Cagrilintide
Class Long-acting amylin receptor agonist (DACRA — dual amylin and calcitonin receptor agonist) Regulatory status ⚠️ INVESTIGATIONAL — NOT APPROVED BY ANY REGULATORY AGENCY (as of April 2026). Novo Nordisk has not filed a standalone cagrilintide monotherapy NDA. Only the CagriSema combination was submitted for approval.
TL;DR
Cagrilintide is a long-acting, weekly-injected amylin analogue with a ~7.5-day half-life. As monotherapy in Phase 2 (26 weeks), it produced ~9.7–10.8% weight loss at the 2.4–4.5 mg doses — comparable to semaglutide monotherapy on raw numbers, but via a pharmacologically distinct amylin receptor pathway. As CagriSema (cagrilintide + semaglutide 2.4 mg combo), it achieved 22.7% weight loss in Phase 3 REDEFINE-1. Cagrilintide activates AMY1/3 receptors and calcitonin receptors directly (DACRA activity), unlike selective AMY-only agents. The monotherapy program was discontinued; cagrilintide’s only path to market is the CagriSema combination.
Key coaching flag: Cagrilintide monotherapy is not approved and may never be approved as a standalone product. Coaches should route interest in amylin pathway weight loss to CagriSema (pending approval) or pramlintide (approved but short-acting).
Why it Matters for Vitals
Amylin receptor agonism is one of the few weight-loss pathways genuinely non-overlapping with GLP-1, GIP, or glucagon agonism. For Vitals users:
- CGM signal (T2D): Amylin suppresses postprandial glucagon directly — distinct from GLP-1’s indirect effect. Relevant for T2D users tracking glucose via CGM.
- GI symptom tracking: Nausea and vomiting are the primary AEs — high-value coaching signal during titration.
- Appetite/satiation: Amylin activates area postrema satiation circuits — coaches should frame as “fullness signal from a different pathway.”
- No wearable biomarker yet validated for amylin receptor activation. HRV, RHR, or sleep architecture effects are unknown.
- Muscle mass: Zero human DXA data for cagrilintide monotherapy. Unknown whether amylin agonism spares lean mass.
Key Facts
| Property | Value |
|---|---|
| Mechanism | DACRA: AMY1R + AMY3R + CTR agonism |
| Half-life | ~180 hours (~7.5 days) |
| Dosing | Once-weekly SC injection |
| Phase 3 monotherapy | Not conducted |
| Registration monotherapy dose | 2.4 mg SC weekly (selected but never filed) |
| Phase 2 monotherapy result | −9.7% at 2.4 mg; −10.8% at 4.5 mg (26 weeks) |
| REDEFINE-4 (vs tirzepatide) | CagriSema 20.2% vs tirzepatide 23.6% at 84 weeks |
| Thyroid safety | Theoretical CTR concern; no human signal observed |
| Regulatory status | Investigational; only CagriSema combo NDA filed |
Mechanism Summary
Amylin Receptor Pharmacology
Cagrilintide is a 37-amino-acid lipdated cyclic amyloid polypeptide. Key structural distinction from native amylin: N14E, V17R, and P37Y substitutions; N-terminal lipidation confers the long half-life.
Receptor targets:
- AMY1R — calcitonin receptor (CTR) + RAMP1 heterodimer
- AMY3R — calcitonin receptor (CTR) + RAMP3 heterodimer
- CTR — directly activated at higher concentrations (DACRA activity)
This distinguishes cagrilintide from:
- Pramlintide — selective AMY1/2/3 agonist only (no CTR activity), short half-life (~20–45 min), FDA-approved for T2D
- Native amylin — 13-minute half-life, rapidly cleared
- GLP-1 RAs — completely different receptor family (class B GPCR, GLP-1R)
Central Nervous System Site of Action
Amylin receptors are concentrated in dorsal vagal complex structures with incomplete blood-brain barrier:
- Area postrema (AP) — primary site; directly accessible to circulating peptide
- Nucleus tractus solitarius (NTS) — hindbrain relay for satiation
Amylin activation produces satiation via:
- Delayed gastric emptying (peripheral)
- Direct postprandial glucagon suppression (metabolic — distinct from GLP-1’s glucose-dependent mechanism)
- Direct AP/NTS neuronal activation (central)
Key distinction from GLP-1: Both pathways use hindbrain nuclei, but cagrilintide acts through AMY receptors, not GLP-1R. The additivity of CagriSema (amylin + GLP-1) confirms pharmacologically distinct pathways.
