Cagrilintide (AM833): Amylin Receptor Agonist Research Guide

Cagrilintide, also called AM833 or NNC0174-0833, is an investigational long-acting amylin analog developed by Novo Nordisk. It engages calcitonin and amylin receptor complexes, with published receptor studies identifying AMY1 and AMY3 as important mediators in preclinical models. Human studies evaluate cagrilintide alone and with semaglutide as CagriSema. The compound name is cagrilintide; cagrilinitide is a common misspelling retained only in this page’s established URL.

Research-only context: This page summarizes published and registered studies. It does not provide medical advice, personal-use guidance, dosing recommendations, or sourcing guidance.

Cagrilintide Research vs Semaglutide Comparison: Which Page Should You Read?

The Phase 3 evidence is combination-specific. REDEFINE 1 included separate cagrilintide and semaglutide arms as well as the combination and placebo, while REDEFINE 2 compared the combination with placebo. Trial completion does not by itself establish regulatory approval or interchangeability with approved GLP-1 medicines.

Cagrilintide Is a Fatty-Acid-Acylated 37-Amino-Acid Amylin Analog

Cagrilintide is a 37-amino acid peptide with structural homology to human amylin but engineered for extended duration of action. Novo Nordisk introduced a C18 fatty acid chain via an eight-carbon linker at position Lys-24. This acylation strategy promotes non-covalent albumin binding in plasma, slowing renal clearance and extending the half-life to approximately six to eight days, suitable for once-weekly dosing.

The compound is not currently indexed in PubChem as a small molecule; it is a therapeutic peptide exceeding 15 amino acids.

Key Properties

• Class: Long-acting amylin receptor agonist (acylated peptide)
• Molecular target: Amylin receptors AMY1 (CALCR + RAMP1) and AMY3 (CALCR + RAMP3)
• Secondary target: Calcitonin receptor (CALCR) directly
• Half-life: ~6-8 days (enables once-weekly subcutaneous administration)
• Route: Subcutaneous injection, once weekly
• Combination program: Studied with semaglutide under the CagriSema name

Cagrilintide Activates AMY1 and AMY3 Amylin Receptor Complexes

Amylin receptors are heterodimeric complexes formed by the calcitonin receptor (CALCR) and receptor activity-modifying proteins (RAMPs). Cagrilintide activates AMY1 (CALCR + RAMP1) and AMY3 (CALCR + RAMP3) expressed in appetite-regulating regions of the hypothalamus and the area postrema of the brainstem.

A 2025 study in EBioMedicine used receptor subtype-specific antagonists in rodents to demonstrate that cagrilintide lowers body weight primarily through brain AMY1 and AMY3 receptors rather than calcitonin receptor alone (PMID: 40609154). Structural and dynamic features of cagrilintide binding to both CALCR and amylin receptors were resolved by cryo-EM and computational methods published in Nature Communications in April 2025 (PMID: 40204768).

flowchart TD
    subgraph Pancreas["Pancreatic Beta Cell"]
        INS["Insulin"]
        AMY["Native Amylin\n(short half-life)"]
    end

    CAG["Cagrilintide\n(long-acting amylin analog)"]

    subgraph Brainstem["Area Postrema / NTS"]
        AMY1["AMY1 Receptor\nCALCR + RAMP1"]
        AMY3["AMY3 Receptor\nCALCR + RAMP3"]
    end

    subgraph Hypothalamus["Hypothalamic Nuclei"]
        ARC["Arcuate\nNucleus"]
        PVN["Paraventricular\nNucleus"]
    end

    CAG -->|Activates| AMY1
    CAG -->|Activates| AMY3
    AMY1 -->|cAMP signaling| Brainstem
    AMY3 -->|cAMP signaling| Brainstem
    Brainstem -->|Satiety signals| ARC
    Brainstem -->|Satiety signals| PVN
    ARC -->|Reduced food intake| FI["Decreased energy\nand body weight"]
    PVN -->|Energy expenditure| FI

    subgraph GLP1["GLP-1 Receptor (CagriSema)"]
        GLP1R["GLP-1R\nSemaglutide target"]
    end

    GLP1R -.->|Complementary pathway| FI

Complementary Signaling with GLP-1

Amylin receptors and GLP-1 receptors signal through overlapping but distinct central pathways. Amylin acts predominantly at the area postrema and hypothalamic amylin receptor circuits, while GLP-1 receptor agonists act at nucleus tractus solitarius neurons and other central nodes. This complementary anatomy is the scientific rationale for combining cagrilintide and semaglutide in CagriSema.

