Cagrilinitide Safety Profile: Adverse Events, Tolerability, and Preclinical Toxicology

Cagrilinitide (AM833, NNC0174-0833) is a once-weekly long-acting amylin receptor agonist developed by Novo Nordisk. Its safety and tolerability have been systematically characterized across a Phase 1 single-ascending-dose (SAD) program, a multiple-ascending-dose (MAD) program, two Phase 2 randomized trials, and the completed Phase 3 REDEFINE program. Results from the REDEFINE 1 and REDEFINE 2 trials were published in the New England Journal of Medicine in August 2025 (PMID 40544433; PMID 40544432).

This page focuses on the adverse event profile, dose-relationship of key safety signals, special-population considerations, contraindications, and potential drug interactions derived from the available published literature. Cagrilinitide is an investigational compound; this content is for research and educational purposes only.

Mechanism-Based Safety Rationale

Cagrilinitide activates amylin receptors AMY1 (CALCR + RAMP1) and AMY3 (CALCR + RAMP3) in the hypothalamus and area postrema, and the calcitonin receptor (CALCR) directly. This receptor profile predicts two broad categories of adverse events:

1. Satiety-pathway effects. Central amylin receptor activation reduces appetite and gastric emptying. Gastrointestinal symptoms, predominantly nausea, vomiting, and constipation, are mechanistically expected and consistently observed.

2. Calcitonin receptor engagement. Calcitonin receptor activation at high or sustained concentrations can affect bone turnover and potentially thyroid C-cell biology. Preclinical toxicology studies in rodents showed C-cell hyperplasia at high doses, consistent with findings in the GLP-1 receptor agonist class; this signal has not been replicated in primates at clinical dose ranges.

flowchart TD
    CAG["Cagrilinitide\n(weekly SC injection)"]

    CAG --> AMY1["AMY1\nCALCR + RAMP1\nHypothalamus / area postrema"]
    CAG --> AMY3["AMY3\nCALCR + RAMP3\nHypothalamus / brainstem"]
    CAG --> CALCR["CALCR direct\n(calcitonin receptor)"]

    AMY1 --> SAT["Satiety signaling\nReduced gastric emptying"]
    AMY3 --> SAT
    SAT --> GI["GI adverse events\n(nausea, vomiting, constipation)"]

    CALCR --> BONE["Bone turnover modulation\n(preclinical: C-cell effect at high dose)"]
    CALCR --> THYROID["C-cell biology\n(rodent signal; not confirmed in primates)"]

    style GI fill:#ffd6d6,stroke:#cc0000
    style BONE fill:#fff3cd,stroke:#856404
    style THYROID fill:#fff3cd,stroke:#856404

Phase 1 Safety Characterization

Single and Multiple Ascending Dose Studies

The Phase 1 SAD study (NCT02300844) established the initial human safety profile of cagrilinitide in overweight and obese male subjects. The subsequent MAD study (NCT02958085) extended characterization to multiple-dose administration in subjects with obesity, evaluating pharmacodynamic signals and adverse events through dose escalation.

Doses evaluated in Phase 1 ranged from 0.3 mg to 4.5 mg once weekly. Gastrointestinal adverse events were the dominant finding at all doses. The events were mild to moderate and concentrated during the escalation phase. No clinically significant abnormalities in laboratory parameters, vital signs, or electrocardiograms were identified in Phase 1 at doses up to 4.5 mg.

Phase 1b Combination Safety (NCT03600480; PMID 33894838)

A Phase 1b trial published in The Lancet in 2021 evaluated the concomitant safety of cagrilinitide at six dose levels (0.16-4.5 mg) combined with semaglutide 2.4 mg once weekly in 96 subjects (mean age 40.6 years, BMI 27.0-39.9 kg/m2). Of 566 adverse events in 92 participants, 207 (37%) were gastrointestinal. Nearly all gastrointestinal events occurred during the escalation phase. The combination was described as “well tolerated with an acceptable safety profile,” and the trial supported advancement to Phase 2.

Thorough QT/QTc Study (NCT05804162; PMID 39279639)

A dedicated cardiac conduction study found no clinically meaningful QTc prolongation at therapeutic doses of cagrilinitide. This addresses the standard regulatory requirement for QT characterization and removes cardiac conduction as a safety concern at studied doses.