DACRA Activity — What It Means
The calcitonin receptor (CTR) co-activation is functionally significant: CTR activation is Gαs-mediated, potentially producing additional cAMP signals not seen with selective AMY-only agonism. The clinical implications of this additional CTR activity are unknown — no human study has isolated the CTR component.
What the Current Evidence Suggests
Monotherapy (Phase 2, 26 weeks)
PMID 34798060 | NCT03940911 | Lau et al., Lancet Diabetes Endocrinol 2021
| Dose | Weight Loss | Notes |
|---|---|---|
| 0.3 mg weekly | ~3% | Lowest dose |
| 0.6 mg weekly | ~5% | |
| 1.2 mg weekly | ~7% | |
| 2.4 mg weekly | ~9.7% | Selected for Phase 3 (registration dose) |
| 4.5 mg weekly | ~10.8% | Higher GI AE burden |
- Dose-dependent across entire range
- Non-inferior to liraglutide 3 mg at 26 weeks (−9.0%)
- No severe hypoglycemia
- GI AEs (nausea, vomiting) dose-dependent
⚠️ Critical gap: No Phase 3 monotherapy trial was ever conducted. The 26-week Phase 2 result is the complete monotherapy evidence base.
vs Pramlintide (Same Class, Different Profile)
| Property | Pramlintide | Cagrilintide |
|---|---|---|
| Receptor | AMY1/2/3 selective (no CTR) | AMY1/3 + CTR (DACRA) |
| Half-life | 20–45 minutes | ~180 hours |
| Dosing | SC 2–3x daily | SC once weekly |
| FDA status | Approved (T2D, MDI insulin) | Investigational |
| Obesity monotherapy data | ~3–4% at 26 weeks | ~9.7–10.8% at 26 weeks |
Pramlintide’s short half-life and TID dosing essentially preclude practical obesity use. Cagrilintide’s weekly dosing solves the compliance problem that doomed pramlintide for obesity.
CagriSema Combination (Primary Development Path)
Cagrilintide’s only viable path to market is CagriSema. REDEFINE-1 (Phase 3, n≈3,417):
- CagriSema −20.4% at 68 weeks (co-primary endpoint met)
- REDEFINE-4 head-to-head: CagriSema 20.2% vs tirzepatide 23.6% at 84 weeks
→ Cagrilintide’s monotherapy differentiation vs GLP-1 monotherapy is modest (~10% vs ~15% semaglutide); its value is additive in the combo.
Glucagon Suppression (Metabolic Distinction)
Amylin directly suppresses postprandial glucagon secretion — this is mechanistically distinct from GLP-1’s glucagon suppression, which is glucose-dependent. Cagrilintide may suppress glucagon even in euglycemic states, though clinical relevance is unknown.
For T2D users: CagriSema’s HbA1c reduction (−1.4 to −2.0% in REDEFINE-2) likely reflects both the GLP-1 and amylin contributions.
Likely Wearable / Vitals Relevance
| Metric | Relevance | Confidence |
|---|---|---|
| Body weight | Direct — primary endpoint in all trials | High |
| CGM glucose (T2D users) | Plausible — direct glucagon suppression | Moderate |
| GI symptom tracking | High — nausea/vomiting are primary AEs | High |
| Resting heart rate | Unknown — no amylin-specific HR data | Very low |
| HRV | Unknown — no amylin-HRV studies | Very low |
| Sleep architecture | Unknown — no polysomnography data | Very low |
| Food intake/satiation | Mechanistically plausible; not measured in trials | Speculative |
Important: No wearable biomarker has been specifically studied for amylin receptor activation. Coaches should not project HRV, RHR, or sleep changes based on amylin mechanism without evidence.
