What is cagrilintide? The amylin analogue and its trials

What is cagrilintide? It is a long-acting amylin analogue: a peptide modelled on amylin, the pancreatic hormone that induces satiety, under investigation for weight management ^[1]. It is under development both as a monotherapy and as a fixed-dose combination with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, called CagriSema, for weight management and type 2 diabetes ^[9].

Pharmacology papers and reviews also call it AM833, and the registry entry of its phase 2 trial calls it NNC0174-0833 ^[2], ^[11], ^[15]. Novo Nordisk funded the phase 2 monotherapy trial, the phase 1b and phase 2 trials of the combination, and the phase 3 trials REDEFINE 1 and REDEFINE 2 ^[1], ^[3], ^[4], ^[5], ^[7].

• Its developers describe it as stable, lipidated and long acting, selected for clinical development with obesity as the indication ^[10].
• It binds the calcitonin receptor and all three amylin receptors, AMY1, AMY2 and AMY3 ^[9].
• The phase 1b, phase 2 and REDEFINE 1 trials gave it by subcutaneous injection once a week ^[1], ^[3], ^[4], ^[6].

Amylin is a 37-amino acid peptide hormone made mainly in the beta cells of the pancreas and released together with insulin in response to ingested nutrients ^[14]. It has a well-established role as a satiety signal, through amylin receptors in the area postrema and the nucleus of the solitary tract of the brain; it also slows gastric emptying and may suppress glucagon secretion through central mechanisms ^[14]. A second review adds that it acts on homeostatic and hedonic brain regions and suppresses the glucagon response to meals ^[15].

It has several characteristics of a satiating hormone: it is released after food, has a short half-life of about 13 minutes, and given to rats decreases food intake in a dose-dependent way, mainly at supraphysiological doses ^[14]. Blocking its receptors with the antagonist AC187, injected into the bloodstream or into the area postrema, acutely increases food intake in rats ^[14].

Each amylin receptor is a pair: a core unit, the calcitonin receptor, joined to one of three receptor activity-modifying proteins, RAMP1 to RAMP3 ^[14]. The pairing is not exclusive, since amylin receptors also respond to calcitonin and related hormones, and the review calls the importance of each individual receptor difficult to establish ^[14].

Native human amylin is hard to give. It tends to aggregate into amyloid fibrils, which are often found in the pancreatic islets of people with type 2 diabetes, and infusions of it often need highly supraphysiological doses to produce little or no effect ^[14]. Cagrilintide's development paper calls that propensity a hallmark of the hormone and a challenge for drug design ^[10].

Several stable amylin analogues have been developed ^[14]. One is pramlintide, approved by the US Food and Drug Administration as an adjunct to mealtime insulin, whose greater stability than human amylin came from three amino acid substitutions inspired by rat amylin ^[10], ^[14]. Its half-life in people is still short, about 20 to 45 minutes ^[14]. In obesity trials described in the same review, it lowered body weight by roughly 2% over 6 weeks in 60 people, and by 3.7% over 4 months in 108, both significantly more than placebo ^[14].

A 2021 review notes that cagrilintide is very similar in sequence to pramlintide, differing by the lipidation of the lysine at its N-terminus and by three amino acid substitutions, N14E, V17R and P37Y ^[15]. Against native human amylin it has 84% homology, with substitutions and other chemical alterations made to enhance stability, potency and biological half-life ^[9].

The review credits the lipidation and the three substitutions together with making it nonselective, an agonist of both amylin receptors and the calcitonin receptor ^[15]. A 2021 pharmacology study gives the rationale: amylin receptor agonists that can also activate the calcitonin receptor may have improved efficacy in obesity, although activating calcitonin receptors selectively is not effective ^[11]. Compared across 25 endpoints of receptor binding, activation and regulation with pramlintide, calcitonins and other lipidated analogues, cagrilintide showed a unique profile ^[11].

The changes show in how long it lasts: its elimination half-life is approximately 180 hours, or 7.5 days, which a 2026 pharmacokinetic paper calls compatible with once-weekly administration ^[9]. In the phase 1b trial, given alongside semaglutide at doses of 0.16 to 4.5 mg, its half-life was 159 to 195 hours, and its exposure rose in proportion to the dose without affecting semaglutide's ^[3].

Two single-dose studies asked whether kidney or liver impairment changes this: 33 adults grouped by kidney function received 0.6 mg, and 32 grouped by liver function received 0.9 mg ^[9]. Total exposure was similar across groups, the ratio of mean exposure against normal function running from 1.18 to 1.23 in kidney impairment and from 0.99 to 1.11 in liver impairment ^[9].

In liver impairment the half-life tended to rise, from 174 hours with normal function to 199 hours with severe impairment ^[9]. Within the limitations of small sample sizes, the authors found no clinically relevant differences in pharmacokinetics in either study ^[9].

