Amycretin
TL;DR
Amycretin — also called zenagamtide, NN9487, and formerly NNC0487-0111 — is an investigational unimolecular dual GLP-1 and amylin receptor co-agonist from Novo Nordisk. It is a single polypeptide engineered to engage both receptors simultaneously, distinct from CagriSema (two separate molecules co-formulated) and from tirzepatide (GIP/GLP-1 dual). Not approved by any regulatory authority.
In a Phase 1b/2a randomized obesity trial (PMID 40550231), once-weekly subcutaneous Amycretin produced dose-dependent weight loss up to −24.3% at 36 weeks at the highest dose tier (60 mg), versus −1.1% to +2.3% placebo. An oral formulation showed approximately −13.1% at 12 weeks at the highest dose in a separate Phase 1 trial (PMID 40550229). Phase 2 in type 2 diabetes reported up to −14.5% weight loss and −1.8% HbA1c at 36 weeks — but this is from a company press release only, not peer-reviewed. Phase 3 (AMAZE program) is actively recruiting.
The amylin co-agonism component is mechanistically distinct but its independent contribution to weight loss in humans has not been quantified. Amylin agonism introduces an additional hypoglycemia risk when combined with insulin or insulin secretagogues.
Why it matters for Vitals
Amycretin is a likely future competitor in the GLP-1/incretin obesity landscape and forces a clean distinction between unimolecular GLP-1+amylin co-agonism versus co-formulated or co-administered dual therapy.
Vitals relevance — explicit:
| Domain | Relevance | Confidence |
|---|---|---|
| Body composition | Rapid weight loss (~20%+) would trigger the same muscle-preservation safeguards as other GLP-1-class agents: protein intake optimization, resistance training, DXA/BIA monitoring. No Amycretin DXA or lean-mass data exist. | Class extrapolation |
| GLP-1 receptor activity | Core mechanism — same incretin pathway as semaglutide, tirzepatide, retatrutide. Will share resting HR elevation, GI side-effect burden, and class-level CV benefit extrapolation. | High |
| Amylin-mediated satiety | Hindbrain area postrema pathway distinct from hypothalamic GLP-1. May produce more durable satiety signaling and gastric-emptying delay. Contribution not independently quantified in humans. | Mechanistic inference |
| HRV / autonomic confound | Weight-loss–mediated HRV changes expected (positive autonomic shift from fat loss). GLP-1–mediated resting HR elevation is a confound during titration. No Amycretin-specific HRV data. | Low–Moderate |
| Sleep | GI symptoms during titration may fragment sleep. No Amycretin-specific sleep architecture data. | Low |
| Glucose (T2D) | CGM improvement expected in T2D subgroup — glucose-dependent insulin secretion + weight loss. Phase 2 excluded insulin users; hypoglycemia risk with insulin/secretagogues is a safety concern extrapolated from pramlintide. | Moderate (T2D only) |
| Cardiorenal biomarkers | No cardiorenal data published. GLP-1 class has established cardiorenal protection (semaglutide, tirzepatide); Amycretin’s specific cardiorenal profile is unknown. | Gap |
Mechanism summary
Amycretin activates two receptor systems via one engineered polypeptide:
GLP-1 receptor (GLP-1R): Full agonism — glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, central hypothalamic satiety. Same incretin pathway as semaglutide, liraglutide, tirzepatide. Half-life supports once-weekly SC dosing but the exact value is proprietary.
Amylin receptor (AMYR/CTR complex): Amylin receptors are calcitonin receptor heterodimers (CTR + RAMP1/2/3 = AMY1/2/3). Expressed in the area postrema and nucleus of the solitary tract — hindbrain regions outside the blood-brain barrier. Amylin agonism slows gastric emptying, induces meal-terminating satiation, reduces postprandial glucagon, and has preclinical signals for increased energy expenditure. The independent contribution of amylin agonism to Amycretin’s weight loss in humans has not been quantified — synergy with GLP-1 is plausible but unproven for this specific molecule.