Risks and Uncertainty
⚠️ Prominent Flags
| Flag | Detail |
|---|---|
REG_INVESTIGATIONAL | Cagrilintide monotherapy NOT approved; do not describe as available or prescribed |
NO_MONOTHERAPY_PHASE3 | 26-week Phase 2 is the complete monotherapy evidence base; 68-week data does not exist for monotherapy |
NO_DXA_DATA | Zero body composition data for cagrilintide; lean mass impact unknown |
THYROID_SIGNAL_ABSENT_BUT_THEORETICAL | DACRA (CTR) activity theoretical MTC concern; no human signal in any trial; long-term surveillance needed |
COMBO_ONLY_PATH | Cagrilintide monotherapy program discontinued; only CagriSema combo filed |
Thyroid / C-Cell Safety
The calcitonin receptor connection to medullary thyroid carcinoma (MTC) is a real pharmacological concern from the calcitonin peptide family. However:
- No thyroid signal observed in any human cagrilintide trial (up to 84 weeks)
- Patients with personal/family history of MTC or MEN2 are excluded from all trials
- Mechanism: CTR is structurally related to the calcitonin receptor; CTR activation in rodents has been associated with MTC
Verdict: Theoretical concern; no human signal; requires long-term post-marketing surveillance if approved.
Pancreatitis
No pancreatitis signal in cagrilintide trials to date. Monitor per GLP-1 class standard.
Comparison to Other Vault Notes
| Note | Comparison |
|---|---|
| CagriSema | CagriSema = cagrilintide + semaglutide combo; this note covers cagrilintide standalone |
| Semaglutide | Cagrilintide monotherapy (9.7%) is numerically less effective than semaglutide (14.9%); mechanism is distinct (AMY vs GLP-1R) |
| Tirzepatide | CagriSema (22.7%) vs tirzepatide (20.9%): combo comparable; no monotherapy cagrilintide vs tirzepatide data |
| Pramlintide | Cagrilintide = much longer half-life, DACRA vs selective AMY; cagrilintide is investigational, pramlintide is approved |
| GLP-1 GIP Glucagon | Amylin receptors (AMY1/3, CTR) are pharmacologically distinct from GLP-1R, GIPR, GCGR; shared hindbrain nuclei do not mean shared receptor |
What Stays Inside This Hub
The following are not split into standalone notes:
- Formulation details (lipidation chemistry)
- Proprietary Novo Nordisk engineering
- N-terminal vs C-terminal structural modifications
- cagrilintide vs other DACRA candidates in development
Related Notes
- CagriSema — cagrilintide + semaglutide combination; primary development path
- Semaglutide — GLP-1 RA; cagrilintide monotherapy is numerically inferior
- Tirzepatide — current best-in-class on raw Phase 3 weight loss
- Pramlintide — short-acting selective AMY agonist; approved for T2D
- GLP-1 GIP Glucagon — amylin receptor biology distinct from GLP-1/GIP/glucagon receptors
- Peptides MOC — peptide hormone notes and stacks
- GLP-1 Muscle Preservation — lean mass mitigation across incretin class
References
| # | PMID | Citation | Used For |
|---|---|---|---|
| 1 | 34798060 | Lau et al., Lancet Diabetes Endocrinol 2021 | Phase 2 dose-finding, monotherapy efficacy |
| 2 | 40544433 | REDEFINE-1 Phase 3 CagriSema (NEJM, Aug 2025) | CagriSema combo efficacy |
| 3 | 40544432 | REDEFINE-2 Phase 3 CagriSema T2D (NEJM, Aug 2025) | CagriSema T2D population |
| 4 | 33894838 | Phase 1b combination PK (2022) | Cagrilintide half-life, no PK interaction with semaglutide |
| 5 | 40847076 | Cryo-EM amylin receptor structure | Molecular mechanism of cagrilintide binding |
| 6 | 26071095 | Hay et al. — Amylin receptor review | Amylin receptor CNS localization (AP/NTS) |
| 7 | 36883831 | Comprehensive amylin review | Amylin biology, PK, CTR activity |
| 8 | PMC11760743 | DVC neuronal populations | Neural substrate mapping for amylin |
Vault note version: 1.0 | Monograph: research/batch-107-2026-04-24/cagrilintide-amylin-analogue-obesity-weight-loss.md | Domain: Vitals obesity/weight management