Organ Impairment Studies

• Renal impairment (NCT04209049): Subjects with mild-to-moderate chronic kidney disease showed cagrilinitide pharmacokinetics within acceptable variation. Dose adjustment was not required.
• Hepatic impairment (NCT05564104): Mild-to-moderate hepatic impairment did not alter cagrilinitide exposure in a clinically meaningful way. Data for severe impairment are not available from published sources.

Phase 2 Adverse Event Profile

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

This 26-week randomized trial in 706 participants with obesity without diabetes compared cagrilinitide at five dose levels (0.3-4.5 mg once weekly) against liraglutide 3.0 mg once daily and placebo. The most common adverse events were nausea, constipation, and vomiting. Treatment discontinuation due to adverse events occurred in approximately 4% of participants across the cagrilinitide arms, comparable to the active control.

A dose-dependent increase in the frequency of gastrointestinal adverse events was observed across the cagrilinitide dose range, consistent with the pharmacological mechanism. The 4.5 mg dose arm showed numerically higher GI event rates than lower doses.

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

Published in The Lancet in August 2023, this 32-week Phase 2 trial enrolled 92 participants with T2D (BMI 27+ kg/m2) randomized to CagriSema, semaglutide 2.4 mg, or cagrilinitide 2.4 mg. CagriSema was described as “well tolerated.” Gastrointestinal events were the primary adverse event category across all three arms. Treatment discontinuation rates were not substantially elevated with CagriSema compared to semaglutide monotherapy.

Phase 3 Safety Data: REDEFINE Program

The REDEFINE Phase 3 program generated the most comprehensive safety database for cagrilinitide and the CagriSema combination.

REDEFINE 1: Obesity Without Type 2 Diabetes (NCT05567796; PMID 40544433)

This 68-week trial enrolled adults with obesity without T2D. The primary safety finding was the gastrointestinal adverse event burden: 79.6% of participants in the CagriSema group reported at least one gastrointestinal adverse event, compared to 39.9% in the placebo group. The most common individual events were nausea, vomiting, diarrhea, constipation, and abdominal pain. Serious adverse events occurred at rates comparable overall between treatment and placebo.

REDEFINE 2: Type 2 Diabetes with Excess Body Weight (NCT05394519; PMID 40544432)

This 68-week trial enrolled 1,206 adults with T2D. The safety profile was consistent with REDEFINE 1: gastrointestinal events predominated, were mostly mild to moderate, and concentrated during dose escalation. The CagriSema arm showed a higher rate of nausea than the placebo arm.

Adverse Events: Summary and Dose Relationship

Most Common Adverse Events

The gastrointestinal adverse event frequency is substantially higher with CagriSema than with either component alone, and is higher with CagriSema than with semaglutide monotherapy. A 2026 meta-analysis (PMID 41834765; 3 RCTs, n=3,545) quantified the risk: CagriSema was associated with a higher rate of nausea versus semaglutide (risk ratio 1.64; 95% CI 1.01-2.66) and a higher rate of administration-site conditions (RR 3.27; 95% CI 1.27-8.46).

Serious Adverse Events

Overall rates of serious adverse events in Phase 3 trials were comparable between treatment and placebo groups for CagriSema. However, for cagrilinitide monotherapy versus semaglutide, the same 2026 meta-analysis identified a modestly elevated serious adverse event risk ratio (RR 1.83; 95% CI 1.03-3.24; PMID 41834765). The absolute incidence of serious events remained low in all arms, and no specific unexpected serious adverse event category drove this signal. Independent replication in additional trials will clarify whether this finding is stable.

Discontinuation due to adverse events was primarily driven by gastrointestinal intolerability. In the Phase 2 monotherapy trial (PMID 34798060), discontinuation for adverse events occurred in approximately 4% of subjects across cagrilinitide dose groups over 26 weeks.

Preclinical Toxicology Signals

Rodent C-Cell Findings

Calcitonin receptor agonism in rodents produces thyroid C-cell hyperplasia and, at sustained high exposures, medullary thyroid carcinoma (MTC). This signal is established for the GLP-1 receptor agonist class (FDA labeling for semaglutide, liraglutide) and is expected to apply to any compound with meaningful CALCR engagement. Cagrilinitide engages CALCR directly in addition to the heterodimeric amylin receptors AMY1 and AMY3.

This rodent signal has not been reproduced in non-human primates at clinical dose ranges. Regulatory agencies consider it a class-level precautionary concern. Clinical trials have excluded subjects with personal or family history of MTC or MEN2 on this basis.