Unimolecular vs combination distinction:
- Tirzepatide: single molecule, GLP-1R + GIPR — not amylin
- CagriSema: semaglutide + cagrilintide — two separate molecules, different PK profiles
- Amycretin: single molecule, GLP-1R + AMYR — shared pharmacokinetics
Preclinical synergy (Mack et al. 2019, DOI 10.1038/s41598-019-44591-8) supports GLP-1 + amylin combination weight-loss effect in animal models. This has not been independently confirmed for Amycretin in humans.
Full incretin receptor biology: see GLP-1 GIP Glucagon. Amylin receptor biology: see Amylin Receptor Biology (aspirational — not yet a standalone vault note; link exists as ghost until a second compound requires it).
What the current evidence suggests
Phase 1b/2a — Subcutaneous obesity trial
PMID 40550231 | NCT06064006 | Lancet 2025 | Supported
Randomized, double-blind, placebo-controlled, dose-escalation. Adults 18–55, BMI 27–39.9 kg/m², no T2D. N=101 active : 24 placebo. Primary endpoint was safety, not weight loss.
| Cohort | Maintenance dose | Duration | Mean weight change | Placebo |
|---|---|---|---|---|
| Part A–D | 1.25 mg SC weekly | 20 weeks | −9.7% | +2.0% |
| Part B–E | 5 mg SC weekly | 28 weeks | −16.2% | +2.3% |
| Part C | 20 mg SC weekly | 36 weeks | −22.0% | +1.9% |
| Part D (highest) | 60 mg escalation | 36 weeks | −24.3% | −1.1% |
All active arms statistically significant vs placebo (p<0.0001 for parts A–D; p=0.0003 for part E).
Caveats: Large number of participant withdrawals; discontinuation-adjusted efficacy uncertain. 60 mg result is from an escalation cohort, not a defined maintenance dose. No DXA body composition data publicly available. Phase 1b/2a design — not a single pivotal registration trial.
Phase 1 — Oral Amycretin obesity trial
PMID 40550229 | NCT05369390 | Lancet 2025 | Supported (exploratory endpoint)
First-in-human, randomized, double-blind, placebo-controlled. 144 participants. Adults 18–55, BMI 25–39.9 kg/m². Fixed-titration cohort up to 100 mg/day for 12 weeks.
Exploratory efficacy: Approximately −13.1% bodyweight vs −1.2% placebo at highest oral dose. This is an exploratory endpoint — the trial was powered for safety, not efficacy. No food restriction or permeation enhancer required (unlike oral semaglutide/Rybelsus).
Phase 2 — Type 2 Diabetes
NCT06542874 | Reported only — press release Novo Nordisk, November 2025
Randomized, quadruple-masked, placebo-controlled dose-finding. 448 participants with T2D on metformin ± SGLT2 inhibitor. Excluded insulin users and patients with hypoglycemia unawareness.
| Outcome | Reported result | Evidence grade |
|---|---|---|
| Bodyweight change | up to −14.5% at 36 weeks | Reported (press release only) |
| HbA1c reduction | up to −1.8% (SC); −1.5% (oral) | Reported |
| HbA1c target achievers (≤6.5% or similar) | 89.1% | Reported |
| Safety | GI events mostly mild-moderate; no new safety signals stated | Reported / incomplete |
No peer-reviewed publication or ClinicalTrials.gov posted results found. Do not present these as confirmed findings.
