Cagrilinitide Evidence Review

Cagrilinitide (AM833, NNC0174-0833) is a once-weekly long-acting amylin analog developed by Novo Nordisk. Its clinical evidence base spans a systematic Phase 1 program, two pivotal Phase 2 trials, a completed Phase 3 REDEFINE program, and two independent meta-analyses published in 2026. This page organizes that evidence by study design, from randomized controlled trials through meta-analyses to preclinical in vivo and in vitro work, with primary identifiers for each source.

Evidence Hierarchy at a Glance

flowchart TD
    A["Cagrilinitide Evidence Base"] --> B["Phase 3 RCTs\n(REDEFINE Program)"]
    A --> C["Phase 2 RCTs"]
    A --> D["Phase 1 / Phase 1b RCTs"]
    A --> E["Meta-Analyses"]
    A --> F["Preclinical In Vivo"]
    A --> G["Preclinical In Vitro / Structural"]

    B --> B1["REDEFINE 1\nObesity without T2D\nNCT05567796 | PMID 40544433"]
    B --> B2["REDEFINE 2\nT2D with Excess Weight\nNCT05394519 | PMID 40544432"]
    B --> B3["REDEFINE 3\nT2D on Metformin\nNCT06065540"]
    B --> B4["REDEFINE 4\nEast Asia\nNCT05813925"]

    C --> C1["Phase 2 Monotherapy vs Liraglutide\nNCT03856047 | PMID 34798060"]
    C --> C2["Phase 2 CagriSema in T2D\nNCT04982575 | PMID 37364590"]

    D --> D1["Phase 1b Combination Safety/PK\nNCT03600480 | PMID 33894838"]
    D --> D2["Thorough QT Study\nNCT05804162 | PMID 39279639"]

    E --> E1["Diabetes Obes Metab Meta-Analysis\nPMID 41834765"]
    E --> E2["Am J Cardiol Meta-Analysis\nPMID 41759565"]

    F --> F1["AMY1/AMY3 Receptor Dissection\nEBioMedicine 2025 | PMID 40609154"]
    F --> F2["Receptor Balance: Cagrilintide vs KBP-336\nPMID 36242844"]
    F --> F3["Tool Compound Characterization\nPMID 40628316"]

    G --> G1["Cryo-EM Structural Biology\nNat Commun 2025 | PMID 40204768"]
    G --> G2["In Vitro Metabolic Profiling\nPMID 41702251"]

Randomized Controlled Trials

Phase 1b: Combination Safety, Pharmacokinetics, and Pharmacodynamics (NCT03600480, PMID 33894838)

Before evaluating efficacy in larger populations, Novo Nordisk conducted a Phase 1b randomized, controlled study to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of escalating cagrilinitide doses co-administered with semaglutide 2.4 mg.

Enebo et al. enrolled 96 participants across six sequential cohorts testing cagrilinitide doses from 0.16 mg to 4.5 mg combined with semaglutide 2.4 mg over 20 weeks (16 weeks of co-escalation, 4 weeks at target dose). Mean age was 40.6 years; 59% were male. Participants had obesity without diabetes.

Key findings:

• Cagrilintide 2.4 mg with semaglutide produced 17.1% mean body weight reduction at week 20 versus 9.8% with semaglutide plus placebo
• Pharmacokinetic exposures were proportional to cagrilinitide dose; co-administration did not alter semaglutide half-life (145-165 hours)
• Cagrilinitide half-life was 159-195 hours across cohorts, confirming the once-weekly dosing rationale
• Gastrointestinal adverse events (predominantly nausea) accounted for 37% of all adverse events; most were mild to moderate

This trial established the pharmacokinetic basis for fixed-dose co-formulation as CagriSema and confirmed that additive weight reduction over semaglutide monotherapy was detectable at Phase 1b. Publication: The Lancet, May 2021 (PMID 33894838).

Phase 2 Monotherapy vs. Liraglutide: NCT03856047 (PMID 34798060)

Lau et al. conducted a 26-week randomized, double-blind, placebo-controlled and active-controlled dose-finding Phase 2 trial at 57 sites in 10 countries. The trial enrolled 706 adults without diabetes with BMI at or above 30 kg/m2 (or at or above 27 kg/m2 with hypertension or dyslipidemia).

Participants were randomized to cagrilinitide 0.3, 0.6, 1.2, 2.4, or 4.5 mg once weekly; liraglutide 3.0 mg; or placebo.