Where it acts was mapped in 2026, in a transcriptomic atlas of over 530,000 caudal brainstem cells from rats, mice and macaques, with spatial mapping of the rat dorsal vagal complex ^[12]. Acute cagrilintide changed gene expression in area postrema neurons carrying Calcr and Ramp3, but activating those neurons directly in rats did not change long-term food intake or body weight ^[12]. Long-term treatment in rats raised the expression of prolactin-releasing hormone (Prlh) in Calcr/Prlh cells of the nucleus of the solitary tract, cells conserved across rodents, macaques and humans ^[12]. Knocking down Prlh in the dorsal vagal complex abolished cagrilintide's effects in rats, and the authors define Calcr/Prlh neurons as mediators of amylin receptor agonist action ^[12].

Among this guide's sources, one trial tested cagrilintide on its own across several doses, a phase 2 dose-finding study published in 2021: multicentre, randomised, double-blind, controlled against placebo and an active drug, at 57 sites in ten countries including the UK ^[1]. It enrolled adults without diabetes with a body-mass index of at least 30, or at least 27 with hypertension or dyslipidaemia ^[1].

Participants were randomised to once-weekly subcutaneous cagrilintide at 0.3, 0.6, 1.2, 2.4 or 4.5 mg, once-daily liraglutide 3.0 mg, or placebo, for 26 weeks of treatment and 6 of follow-up ^[1]. The registry entry adds talks with study staff on food choices and physical activity ^[2]. Between March and August 2019, 706 participants were randomised in all: 100 to 102 per cagrilintide dose, 99 to liraglutide and 101 to placebo ^[1], ^[15].

The primary endpoint, the percentage change in body weight at week 26, was analysed two ways: the trial product estimand assumes everyone kept to treatment, and the treatment policy estimand counts everyone regardless of adherence ^[1]. Under the trial product estimand, mean weight reductions were 6.0% to 10.8% across the doses against 3.0% on placebo (p<0.001), with similar results under treatment policy; 4.5 mg also exceeded liraglutide, 10.8% against 9.0% (p=0.03) ^[1].

The registry entry reports the same endpoint descriptively, over the in-trial period from randomisation to last contact: -6.1% on 0.3 mg, -6.9% on 0.6 mg, -8.5% on 1.2 mg, -9.5% on 2.4 mg and -10.8% on 4.5 mg, against -8.5% on liraglutide and -3.0% on placebo ^[2]. Those descriptive figures are a different summary from the paper's estimand, so the chart uses them alone.

The trialists concluded that cagrilintide led to significant reductions in body weight, supporting the development of molecules with novel mechanisms of action for weight management ^[1]. Cagrilintide alone also had arms in two later trials. In the phase 2 trial in type 2 diabetes, 30 participants on cagrilintide 2.4 mg changed body weight by -8.1% and HbA1c by -0.9 percentage points over 32 weeks ^[4]. In REDEFINE 1, 302 adults were randomised to cagrilintide 2.4 mg alone for 68 weeks ^[5]; a 2026 analysis of that trial quotes the arm's weight loss, set out with the CagriSema results below ^[6].

CagriSema pairs cagrilintide with semaglutide, a GLP-1 receptor agonist, on the rationale that the two may have complementary effects on appetite and glucose regulation ^[9]. In rats, knocking down Prlh in the dorsal vagal complex abolished the effects of cagrilintide but not those of semaglutide ^[12].

A phase 1b trial of the pair ran at a single US centre: 96 otherwise healthy adults aged 18 to 55 with a body-mass index of 27.0 to 39.9 were randomised 3:1 to once-weekly cagrilintide at 0.16 to 4.5 mg or placebo, all with once-weekly semaglutide 2.4 mg ^[3]. At week 20, after 16 weeks of escalating both drugs together and 4 weeks at each arm's assigned dose, body weight had fallen by 15.7% with cagrilintide 1.2 mg and 17.1% with 2.4 mg against 9.8% for pooled placebo, and by 15.4% with 4.5 mg against 8.0% for its matched placebo ^[3].

A phase 2 trial in type 2 diabetes randomised 92 adults on metformin, with or without an SGLT2 inhibitor, to once-weekly CagriSema, semaglutide or cagrilintide, each escalated to 2.4 mg, for 32 weeks ^[4]. HbA1c fell by 2.2, 1.8 and 0.9 percentage points respectively, the combination's fall greater than cagrilintide's but not significantly greater than semaglutide's; body weight changed by -15.6%, -5.1% and -8.1%, more with the combination than with either component ^[4].

The phase 3a trial REDEFINE 1 randomised 3417 adults without diabetes, with a body-mass index of 30 or more or of 27 or more with an obesity-related complication, 21:3:3:7 to the combination, semaglutide alone, cagrilintide alone or placebo, each drug at 2.4 mg with lifestyle intervention, for 68 weeks ^[5]. Under the treatment policy estimand, consistent with the intention-to-treat principle, the estimated mean change in body weight was -20.4% on the combination against -3.0% on placebo ^[5].