Conditioned Taste Avoidance

A comparative study examining eloralintide (PMID 41109426) reported that cagrilinitide, characterized as a non-selective amylin receptor agonist, induced significantly greater conditioned taste avoidance in lean rats than the AMY1-selective eloralintide. Conditioned taste avoidance is a proxy measure of nausea-like aversive responses in rodent models and may mechanistically contribute to the GI adverse event profile observed clinically.

The relative contribution of non-selective CALCR engagement versus AMY1/AMY3-mediated signaling to human nausea has not been resolved definitively. Receptor subtype-selective amylin analogs in development may offer a basis for comparison.

Contraindications and Precautions

Cagrilinitide is an investigational compound without approved product labeling. The following are based on clinical trial exclusion criteria, class-effect considerations from GLP-1 and calcitonin receptor pharmacology, and general peptide safety principles.

Calcitonin Receptor Class Caution

Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) is a contraindication applied across all Phase 2 and Phase 3 trials, consistent with regulatory expectations for calcitonin receptor agonists. This exclusion reflects the preclinical rodent C-cell signal, not established human risk.

Pancreatitis

A history of pancreatitis was an exclusion criterion in REDEFINE trials, consistent with the class-level precautionary approach used for GLP-1 receptor agonists. Cagrilinitide has not been studied in subjects with prior acute pancreatitis.

Pregnancy

Cagrilinitide trials excluded pregnant or breastfeeding participants. No human pregnancy or lactation safety data exist. Animal studies of reproductive toxicity have not been published in the accessible literature.

Severe Organ Impairment

Severe renal or hepatic impairment was excluded from pharmacokinetic impairment studies. Published data cover only mild-to-moderate stages of each condition.

Drug Interactions

Pharmacokinetic Interactions

Cagrilinitide is an acylated peptide subject to enzymatic peptide bond cleavage. It is not a substrate for cytochrome P450 enzymes and is not expected to inhibit or induce CYP enzymes. No formal CYP-based drug-drug interaction studies are published in the accessible literature, and none are expected to be clinically significant based on the molecule’s class.

Gastric Emptying Effects

Cagrilinitide slows gastric emptying. This can alter the absorption rate of orally administered drugs, particularly those with narrow therapeutic windows or time-sensitive absorption requirements. Oral contraceptives and oral hypoglycemic agents may theoretically be affected. This mechanism is shared with the GLP-1 receptor agonist class and has been discussed in regulatory assessments for semaglutide.

Combined Satiety-Pathway Pharmacology

When co-administered with GLP-1 receptor agonists (as in the CagriSema formulation), additive GI adverse events are observed (nausea RR 1.64; PMID 41834765). The combination amplifies the satiety pharmacology of each component, producing more frequent and potentially more severe nausea and vomiting compared to monotherapy. This is a pharmacodynamic interaction rather than a pharmacokinetic one.

Insulin and Antidiabetic Agents

Cagrilinitide suppresses post-prandial glucagon. In subjects with T2D on insulin or sulfonylureas, the risk of hypoglycemia may increase when cagrilinitide is added. Trial protocols for REDEFINE 2 managed this by requiring dose adjustment or discontinuation of insulin at enrollment. No spontaneous hypoglycemia cases attributed specifically to cagrilinitide are reported in the published summaries.

Special Populations

Type 2 Diabetes

The REDEFINE 2 trial provides the primary safety data in T2D. The adverse event profile was similar to the non-diabetes cohort. Hypoglycemia was managed through pre-specified dose adjustments of background antidiabetic therapy.

Ethnic Subpopulations

Phase 1 PK studies specifically designed to characterize cagrilinitide exposure in Japanese (NCT03787225), Caucasian, and Chinese (NCT05254158) subjects found no clinically meaningful PK differences across these groups. REDEFINE 4 was conducted specifically in East Asian populations to support regional regulatory submissions.

Pediatric Population

No pediatric safety data are published. A Phase 3 trial in children and adolescents with excess body weight (NCT07253285) was initiated in 2025 and will provide the first prospective pediatric safety data.

Elderly and Frail Subjects

The REDEFINE Phase 3 trials enrolled broad adult populations, including older adults. Subset analyses by age have not been separately published. General peptide and satiety-class considerations suggest monitoring for adequate nutrition and hydration in elderly subjects with reduced appetite.