Weight loss by arm at 26 weeks:

All active cagrilinitide doses produced significantly greater weight loss than placebo (all p<0.001). The dose-response relationship was approximately linear from 0.3 mg to 4.5 mg. Cagrilinitide 4.5 mg and liraglutide 3.0 mg showed numerically comparable reductions.

Safety findings: Gastrointestinal adverse events occurred in 41%-63% of cagrilinitide-treated participants versus 32% with placebo. Nausea rates were 20%-47% with cagrilinitide versus 18% with placebo. Discontinuation due to adverse events was approximately 10%. No calcitonin-related adverse effects and no clinically relevant hypocalcemia were observed.

This trial was the first to characterize the dose-response relationship for cagrilinitide monotherapy in humans. The 2.4 mg dose was selected for Phase 3 CagriSema development based on these data. Publication: The Lancet, December 2021 (PMID 34798060).

Phase 2 CagriSema in Type 2 Diabetes: NCT04982575 (PMID 37364590)

Frias et al. evaluated co-administered once-weekly cagrilinitide 2.4 mg with semaglutide 2.4 mg in a randomized, double-blind, active-controlled Phase 2 trial in adults with type 2 diabetes. The trial enrolled 92 participants across three arms: CagriSema (n=31), semaglutide 2.4 mg (n=31), and cagrilinitide 2.4 mg (n=30). The primary endpoint was HbA1c change from baseline to week 32.

Efficacy at 32 weeks:

CagriSema produced superior HbA1c reduction compared to semaglutide monotherapy (-2.2 vs -1.8 pp) and achieved three times the weight loss of semaglutide alone (-15.6% vs -5.1%). No level 2 or level 3 hypoglycemia was reported in any arm. Gastrointestinal adverse events were mild to moderate.

This trial provided the pivotal evidence that cagrilinitide adds meaningful glycemic and weight benefit over GLP-1 receptor agonism alone in T2D. It directly informed the design of REDEFINE 2. Publication: The Lancet, August 2023 (PMID 37364590).

REDEFINE 1: Phase 3a in Obesity Without T2D (NCT05567796, PMID 40544433)

Garvey, Bluher, and colleagues conducted the pivotal REDEFINE 1 trial: a 68-week, multicenter, double-blind, placebo-controlled and active-controlled Phase 3a trial in adults with obesity or overweight with at least one weight-related comorbidity, without type 2 diabetes. A total of 3,417 participants were randomized. The CagriSema arm included 2,108 participants receiving cagrilinitide 2.4 mg plus semaglutide 2.4 mg once weekly.

Primary and key secondary outcomes:

• Mean body weight change from baseline: -20.4% (CagriSema) vs -3.0% (placebo); treatment difference -17.3 percentage points (95% CI not explicitly reported in public summary; p<0.001)
• Proportion achieving at least 5% weight loss: significantly higher with CagriSema (p<0.001)
• Proportion achieving at least 20%, 25%, and 30% weight loss: significantly higher with CagriSema (all p<0.001)
• Waist circumference reduction: 9.41 cm greater with CagriSema versus control per the American Journal of Cardiology meta-analysis that included this trial (PMID 41759565)

Safety: Gastrointestinal adverse events were reported by 79.6% of CagriSema participants versus 39.9% placebo. Nausea, vomiting, diarrhea, constipation, and abdominal pain were the most common. Events were predominantly transient and mild to moderate.

A pre-specified secondary analysis published in Hypertension (2026; PMID 41328546) reported that CagriSema significantly reduced systolic and diastolic blood pressure versus placebo, extending the cardiovascular risk factor benefit beyond weight alone.

Publication: New England Journal of Medicine, August 2025 (PMID 40544433).

REDEFINE 2: Phase 3a in Type 2 Diabetes (NCT05394519, PMID 40544432)

REDEFINE 2 was a 68-week, randomized, double-blind, placebo-controlled Phase 3a trial conducted in 12 countries. It enrolled 1,206 adults with type 2 diabetes (HbA1c 7%-10%) and excess body weight (BMI at or above 27 kg/m2), randomized 3:1 to CagriSema (n=904) or placebo (n=302). Both groups received lifestyle intervention.

Primary endpoints (week 68):

Cagrilinitide’s glucagon-suppressing mechanism, additive to semaglutide’s insulin-secretagogue and glucagon-lowering effects, likely explains the substantial HbA1c improvements. The proportion achieving HbA1c below 5.7% (normoglycemic range) was not reported in public summaries but is expected to be described in the full publication.