Phase 3 — AMAZE program
| Trial | NCT | Population | Primary endpoint | Status |
|---|---|---|---|---|
| AMAZE-1 | NCT07339423 | Obesity (no T2D) | Weight change, week 84 | Recruiting |
| AMAZE-2 | NCT07533175 | T2D | Weight change, week 84 | Not yet recruiting |
| AMAZE-8 | NCT07400107 | T2D vs semaglutide 2.4 mg | Weight change, week 84 | Not yet recruiting |
| AMAZE-12 | NCT07503210 | Weight maintenance | Weight change, weeks 40–92 | Not yet recruiting |
| AMAZE-5 | NCT07481630 | Knee OA + obesity | Weight + WOMAC pain, week 80+ | Not yet recruiting |
| AMAZE-6 | NCT07509307 | Knee OA + obesity | Weight + WOMAC pain, week 80+ | Not yet recruiting |
AMAZE-8 is the key comparative trial — direct head-to-head vs semaglutide 2.4 mg. No Phase 3 results are available.
Safety
Amycretin-specific data
Oral Phase 1 (NCT05369390, 144 participants, up to 12 weeks):
- 364 treatment-emergent AEs in 89/144 participants (62%)
- All AEs were mild or moderate in severity
- Gastrointestinal: 180/364 (49%) — nausea, vomiting, diarrhea, decreased appetite
- 81% of participants reporting AEs had GI events
- No deaths reported
Subcutaneous Phase 1b/2a (NCT06064006, 125 participants, up to 36 weeks):
- Most common AEs: gastrointestinal, mild-to-moderate, majority resolved
- Large number of participant withdrawals; many discontinuations were unrelated to AEs
- Numeric SAE counts, injection-site reaction rates, and pancreatitis rates not publicly reported
Evidence gaps (Amycretin-specific):
| Safety parameter | Status |
|---|---|
| Serious adverse event rates (Phase 1/2) | Not publicly reported |
| Pancreatitis events | Not reported in amycretin publications |
| Gallbladder disease events | Not reported |
| Injection-site reaction rates | Not reported |
| Thyroid / calcitonin changes | Trial excluded calcitonin ≥50 ng/L at screening; no follow-up data |
| Hypoglycemia in T2D | Phase 2 excluded insulin users; no event rates posted |
| Anti-drug antibodies / immunogenicity | Not reported |
| Long-term safety (>36 weeks) | No data |
Class safety context
GLP-1 class (semaglutide label):
- Boxed warning: thyroid C-cell tumors in rodents — contraindicated in personal/family history of MTC or MEN2
- Acute pancreatitis — requires discontinuation if suspected
- Gallbladder disease (cholelithiasis, cholecystitis)
- GI events (nausea, vomiting, diarrhea) — leading cause of discontinuation
Amylin class (pramlintide/Symlin label — applies by mechanism extrapolation):
- Boxed warning: severe hypoglycemia when combined with insulin — especially in Type 1 DM, typically within 3 hours of injection; requires 50% mealtime insulin reduction
- Contraindications: hypoglycemia unawareness, gastroparesis, known hypersensitivity
- Gastic-emptying delay: can delay absorption of concomitant oral medications — separate critical oral drugs by ≥1 hour before or ≥2 hours after pramlintide
- Pancreatitis: listed in postmarketing adverse reactions
Amycretin-specific relevance: Amylin agonism adds a hypoglycemia risk when combined with insulin or insulin secretagogues — this is the primary clinical safety distinction from pure GLP-1 agents. Amycretin Phase 3 in T2D will need to manage this risk carefully. Coaches should flag this to prescribing clinicians.
Drug-drug interactions
- NCT06461039 (completed): amycretin’s effect on ethinylestradiol/levonorgestrel and acetaminophen PK — results not yet posted
- CYP3A4/P-gp interaction profile: not characterized
- Gastric-emptying delay from amylin agonism may affect oral drug absorption (class-level concern from pramlintide)
Wearable / Vitals relevance
Coaching status: Investigational — no Amycretin-specific wearable protocol is validated.
