three amylin receptors and the calcitonin receptor. In a 68-week phase 3 trial, mean weight loss was 11.5% with cagrilintide alone and 20.4% with CagriSema, its combination with semaglutide. Neither is approved.
Amylin is a satiety hormone from the pancreas, long overshadowed by the gut hormone GLP-1, partly because it is hard to make into a drug. Cagrilintide, developed by Novo Nordisk as AM833, is the most advanced long-acting amylin analogue.
What amylin does
Amylin is a 37-amino-acid hormone released with insulin from pancreatic beta cells (Hay et al., 2015). It slows gastric emptying, suppresses glucagon after meals and promotes satiation through the brain, acting mainly on circumventricular regions such as the area postrema (Hay et al., 2015; Fischer et al., 2026).
It is an awkward drug template. Human amylin readily aggregates into amyloid fibrils (Kruse et al., 2021). Pramlintide, modelled on non-aggregating rat amylin, is approved for diabetes as an adjunct to insulin, but its short half-life limited its practicality (Bailey et al., 2026; Kruse et al., 2021).
How cagrilintide was engineered
Novo Nordisk published the structure-activity work in 2021, describing a stable, lipidated, long-acting analogue selected for clinical development in obesity (Kruse et al., 2021). Cagrilintide differs from pramlintide at three positions and carries a lipid at its N-terminus; later structural work explained each change (Cao et al., 2025):
- Helix-stabilising substitutions. Glutamic acid and arginine replace asparagine 14 and valine 17, forming a salt bridge that stabilises the N-terminal helix and counters fibril formation.
- A C-terminal proline. An amidated proline replaces amylin's tyrosine. In earlier receptor studies this swap raised activity at both calcitonin and amylin receptors, sometimes reducing selectivity between them.
- A fatty acid side chain. The N-terminal lysine carries a gamma-glutamic acid linker and a 20-carbon fatty diacid. Lipidation of this kind allows reversible binding to serum albumin, slowing clearance (Fischer et al., 2026). A lipid-free version kept its potency at the amylin 3 receptor in cell assays.
In a phase 1b study, cagrilintide's half-life was 159 to 195 hours, close to a week (Enebo et al., 2021). Its CAS number is 1415456-99-3 and its molecular weight about 4.4 kDa.
Receptor profile: amylin and calcitonin receptors
Amylin receptors are built from the calcitonin receptor paired with one of three receptor activity-modifying proteins (RAMP1, RAMP2 or RAMP3), giving AMY1R, AMY2R and AMY3R (Hay et al., 2015). The calcitonin receptor alone responds strongly to calcitonin and weakly to amylin (Cao et al., 2025).
Cagrilintide activates all four. A 25-endpoint pharmacology study classed it as a non-selective agonist with a profile distinct from pramlintide and salmon calcitonin (Fletcher et al., 2021), and cryo-electron microscopy structures of all four complexes show a broadly amylin-like binding mode (Cao et al., 2025).
Whether the calcitonin receptor matters is debated. Selective calcitonin receptor activation has not controlled weight, yet dual agonists have been reported to outperform amylin-selective ones, mostly in animal studies (Fletcher et al., 2021; Cao et al., 2025). In rodents:
- In obese mice lacking RAMP1 and RAMP3, cagrilintide's weight-lowering effect was blunted, implicating AMY1R and AMY3R (Carvas et al., 2025).
- In rats, its longer-term effects ran through brainstem neurons that make prolactin-releasing hormone. Knocking that hormone down blocked the effects of cagrilintide but not semaglutide (Ludwig et al., 2026).
In Eli Lilly's rat studies, its AMY1R-preferring eloralintide caused less conditioned taste avoidance, a marker of aversion, than cagrilintide (Briere et al., 2025). Reviewers have asked whether calcitonin receptor engagement pushes reduced eating towards aversion (Fischer et al., 2026); no human trial has tested it directly.
The clinical trial programme
Cagrilintide has been studied alone and with semaglutide as CagriSema. The main published randomised trials:
| Trial | Participants | Comparison | Length | Headline result |
|---|---|---|---|---|
| Phase 1b (Enebo et al., 2021) | 96 adults with overweight or obesity | Cagrilintide or placebo, each with semaglutide | 20 weeks | Safety primary; exploratory weight loss up to 17.1% vs 9.8% |
| Phase 2 (Lau et al., 2021) | 706 adults without diabetes | Five cagrilintide arms vs placebo and liraglutide | 26 weeks | Weight down 6.0% to 10.8% vs 3.0% (placebo) and 9.0% (liraglutide) |
| Phase 2 (Frias et al., 2023) | 92 adults with type 2 diabetes | CagriSema vs semaglutide vs cagrilintide | 32 weeks | HbA1c down 2.2, 1.8 and 0.9 points; weight down 15.6%, 5.1% and 8.1% |
| REDEFINE 1 (Garvey et al., 2025) | 3,417 adults without diabetes | CagriSema vs semaglutide, cagrilintide and placebo | 68 weeks | Weight down 20.4% vs 14.9%, 11.5% and 3.0% |
| REDEFINE 2 (Davies et al., 2025) | 1,206 adults with type 2 diabetes | CagriSema vs placebo | 68 weeks | Weight down 13.7% vs 3.4% |
| REIMAGINE 2 (Buse et al., 2026) | 2,713 adults with type 2 diabetes | CagriSema vs semaglutide, cagrilintide and placebo | 68 weeks | HbA1c down 1.91 vs 1.75 points (semaglutide) |
Mean changes from baseline; estimands and populations differ between trials.