Safety: Gastrointestinal adverse events were reported by 72.5% of CagriSema participants versus 34.4% of placebo. No unexpected safety signals were identified. Discontinuation rates due to adverse events were higher in the CagriSema group, consistent with the profile seen in Phase 2.

Publication: New England Journal of Medicine, August 2025 (PMID 40544432).

REDEFINE 3: CagriSema vs. Semaglutide vs. Cagrilinitide vs. Placebo (NCT06065540)

REDEFINE 3 enrolled adults with type 2 diabetes managed with metformin, with or without an SGLT2 inhibitor. Its four-arm design (CagriSema, semaglutide, cagrilinitide, and placebo) provides the most granular decomposition of individual and combined contributions to weight and glycemic outcomes. Full results have not been published in indexed form as of the published date of this page. This trial’s data will clarify whether the additive weight benefit of cagrilinitide over semaglutide persists in the context of background SGLT2 inhibitor use.

Thorough QT Study (NCT05804162, PMID 39279639)

Cardiac safety is a mandatory assessment for any drug affecting the QTc interval before large-scale trials proceed. Novo Nordisk and Parexel conducted a randomized, double-blind, placebo-controlled thorough QT study in 105 healthy participants (53 cagrilinitide, 52 placebo). Cagrilinitide was dose-escalated to 4.5 mg once weekly, the highest dose evaluated clinically.

The primary finding was that no clinically relevant QTcF prolongation occurred at the 4.5 mg dose. All measured QTcF intervals across the four post-dose time points (12, 24, 48, and 72 hours) remained below the 10 ms threshold that defines clinical concern. The study rules out increased risk of ventricular tachyarrhythmia at therapeutic cagrilinitide doses.

Publication: Diabetes, Obesity and Metabolism, December 2024 (PMID 39279639).

Meta-Analyses

Cagrilintide and CagriSema vs. Semaglutide: Diabetes, Obesity and Metabolism (PMID 41834765)

Ahmed et al. (2026) conducted a systematic review and meta-analysis pooling data from three randomized controlled trials (n=3,545) comparing cagrilintide monotherapy or CagriSema against semaglutide. This analysis synthesized data from the Phase 2 T2D trial (PMID 37364590) and two REDEFINE Phase 3 trials (PMID 40544433, PMID 40544432).

Primary efficacy findings:

• CagriSema produced significantly greater percentage weight loss than semaglutide: mean difference -7.47%
• CagriSema produced significantly greater absolute weight loss: mean difference -7.60 kg
• Cagrilinitide monotherapy showed comparable weight loss to semaglutide monotherapy

Safety signal: CagriSema increased administration-site conditions (RR 3.27) and nausea (RR 1.64) relative to semaglutide. Overall serious adverse events were similar between CagriSema and semaglutide, though cagrilinitide monotherapy showed elevated serious adverse event risk in this pooled analysis. LDL-C was modestly higher with CagriSema than semaglutide (MD 0.29 mmol/L), a finding that warrants monitoring in longer-term cardiovascular outcome trials.

Publication: Diabetes, Obesity and Metabolism, March 2026 (PMID 41834765).

Cardiovascular Risk Markers: American Journal of Cardiology (PMID 41759565)

Gadelmawla et al. (2026) pooled four randomized controlled trials (n=4,419; CagriSema n=3,055; controls n=1,364) to evaluate CagriSema effects on body composition and cardiovascular risk factors versus semaglutide or placebo.

Key quantitative findings:

• Percentage weight loss: Cohen’s d -1.38 (95% CI -1.84 to -0.91); absolute weight loss 11 kg greater than controls
• Waist circumference reduction: 9.41 cm greater with CagriSema
• Systolic blood pressure reduction: 7.06 mmHg greater with CagriSema
• Gastrointestinal adverse events: more frequent with CagriSema (RR 1.32)

The blood pressure reduction is a clinically meaningful finding given that both obesity and GLP-1-class weight loss drugs produce variable blood pressure changes depending on baseline characteristics and concurrent antihypertensive medication use.

Publication: American Journal of Cardiology, February 2026 (PMID 41759565).

Preclinical In Vivo Evidence

Amylin Receptor Subtype Dissection: EBioMedicine (PMID 40609154)

Carvas, Le Foll, Lutz, and colleagues at the University of Zurich and Novo Nordisk published a mechanistic in vivo study in EBioMedicine (August 2025) using RAMP1/RAMP3 double-knockout mice on a high-fat diet. RAMP1 and RAMP3 are required for formation of functional AMY1 (CALCR+RAMP1) and AMY3 (CALCR+RAMP3) amylin receptors.