The 2021 Phase 1b trial evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics across ascending cagrilintide cohorts given with semaglutide. It reported the combination as generally well tolerated in that study and documented greater body-weight change than the pooled placebo-plus-semaglutide group at week 20 (PMID 33894838).

Discovery and Development History

Novo Nordisk developed NNC0174-0833 as a long-acting amylin analog and later studied it alongside semaglutide. The program tests whether two distinct receptor systems can produce complementary metabolic effects without treating the compounds as mechanistically interchangeable.

Development Timeline

• December 2014: First-in-human Phase 1 single ascending dose trial started (NCT02300844)
• 2016-2018: Multiple ascending dose and pharmacokinetics studies in subjects with obesity (NCT02958085)
• 2018: Phase 1 combination study with semaglutide initiated (NCT03600480)
• March 2019: Phase 2 monotherapy study versus liraglutide started (NCT03856047)
• 2019: Japanese/Caucasian pharmacokinetics study completed (NCT03787225)
• 2021: Phase 1b Lancet publication confirmed additive weight reduction with semaglutide (PMID: 33894838)
• 2023: Phase 2 Lancet publication in T2D; CagriSema showed glycemic and weight benefits over semaglutide 2.4 mg monotherapy (PMID: 37364590)
• 2025: REDEFINE Phase 3 program results published in the New England Journal of Medicine (PMID: 40544433; PMID: 40544432)
• January 2026: The pediatric Phase 3 study NCT07253285 started

Cagrilintide Clinical Trials: From AM833 Monotherapy to CagriSema Phase 3

Phase 1: Safety and Pharmacokinetics

Novo Nordisk conducted a systematic Phase 1 program to characterize cagrilintide’s safety, tolerability, and pharmacokinetics across multiple populations.

NCT02300844 established the single ascending dose safety and PK profile in overweight and obese male subjects in the United States. NCT02958085 extended this with multiple dosing, examining pharmacodynamic markers of weight and appetite. NCT03787225 and NCT05254158 assessed whether PK profiles were consistent across Japanese, Caucasian, and Chinese subjects.

Dedicated renal, hepatic, and cardiac-repolarization studies are registered as NCT04209049, NCT05564104, and NCT05804162. The registry records confirm that the studies were completed, but they do not post results. This page therefore does not infer dose-adjustment or QT conclusions from completion status alone.

Phase 2: Monotherapy and Combination Efficacy

Phase 2 Monotherapy (NCT03856047)

This randomized, double-blind trial compared NNC0174-0833 at multiple dose levels versus liraglutide 3.0 mg versus placebo in subjects with overweight or obesity over 26 weeks. The trial was the first to characterize the dose-response relationship for cagrilintide’s weight-lowering effect in humans.

Phase 2 CagriSema in T2D (PMID: 37364590)

A Phase 2 trial published in The Lancet in August 2023 evaluated co-administered once-weekly cagrilintide 2.4 mg with semaglutide 2.4 mg in adults with T2D. The primary endpoint was HbA1c reduction at 32 weeks. The mean HbA1c changes at week 32 were -2.2 percentage points with CagriSema, -1.8 with semaglutide, and -0.9 with cagrilintide. The CagriSema-versus-semaglutide HbA1c difference did not reach statistical significance (p=0.075), while mean body-weight change was -15.6% with CagriSema versus -5.1% with semaglutide (PMID 37364590).

REDEFINE Trials Separate Published Results from Registered Comparators

REDEFINE 1 (NCT05567796; PMID 40544433) randomized 3,417 adults with overweight or obesity and without diabetes to cagrilintide-semaglutide, semaglutide, cagrilintide, or placebo. At week 68, the treatment-policy estimand for mean body-weight change was -20.4% with the combination and -3.0% with placebo. Gastrointestinal adverse events were reported in 79.6% and 39.9%, respectively, and were mainly transient and mild to moderate.

