Cagrilintide

Cagrilintide is a lipidated, long-acting analogue of amylin — the hormone that pancreatic beta cells release alongside insulin at every meal. Its development code is AM833 (Fletcher et al., J Pharmacol Exp Ther 2021). Evidence tier: clinical-stage. It is investigational in every jurisdiction; no cagrilintide product carries a US label (a DailyMed search returns no entry for either cagrilintide or CagriSema).

The thing that makes it interesting is that it is not a GLP-1 drug and does not behave like one. In its dose-finding phase 2 trial, cagrilintide on its own produced more weight loss than liraglutide 3.0 mg, an approved GLP-1 medicine, while acting through a completely separate receptor system (Lau et al., Lancet 2021).

Amylin does not have a receptor of its own. Amylin receptors are built by pairing the calcitonin receptor (CTR) with one of three receptor activity-modifying proteins: CTR plus RAMP1 gives AMY1, plus RAMP2 gives AMY2, plus RAMP3 gives AMY3 (Hay et al., IUPHAR Review 25, Br J Pharmacol 2018). These complexes are concentrated in hindbrain regions — the area postrema and nucleus tractus solitarius — that read circulating signals about a meal and translate them into meal termination.

Cagrilintide was characterised head-to-head against six other agonists and behaves as a non-selective agonist of the calcitonin receptor family: it activates the amylin receptors and, independently, the calcitonin receptor itself. The authors argue that this dual activity may be an advantage rather than an impurity of design, because unselective amylin-receptor agonists showed greater efficacy for obesity than selective ones (Fletcher et al., 2021). Downstream, amylin signalling slows gastric emptying, suppresses glucagon after meals, and increases satiety.

This is why cagrilintide is paired with GLP-1 agonists rather than compared with them. GLP-1 receptors and calcitonin-family receptors are separate targets with partly separate hindbrain circuitry, so combining them is an attempt to add two appetite signals rather than push one receptor harder.

There is no approved indication for cagrilintide anywhere in the world, alone or combined. Its clinical programme has targeted chronic weight management in overweight and obesity, and — via the combination — type 2 diabetes with obesity.

Because the molecule is unapproved, material sold online under the name is not the trial product: it has no pharmacopoeial identity or purity standard behind it, and no dispensing framework. That is a different situation from an off-label use of an approved drug.

Gastrointestinal effects dominate, and they are dose-related. In the 26-week phase 2 monotherapy trial, nausea occurred in 20–47% of participants across the cagrilintide dose range versus 18% on placebo, and about 10% of participants discontinued, mainly because of adverse events (Lau et al., 2021). In combination with semaglutide over 68 weeks, gastrointestinal adverse events — nausea, vomiting, diarrhoea, constipation, or abdominal pain — affected 79.6% of participants versus 39.9% on placebo, and were described as mainly transient and mild-to-moderate (Garvey et al., REDEFINE 1, NEJM 2025).

Injection-site reactions and reduced appetite are also reported. Longer-term questions — rare events, cardiovascular outcomes, effects on lean mass — have not been answered for cagrilintide specifically, since no dedicated outcomes trial has reported.

Cagrilintide is given subcutaneously once weekly. That interval is possible because acylation extends its persistence dramatically relative to native amylin: in the phase 1b study, cagrilintide and semaglutide both showed half-lives in the range of roughly 145–195 hours, or about 6–8 days (Enebo et al., Lancet 2021). Cagrilintide did not alter semaglutide's pharmacokinetics.

In trials cagrilintide has appeared in two forms: as a single agent, and co-formulated with semaglutide as CagriSema, a fixed once-weekly injection at 2.4 mg of each molecule. The fixed ratio was settled during phase 1b/2 development and is the only version taken into phase 3; see the separate cagrilintide + semaglutide entry for the REDEFINE results.

Cagrilintide is not the only amylin-receptor agonist in play. Pramlintide, a short-acting amylin analogue, is already an approved adjunct in insulin-requiring diabetes and requires mealtime dosing (Hay et al., 2018) — the practical contrast that a weekly analogue is designed to remove.

• Phase 2 monotherapy (Lancet 2021, n=706, 26 weeks, 57 sites in ten countries). Weight reduction was 6.0–10.8% across cagrilintide 0.3–4.5 mg versus 3.0% with placebo. At the top dose, cagrilintide 4.5 mg gave 10.8% (11.5 kg) against 9.0% (9.6 kg) for the active comparator liraglutide 3.0 mg (Lau et al.).

• Phase 1b with semaglutide (Lancet 2021, n=95 exposed, 20 weeks). Weight reductions of 15.4–17.1% with cagrilintide 1.2–4.5 mg plus semaglutide 2.4 mg, versus 8.0–9.8% for pooled placebo-plus-semaglutide (Enebo et al.).

• Phase 2 in type 2 diabetes (Lancet 2023, n=92, 32 weeks). The combination reduced weight by 15.6% and HbA1c by 2.2 percentage points, versus 0.9 points for cagrilintide alone (Frias et al.) — cagrilintide is a weight drug more than a glucose drug.

• Phase 3 (NEJM 2025). REDEFINE 1 randomised 3,417 adults for 68 weeks and included stand-alone cagrilintide and semaglutide arms of 302 participants each; the combination reached −20.4% versus −3.0% on placebo (Garvey et al.). No phase 3 trial has tested cagrilintide as monotherapy.

The gap in this record is deliberate and worth naming: cagrilintide's own development pivoted to the combination after phase 2, so the largest and longest data on the molecule describe it in company with semaglutide rather than on its own.

For deeper dives on this peptide, see:

• Cagrilintide benefits and areas of interest
• Cagrilintide side effects and safety context
• Cagrilintide dosing concepts (educational)
• Cagrilintide research and evidence overview

Is cagrilintide a GLP-1 drug? No. It is a long-acting amylin analogue that works through calcitonin-family receptors — the calcitonin receptor paired with RAMP proteins — mainly in the hindbrain. That is a parallel pathway to GLP-1, which is why the two are combined rather than swapped (Fletcher et al., 2021).

How much weight loss has cagrilintide shown by itself? 6.0% to 10.8% across doses over 26 weeks versus 3.0% for placebo, with the 4.5 mg dose edging out liraglutide 3.0 mg at 10.8% versus 9.0%. That is its only monotherapy efficacy trial (Lancet 2021).

Can you get cagrilintide as an approved medicine? No. It is investigational everywhere — no standalone approval exists, and the combination with semaglutide is not approved either. Vials sold online are unregulated research chemicals, not the trial product.

What is CagriSema? The fixed once-weekly combination of cagrilintide 2.4 mg and semaglutide 2.4 mg. In REDEFINE 1 it produced 20.4% average weight loss over 68 weeks versus 3.0% with placebo in 3,417 adults (NEJM 2025).

What are cagrilintide's main side effects? Gastrointestinal ones. Nausea affected 20–47% across doses in the monotherapy trial versus 18% on placebo, alongside constipation and diarrhoea — mostly early and mild-to-moderate, which is the reason trials escalate the dose over weeks rather than starting at target.