Cagrilinitide at 3 nmol/kg subcutaneous daily for 3 weeks produced significant weight loss (-3.4 g) in wild-type obese mice. This effect was abrogated in RAMP1/RAMP3 knockout mice, confirming that brain AMY1 and AMY3 receptors mediate the weight-lowering effect. In contrast, salmon calcitonin (which acts preferentially at CALCR without RAMP proteins) showed opposite results, increasing weight in wild-type mice but demonstrating improved efficacy in knockouts.

Neuronal activation mapping (cFos immunostaining) and gene expression analysis in the dorsal vagal complex and parabrachial nucleus confirmed that cagrilinitide’s central appetite-regulating effects require functional amylin receptors. These findings explain why the selective receptor profile of cagrilinitide (AMY1/AMY3 bias over CALCR) is important for efficacy, and provide mechanistic support for the dose-response relationship observed in Phase 2 clinical trials.

flowchart LR
    CAG["Cagrilinitide\n(subcutaneous)"] --> AMY1["AMY1R\nCALCR + RAMP1"]
    CAG --> AMY3["AMY3R\nCALCR + RAMP3"]

    AMY1 --> DVC["Dorsal Vagal Complex\n(Area Postrema / NTS)"]
    AMY3 --> DVC
    DVC --> PBN["Parabrachial Nucleus"]
    DVC --> HYP["Hypothalamic Nuclei\n(Arcuate, PVN)"]
    PBN --> SAT["Satiety Signal\n↓ Food Intake"]
    HYP --> SAT
    SAT --> WL["Body Weight Reduction"]

    KO["RAMP1/RAMP3\nKnockout Mice"] -.->|"Effect abrogated\n(PMID 40609154)"| WL

Receptor Balance: Cagrilinitide vs. KBP-336 in Preclinical Models (PMID 36242844)

Larsen et al. (Biomedicine and Pharmacotherapy, December 2022) compared cagrilinitide and KBP-336, two dual amylin and calcitonin receptor agonists (DACRAs) with distinct receptor activation profiles. KBP-336 shows a calcitonin receptor bias; cagrilinitide derives from an amylin backbone with less CALCR preferentiality.

In high-fat diet (HFD) rats, both compounds produced potent, dose-dependent weight loss. In Zucker Diabetic Fatty (ZDF) rats, DACRA treatment improved fasting blood glucose, HbA1c, and insulin sensitivity in both groups, with KBP-336 achieving greater glycemic improvement than cagrilinitide at matched doses. The study concluded that receptor activation balance influences the metabolic outcome profile, supporting the hypothesis that optimizing CALCR-to-amylin receptor ratio may tune the glycemic-to-weight loss ratio.

This preclinical receptor balance work is directly relevant to the clinical observation that CagriSema achieves better glycemic control than cagrilinitide monotherapy, since semaglutide’s GLP-1R agonism provides complementary glycemic benefit through an independent pathway.

Tool Compound Characterization: Compound 0839 (PMID 40628316)

Gabery et al. from Novo Nordisk (Life Sciences, October 2025) characterized compound 0839, a research tool analog sharing 95% sequence homology with cagrilinitide (0833). The tool compound was made available for academic mechanistic research to avoid pharmacovigilance restrictions on the clinical development candidate.

Key findings from side-by-side comparisons in rodent models:

• In normal-weight rats, both compounds reduced food intake dose-dependently with comparable potency
• In obese mice and rats, 0839 and 0833 achieved equivalent weight reduction, with fat mass as the primary component
• Both compounds enhanced semaglutide’s effects on appetite suppression and body weight in combination experiments
• Metabolic parameters including blood glucose and insulin sensitivity improved equivalently between the two analogs

This validation study establishes 0839 as a reliable surrogate for mechanistic mode-of-action research, enabling academic investigation of amylin receptor pharmacology in preclinical models.

Review: Amylin Receptor CNS Pathways (PMID 39426704)

Hankir and Le Foll (Biochimie, February 2025) reviewed the CNS pathways by which amylin and long-acting analogs including cagrilinitide regulate food intake. The review characterized distinct neuronal subpopulations across:

• Caudal hindbrain: Area postrema and nucleus tractus solitarius (NTS); primary site of amylin receptor expression governing satiety
• Rostral hindbrain: Lateral parabrachial nucleus; relay for anorexigenic signals from NTS
• Midbrain: Lateral dorsal tegmentum and ventral tegmental area; dopaminergic circuits modulating reward-driven eating
• Hypothalamus: Arcuate nucleus and paraventricular nucleus; integrators of peripheral satiety signals and long-term energy balance

The review noted that amylin and calcitonin receptor agonists “directly or indirectly target genetically distinct neurons” through receptor activation, providing the anatomical basis for why cagrilinitide’s AMY1/AMY3 selectivity (established in PMID 40609154) translates into weight reduction rather than the bone-related effects of pure calcitonin receptor agonism.