REDEFINE 2 (NCT05394519; PMID 40544432) randomized 1,206 adults with overweight or obesity and type 2 diabetes to cagrilintide-semaglutide or placebo. At week 68, the corresponding mean body-weight changes were -13.7% and -3.4%. This trial did not include a semaglutide monotherapy arm.

Several additional completed or active registry studies answer different questions and should not be conflated with those publications:

• NCT06131437 compares CagriSema with tirzepatide in adults with obesity. It is not REDEFINE 1 and has no posted registry results.
• NCT06065540 compares two CagriSema dose pairs with semaglutide, cagrilintide, and placebo in type 2 diabetes. No registry results are posted.
• NCT05813925 studies CagriSema in East Asian participants with overweight or obesity.
• NCT06221969 compares CagriSema with tirzepatide in type 2 diabetes. Its registry status is completed, with no posted results.
• NCT07253285 studies cagrilintide and CagriSema in children and adolescents with excess body weight.

Meta-Analytic Evidence

A 2026 systematic review and meta-analysis in Diabetes, Obesity and Metabolism (PMID: 41834765) pooled randomized controlled trial data on cagrilintide and CagriSema. Findings confirmed that CagriSema produces greater percentage body weight reduction than semaglutide monotherapy, with a consistent and quantified treatment difference across trials.

A separate systematic review and meta-analysis in the American Journal of Cardiology (PMID: 41759565) pooled four randomized trials comparing CagriSema with semaglutide or placebo. Its reported outcomes included weight, waist circumference, systolic blood pressure, and gastrointestinal adverse events.

Primary Research Areas

Obesity and Weight Management

Weight management is the central research program for cagrilintide. The amylin receptor mechanism contributes to satiety by:

1. Slowing gastric emptying (reducing post-meal nutrient absorption rate)
2. Suppressing glucagon secretion
3. Generating central satiety signals via area postrema and hypothalamic pathways

These effects are additive to GLP-1 receptor-mediated satiety, producing the enhanced weight reduction observed in CagriSema trials.

Type 2 Diabetes

Beyond weight, cagrilintide suppresses post-prandial glucagon, complementing the GLP-1-mediated insulin secretagogue effect of semaglutide. The Phase 2 trial reported mean HbA1c changes of -2.2 percentage points with CagriSema and -1.8 with semaglutide at week 32; the between-group HbA1c comparison was not statistically significant, while the body-weight comparison favored CagriSema (PMID 37364590).

Cardiovascular Risk Markers

Obesity and T2D both carry elevated cardiovascular risk. REDEFINE 1 secondary and post hoc analyses reported greater blood pressure reductions with CagriSema than placebo (PMID: 41328546). Dedicated cardiovascular outcomes evidence for cagrilintide or CagriSema remains unavailable.

Muscle Composition

A 2026 Phase 1 mechanistic trial (NCT07527195) is designed to evaluate the effect of CagriSema, cagrilintide, and semaglutide on muscle health and lean mass composition during weight loss. This directly addresses the concern that GLP-1-driven weight loss includes loss of lean mass. Amylin receptor agonism may differentially preserve or affect muscle through pathways distinct from GLP-1, including direct effects on skeletal muscle metabolism (PMID: 41852165).

Pediatric Obesity

The pediatric Phase 3 trial NCT07253285 started in January 2026, extending the research program to children and adolescents. The registered study evaluates cagrilintide and CagriSema in younger populations with excess body weight.

Structural Biology

A 2025 Nature Communications study (PMID: 40204768) resolved the structural basis of cagrilintide binding using cryo-EM structures of the compound bound to calcitonin receptor and amylin receptor complexes. The study characterized which receptor features determine subtype selectivity and receptor activation. This structural information is relevant for understanding how cagrilintide differs from native amylin and why acylation affects receptor engagement dynamics.

A separate 2025 EBioMedicine study (PMID: 40609154) used selective receptor antagonists in rodent models to dissect which amylin receptor subtypes mediate the weight-lowering effects. The data implicated AMY1 and AMY3 in the hypothalamus and brainstem as the primary targets.

How Cagrilintide Differs from GLP-1 Drugs and Other Amylin Analogs

Cagrilintide’s primary distinction from pramlintide is duration of action. Its distinction from GLP-1 agents is receptor class: amylin receptors are structurally and anatomically distinct from GLP-1 receptors, enabling combination without receptor cross-reactivity.

