Cagrilintide
AM833, NNC0174-0833, long-acting amylin analogue
Cagrilintide is a long-acting synthetic version of amylin, a hormone the pancreas releases alongside insulin that signals fullness. It is being developed mainly as a partner to semaglutide rather than as a standalone drug. It is not approved anywhere; the combination product is under regulatory review.
Mechanism
Cagrilintide is an acylated analogue of human amylin (islet amyloid polypeptide), a 37-amino-acid hormone co-secreted with insulin from pancreatic beta cells in response to meals. Native human amylin is difficult to use as a drug because it aggregates into amyloid fibrils. Cagrilintide's backbone is engineered around this problem, drawing on the more soluble calcitonin family, and carries a fatty-acid modification that produces reversible albumin binding and a roughly week-long half-life.
Pharmacologically it is a non-selective agonist across the amylin receptor family, which are heterodimers of the calcitonin receptor with receptor activity-modifying proteins (AMY1, AMY2, AMY3), and it also activates the calcitonin receptor itself. Its actions are principally central: amylin receptors in the area postrema and the nucleus tractus solitarius mediate meal-termination signals, and cagrilintide reduces food intake by increasing satiation, that is by making meals end sooner, rather than only by reducing hunger between meals. Rodent work published in 2025 localised the weight-lowering effect specifically to brain amylin receptors 1 and 3 (Carvas et al., cited below). This is a genuinely different mechanism from incretin agonism, which is the rationale for combining it with semaglutide: two distinct satiety pathways acting in parallel. A further hypothesis that amylin signalling partially restores leptin sensitivity is frequently repeated but rests on animal data and should not be presented as established in humans.
What the research shows
Cagrilintide as a standalone agent has been tested in a single published phase 2 dose-finding trial. In 706 adults with overweight or obesity, once-weekly cagrilintide across doses from 0.3 to 4.5 mg produced weight reductions of roughly 6% to 10.8% at 26 weeks, against 3.0% for placebo and 9.0% for liraglutide 3.0 mg. That is a respectable but not remarkable result, and cagrilintide monotherapy has not been advanced through phase 3.
The real development programme is the fixed-dose combination with semaglutide. An early phase 1b study in 95 participants established that the two could be co-administered without unfavourable pharmacokinetic interaction. The REDEFINE phase 3 programme then tested the combination: REDEFINE 1, in 3,417 adults with obesity and without diabetes, reported a mean body weight reduction of roughly 20.4% at 68 weeks against 3.0% for placebo, and REDEFINE 2, in 1,206 adults with overweight or obesity and type 2 diabetes randomised 3:1, reported reduced body weight and improved glycaemic control. The honest reading is that these are strong results but that the incremental benefit of adding cagrilintide to semaglutide has been more modest than early expectations, and the combination has not clearly outperformed tirzepatide in cross-trial comparison. A regulatory submission for the fixed-dose combination has been made to the FDA; this audit could not independently confirm the exact filing date or the target action date, and the draft's specific claims of a December 2025 filing and a fourth-quarter 2026 decision should not be relied upon without checking. No cardiovascular or other hard-outcome trial of cagrilintide, alone or in combination, has been published.
Evidence assessment
Mixed evidence
A single published phase 2 monotherapy dose-finding trial supports cagrilintide alone, with the substantial phase 3 evidence relating to the fixed-dose combination with semaglutide rather than to cagrilintide as an individual agent; all five citations were verified against PubMed, but no regulatory approval and no outcome data yet exist.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
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 Mixed evidence
Cagrilintide monotherapy produced dose-dependent weight reductions of roughly 6.0% to 10.8% versus 3.0% for placebo and 9.0% for liraglutide 3.0 mg.
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 Limited evidence
Co-administration of cagrilintide and semaglutide 2.4 mg was tolerated without unfavourable pharmacokinetic interaction, supporting development of a fixed-dose combination.
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity High-quality evidence
The cagrilintide-semaglutide combination produced a mean body weight reduction of approximately 20.4% versus 3.0% with placebo at 68 weeks.
Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes High-quality evidence
The cagrilintide-semaglutide combination reduced body weight and improved glycaemic control in adults with overweight or obesity and type 2 diabetes.
Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3 Preclinical only
The weight-lowering effect of cagrilintide was localised to amylin receptors 1 and 3 in the brain, clarifying the receptor subtypes responsible.
Safety
In the phase 2 monotherapy trial and the phase 3 combination trials, gastrointestinal adverse events predominated: nausea, vomiting, constipation and diarrhoea, dose-related and concentrated during escalation. When combined with semaglutide, gastrointestinal rates are higher than with either component alone, which is unsurprising given two convergent satiety mechanisms. Injection-site reactions have been reported. Because amylin receptor signalling overlaps with the calcitonin receptor, effects on calcium and bone metabolism are a theoretical consideration but have not emerged as a clinical problem in trials to date. The critical limitation is that cagrilintide has never been through a phase 3 monotherapy programme and has no completed outcome trial, so its independent long-term safety profile is not separately characterised; almost all long-duration human safety data for cagrilintide come from the combination product, where effects cannot be cleanly attributed between components. Cagrilintide sold to consumers, whether alone or in unlicensed combinations, is an unapproved drug of unverified composition; it is not the clinical-grade material used in the trials described here.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Not licensed by the MHRA, alone or in combination. Available in the UK only through participation in a registered clinical trial. |
| United States | Not approved as a standalone agent and not approved in combination. A New Drug Application for the fixed-dose cagrilintide-semaglutide combination has been submitted to the FDA; the precise filing date and target action date could not be independently confirmed for this entry and are stated here without a specific date rather than guessed. Cagrilintide sold directly to consumers is an unapproved drug distributed outside the regulatory system. |
| WADA (sport) | Not specifically named on the WADA Prohibited List. As a non-approved pharmacological substance it falls within class S0 (Non-Approved Substances) and is therefore prohibited at all times for athletes under the Code. |
Questions
They are separate satiety systems. GLP-1 receptor agonists reduce hunger and slow gastric emptying, acting through the hypothalamus and hindbrain. Amylin acts mainly on the area postrema and nucleus tractus solitarius to promote satiation, meaning meals end sooner. Because the pathways are distinct, combining them was expected to be additive. A further hypothesis that amylin signalling partially restores leptin sensitivity comes from animal work and has not been demonstrated in people.
No. Neither cagrilintide alone nor the fixed-dose combination with semaglutide is approved in any jurisdiction as of August 2026. A regulatory submission for the combination has been made to the FDA, though this library has not been able to confirm the exact filing and decision dates. Anything sold as cagrilintide to consumers is an unapproved drug of unverified composition.
Partly. REDEFINE 1 showed roughly 20.4% weight loss at 68 weeks, which is a strong result in absolute terms. But it fell short of pre-trial market expectations and did not clearly separate from tirzepatide in cross-trial comparison, and the incremental gain attributable to cagrilintide over semaglutide alone is more modest than the headline figure suggests. This is a case where the honest read differs noticeably from the promotional framing.
No. The only published standalone randomised trial is the 706-person phase 2 dose-finding study, which ran 26 weeks and produced weight loss broadly comparable to liraglutide 3.0 mg. Monotherapy was not advanced. That means cagrilintide's independent long-term efficacy and safety profile has never been established; almost everything known about extended exposure comes from the combination product.