Preclinical In Vitro and Structural Evidence

Cryo-EM Structural Biology: Nature Communications (PMID 40204768)

A 2025 study published in Nature Communications resolved cryo-EM structures of cagrilinitide bound to both the calcitonin receptor and amylin receptor complexes. The structural data characterized which receptor features determine subtype selectivity and how fatty acid acylation affects receptor engagement dynamics.

This structural resolution is relevant for two reasons. First, it provides a molecular explanation for cagrilinitide’s preference for AMY1/AMY3 over CALCR. Second, it informs the design of next-generation amylin analogs that might optimize receptor selectivity to tune the weight-to-glycemia benefit ratio, extending the insights from the preclinical receptor balance work (PMID 36242844).

In Vitro Metabolic Profiling for Anti-Doping Research (PMID 41702251)

Alhalabi et al. (Journal of Pharmaceutical and Biomedical Analysis, 2026) characterized the in vitro metabolic profiles of cagrilinitide, pramlintide, and KBP-066 using human skin and kidney tissue fractions plus biological fluid matrices. The study found that all three peptides undergo N-terminal and C-terminal degradation, yielding stable metabolic products.

While the study’s immediate application is anti-doping detection methodology for sporting contexts, the characterized metabolites provide information relevant to understanding cagrilinitide’s metabolic stability and biodegradation pathways in human tissues, complementing the in vivo pharmacokinetic data from clinical trials.

Quantitative Evidence Summary

Evidence Gaps and Active Research

REDEFINE 3 full publication: Results from NCT06065540 (CagriSema vs. semaglutide vs. cagrilinitide vs. placebo in T2D on metformin) have not yet been indexed in PubMed as of this page’s published date. The four-arm design will provide the cleanest decomposition of individual agent contributions.

REDEFINE 5 vs. tirzepatide in T2D (NCT06221969): This active trial compares CagriSema against tirzepatide (GIP+GLP-1 dual agonist) specifically in T2D treated with metformin. Results will address whether amylin+GLP-1 dual agonism is superior, inferior, or equivalent to GIP+GLP-1 dual agonism for glycemic and weight endpoints.

Pediatric Phase 3 (NCT07253285): Initiated in 2025, this trial recruits children and adolescents with excess body weight to evaluate cagrilintide and CagriSema. No pediatric efficacy data are currently available.

Muscle and lean mass composition: A 2026 Phase 1 mechanistic trial (NCT07527195) is evaluating the effect of CagriSema, cagrilinitide, and semaglutide on muscle health and lean mass during weight loss. GLP-1-class drugs have been associated with lean mass loss in addition to fat loss; whether amylin receptor agonism modifies this is biologically plausible but not yet characterized in humans. A 2026 in vitro and in vivo study (PMID 41852165) found that incretin-based therapies including compounds similar to CagriSema temporarily affected mitochondrial function in muscle tissue, a finding requiring follow-up in clinical populations.

Long-term cardiovascular outcomes: Neither REDEFINE 1 nor REDEFINE 2 was powered for hard cardiovascular events (MACE). A cardiovascular outcomes trial for CagriSema has not been publicly announced as of the published date of this page. The 7.06 mmHg systolic blood pressure reduction seen in meta-analysis (PMID 41759565) is directionally favorable, but long-term cardiovascular event data are absent from the current evidence base.

LDL-C signal: The modest LDL-C increase observed in the meta-analysis (PMID 41834765; MD 0.29 mmol/L with CagriSema vs. semaglutide) warrants attention in longer-term trials and in populations with existing cardiovascular risk or statin therapy. The mechanistic origin of this signal is not established from current data.

Key Primary Citations

For receptor pharmacology and central signaling mechanisms underlying these findings, see the Cagrilinitide Mechanism page. For a broader overview of the compound, its development history, and the full REDEFINE trial program, see the Cagrilinitide Research hub.

See also

More on Cagrilinitide:

• Cagrilinitide research overview
• Cagrilinitide: Mechanism of action
• Cagrilinitide: Safety profile
• Cagrilinitide: Pharmacokinetics
• Cagrilinitide: Dose-response

Head-to-head comparisons:

• Semaglutide vs Cagrilinitide