For a full side-by-side research comparison of semaglutide and cagrilintide, including GLP-1 versus amylin receptor signaling, indication coverage, and evidence depth, see the semaglutide vs cagrilintide comparison.

Cagrilintide Safety Evidence Is Clinical but Still Investigational

The Phase 1 program established cagrilintide’s tolerability across dose escalation from 0.3 mg to 4.5 mg in subjects with obesity. The most common adverse events in clinical trials mirror those of GLP-1 receptor agonists, reflecting shared satiety pathways:

• Nausea (most common, typically mild-to-moderate, decreasing with time)
• Vomiting
• Decreased appetite
• Constipation

The completed QT, renal-impairment, and hepatic-impairment registries do not currently post results. Their existence supports study coverage, not a conclusion that no adjustment or cardiac concern exists.

Detailed adverse event data, discontinuation rates, and long-term safety from the REDEFINE program are covered in the Cagrilintide Safety page.

Pharmacokinetics Summary

Published Phase 1b data describe a multi-day apparent half-life compatible with weekly study intervals and exposure characterization across ascending cohorts. Albumin binding through fatty-acid acylation is the principal half-life-extension strategy. This overview does not infer unposted bioavailability or special-population conclusions from registry entries.

Full pharmacokinetic details, including volume of distribution, clearance, and drug-drug interaction data, are covered in the cagrilintide half-life and pharmacokinetics page.

Dose-Response Relationship

Phase 1 and Phase 2 dose-escalation studies characterized the dose-response relationship for body weight reduction and gastrointestinal tolerability. Dose escalation was used in the cited clinical trials to study tolerability. The Phase 2 monotherapy trial (NCT03856047) tested multiple doses to identify the optimal therapeutic dose for Phase 3 (2.4 mg once weekly for CagriSema).

Detailed dose-response data are covered in the cagrilintide dose-response in clinical trials page.

Mechanism of Action Detail

The molecular pharmacology of cagrilintide at calcitonin and amylin receptor subtypes, downstream cAMP signaling cascades, and interactions with hypothalamic neuropeptide circuits are covered in depth on the cagrilintide AMY1 and AMY3 mechanism page.

Clinical Evidence Summary

Quantitative outcomes from Phase 2 and Phase 3 REDEFINE trials, subgroup analyses, and comparison with active comparators including semaglutide and tirzepatide are covered in the cagrilintide clinical evidence page.

Frequently Asked Questions

What is cagrilintide and who developed it?

Cagrilintide, also called AM833 or NNC0174-0833, is an investigational long-acting amylin analog developed by Novo Nordisk. Its published evidence spans Phase 1 combination research, structural receptor studies, and Phase 3 CagriSema trials.

How does cagrilintide differ from native amylin or pramlintide?

Fatty-acid acylation and albumin binding extend cagrilintide exposure into a multi-day range. Native amylin is short-lived, and pramlintide is a shorter-acting approved amylin analog. Those pharmacokinetic differences do not establish therapeutic interchangeability.

What is CagriSema?

CagriSema is the clinical-study name for co-administered cagrilintide and semaglutide. REDEFINE 1 and REDEFINE 2 studied the combination in distinct adult populations (PMID 40544433; PMID 40544432).

What did REDEFINE 1 report?

REDEFINE 1 was NCT05567796, not NCT06131437. In the treatment-policy estimand, mean body-weight change at week 68 was -20.4% with cagrilintide-semaglutide and -3.0% with placebo. The trial also included separate semaglutide and cagrilintide arms.

What is cagrilintide’s regulatory status?

The studies cited on this page describe cagrilintide as investigational. Current regulatory status should be verified from FDA or EMA records and should not be inferred from Phase 3 completion alone.

Related Research

• Cagrilintide AMY1 and AMY3 mechanism, receptor pharmacology and central satiety signaling cascades
• Cagrilintide clinical evidence, Phase 2 and Phase 3 quantitative outcomes
• Cagrilintide half-life and pharmacokinetics, exposure and drug interaction context
• Cagrilintide dose-response in clinical trials, dose escalation and therapeutic window
• Cagrilintide safety data, adverse event profile and tolerability data
• Semaglutide vs cagrilintide comparison, GLP-1 receptor agonist vs amylin analog research context
• AMPK Pathway, downstream metabolic signaling shared across anti-obesity mechanisms