Cagrilintide: Research Overview

Cagrilintide (NN9838) is a long-acting synthetic analogue of amylin, a 37-amino acid pancreatic peptide co-secreted with insulin. Developed by Novo Nordisk and classified as a dual amylin and calcitonin receptor agonist (DACRA), cagrilintide has been evaluated as a once-weekly subcutaneous agent for weight management, both alone and in combination with semaglutide in a co-formulation referred to as CagriSema. This overview summarizes its structure, mechanism, pharmacokinetics, and clinical trial findings.

What Is Cagrilintide?

Native amylin is co-released with insulin from pancreatic beta cells in response to meals. It complements insulin by slowing gastric emptying, suppressing post-meal glucagon, and signaling satiety through receptors in the brainstem and hypothalamus. However, native amylin is unsuitable for pharmaceutical development because of rapid aggregation and a very short half-life.

Cagrilintide was engineered from the human amylin backbone with structural inspiration from calcitonin, incorporating several key modifications: substitutions to reduce fibrillation risk, a C-terminal proline modification, and a C20 fatty diacid side chain that enables reversible non-covalent albumin binding. This albumin-binding mechanism is similar in principle to the modifications used in liraglutide and semaglutide to extend half-life. The result is a compound suitable for once-weekly subcutaneous dosing with a half-life of approximately 7–8 days (159–195 hours across the evaluated dose range).

Mechanism of Action

Cagrilintide acts as a dual agonist at amylin receptor subtypes 1 and 3 (AMY₁ and AMY₃), which are heterodimeric complexes of the calcitonin receptor and receptor activity-modifying proteins (RAMP1 and RAMP3). It also binds the calcitonin receptor itself. Activation of these receptors in the brainstem area postrema and nucleus tractus solitarius reduces appetite and food intake through neural circuits distinct from the GLP-1 pathway. Because amylin and GLP-1 receptors are expressed in overlapping but non-identical brain regions, the combination of a DACRA with a GLP-1 receptor agonist engages complementary satiety pathways, which is the rationale behind the CagriSema co-formulation.

Cagrilintide does not bind the GLP-1 receptor and has negligible activity at GIP, glucagon, or insulin receptors, making its mechanism pharmacologically distinct from GLP-1 agonists.

What the Research Shows

Phase 2 Dose-Finding Trial (Monotherapy)

The primary phase 2 dose-finding study (Enebo et al., Lancet, 2021; PMID 34798060) enrolled 706 adults with obesity or overweight with comorbidities across 57 sites in 10 countries. Participants were randomized to once-weekly cagrilintide at doses of 0.3, 0.6, 1.2, 2.4, or 4.5 mg; once-daily liraglutide 3.0 mg (active reference arm); or placebo, for 26 weeks. At the top dose of 4.5 mg, cagrilintide produced a mean weight reduction of approximately 10.8% from baseline, compared with approximately 3.0% for placebo. A dose-response relationship was evident across all cagrilintide doses, with tolerability acceptable across the range. The most common adverse effects were gastrointestinal (nausea, diarrhea), consistent with the amylin class.

Phase 2 Combination Trial (with Semaglutide)

A phase 1b trial (Lau et al., Lancet, 2021; PMID 33894838) evaluated the pharmacokinetics and pharmacodynamics of co-administered cagrilintide 2.4 mg and semaglutide 2.4 mg in adults with overweight or obesity. Coadministration was safe and well tolerated, with no clinically relevant pharmacokinetic interaction between the two compounds. Weight reductions exceeded those seen with either compound administered alone in separate trials. Subsequent phase 2 data in type 2 diabetes (PMID 37364590) similarly showed additive weight and glycemic effects.

Phase 3 Program (REDEFINE)

The REDEFINE phase 3 program, which completed enrollment and reported results in 2025, compared CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg once weekly) against either agent alone and placebo. Preliminary data indicated that CagriSema produced substantially greater weight loss than semaglutide 2.4 mg monotherapy — the most extensively studied GLP-1 agonist for obesity — suggesting a meaningful clinical differentiation for the combination. Full peer-reviewed publication of the REDEFINE results was underway as of early 2026.

Pharmacokinetics

Across the clinical dose range (0.16–4.5 mg), cagrilintide demonstrates a half-life of 159–195 hours (approximately 7–8 days), supporting once-weekly subcutaneous dosing. The median time to peak plasma concentration (Tmax) is 24–72 hours post-injection. Steady-state exposure is reached after approximately 4–5 weekly doses. Albumin binding is the primary mechanism of protracted action. No clinically significant pharmacokinetic interaction with semaglutide was identified in the phase 1b study.

Common Research Dose Ranges

DISCLAIMER: The following dose ranges are drawn from published clinical trial literature and are provided for informational and research reference purposes only. They are not medical advice, prescribing guidance, or a recommendation to use this compound. Cagrilintide is not FDA-approved; it remains under clinical investigation.

Published phase 2 literature reports once-weekly subcutaneous doses ranging from 0.3 mg to 4.5 mg in the dose-finding monotherapy trial (Enebo et al., 2021). The phase 1b pharmacokinetic study and subsequent combination trials used 2.4 mg once weekly. The REDEFINE phase 3 program used cagrilintide 2.4 mg once weekly as the target maintenance dose in the CagriSema combination.

Literature reports dose escalation starting at 0.25 mg once weekly with stepwise increases to minimize gastrointestinal adverse effects, reaching maintenance over several months.

Storage

Research-grade lyophilized cagrilintide should be stored at −20 °C prior to reconstitution. Reconstituted solutions should be maintained at 2–8 °C and used within 28 days per standard research peptide guidelines. The compound should not be frozen after reconstitution.

What Cagrilintide Is NOT

Cagrilintide is not a GLP-1 receptor agonist and does not bind the GLP-1 receptor; its mechanism of action is entirely amylin/calcitonin receptor-mediated. It is not pramlintide (Symlin) — while both are amylin analogues, pramlintide has a much shorter half-life (approximately 48 minutes) and requires meal-time dosing. Cagrilintide is not approved by the FDA or any major regulatory agency as of the date of this writing. Research-grade material sold by peptide vendors has not undergone pharmaceutical-grade quality controls.

References

See citations below.