A 2026 blood pressure analysis of the trial quotes weight loss in all four arms, 22.7% with CagriSema, 16.1% with semaglutide, 11.8% with cagrilintide and 2.3% with placebo ^[6]. It quotes them alongside results it labels as the trial product estimand ^[6], which assumes participants stayed on treatment ^[1], so they are kept apart here from the primary paper's treatment policy result ^[5].

That analysis's own subject was blood pressure: systolic pressure fell by 10.9 mm Hg on CagriSema against 2.8 on placebo, and 63.0% against 32.0% reached blood pressure targets at week 68 ^[6].

REDEFINE 2 randomised 1206 adults with type 2 diabetes, a body-mass index of 27 or more and an HbA1c of 7 to 10%, 3:1 to the combination or placebo, with lifestyle intervention, for 68 weeks ^[7]. Under the treatment policy estimand, the estimated mean change in body weight was -13.7% against -3.4% on placebo ^[7]. An HbA1c of 6.5% or less was reached by 73.5% on the combination against 15.9% on placebo ^[7].

A registered trial comparing CagriSema with tirzepatide in people with obesity is listed as completed, and its entry calls CagriSema a new investigational medicine not yet being prescribed by doctors ^[8]. No results from it are among this guide's sources.

A 2026 study in diet-induced obese male rats gave cagrilintide daily together with retatrutide, a GLP-1, GIP and glucagon receptor tri-agonist ^[13]. In those rats the pair reduced body weight and food intake in a dose-dependent way, more than equimolar doses of either compound alone ^[13]. No human study of cagrilintide with retatrutide is among this guide's sources.

In the phase 2 monotherapy trial the most frequent adverse events were gastrointestinal disorders, such as nausea, constipation and diarrhoea, and administration-site reactions ^[1]. Gastrointestinal events affected 41% to 63% of participants across the cagrilintide doses against 32% on placebo, primarily nausea, at 20% to 47% against 18% ^[1]. In all, 73 participants (10%) stopped treatment permanently, in similar numbers across groups; adverse events were the main reason, for 30 of them ^[1].

On the registry entry, injection-site reactions were recorded in 4 to 12 participants per cagrilintide arm against none on placebo, and serious adverse events in 2 to 7 per cagrilintide arm against 3 on placebo ^[2]. The authors described cagrilintide as well tolerated in this trial ^[1].

In the phase 1b combination trial, 207 (37%) of 566 adverse events were gastrointestinal disorders and most events were mild to moderate ^[3]. In the phase 2 trial in type 2 diabetes, adverse events were reported by 68% on CagriSema, 71% on semaglutide and 80% on cagrilintide, with no level 2 or 3 hypoglycaemia ^[4]. Gastrointestinal events affected 79.6% on the combination against 39.9% on placebo in REDEFINE 1, and 72.5% against 34.4% in REDEFINE 2, mostly transient and mild to moderate ^[5], ^[7]. The single-dose renal and hepatic studies reported no serious adverse events, no withdrawals because of adverse events and no deaths, and no rise in adverse events with worsening impairment ^[9].

Cagrilintide is investigational: the phase 2 report describes it as under investigation, a 2021 review as an investigational drug, and a 2026 paper as under development, alone and as a fixed-dose combination with semaglutide ^[1], ^[9], ^[15]. The registry entry for a CagriSema trial calls CagriSema a new investigational medicine that is not yet being prescribed by doctors ^[8]. On 16 October 2026, the date of this guide, the MHRA's products register, the EMA's medicines database and the FDA's Drugs@FDA listed no marketing authorisation for cagrilintide, alone or as CagriSema.

Much remains open. In this guide's evidence, the only trial of cagrilintide alone across several doses lasted 26 weeks, and longer data on it alone come from single arms inside combination trials ^[1], ^[4], ^[6]. The phase 1b authors called for larger and longer trials to fully assess the combination, the organ-impairment studies were limited by small sample sizes, and the brainstem pathway was defined in rats ^[3], ^[9], ^[12].

1. 2018

   The phase 1b trial with semaglutide begins screening in July.[3]

2. 2019

   The phase 2 monotherapy trial randomises its participants; the first of the two organ-impairment studies is registered.[1], [9]

3. 2020

   A review sets out the physiology of amylin and calcitonin and the case for drugs based on them.[14]

4. 2021

   The phase 2 and phase 1b results, the development paper and the receptor pharmacology study are published.[1], [3], [10], [11]

5. 2022

   The second organ-impairment study is registered.[9]

6. 2023

   The phase 2 trial in type 2 diabetes is published; a comparison with tirzepatide is registered.[4], [8]

7. 2025

   REDEFINE 1 and REDEFINE 2, phase 3a trials of the combination, are published.[5], [7]

8. 2026

   The renal and hepatic studies, the brainstem atlas, the blood pressure analysis and a rat study with retatrutide are published.[6], [9], [12], [13]