Long-Term Safety Considerations

Phase 3 REDEFINE trials extended to 68 weeks, providing the longest safety follow-up available from published data. This duration is longer than Phase 2 (26-32 weeks) but shorter than the multi-year safety datasets available for approved GLP-1 receptor agonists. Key long-term considerations include:

• Sustained GI tolerability. Nausea tends to attenuate after dose escalation is complete, but constipation can persist. Long-term GI symptom burden was not characterized independently of efficacy outcomes in published summaries.
• Lean mass effects. Substantial weight loss, whether from cagrilinitide or CagriSema, reduces both fat and lean mass. A Phase 1 mechanistic trial (NCT07527195) was initiated in 2026 to specifically characterize the effect of cagrilinitide on muscle health and composition. Results are not yet published.
• Cardiovascular monitoring. A secondary analysis of REDEFINE 1 published in Hypertension in 2026 (PMID 41328546) reported that CagriSema significantly reduced systolic and diastolic blood pressure versus placebo, suggesting cardiovascular risk-marker benefit rather than harm at Phase 3 study durations.
• Lipid effects. The 2026 meta-analysis (PMID 41834765) identified a modest LDL-C increase with CagriSema versus semaglutide monotherapy (MD 0.29 mmol/L; 95% CI 0.02-0.55; p=0.03). The clinical significance of this finding requires evaluation in long-term cardiovascular outcomes data.

Regulatory Context

Cagrilinitide and CagriSema are investigational. As of April 2026, neither compound has received FDA or EMA marketing approval. Novo Nordisk has not published regulatory submission details. The Phase 3 REDEFINE dataset supports submissions in obesity and type 2 diabetes indications.

The rodent C-cell signal requires a precautionary black-box warning for approved GLP-1 receptor agonists, and this requirement is expected to apply to CagriSema given cagrilinitide’s CALCR engagement. The specific regulatory language has not been publicly determined.

Summary of the Safety Evidence

Cagrilinitide’s safety profile through Phase 3 is characterized by:

1. Dominant gastrointestinal adverse events. Nausea and vomiting are expected from the mechanism, dose-dependent, concentration in the escalation phase, and the primary driver of treatment discontinuation.
2. Amplification in combination. CagriSema produces higher GI adverse event rates than either monotherapy (nausea RR 1.64 vs. semaglutide; PMID 41834765).
3. Acceptable serious adverse event rate. Serious adverse events with CagriSema were comparable overall to placebo in Phase 3. A modest signal for cagrilinitide monotherapy versus semaglutide (RR 1.83; PMID 41834765) requires further evaluation.
4. No cardiac conduction concern. Thorough QT study (NCT05804162; PMID 39279639) found no clinically meaningful QTc prolongation.
5. No organ-toxicity signal in humans. Renal and hepatic impairment studies found acceptable PK without dose adjustment requirements.
6. Class-based precautionary considerations. Rodent C-cell hyperplasia from CALCR engagement informs MTC/MEN2 exclusions. Gastric emptying slowing informs oral drug absorption and hypoglycemia precautions.

For quantitative efficacy outcomes from Phase 2 and Phase 3 REDEFINE trials, see the Cagrilinitide Evidence page.

For the molecular pharmacology underlying these safety signals, see the Cagrilinitide Mechanism page.

For pharmacokinetic parameters relevant to organ impairment and drug interaction assessment, see the Cagrilinitide Pharmacokinetics page.

Key References

• PMID 33894838: Phase 1b combination safety/PK, The Lancet 2021
• PMID 34798060: Phase 2 monotherapy dose-finding, The Lancet 2022
• PMID 37364590: Phase 2 CagriSema in T2D, The Lancet 2023
• PMID 39279639: Thorough QT/QTc study, 2024
• PMID 40544433: REDEFINE 1 Phase 3, N Engl J Med 2025
• PMID 40544432: REDEFINE 2 Phase 3, N Engl J Med 2025
• PMID 41109426: Eloralintide vs. cagrilintide CTA comparison, Mol Metab 2025
• PMID 41328546: Blood pressure secondary analysis, Hypertension 2026
• PMID 41834765: Meta-analysis efficacy and safety, Diabetes Obes Metab 2026

NCT identifiers cited: NCT02300844, NCT02958085, NCT03600480, NCT03856047, NCT04209049, NCT04982575, NCT05394519, NCT05564104, NCT05567796, NCT05804162, NCT07527195, NCT07253285

See also

More on Cagrilinitide:

• Cagrilinitide research overview
• Cagrilinitide: Mechanism of action
• Cagrilinitide: Clinical & preclinical evidence
• Cagrilinitide: Pharmacokinetics
• Cagrilinitide: Dose-response

Head-to-head comparisons:

• Semaglutide vs Cagrilinitide