Cagrilintide on its own
In phase 2, every cagrilintide arm beat placebo and the top arm edged out liraglutide (Lau et al., 2021). In REDEFINE 1 the 302-person cagrilintide arm lost less than semaglutide alone, but a substantial amount for a single non-incretin mechanism (Garvey et al., 2025). A dedicated phase 3 programme, RENEW, began in November 2025 and has not reported.
Cagrilintide with semaglutide (CagriSema)
The rationale is that amylin and GLP-1 act through partly different circuits. The phase 1b weight data were exploratory, from a small safety study (Enebo et al., 2021), and in phase 2 CagriSema's HbA1c advantage over semaglutide was not statistically significant (Frias et al., 2023). Phase 3 confirmed the weight effect at scale. In REDEFINE 2, 73.5% of the CagriSema group reached an HbA1c of 6.5% or lower against 15.9% on placebo (Davies et al., 2025), while in REIMAGINE 2 its HbA1c margin over semaglutide was a small 0.16 percentage points (Buse et al., 2026).
Against tirzepatide
Two head-to-head trials have been less favourable. Novo Nordisk reported in February 2026 that REDEFINE 4, an open-label 84-week trial in 809 people, did not show CagriSema to be non-inferior to tirzepatide for weight loss (20.2% against 23.6%), and in August 2026 that REIMAGINE 4, in type 2 diabetes, met non-inferiority for weight but not for HbA1c. Neither is published yet, so these remain company figures.
Adverse events reported in the trials
The pattern resembles the GLP-1 class. In phase 2, gastrointestinal events affected 41% to 63% of cagrilintide groups against 32% on placebo, mostly nausea, constipation and diarrhoea (Lau et al., 2021). With CagriSema the figures were 79.6% against 39.9% in REDEFINE 1 and 72.5% against 34.4% in REDEFINE 2, mainly transient and mild to moderate (Garvey et al., 2025; Davies et al., 2025). Across the class, nausea is most common early in treatment and mostly resolves (Bailey et al., 2026). Published follow-up stops at 68 weeks; REDEFINE 3, a cardiovascular outcomes trial of about 7,000 people (NCT05669755), is still running.
Where cagrilintide sits in the amylin class
Receptor selectivity is a key difference among long-acting amylin analogues (Fischer et al., 2026):
- Cagrilintide (Novo Nordisk): non-selective, with the largest phase 3 dataset, mostly as CagriSema.
- Eloralintide (Eli Lilly): designed to favour AMY1R (Briere et al., 2025).
- Petrelintide (Zealand Pharma): another long-acting analogue in clinical development.
- Amycretin, now named zenagamtide (Novo Nordisk): one molecule with GLP-1 and amylin receptor activity (Bailey et al., 2026).
Our eloralintide vs cagrilintide comparison sets the two leaders side by side. No head-to-head human trial between amylin analogues has been published, so tolerability claims rest on rodent work and cross-trial comparison.
Regulatory status
At the end of September 2026, Novo Nordisk still described CagriSema as investigational. It was submitted to the US FDA in December 2025, with a decision expected in the fourth quarter of 2026. Neither it nor cagrilintide alone has a UK marketing authorisation; research-grade material is for laboratory use only, and UK supply details are on our cagrilintide UK page.
The bottom line
Cagrilintide is precise peptide engineering with a deliberately broad receptor profile. The human evidence is strongest for CagriSema, from large phase 3 trials. The open questions are long-term outcomes, the tirzepatide comparisons once published, the RENEW results, and whether calcitonin receptor activity is an asset or a cost.
References
- Hay DL, et al. (2015). Amylin: Pharmacology, Physiology, and Clinical Potential. Pharmacological Reviews 67(3):564-600. PubMed 26071095
- Fischer SL, et al. (2026). Beyond GLP-1: Amylin-based pharmacotherapy and the search for better-tolerated weight-loss drugs. Pharmacological Research 232:108382. PubMed 42586227
- Kruse T, et al. (2021). Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry 64(15):11183-11194. PubMed 34288673
- Bailey CJ, et al. (2026). Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes. Peptides 196:171480. PubMed 41747885
- Cao J, et al. (2025). Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature Communications 16(1):3389. PubMed 40204768
- Enebo LB, et al. (2021). 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 397(10286):1736-1748. PubMed 33894838
- Fletcher MM, et al. (2021). AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists. Journal of Pharmacology and Experimental Therapeutics 377(3):417-440. PubMed 33727283
- Carvas AO, et al. (2025). Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3. EBioMedicine 118:105836. PubMed 40609154
- Ludwig MQ, et al. (2026). A cross-species atlas of the dorsal vagal complex reveals neural mediators of the effects of cagrilintide on energy balance. Nature Metabolism 8(6):1350-1367. PubMed 42260119
- Briere DA, et al. (2025). Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept. Molecular Metabolism 102:102271. PubMed 41109426
- Lau DCW, et al. (2021). 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 398(10317):2160-2172. PubMed 34798060
- Frias JP, et al. (2023). 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 402(10403):720-730. PubMed 37364590
- Garvey WT, et al. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine 393(7):635-647. PubMed 40544433
- Davies MJ, et al. (2025). Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. New England Journal of Medicine 393(7):648-659. PubMed 40544432
- Buse JB, et al. (2026). Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study. The Lancet Diabetes & Endocrinology 14(8):662-677. PubMed 42251859