Wearable-accessible endpoints relevant to Amycretin if/when approved:
| Endpoint | Wearable source | Confidence | Notes |
|---|---|---|---|
| Body weight trend | Scale | High | Primary endpoint; weight trajectory monitorable |
| Resting heart rate | Wrist HR / chest strap | Moderate | GLP-1 class effect: resting HR elevation of +3–5 bpm typical |
| HRV / autonomic balance | Wrist HRV | Low–Moderate | Weight-loss–mediated HRV improvement expected; GLP-1 titration confound real |
| Sleep fragmentation | Wrist accelerometer | Low–Moderate | GI symptoms during titration may disrupt sleep |
| Glucose (T2D population) | CGM | Moderate | T2D subgroup; glucose-dependent insulin secretion + weight loss |
| Food noise / appetite | Self-report only | Not wearable | Amylin may reduce food noise via hindbrain pathway — not instrumentally trackable |
Practical coaching notes:
- No validated wearable signature for Amycretin response or non-response exists
- GI tolerability management protocol for semaglutide/tirzepatide would be applicable by class extrapolation
- Human sign-off required before any operationalization
- Autonomic metrics during titration (weeks 1–8) should be interpreted with caution due to acute GI stress
Risks and uncertainty
| Risk / uncertainty | Why it matters | Current status |
|---|---|---|
| Phase 3 efficacy | Current evidence is early-phase with design limitations | AMAZE-1 readout ~2029 |
| Cardiovascular outcomes | No CVOT announced or registered — significant evidence gap | Watch for CVOT announcement |
| Hypoglycemia in T2D | Amylin + insulin/secretagogues = severe hypoglycemia risk | Phase 3 hypoglycemia endpoints; human sign-off required |
| Oral formulation efficacy | May change access paradigm if sufficient efficacy at viable dose | Phase 2 oral dose-response |
| Long-term safety (>36 weeks) | Unknown autoimmune, pancreatic, thyroid signals | Phase 3 safety monitoring |
| Head-to-head vs tirzepatide | Competitive differentiation unknown | AMAZE-8 vs semaglutide only |
| Discontinuation-adjusted efficacy | High dropout in Phase 1b/2a; true efficacy uncertain | Phase 3 full analysis set |
| Immunogenicity | Novel dual-receptor molecule; anti-drug antibody risk | Phase 3 ADA data |
| Lean mass / DXA | No body composition data published | Unknown — critical for Vitals coaching |
| Amylin synergy quantification | Independent contribution of amylin agonism unknown | Mechanistic inference only |
Best stack context
If Amycretin is approved in the future, the following vault notes represent the likely coaching and stack context:
Body composition:
- GLP-1 Body Composition — body composition changes across GLP-1 class
- Incretin Sarcopenia GLP-1 Prevention Protocol — lean mass preservation during weight loss
- Protein Intake GLP-1 Glucagon — protein and resistance training protocol for GLP-1-class weight loss
Safety monitoring:
- GLP-1 RA NAION Safety Signal — GLP-1 class ophthalmologic safety
- GLP-1 RA Pancreatitis Safety Signal — pancreatitis risk monitoring
- GLP-1 RA Skeletal Safety — bone mineral density and fracture risk
- GLP-1 Muscle Preservation — muscle preservation during GLP-1 therapy
Mechanism / comparison:
- GLP-1 GIP Glucagon — incretin and glucagon receptor comparison frame
- CagriSema — semaglutide + cagrilintide; not the same as Amycretin
- Cagrilintide — amylin pathway anchor
- Pramlintide — approved amylin analog; relevant for hypoglycemia risk context
Tier 2 / aspirational links (ghost links — note does not yet exist):
- Amylin Receptor Biology — amylin receptor CTR/RAMP heterodimers, area postrema; aspirational note for when a second compound needs it
What stays inside this hub
The following are kept inline in this hub rather than split into standalone notes:
- Proprietary PK parameters — half-life, bioavailability, Cmax, AUC are not publicly disclosed; no standalone PK note warranted
- Formulation details — salt form, storage requirements, injection device not publicly described; no separate note
- Obscure metabolite names — active metabolites uncharacterized; no note
- Company development trivia — pipeline positioning, competitive strategy; inline only
- NCT06049329 (Japanese males Phase 1) — single-population study, not decision-relevant for Vitals; inline only
- NCT06461039 drug-interaction study — registered but results not posted; watchpoint, not standalone note
Evidence summary table
| Claim | Evidence grade | Source | Boundary |
|---|---|---|---|
| Amycretin = NN9487 = zenagamtide = NNC0487-0111 | Supported | Batch 180 synthesis + canonical KB | Avoid NN9931 (semaglutide/MASH) and NN9838 (cagrilintide/CagriSema) misidentification |
| Unimolecular GLP-1R + amylin receptor co-agonist | Supported | PMID 40550231, 40550229 | Mechanism does not prove clinical superiority to other incretin agents |
| −24.3% bodyweight at 36 weeks (60 mg SC) | Supported | PMID 40550231 | Highest dose escalation cohort; Phase 1b/2a; primary endpoint was safety |
| −22.0% at 36 weeks (20 mg SC) | Supported | PMID 40550231 | Phase 1b/2a; likely more realistic maintenance signal |
| −16.2% at 28 weeks (5 mg SC) | Supported | PMID 40550231 | Phase 1b/2a |
| −9.7% at 20 weeks (1.25 mg SC) | Supported | PMID 40550231 | Phase 1b/2a |
| Oral Amycretin −13.1% at 12 weeks (100 mg/day) | Supported (exploratory) | PMID 40550229 | Exploratory endpoint; trial powered for safety |
| Phase 2 T2D: −14.5% weight, −1.8% HbA1c | Reported | Novo Nordisk press release Nov 2025 | Not peer-reviewed; not confirmed |
| Phase 2 T2D: 89.1% HbA1c target achievers | Reported | Novo Nordisk press release Nov 2025 | Not peer-reviewed |
| Six AMAZE Phase 3 trials registered | Supported | ClinicalTrials.gov | No outcomes yet |
| AMAZE-8 is head-to-head vs semaglutide 2.4 mg | Supported | NCT07400107 | Results pending |
| GLP-1 + amylin synergy in animals | Supported (preclinical) | Mack et al. 2019 | Not isolated in Amycretin human studies |
| Amylin component adds hypoglycemia risk with insulin | Supported (class) | Pramlintide/Symlin label | Amycretin-specific risk not quantified |
| Wearable signature validated | Gap | No Amycretin-specific wearable studies | Class extrapolation only |
| Long-term safety / CVOT | Gap | No >36-week safety; no CVOT | Cannot claim cardiovascular protection |
| No regulatory approval anywhere | Confirmed | All sources | Investigational only |
Related notes
- Substances MOC — map entry for this hub
- Vitals Knowledge Map — high-level index
- GLP-1 GIP Glucagon — incretin and glucagon receptor comparison frame
- CagriSema — semaglutide + cagrilintide co-formulation; not the same as Amycretin
- Cagrilintide — amylin pathway anchor; CagriSema component
- Pramlintide — approved amylin analog; hypoglycemia risk context
- Retatrutide — triple-agonist comparator (GIP + GLP-1 + glucagon)
- Tirzepatide — GIP/GLP-1 dual agonist; approved comparator
- Orforglipron — approved oral GLP-1 small-molecule comparator
- GLP-1 Body Composition — body composition changes across GLP-1 class
- Incretin Sarcopenia GLP-1 Prevention Protocol — muscle preservation during GLP-1 weight loss
- GLP-1 Muscle Preservation — muscle preservation mechanism and protocols
- GLP-1 RA NAION Safety Signal — GLP-1 class ophthalmologic safety signal
- GLP-1 RA Pancreatitis Safety Signal — pancreatitis risk across GLP-1 class
- GLP-1 RA Skeletal Safety — bone fracture and skeletal safety across GLP-1 class
- Protein Intake GLP-1 Glucagon — protein and resistance training protocol anchor for GLP-1-class weight loss
- Amylin Receptor Biology — (aspirational ghost link — not yet a standalone note)